cssi/SciSciGPT-SciSciNet huggingface dataset:
Cholinergic interneurons as a novel target of CRF in the striatum that is spared by repeated stress

Acute stressors can stimulate appetitive and exploratory behaviors, not just produce negative affect that impair performance. Corticotropin releasing factor (CRF), which is released in the brain in response to stress, acts on different targets and circuits to mediate both the negative and positive effects of stress. In the nucleus accumbens, CRF facilitates appetitive behavior through mechanisms not fully understood. Here we report that cholinergic interneurons (CINs) are a novel target for CRF actions in the striatum. CRF enhances the spontaneous firing via activation of CRF-type 1 receptors expressed on CINs. This causes the activation muscarinic acetylcholine receptors type 5, which mediate CRF potentiation of dopamine transmission in the striatum. Repeated stress selectively dampens some CRF functions but spare effect on CINs and changes CRF-R1 expression in a cell-specific manner. These data highlight the existence of diverse CRF targets within the striatum, which vary in their resilience to stress.
Not all crashes are created equal: Associations between the built environment and disparities in bicycle collisions

Historically disadvantaged populations are disproportionately represented in bicycle crashes. Previous research has found that Black and Hispanic bicyclists and areas with higher populations of non-White residents, lower median income, and high poverty experience bicycle crashes more frequently than others. Although existing research has explored the role of socioeconomic status and the built environment in predicting crash frequency, few scholars have studied how these factors account for disparities along racial and ethnic lines. Using a database of 7,088 bicycle crashes over a three-year period in the San Francisco Bay Area, this study examines the influence of socioeconomic, transportation, and land-use characteristics as potential causes of differences in bicycle crash occurrences among racial and ethnic groups in the San Francisco Bay Area. While areas of high poverty and high land-use intensity are associated with higher numbers of bicycle crashes overall, lower-traffic streets and bicycle infrastructure do not affect the frequency of crashes involving Black and Hispanic cyclists. Black bicyclists have a disproportionate risk of being involved in a crash in poor urban neighborhoods, controlling for other factors. These findings draw attention to the need for planners to consider how socioeconomic differences and vulnerability at the neighborhood level play a role in safety.
Elemental Cognitive Acts, and Their Architecture.

The elemental constituent functions of human minds are not yet known, and the paths to identifying these basic “cognitive acts” are constrained at each end by biology and behavior. A coherent architecture derived bottom-up from brain circuits is proffered. We posit principles and pose questions about architectures, their composition, and their applicability to a described range of formidable tasks, with the primary intent of aiding in setting guideposts and challenges for ongoing architecture studies.
Do Local Investors Always Know Better? Evidence from China's Market Segmentation

SYNOPSIS It is well documented that domestic investors have an information advantage over foreign investors. We utilize the market segmentation of Chinese A- and B-shares to disentangle the informa...
Ryoan: A Distributed Sandbox for Untrusted Computation on Secret Data

Users of modern data-processing services such as tax preparation or genomic screening are forced to trust them with data that the users wish to keep secret. Ryoan1 protects secret data while it is processed by services that the data owner does not trust. Accomplishing this goal in a distributed setting is difficult, because the user has no control over the service providers or the computational platform. Confining code to prevent it from leaking secrets is notoriously difficult, but Ryoan benefits from new hardware and a request-oriented data model. Ryoan provides a distributed sandbox, leveraging hardware enclaves (e.g., Intel’s software guard extensions (SGX) [40]) to protect sandbox instances from potentially malicious computing platforms. The protected sandbox instances confine untrusted data-processing modules to prevent leakage of the user’s input data. Ryoan is designed for a request-oriented data model, where confined modules only process input once and do not persist state about the input. We present the design and prototype implementation of Ryoan and evaluate it on a series of challenging problems including email filtering, health analysis, image processing and machine translation.
Integrated FISH, Karyotyping and aCGH Analyses for Effective Prenatal Diagnosis of Common Aneuploidies and Other Cytogenomic Abnormalities

