cssi/SciSciGPT-SciSciNet huggingface dataset:
Contextual Bandit with Adaptive Feature Extraction

We consider an online decision making setting known as contextual bandit problem, and propose an approach for improving contextual bandit performance by using an adaptive feature extraction (representation learning) based on online clustering. Our approach starts with an off-line pre-training on unlabeled history of contexts (which can be exploited by our approach, but not by the standard contextual bandit), followed by an online selection and adaptation of encoders. Specifically, given an input sample (context), the proposed approach selects the most appropriate encoding function to extract a feature vector which becomes an input for a contextual bandit, and updates both the bandit and the encoding function based on the context and on the feedback (reward). Our experiments on a variety of datasets, and both in stationary and non-stationary environments of several kinds demonstrate clear advantages of the proposed adaptive representation learning over the standard contextual bandit based on "raw" input contexts.
Heterogeneous Layoff Effects of the US Short‐Time Compensation Program

The Short‐Time Compensation (STC) program enables US firms to reduce work hours via pro‐rated Unemployment Insurance (UI) benefits, rather than relying on layoffs as a cost‐cutting tool. Despite the program's potential to preclude skill loss and rehiring/retraining costs, firms' participation rates are still very low in response to economic downturns. Using firm‐level UI administrative data and semi‐parametric methods, we show why by illustrating which type of firms benefit from the program and which do not. A key finding is that cyclically sensitive firms have about 14% lower layoff rates when they use STC, but we find no difference for more cyclically stable firms.
Uncertainty Shocks as Second-Moment News Shocks

We provide evidence on the relationship between aggregate uncertainty and the macroeconomy. Identifying uncertainty shocks using methods from the news shocks literature, the analysis finds that innovations in realized stock market volatility are robustly followed by contractions, while shocks to forward-looking uncertainty have no significant effect on the economy. Moreover, investors have historically paid large premia to hedge shocks to realized but not implied volatility. A model in which fundamental shocks are skewed left can match those facts. Aggregate volatility matters, but it is the realization of volatility, rather than uncertainty about the future, that has been associated with declines.
How Do Immigrants Respond to Discrimination? The Case of Germans in the US During World War I

I study the effect of taste-based discrimination on the assimilation decisions of immigrant minorities. Do discriminated minority groups increase their assimilation efforts in order to avoid discrimination and public harassment or do they become alienated and retreat in their own communities? I exploit an exogenous shock to native attitudes, anti-Germanism in the United States during World War I, to empirically identify the reactions of German immigrants to increased native hostility. I use two measures of assimilation efforts: naming patterns and petitions for naturalization. In the face of increased discrimination, Germans increase their assimilation investments by Americanizing their own and their children’s names and filing more petitions for US citizenship. These responses are stronger in states that registered higher levels of anti-German hostility, as measured by voting patterns and incidents of violence against Germans.
Unconstitutional supranational arrangements for patent law: leaving out the elected legislators and the people’s participatory rights

Substantive economic law in the context of patents creates industrial property rights and monopolies in almost all fields of technology, affecting considerably the economic and social well-being of the state and its people. The mass nationalisation of the international patents of the European Patent Office (EPO) has long raised serious questions about democratic control, in view of the reality that most of its patents are taken by large companies and corporations from a small number of states, mostly from outside the EU. The EU has recently expanded this system by creating a federal (unitary) patent framework consisting of the EPO and a new international court, the Unified Patent Court (UPC), that abolishes the already limited national control. But how can national control ever be totally abolished, especially in such an important social–economic context? And, can the EU exercise effective democratic control of the federal system that it has created? The observed constitutional asymmetries of a federal/unitary patent system that is created in the absence of a federation and is based on two non-EU bodies (EPO, UPC) no longer guarantee the democratic participatory rights of the people for whose benefit economic rules and property rights are justified, regulated and applied.
Pliant: Leveraging Approximation to Improve Datacenter Resource Efficiency

Cloud multi-tenancy is typically constrained to a single interactive service colocated with one or more batch, low-priority services, whose performance can be sacrificed when deemed necessary. Approximate computing applications offer the opportunity to enable tighter colocation among multiple applications whose performance is important. We present Pliant, a lightweight cloud runtime that leverages the ability of approximate computing applications to tolerate some loss in their output quality to boost the utilization of shared servers. During periods of high resource contention, Pliant employs incremental and interference-aware approximation to reduce contention in shared resources, and prevent QoS violations for co-scheduled interactive, latency-critical services. We evaluate Pliant across different interactive and approximate computing applications, and show that it preserves QoS for all co-scheduled workloads, while incurring a 2.1\% loss in output quality, on average.
Female lower urinary tract microbiota do not associate with IC/PBS symptoms: a case-controlled study.

The current etiology of interstitial cystitis/painful bladder syndrome (IC/PBS) is poorly understood and multifactorial. Recent studies suggest the female urinary microbiota (FUM) contribute to IC/PBS symptoms. This study was designed to determine if the FUM, analyzed using mid-stream voided urine samples, differs between IC/PBS patients and controls. This prospective case-controlled study compared the voided FUM of women with symptoms of urinary frequency, urgency, and bladder pain for > 6 months with the voided FUM of healthy female controls without pain. Bacterial identification was performed using 16S rRNA gene sequencing and EQUC, a validated enhanced urine culture approach. Urotype was defined by a genus present at > 50% relative abundance. If no genus was present above this threshold, the urotype was classified as ‘mixed.’ Group comparisons were performed for urotype and diversity measures. A mid-stream voided specimen was collected from 21 IC/PBS patients and 20 asymptomatic controls. The two groups had similar demographics. Urotypes did not differ between cohorts as assessed by either EQUC or 16S rRNA gene sequencing. We detected no significant differences between cohorts by alpha diversity. Cohorts also were not distinct using principle component analysis or hierarchical clustering. Detection by EQUC of bacterial species considered uropathogenic was high in both cohorts, but detection of these uropathogenic species did not differ between groups (p = 0.10). Enhanced culture and DNA sequencing methods provide evidence that IC/PBS symptoms may not be related to differences in the FUM, at least not its bacterial components. Future larger studies are needed to confirm this preliminary finding.
Diamond Phononic Crystal Spin-Mechanical Resonators with Spectrally-Stable Nitrogen Vacancy Centers

We report the design and fabrication of GHz diamond spin-mechanical resonators embedded in a two-dimensional phononic crystal lattice. Spectrally-stable nitrogen vacancy centers are observed after a soft-etching surface treatment.
MIDAS: Multilinear detection at scale

Abstract We focus on two classes of problems in graph mining: (1) finding trees and (2) anomaly detection in complex networks using scan statistics. These are fundamental problems in a broad class of applications. Most of the parallel algorithms for such problems are either based on heuristics, which do not scale very well, or use techniques like color coding, which have a high memory overhead. In this paper, we develop a novel approach for parallelizing both these classes of problems, using an algebraic representation of subgraphs as monomials—this methodology involves detecting multilinear terms in multivariate polynomials. Our algorithms show good scaling over a large regime, and they run on networks with close to half one billion edges. The resulting parallel algorithm for trees is able to scale to subgraphs of size 18, which has not been done before, and it significantly outperforms the best prior color coding based method (FASCIA) by more than two orders of magnitude. Our algorithm for network scan statistics is the first such parallelization, and it is able to handle a broad class of scan statistics functions with the same approach.
Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection.

Abstract Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido[3,2-d]pyrimidines were developed. Comparison of the amino acid residues in the active site of pjDHFR and human DHFR (hDHFR) revealed prominent amino acid differences which could be exploited to structurally design potent and selective pjDHFR inhibitors. Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC50 of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors.
Retro-Claisen condensation versus pyrrole formation in reactions of amines and 1,3-diketones

Abstract Cyclic amines and 1,3-diketones readily react under microwave irradiation to form ring-fused pyrroles in a single operation. A competing retro-Claisen pathway is efficiently suppressed by employing p -toluenesulfonic acid as an additive.
Broad antifungal resistance mediated by RNAi-dependent epimutation in the basal human fungal pathogen Mucor circinelloides

Mucormycosis—an emergent, deadly fungal infection—is difficult to treat, in part because the causative species demonstrate broad clinical antifungal resistance. However, the mechanisms underlying drug resistance in these infections remain poorly understood. Our previous work demonstrated that one major agent of mucormycosis, Mucor circinelloides, can develop resistance to the antifungal agents FK506 and rapamycin through a novel, transient RNA interference-dependent mechanism known as epimutation. Epimutations silence the drug target gene and are selected by drug exposure; the target gene is re-expressed and sensitivity is restored following passage without drug. This silencing process involves generation of small RNA (sRNA) against the target gene via core RNAi pathway proteins. To further elucidate the role of epimutation in the broad antifungal resistance of Mucor, epimutants were isolated that confer resistance to another antifungal agent, 5-fluoroorotic acid (5-FOA). We identified epimutant strains that exhibit resistance to 5-FOA without mutations in PyrF or PyrG, enzymes which convert 5-FOA into the active toxic form. Using sRNA hybridization as well as sRNA library analysis, we demonstrate that these epimutants harbor sRNA against either pyrF or pyrG, and further show that this sRNA is lost after reversion to drug sensitivity. We conclude that epimutation is a mechanism capable of targeting multiple genes, enabling Mucor to develop resistance to a variety of antifungal agents. Elucidation of the role of RNAi in epimutation affords a fuller understanding of mucormycosis. Furthermore, it improves our understanding of fungal pathogenesis and adaptation to stresses, including the evolution of drug resistance.
Five- and six-membered spirocyclic cyclotriphosphazene derivatives with methacryloyl substituents on the spirocyclic ring