Current prenatal genetic evaluation showed a significantly increase in non-invasive screening and the reduction of invasive diagnostic procedures. To evaluate the diagnostic efficacy on detecting common aneuploidies, structural chromosomal rearrangements, and pathogenic copy number variants (pCNV), we performed a retrospective analysis on a case series initially analyzed by aneuvysion fluorescence in situ hybridization (FISH) and karyotyping then followed by array comparative genomic hybridization (aCGH). Of the 386 cases retrieved from the past decade, common aneuploidies were detected in 137 cases (35.5%), other chromosomal structural rearrangements were detected in four cases (1%), and pCNV were detected in five cases (1.3%). The relative frequencies for common aneuploidies suggested an under detection of sex chromosome aneuploidies. Approximately 9.5% of cases with common aneuploidies showed a mosaic pattern. Inconsistent results between FISH and karyotyping were noted in cases with pseudo-mosaicism introduced by culture artifact or variable cellular proliferation from cells with mosaic karyotypic complements under in vitro cell culture. Based on findings from this case series, cell-based FISH and karyotyping should be performed to detect common aneuploidies, structural chromosomal abnormalities, and mosaic pattern. DNA-based aCGH and reflex FISH should be performed to detect and confirm genomic imbalances and pCNV. Practice points to ensure the diagnostic accuracy and efficacy were summarized.
Benchmarking of a Free Vortex Wake Model for Prediction of Wake Interactions

Abstract Turbine-wake interactions pose significant challenges in the development of wind farms. These interactions can lead to an increase in wind energy cost through reduction in wind farm power efficiency as well as a reduction of functional turbine lifetime. The overall objective of this work is to assess the free vortex wake (FVW) approach for capturing wind farm interactions in the context of improved wind farm optimization. Specific focus areas include (1) analyzing the effects of turbine-wake interaction and (2) benchmarking of the model against experimental wind farm measurements. The effects of turbine-wake interactions are analyzed in terms of wake structure, rotor power, and structural response. The FVW model predicts increased unsteadiness in wake-influenced turbine rotor power and out-of-plane blade root bending moment. This could have implications for prediction of turbine life and suggests that the transient as well as average response of turbines should be considered to fully capture the effects of wake interaction. Comparisons between the FVW predictions and experimental measurements of relative rotor power are made over varying yaw angle and freestream velocity. Overall trends are predicted by the FVW approach, with less than 13 % error on average when compared to wind farm measurements. These results indicate the FVW method is a useful tool for carrying out improved optimization of wind farms.
Chapter 4 – Uniaxial tension in elasto-plastic metal matrix composites: Vector formulation of the overall approach

Publisher Summary This chapter discusses the initiation and evolution of damage and elasto-plastic deformation in metal–matrix laminae using an overall approach. An overall approach to the characterization of damage in elasto-plastic fiber-reinforced metal–matrix composites is formulated using simple mathematical techniques. A vector formulation of the model is presented in a simple form without the use of tensors or advanced mathematics. Damage is modeled according to the overall approach in which one damage variable is used to describe damage in the lamina including the initiation, growth, and coalescence of voids and cracks in the matrix, fiber fracture, and debonding. A governing system of nine simultaneous ordinary differential equations is established for this problem. The system is solved numerically, and the results are discussed. This problem is selected because it can be solved numerically without the use of the finite element method.
Substratification of patients with newly diagnosed standard-risk multiple myeloma

Despite the absence of high-risk cytogenetics and lower International Staging System (ISS) stages, a subset of patients with multiple myeloma (MM) experience poor overall survival (OS). We studied 1461 patients with newly diagnosed MM to identify patient and disease characteristics that predict a high-risk phenotype among standard-risk patients. Fifty-six percent of all patients presented with standard-risk disease. Among them, advanced age, extremes of body mass index, non-hyperdiploid karyotype and abnormal lymphocyte counts were associated with worse OS. Standard-risk patients with 0-1 of these adverse factors (hazard ratio [HR] 0·32, 95% confidence interval [CI] 0·24-0·43, P < 0·001) and 2 adverse factors (HR 0·54, 95% CI 0·41-0·72, P < 0·001) experienced better OS than high-risk patients. Two or more adverse factors were present in 17% of standard-risk patients and were associated with OS comparable to high-risk patients (HR 0·91, 95% CI 0·67-1·24, P = 0·548). Predictive power among standard-risk patients was improved using score groups compared to ISS stages. Patients with standard-risk MM are a heterogeneous group with one in six patients experiencing OS comparable to high-risk disease. Patients at risk can be identified using readily available patient and disease characteristics. These findings emphasize the importance of accurate risk stratification and help explain part of the heterogeneity observed in clinical practice.
Revenue Implications of Destination-Based Cash-Flow Taxation

We estimate the revenue implications of a destination-based cash-flow tax (DBCFT) for 80 countries. On a global average, DBCFT revenues under unchanged tax rates would remain similar to the existing corporate income tax (CIT) revenue, but with sizable redistribution of revenue across countries. Countries are more likely to gain revenue if they have trade deficits, are not reliant on the resource sector, and/or—perhaps surprisingly—are developing economies. DBCFT revenues tend to be more volatile than CIT revenues. Moreover, we consider the revenue losses resulting from spillovers in case of unilateral implementation of a DBCFT. Results suggest that these spillover effects are sizeable if the adopting country is large and globally integrated. These spillovers generate strong revenue-based incentives for many—but not all—other countries to follow the DBCFT adoption.
Prospective and Retrospective Studies

Prospective and retrospective studies differ in whether the explanatory variable or the outcome variable is used to select the individuals in the study. The relative risk is frequently used to measure association for a prospective study. The odds ratio is frequently used to measure association for a retrospective study. Keywords: prospective study; retrospective study; relative risk; odds ratio; cross-sectional study; randomized clinical trial
HIV pre-exposure prophylaxis uptake by advanced practice nurses: Interplay of agency, community and attitudinal factors.

AIMS To identify associations among agency, community, personal and attitudinal factors that affect advanced practice nurses' uptake of HIV pre-exposure prophylaxis, an intervention consists of emtricitabine/tenofovir once-daily pill, along with sexual risk reduction education. DESIGN Cross-sectional. METHODS During March-May 2017, randomly selected Indiana advanced practice nurses were invited to complete an online survey, consisted of several validated self-rating measures (N = 1,358; response = 32.3%). Final sample (N = 369) was predominantly White, non-Hispanic, female advanced practice nurses in urban practices (mean age = 46). Conceptual model for structural equation model included 29 original/composite variables and five latent factors. RESULTS Final model consisted of 11 variables and four factors: agency, community, HIV prevention practices (including screening) and motivation to adopt evidence-based practices overall. Community had direct effects on HIV prevention practices (estimate = 0.28) and agency (estimate = 0.29). Agency had direct effects on HIV prevention practices (estimate = 0.74) and motivation to adopt evidence-based practices (estimate = 0.24). Community had indirect effects, through agency, on the two remaining factors. CONCLUSION Barriers exist against pre-exposure prophylaxis implementation, although practice guidelines are available. HIV prevention practices must be integrated across organizational structures, especially in high-risk communities, whereas practice change is more effective when focused on changing providers' attitudes towards intervention. When planning a pre-exposure prophylaxis intervention, advancing inputs from healthcare professionals, organizational leadership and community members, is crucial to success. IMPACT In settings where advanced practice nurses are primary contact points for health care, they may be best positioned to have an impact on implementation of HIV risk reduction strategies. Further research is needed to optimize their contributions to pre-exposure prophylaxis implementation.
To Sleep, Perchance to Dream: Acute and Chronic Sleep Deprivation in Acute Care Surgeons

Background Acute and chronic sleep deprivation are significantly associated with depressive symptoms and are thought to be contributors to the development of burnout. In-house call inherently includes frequent periods of disrupted sleep and is common among acute care surgeons. The relationship between in-house call and sleep deprivation among acute care surgeons has not been previously studied. The goal of this study was to determine prevalence and patterns of sleep deprivation in acute care surgeons. Study Design A prospective study of acute care surgeons with in-house call responsibilities from 2 level I trauma centers was performed. Participants wore a sleep-tracking device continuously over a 3-month period. Data collected included age, sex, schedule of in-house call, hours and pattern of each sleep stage (light, slow wave, and rapid eye movement [REM]), and total hours of sleep. Sleep patterns were analyzed for each night, excluding in-house call, and categorized as normal, acute sleep deprivation, or chronic sleep deprivation. Results There were 1,421 nights recorded among 17 acute care surgeons (35.3% female; ages 37 to 65 years, mean 45.5 years). Excluding in-house call, the average amount of sleep was 6.54 hours, with 64.8% of sleep patterns categorized as acute sleep deprivation or chronic sleep deprivation. Average amount of sleep was significantly higher on post-call day 1 (6.96 hours, p = 0.0016), but decreased significantly on post-call day 2 (6.33 hours, p = 0.0006). Sleep patterns with acute and chronic sleep deprivation peaked on post-call day 2, and returned to baseline on post-call day 3 (p = 0.046). Conclusions Sleep patterns consistent with acute and chronic sleep deprivation are common among acute care surgeons and worsen on post-call day 2. Baseline sleep patterns were not recovered until post-call day 3. Future study is needed to identify factors that affect physiologic recovery after in-house call and further elucidate the relationship between sleep deprivation and burnout.
Differential changes in bone strength of two inbred mouse strains following administration of a sclerostin-neutralizing antibody during growth.