Synthetic procedures have been devel-oped for the preparation of spiro(2,3-dioxypropyl-methacryloyltetrachlorcyclotriphosphazene, N3P3Cl4-[OCH2CH(OC(O)=CH2)O] (2) and spiro((2-meth-yl-3-oxy-2-(oxymethyl)propyl)methacryloyltetrachlo-rocyclotriphosphazene, N3P3Cl4[OCH2CMe(CH2OC-(O)=CH2)CH2O] (3). The 1H, 13C and 31P NMR spectra have been analyzed using two-dimensional (COSY and HETCOR) techniques and spectra simulation methods. The crystal and molecular structure of 3 has been investigated by single-crystal X-ray diffraction techniques. The crystals are monoclinic with the space group P21/C with a = 12.154(5), b = 7.825(5), and c = 20.208(10) A and β = 103.240° with V = 1870.8(17) A° and Z = 4. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9: 669–677, 1998
Thermodynamics of Phase Formation of the Cobalt Silicides

Vaporization thermodynamics in the cobalt−silicon binary system has been studied by both reactive and simple Knudsen effusion mass spectrometry. The equilibrium partial pressures of SiO(g) over mix...
Do dams also stop frogs? Assessing population connectivity of coastal tailed frogs (Ascaphus truei) in the North Cascades National Park Service Complex

We investigated the effects of three hydroelectric dams and their associated lakes on the population structure and connectivity of the coastal tailed frog, Ascaphus truei, in the North Cascades National Park Service Complex. Three dams were erected on the Skagit River in northern-central Washington state between 1924 and 1953 and subsequently changed the natural shape and movement of the Skagit River and its tributaries. We collected 183 frogs and tadpoles from 13 tributaries and generated a dataset of >2500 loci (unlinked SNPs) using double digestion restriction site-associated DNA sequencing (ddRADseq). An analysis of molecular variance (AMOVA) identified $$\sim$$ 99% of the genetic variation within groups, and the remaining variation among groups separated by dams, or the Skagit River. All populations exhibited low F $$_{ST}$$ values with a maximum of 0.03474. A “de novo” discriminant analysis of principal components revealed two populations with no geographic structure. However, testing groups that were partitioned a priori by the dams revealed distinctiveness of groups down-river of the lowest dam (Gorge Dam). Coalescent-based analyses of recent migration suggest that up to 17.3% of each population is composed of migrants from other populations, and an estimation of effective migration rates revealed high levels of migration heterogeneity and population connectivity throughout the study area. Our results suggest that although the populations down-river from Gorge Dam are distinguishable using SNPs, A. truei population connectivity is high throughout the North Cascades National Park Service Complex.
LiAl(OC(Ph)(CF3)2)4: A Hydrocarbon-Soluble Catalyst for Carbon−Carbon Bond-Forming Reactions

The compound LiAl(OC(Ph)(CF3)2)4 (1), prepared from LiAlH4 and HOC(Ph)(CF3)2, is an active Lewis acid catalyst in toluene solution for the 1,4-conjugate addition of silyl ketene acetals to α,β-unsa...
A convenient procedure for the reduction of S-(+)-silyl serine methyl ester to chiral serinol derivatives

Abstract The reduction of S-(+)-serine methyl ester silyl ether with NaBH 4 followed by acidic workup produced the chiral serinol derivatives with minimum racemization. Addition of MeMgBr gave the functionalized amine diol in high yield with no racemization.
On the Possibility of Metal Borides for Hydrodesulfurization

We have explored cobalt and nickel boride-based catalysts for the hydrodesulfurization (HDS) of thiophene and evaluate their overall catalytic activity, mode of desulfurization, and stability to su...
KBa2InAs3 with Coexisting Monomers of [In2As7]13- and Their One-Dimensional Polymers

The title compound was made by fusion of a stoichiometric mixture of the pure elements. The structure (orthorhombic, Cmc2 1 , Z = 16, a = 10.129(2) A, b = 25.208(4) A. c = 13.884(3) A) is made of isolated units of [In 2 As 7 ] 1 3 - and a polymer chain of 1∞[In2As5]7- made of the same units. According to magnetic measurement, KBa 2 InAs 3 is a closed-shell compound, a Zintl phase.
Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network.

Drosophila provides an inexpensive and quantitative platform for measuring whole animal drug response. A complementary approach is virtual screening, where chemical libraries can be efficiently screened against protein target(s). Here, we present a unique discovery platform integrating structure-based modeling with Drosophila biology and organic synthesis. We demonstrate this platform by developing chemicals targeting a Drosophila model of Medullary Thyroid Cancer (MTC) characterized by a transformation network activated by oncogenic dRetM955T. Structural models for kinases relevant to MTC were generated for virtual screening to identify unique preliminary hits that suppressed dRetM955T-induced transformation. We then combined features from our hits with those of known inhibitors to create a ‘hybrid’ molecule with improved suppression of dRetM955T transformation. Our platform provides a framework to efficiently explore novel kinase inhibitors outside of explored inhibitor chemical space that are effective in inhibiting cancer networks while minimizing whole body toxicity.
Enantiospecific routes to 3,4 disubstituted azetidinones