Administration of sclerostin-neutralizing antibody (Scl-Ab) treatment has been shown to elicit an anabolic bone response in growing and adult mice. Prior work characterized the response of individual mouse strains but did not establish whether the impact of Scl-Ab on whole bone strength would vary across different inbred mouse strains. Herein, we tested the hypothesis that two inbred mouse strains (A/J and C57BL/6J (B6)) will show different whole bone strength outcomes following sclerostin-neutralizing antibody (Scl-Ab) treatment during growth (4.5–8.5 weeks of age). Treated B6 femurs showed a significantly greater stiffness (S) (68.8% vs. 46.0%) and maximum load (ML) (84.7% vs. 44.8%) compared to A/J. Although treated A/J and B6 femurs showed greater cortical area (Ct.Ar) similarly relative to their controls (37.7% in A/J and 41.1% in B6), the location of new bone deposition responsible for the greater mass differed between strains and may explain the greater whole bone strength observed in treated B6 mice. A/J femurs showed periosteal expansion and endocortical infilling, while B6 femurs showed periosteal expansion. Post-yield displacement (PYD) was smaller in treated A/J femurs (-61.2%, p < 0.001) resulting in greater brittleness compared to controls; an effect not present in B6 mice. Inter-strain differences in S, ML, and PYD led to divergent changes in work-to-fracture (Work). Work was 27.2% (p = 0.366) lower in treated A/J mice and 66.2% (p < 0.001) greater in treated B6 mice relative to controls. Our data confirmed the anabolic response to Scl-Ab shown by others, and provided evidence suggesting the mechanical benefits of Scl-Ab administration may be modulated by genetic background, with intrinsic growth patterns of these mice guiding the location of new bone deposition. Whether these differential outcomes will persist in adult and elderly mice remains to be determined.
Interventions to increase patient portal use in vulnerable populations: a systematic review

Background More than 100 studies document disparities in patient portal use among vulnerable populations. Developing and testing strategies to reduce disparities in use is essential to ensure portals benefit all populations. Objective To systematically review the impact of interventions designed to: (1) increase portal use or predictors of use in vulnerable patient populations, or (2) reduce disparities in use. Materials and methods A librarian searched Ovid MEDLINE, EMBASE, CINAHL, and Cochrane Reviews for studies published before September 1, 2018. Two reviewers independently selected English-language research articles that evaluated any interventions designed to impact an eligible outcome. One reviewer extracted data and categorized interventions, then another assessed accuracy. Two reviewers independently assessed risk of bias. Results Out of 18 included studies, 15 (83%) assessed an intervention's impact on portal use, 7 (39%) on predictors of use, and 1 (6%) on disparities in use. Most interventions studied focused on the individual (13 out of 26, 50%), as opposed to facilitating conditions, such as the tool, task, environment, or organization (SEIPS model). Twelve studies (67%) reported a statistically significant increase in portal use or predictors of use, or reduced disparities. Five studies (28%) had high or unclear risk of bias. Conclusion Individually focused interventions have the most evidence for increasing portal use in vulnerable populations. Interventions affecting other system elements (tool, task, environment, organization) have not been sufficiently studied to draw conclusions. Given the well-established evidence for disparities in use and the limited research on effective interventions, research should move beyond identifying disparities to systematically addressing them at multiple levels.
Is a Single Embedding Enough? Learning Node Representations that Capture Multiple Social Contexts

Recent interest in graph embedding methods has focused on learning a single representation for each node in the graph. But can nodes really be best described by a single vector representation? In this work, we propose a method for learning multiple representations of the nodes in a graph (e.g., the users of a social network). Based on a principled decomposition of the ego-network, each representation encodes the role of the node in a different local community in which the nodes participate. These representations allow for improved reconstruction of the nuanced relationships that occur in the graph - a phenomenon that we illustrate through state-of-the-art results on link prediction tasks on a variety of graphs, reducing the error by up to 90%. In addition, we show that these embeddings allow for effective visual analysis of the learned community structure.
Resiliency and Stock Returns

We present resiliency as a measure of liquidity and assess its relationship to expected returns. We establish a covariance-based measure, RES, that captures opening period resiliency, and use it to find a significant nonresiliency premium that ranges from 33 to 57 basis points per month. The premium persists after accounting for an extensive list of other liquidity-related measures and control variables. The results are significant for both value-weighted and equal-weighted returns, when micro-cap stocks are excluded, and for a sample of large cap stocks. The premium is particularly pronounced when trading volume is high.Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Does Greater Regulatory Burden Lead to More Corruption? Evidence Using Firm-Level Survey Data for Developing Countries

Regulation often creates opportunities for public officials to extract bribes. If this is true, deregulation offers a simple way to combat corruption. However, empirical evidence on the corruption and regulation nexus is limited. Further, the corruption indices used are based on experts' opinions, which may suffer from perception bias. The present paper attempts to address these shortcomings using firm-level survey data for 131 mostly developing countries on the experiences of the firms with bribery and regulatory burden. Exploiting within-country and industry-level variation in regulatory burden, the analysis finds a large, positive effect of regulatory burden on corruption. For the baseline results, the bribery rate is higher by about 0.03 percentage point for each percentage point increase in the regulatory burden. The finding is robust to several endogeneity checks.
Reducing mitochondrial reads in ATAC-seq using CRISPR/Cas9

ATAC-seq is a high-throughput sequencing technique that identifies open chromatin. Depending on the cell type, ATAC-seq samples may contain ~20–80% of mitochondrial sequencing reads. As the regions of open chromatin of interest are usually located in the nuclear genome, mitochondrial reads are typically discarded from the analysis. We tested two approaches to decrease wasted sequencing in ATAC-seq libraries generated from lymphoblastoid cell lines: targeted cleavage of mitochondrial DNA fragments using CRISPR technology and removal of detergent from the cell lysis buffer. We analyzed the effects of these treatments on the number of usable (unique, non-mitochondrial) reads and the number and quality of peaks called, including peaks identified in enhancers and transcription start sites. Both treatments resulted in considerable reduction of mitochondrial reads (1.7 and 3-fold, respectively). The removal of detergent, however, resulted in increased background and fewer peaks. The highest number of peaks and highest quality data was obtained by preparing samples with the original ATAC-seq protocol (using detergent) and treating them with CRISPR. This strategy reduced the amount of sequencing required to call a high number of peaks, which could lead to cost reduction when performing ATAC-seq on large numbers of samples and in cell types that contain a large amount of mitochondria.
Tungsten carbonyl-induced cyclizations of alkynyl alcohols to dihydropyranylidene carbenes and α-stannyl dihydropyrans

Abstract Reaction of 1-alkyn-5-ols with tetrahydrofuran-tungsten pentacarbonyl induces cyclization to the corresponding tungsten dihydropyranylidene carbenes. These carbenes can be converted into α-stannyl dihydropyrans upon reaction with tributyltin triflate and triethylamine. This strategy provides the first general preparation of six-membered ring oxacarbenes of the group VI metals, and a novel synthesis of α-stannyl dihydropyrans from acyclic compounds.
Population genomic analysis uncovers African and European admixture in Drosophila melanogaster populations from the south-eastern United States and Caribbean Islands.