Abstract Enantiospecific routes to 3,4 disubstituted azetidinones are outlined which commence with readily available β-ketoester precursors.
Microwave-Assisted Iridium-Catalyzed Synthesis of Nicotine and Anabasine Derivatives

Various functionalized nicotine and anabasine analogues are synthesized via a three-step sequence that exploits a microwave-assisted iridium-catalyzed N-heterocyclization of 1,4- and 1,5-diols for the construction of the pyrrolidine and piperidine ring systems. The microwave-assisted N-heterocyclization furnishes derivatives of nicotine and anabasine in good yields (50–75%) with overall yields ranging from 30–50%.
Isolation of germanate sheets with three-membered rings: A possible precursor to three-dimensional zeolite-type germanates

The generation of 4-connnected three-dimensional zeolite-type framework can be conceptually considered as resulting from the linking of two-dimensional sheets. The experimental evidence for the presence of these two-dimensional sheets is, however, rather rare. By using alkali metal cations (K+) to replace organic structure-directing agents, one such two-dimensional sheet has been preserved in a crystalline product denoted as UCSB-9L, a hydrated layered germanate with three- and nine-membered rings. The implication of this work on the self-assembly mechanism is that the structure-directing effect of organic molecules may only need to be active in a narrow range along the reaction coordinate.
Alkylation reactions of 3-(phenylsulfonyl)methyl substituted cyclopentenones

Abstract The readily available 2,3-dibromo-1-(phenylsulfonyl)-1-propene (DBP) undergoes facile reaction with several 1,3-dicarbonyl compounds under basic conditions to give (phenylsulfonyl)methyl substituted cyclopentenones. The pendant sulfonyl group at the C3 position of the cyclopentenone ring offers a versatile site for further elaboration via alkylation. These cyclic α-enone systems are easily metallated with sodium hydride, and the resultant carbanion undergoes both bimolecular and intramolecular alkylations. The overall sequence provides a simple and efficient route to functionalized cyclopentenones. The alkylated sulfones were easily desulfonylated upon heating with tri n-butyltin hydride and AIBN in toluene at 110 °C. A novel base-induced transformation was observed using 3-(phenylsulfonyl)methyl-2-(4-iodobutyl)cyclopentenone. Treatment of this compound with one equivalent of NaH in the presence of HMPA afforded 4-methylene-spiro[4.4]non-2-en-1-one. This reaction proceeds by initial γ-alkylation followed by a 1,3-hydrogen shift and subsequent 1,4-elimination of sulfinate anion.
A Novel Route to Pyrrolo[2,1-c][1,4]benzodiazepin-5-ones. Formal Total Synthesis of (±)-DC-81

Compounds 3a and 3b were synthesized from N-allylisatoic anhydrides 5a and 5b in six and seven steps, respectively. Synthesis of 3b constitutes a formal total synthesis of (±)-DC-81.
Combinatorial synthesis of oxide powders with an autopipetting system.

We describe development of a relatively simple, rapid route to produce combinatorial compositional oxide powder libraries by autopipetting of liquid precursors. This partitioning approach should apply equally well to any low viscosity, liquid precursors for the synthesis of oxide powders. A commercial autopipet is modified by fitting a plastic “mask” assembly beneath the pipet array in order to partition and direct liquids into crucibles. A series of 10 mixtures from two precursor solutions can be produced quickly. After they are dispensed, the liquid mixtures are dried in the crucibles and reacted at elevated temperatures to produce oxide powders. In the present work, the viability of the pipetting process is demonstrated by using a polymerizable complex powder synthesis method to produce (1-x) LaAlO3 − x SrTiO3 powders. For this system, a reaction at 900 °C for 2 h in air was sufficient to yield solid solutions in this system. X-ray powder diffraction was used to determine the pseudocubic unit cell latt...
Comprehensive characterization of toxicity of fermentative metabolites on microbial growth.

Volatile carboxylic acids, alcohols, and esters are natural fermentative products, typically derived from anaerobic digestion. These metabolites have important functional roles to regulate cellular metabolisms and broad use as food supplements, flavors and fragrances, solvents, and fuels. Comprehensive characterization of toxic effects of these metabolites on microbial growth under similar conditions is very limited. We characterized a comprehensive list of thirty-two short-chain carboxylic acids, alcohols, and esters on microbial growth of Escherichia coli MG1655 under anaerobic conditions. We analyzed toxic effects of these metabolites on E. coli health, quantified by growth rate and cell mass, as a function of metabolite types, concentrations, and physiochemical properties including carbon number, chemical functional group, chain branching feature, energy density, total surface area, and hydrophobicity. Strain characterization revealed that these metabolites exert distinct toxic effects on E. coli health. We found that higher concentrations and/or carbon numbers of metabolites cause more severe growth inhibition. For the same carbon numbers and metabolite concentrations, we discovered that branched chain metabolites are less toxic than the linear chain ones. Remarkably, shorter alkyl esters (e.g., ethyl butyrate) appear less toxic than longer alkyl esters (e.g., butyl acetate). Regardless of metabolites, hydrophobicity of a metabolite, governed by its physiochemical properties, strongly correlates with the metabolite’s toxic effect on E. coli health. Short-chain alcohols, acids, and esters exhibit distinctive toxic effects on E. coli health. Hydrophobicity is a quantitative predictor to evaluate the toxic effect of a metabolite. This study sheds light on degrees of toxicity of fermentative metabolites on microbial health and further helps in the selection of desirable metabolites and hosts for industrial fermentation to overproduce them.
Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels

DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ∼300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 cis methylation QTLs (meQTLs)—i.e., CpG sites in which changes in DNA methylation are associated with genetic variation at proximal loci. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNase I accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs.
Solvent Effects on the Barrier to Rotation in Carbamates.

In the 40 years since the inception of dynamic NMR methods, much effort has been invested to quantify and understand the barrier to rotation about the C-N bond in amides.1 Carbamates, which also exhibit the approximately planar N-CdO framework responsible for hindered rotation in amides, have received considerably less attention, although they are important biologically as anticonvulsants, local anesthetics, sedatives, muscle relaxants,2 enzyme inhibitors,3 and surrogates for amides in enzyme mimetics.4 Although amides and carbamates share common features, the additional oxygen of the carbamate functionality exerts unique steric and electronic perturbations. One consequence of this difference is that the barriers to rotation in carbamates are usually 3-4 kcal/mol (about 15-20%) lower than those in the corresponding amides. During a study on the catalysis of cis-trans amide and carbamate isomerization, we observed that the barriers to rotation (∆G‡) in prolyl carbamates were surprisingly insensitive to solvent effects. This behavior contrasts that of amides, where it is common for ∆G‡ to increase by as much as 3 kcal/mol (>100-fold rate decrease) upon a change in environment from a nonpolar, non-hydrogen bonding solvent to water.5 In this paper, we report the first systematic investigation of solvent effects on ∆G‡ for hindered C-N bond rotation in carbamates and that this process occurs with a negative ∆S‡ for acyclic tertiary carbamates in aqueous solution. We began our investigation by studying the effect of solvent on ∆G‡ for the interconversion of the cis and trans forms of the related proline derivatives 1 and 2 (eq 1). The
High-performance virtual screening by targeting a high-resolution RNA dynamic ensemble.

Dynamic ensembles hold great promise in advancing RNA-targeted drug discovery. Here we subjected the transactivation response element (TAR) RNA from human immunodeficiency virus type-1 to experimental high-throughput screening against ~100,000 drug-like small molecules. Results were augmented with 170 known TAR-binding molecules and used to generate sublibraries optimized for evaluating enrichment when virtually screening a dynamic ensemble of TAR determined by combining NMR spectroscopy data and molecular dynamics simulations. Ensemble-based virtual screening scores molecules with an area under the receiver operator characteristic curve of ~0.85–0.94 and with ~40–75% of all hits falling within the top 2% of scored molecules. The enrichment decreased significantly for ensembles generated from the same molecular dynamics simulations without input NMR data and for other control ensembles. The results demonstrate that experimentally determined RNA ensembles can significantly enrich libraries with true hits and that the degree of enrichment is dependent on the accuracy of the ensemble. A new way to virtually screen HIV-1 TAR RNA using dynamic ensembles better identifies small molecules targeting RNA secondary structures for development.
Wnt/β-catenin regulates an ancient signaling network during zebrafish scale development.

Hair, feathers or scales cover the skin of most land animals. Despite their apparent diversity, these appendages share many features: they are mainly formed of the protein keratin, are produced by the topmost layer of the skin and they start to form with skin cells moving inwards to form a pit. Across species, the same genes are also involved in controlling the development of these structures. This suggests that they have all evolved from a shared ancestral appendage, which may have been fish scales. However, scales in fish are formed of bones, not keratin, and they come from a different skin layer. Here, Aman et al. explore the molecular mechanisms that control how zebrafish scales form and get their shape, which is a little-studied area of research. Cells at the surface of the fish were imaged live on the animal as they were developing and creating scales. The experiments involved manipulating the genetic information of these cells to tease out the molecular mechanisms that drive the creation of scales. This revealed that the genes that control the formation of the scales and of the appendages of land animals are the same and interact in similar ways. In particular, scales also require the skin to form a pit to develop, and the same genes direct this process in zebrafish and in furred or feathered creatures. The work by Aman et al. suggests that all skin appendages, regardless of being sported by fish, birds or mammals, descend from the same structure. It also puts forward the zebrafish and its scales as a good model for scientists to study so they can understand better how certain hair and teeth disorders arise in humans.
TiCl4-mediated amination of propargylic esters

Abstract The TiCl4-mediated substitution of propargylic esters with amides afforded the corresponding α-substituted propargylic amides.
Facilitated Dissociation of Transcription Factors from Single DNA Binding Sites

The binding of transcription factors (TFs) to DNA controls most aspects of cellular function, making the understanding of their binding kinetics imperative. The standard description of bimolecular interactions posits that TF off rates are independent of TF concentration in solution. However, recent observations have revealed that proteins in solution can accelerate the dissociation of DNA-bound proteins. To study the molecular basis of facilitated dissociation (FD), we have used single-molecule imaging to measure dissociation kinetics of Fis, a key Escherichia coli TF and major bacterial nucleoid protein, from single dsDNA binding sites. We observe a strong FD effect characterized by an exchange rate [Formula: see text], establishing that FD of Fis occurs at the single-binding site level, and we find that the off rate saturates at large Fis concentrations in solution. Although spontaneous (i.e., competitor-free) dissociation shows a strong salt dependence, we find that FD depends only weakly on salt. These results are quantitatively explained by a model in which partially dissociated bound proteins are susceptible to invasion by competitor proteins in solution. We also report FD of NHP6A, a yeast TF with structure that differs significantly from Fis. We further perform molecular dynamics simulations, which indicate that FD can occur for molecules that interact far more weakly than those that we have studied. Taken together, our results indicate that FD is a general mechanism assisting in the local removal of TFs from their binding sites and does not necessarily require cooperativity, clustering, or binding site overlap.
Synthesis of enediynes by reaction of bicycloalkenyldiiodonium salts with lithium alkynylcuprates

BicycloalkenyIdiiodonium salts, di[phenyl(trifluoromethanesulfonyloxy)iodo]norbornadiene (1a) and di[phenyl(trifluoromethanesulfonyloxy)iodo]-3,5-epoxy-1,4-cyclohexadiene (1b) react under mild conditions, with a number of lithium alkynylcuprates, generated in situ from the corresponding lithium acetylides and copper(I) cyanide, to give the respective enediynes 2 in moderate to good isolated fields
Defining the dynamic chromatin landscape of mouse nephron progenitors.

Six2 + cap mesenchyme cells, also called nephron progenitor cells (NPC), are precursors of all epithelial cell types of the nephron, the filtering unit of the kidney. Current evidence indicates that perinatal “old” NPC have a greater tendency to exit the progenitor niche and differentiate into nascent nephrons than their embryonic “young” counterpart. Understanding the underpinnings of NPC development may offer insights to rejuvenate old NPC and expand the progenitor pool. Here, we compared the chromatin landscape of young and old NPC and found common features reflecting their shared lineage but also intrinsic differences in chromatin accessibility and enhancer landscape supporting the view that old NPC are epigenetically poised for differentiation. Annotation of open chromatin regions and active enhancers uncovered the transcription factor Bach2 as a potential link between the pro-renewal MAPK/AP1 and pro-differentiation Six2/b-catenin pathways that might be of critical importance in regulation of NPC fate. Our data provide the first glimpse of the dynamic chromatin landscape of NPC and serve as a platform for future studies of the impact of genetic or environmental perturbations on the epigenome of NPC.
Preparation and crystal structure of a new barium silicon nitride, Ba5Si2N6

Abstract Single crystals of a new ternary nitride, Ba5Si2N6, were synthesized by slow cooling from 750°C using a starting mixture of Ba, Si, Na and NaN3, where Na and NaN3 were a flux and a nitrogen source respectively. It crystallizes with orthorhombic symmetry: space group P2 1 2 1 2 1 ( No. 19), a = 6.159, b = 10.305, c = 15.292 A , and Z = 4 . The crystal structure was determined from single-crystal data and refined to R1 = 0.0495 for all 1637 observed reflections and 89 variables. A pair of SiN4 tetrahedra contained in the structure forms a nitridometallate anion of [Si2N6]10 by edge sharing.
Multichannel sleep spindle detection using sparse low-rank optimization.

Abstract Background Automated single-channel spindle detectors, for human sleep EEG, are blind to the presence of spindles in other recorded channels unlike visual annotation by a human expert. New method We propose a multichannel spindle detection method that aims to detect global and local spindle activity in human sleep EEG. Using a non-linear signal model, which assumes the input EEG to be the sum of a transient and an oscillatory component, we propose a multichannel transient separation algorithm. Consecutive overlapping blocks of the multichannel oscillatory component are assumed to be low-rank whereas the transient component is assumed to be piecewise constant with a zero baseline. The estimated oscillatory component is used in conjunction with a bandpass filter and the Teager operator for detecting sleep spindles. Results and comparison with other methods The proposed method is applied to two publicly available databases and compared with 7 existing single-channel automated detectors. F1 scores for the proposed spindle detection method averaged 0.66 (0.02) and 0.62 (0.06) for the two databases, respectively. For an overnight 6 channel EEG signal, the proposed algorithm takes about 4 min to detect sleep spindles simultaneously across all channels with a single setting of corresponding algorithmic parameters. Conclusions The proposed method attempts to mimic and utilize, for better spindle detection, a particular human expert behavior where the decision to mark a spindle event may be subconsciously influenced by the presence of a spindle in EEG channels other than the central channel visible on a digital screen.
Tracking and Improving Information in the Service of Fairness

As algorithmic prediction systems have become widespread, fears that these systems may inadvertently discriminate against members of underrepresented populations have grown. With the goal of understanding fundamental principles that underpin the growing number of approaches to mitigating algorithmic discrimination, we investigate the role of information in fair prediction. A common strategy for decision-making uses a predictor to assign individuals a risk score; then, individuals are selected or rejected on the basis of this score. In this work, we study a formal framework for measuring the information content of predictors. Central to the framework is the notion of a refinement; intuitively, a refinement of a predictor z increases the overall informativeness of the predictions without losing the information already contained in z. We show that increasing information content through refinements improves the downstream selection rules across a wide range of fairness measures (e.g. true positive rates, false positive rates, selection rates). In turn, refinements provide a simple but effective tool for reducing disparity in treatment and impact without sacrificing the utility of the predictions. Our results suggest that in many applications, the perceived "cost of fairness" results from an information disparity across populations, and thus, may be avoided with improved information.
Synthesis of Stereopentad Subunits of Zincophorin and Rifamycin-S through Use of Chiral Allenyltin Reagents

The anti,anti adduct 3, from addition of the allenic stannane (P)-2 to the α-methyl-β-OBn aldehyde (S)-1 promoted by SnCl4, was converted to the stereopentad 6 by a sequence involving reduction to the (E)-allylic alcohol with Red-Al, Sharpless asymmetric epoxidation, and addition of the higher-order methyl cyanocuprate to the derived epoxide 5. Stereopentad 6 was converted to the acetonide acetal 15, an intermediate in Danishefsky's synthesis of zincophorin. By a similar sequence, adduct ent-4 was converted, via diol 19, to stereopentad 22, an intermediate in Kishi's synthesis of rifamycin-S. An alternative route to diol 19 was achieved from the MOM-protected derivative 28 of epoxy diol 18.
Neural Networks for Efficient Bayesian Decoding of Natural Images from Retinal Neurons

Decoding sensory stimuli from neural signals can be used to reveal how we sense our physical environment, and is valuable for the design of brain-machine interfaces. However, existing linear techniques for neural decoding may not fully reveal or exploit the fidelity of the neural signal. Here we develop a new approximate Bayesian method for decoding natural images from the spiking activity of populations of retinal ganglion cells (RGCs). We sidestep known computational challenges with Bayesian inference by exploiting artificial neural networks developed for computer vision, enabling fast nonlinear decoding that incorporates natural scene statistics implicitly. We use a decoder architecture that first linearly reconstructs an image from RGC spikes, then applies a convolutional autoencoder to enhance the image. The resulting decoder, trained on natural images and simulated neural responses, significantly outperforms linear decoding, as well as simple point-wise nonlinear decoding. These results provide a tool for the assessment and optimization of retinal prosthesis technologies, and reveal that the retina may provide a more accurate representation of the visual scene than previously appreciated.
A Nasal Brush-based Classifier of Asthma Identified by Machine Learning Analysis of Nasal RNA Sequence Data

Asthma is a common, under-diagnosed disease affecting all ages. We sought to identify a nasal brush-based classifier of mild/moderate asthma. 190 subjects with mild/moderate asthma and controls underwent nasal brushing and RNA sequencing of nasal samples. A machine learning-based pipeline identified an asthma classifier consisting of 90 genes interpreted via an L2-regularized logistic regression classification model. This classifier performed with strong predictive value and sensitivity across eight test sets, including (1) a test set of independent asthmatic and control subjects profiled by RNA sequencing (positive and negative predictive values of 1.00 and 0.96, respectively; AUC of 0.994), (2) two independent case-control cohorts of asthma profiled by microarray, and (3) five cohorts with other respiratory conditions (allergic rhinitis, upper respiratory infection, cystic fibrosis, smoking), where the classifier had a low to zero misclassification rate. Following validation in large, prospective cohorts, this classifier could be developed into a nasal biomarker of asthma.
Protein evolution depends on multiple distinct population size parameters.

That population size affects the fate of new mutations arising in genomes, modulating both how frequently they arise and how efficiently natural selection is able to filter them, is well established. It is therefore clear that these distinct roles for population size that characterize different processes should affect the evolution of proteins and need to be carefully defined. Empirical evidence is consistent with a role for demography in influencing protein evolution, supporting the idea that functional constraints alone do not determine the composition of coding sequences. Given that the relationship between population size, mutant fitness and fixation probability has been well characterized, estimating fitness from observed substitutions is well within reach with well-formulated models. Molecular evolution research has, therefore, increasingly begun to leverage concepts from population genetics to quantify the selective effects associated with different classes of mutation. However, in order for this type of analysis to provide meaningful information about the intra- and inter-specific evolution of coding sequences, a clear definition of concepts of population size, what they influence, and how they are best parameterized is essential. Here, we present an overview of the many distinct concepts that “population size” and “effective population size” may refer to, what they represent for studying proteins, and how this knowledge can be harnessed to produce better specified models of protein evolution.
Systematic Study of New Rare Earth Element−Iron−Antimony Skutterudites Synthesized Using Multilayer Precursors

We have synthesized a series of stable and metastable rare earth element−iron antimonides, controlling both composition and structure using multilayer reactants. The stable rare earth iron element antimonides have the filled skutterudite structure (LaFe4P12) with a stoichiometry of 1 for the rare earth element. The metastable rare earth element−iron antimonides could be prepared with the entire sequence of rare earth elements. The lattice parameters of these metastable compounds were always larger than those of the corresponding more stable analog, and the occupancy of the rare earth element cation was found to be less than 1. Reitveld analysis of Lu1-xFe4Sb12 suggests that the late rare earth element compounds have a new distorted filled skutterudite structure. Structural trends are discussed in terms of their potential use as thermoelectric materials.
Unexpected Truce–Smiles type rearrangement of 2-(2′-pyridyloxy) phenylacetic esters: synthesis of 3-pyridyl-2-benzofuranones

Abstract Enolization of 2-(2′-pyridyloxy)phenylacetic acid esters with either potassium or sodium hydride induced a Truce–Smiles rearrangement, producing pyridine substituted 2-benzofuranones. Rearrangement of a 2-(4-nitrophenoxy)phenylacetate and a 2-(2′-pyrimidyloxy)phenylacetate produced similar results.
Continuous Evaluation of Ligand Protein Predictions: A Weekly Community Challenge for Drug Docking

Summary Docking calculations can accelerate drug discovery by predicting the bound poses of ligands for a targeted protein. However, it is not clear which docking methods work best. Furthermore, predicting poses requires steps outside the docking algorithm itself, such as preparation of the protein and ligand, and it is not known which components are most in need of improvement. The Continuous Evaluation of Ligand Protein Predictions (CELPP) is a blinded prediction challenge designed to address these issues. Participants create a workflow to predict protein-ligand binding poses, which is then tasked with predicting 10–100 new protein-ligand crystal structures each week. CELPP evaluates the accuracy of each workflow's predictions and posts the scores online. The results can be used to identify the strengths and weaknesses of current approaches, help map docking problems to the algorithms most likely to overcome them, and illuminate areas of unmet need in structure-guided drug design.
“Short-Dot”: Computing Large Linear Transforms Distributedly Using Coded Short Dot Products

We consider the problem of computing a matrix-vector product $Ax$ using a set of $P$ parallel or distributed processing nodes prone to “straggling,” i.e. , unpredictable delays. Every processing node can access only a fraction $({s}/{N})$ of the $N$ -length vector $x$ , and all processing nodes compute an equal number of dot products. We propose a novel error correcting code-that we call “Short-Dot”–that introduces redundant, shorter dot products such that only a subset of the nodes’ outputs are sufficient to compute $Ax$ . To address the problem of straggling in computing matrix-vector products, prior work uses replication or erasure coding to encode parts of the matrix $A$ , but the length of the dot products computed at each processing node is still $N$ . The key novelty in our work is that instead of computing the long dot products as required in the original matrix-vector product, we construct a larger number of redundant and short dot products that only require a fraction of $x$ to be accessed during the computation. Short-Dot is thus useful in a communication-constrained scenario as it allows for only a fraction of $x$ to be accessed by each processing node. Further, we show that in the particular regime where the number of available processing nodes is greater than the total number of dot products, Short-Dot has lower expected computation time under straggling under an exponential model compared to existing strategies, e.g. replication, in a scaling sense. We also derive fundamental limits on the trade-off between the length of the dot products and the recovery threshold, i.e., the required number of processing nodes, showing that Short-Dot is near-optimal.
A multi-modes Monte Carlo finite element method for elliptic partial differential equations with random coefficients

This paper develops and analyzes an efficient numerical method for solving elliptic partial differential equations, where the diffusion coefficients are random perturbations of deterministic diffusion coefficients. The method is based upon a multi-modes representation of the solution as a power series of the perturbation parameter, and the Monte Carlo technique for sampling the probability space. One key feature of the proposed method is that the governing equations for all the expanded mode functions share the same deterministic diffusion coefficients, thus an efficient direct solver by repeated use of the $LU$ decomposition matrices can be employed for solving the finite element discretized linear systems. It is shown that the computational complexity of the whole algorithm is comparable to that of solving a few deterministic elliptic partial differential equations using the $LU$ director solver. Error estimates are derived for the method, and numerical experiments are provided to test the efficiency of the algorithm and validate the theoretical results.