Drosophila melanogaster is postulated to have colonized North America in the past several 100 years in two waves. Flies from Europe colonized the east coast United States while flies from Africa inhabited the Caribbean, which if true, make the south-east US and Caribbean Islands a secondary contact zone for African and European D. melanogaster. This scenario has been proposed based on phenotypes and limited genetic data. In our study, we have sequenced individual whole genomes of flies from populations in the south-east US and Caribbean Islands and examined these populations in conjunction with population sequences from the west coast US, Africa, and Europe. We find that west coast US populations are closely related to the European population, likely reflecting a rapid westward expansion upon first settlements into North America. We also find genomic evidence of African and European admixture in south-east US and Caribbean populations, with a clinal pattern of decreasing proportions of African ancestry with higher latitude. Our genomic analysis of D. melanogaster populations from the south-east US and Caribbean Islands provides more evidence for the Caribbean Islands as the source of previously reported novel African alleles found in other east coast US populations. We also find the border between the south-east US and the Caribbean island to be the admixture hot zone where distinctly African-like Caribbean flies become genomically more similar to European-like south-east US flies. Our findings have important implications for previous studies examining the generation of east coast US clines via selection.
Preparation, Structure, and Properties of Symmetrically 1,3-Difunctionalized Penta- and Hexafluorobicyclo[1.1.1]pentanes

Exhaustive direct fluorination of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate leads to dimethyl pentafluorobicyclo[1.1.1]pentane-1,3-dicarboxylate (2) and hexafluorobicyclo[1.1.1]pentane-1,3-d...
Crystallization of LnCu2O4 (Ln = La, Nd, Sm, Eu, Gd, Dy, Ho, Y, Er) from Hydroxide Melts: Synthesis and Structure

The synthesis and structure of LnCu2O4 with Ln = La, Nd, Sm, Eu, Gd, Dy, Ho, Y, and Er are reported. These cuprates were synthesized by precipitation from NaOH/KOH at 350−400 °C under ambient conditions. The effects of changing the relative amounts of NaOH and KOH, the quantities of the starting reagents, the reaction temperature, and the time at which the reagents were added on the yield, purity, and crystallinity of LnCu2O4 are described. Generally, the formation of LnCu2O4 is favored in dry, highly oxidizing melts with large quantities of dissolved reactants. Powder X-ray diffraction data were used to refine the structure of the various analogues using Rietveld profile analysis. The lattice parameters and average Ln−O distances decrease with decreasing size of the lanthanide ion. The average Cu−O bond distances, on the other hand, do not significantly change with the size of the lanthanide ion.
Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing

Summary Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that the majority of adult microglia expressing homeostatic genes are remarkably similar in transcriptomes, regardless of brain region. By contrast, early postnatal microglia are more heterogeneous. We discovered a proliferative-region-associated microglia (PAM) subset, mainly found in developing white matter, that shares a characteristic gene signature with degenerative disease-associated microglia (DAM). Such PAM have amoeboid morphology, are metabolically active, and phagocytose newly formed oligodendrocytes. This scRNA-seq atlas will be a valuable resource for dissecting innate immune functions in health and disease.
Enantioselective fluoride ring opening of aziridines enabled by cooperative Lewis acid catalysis

The enantioselective ring opening of aziridines using a latent source of HF is described. A combination of two Lewis acids, (salen)Co and an achiral Ti(IV) cocatalyst, provided optimal reactivity and enantioselectivity for the trans β-fluoroamine product. The use of a chelating aziridine protecting group was crucial. Acyclic and cyclic meso N-picolinamide aziridines underwent fluoride ring opening in up to 84% ee, and the kinetic resolution of a piperidine-derived aziridine was performed with krel=6.6. The picolinamide group may be readily removed without epimerization of the fluoroamine. Preliminary studies revealed a bimetallic mechanism wherein the chiral (salen)Co catalyst delivers the nucleophile and the Ti(IV) cocatalyst activates the aziridine.
The TMEM16A channel mediates the fast polyspermy block in Xenopus laevis.

In externally fertilizing animals, such as sea urchins and frogs, prolonged depolarization of the egg immediately after fertilization inhibits the entry of additional sperm—a phenomenon known as the fast block to polyspermy. In the African clawed frog Xenopus laevis, this depolarization is driven by Ca2+-activated Cl− efflux. Although the prominent Ca2+-activated Cl− currents generated in immature X. laevis oocytes are mediated by X. laevis transmembrane protein 16a (xTMEM16A) channels, little is known about the channels that contribute to the fast block in mature eggs. Moreover, the gamete undergoes a gross transformation as it develops from an immature oocyte into a fertilization-competent egg. Here, we report the results of our approach to identify the Ca2+-activated Cl− channel that triggers the fast block. By querying published proteomic and RNA-sequencing data, we identify two Ca2+-activated Cl− channels expressed in fertilization-competent X. laevis eggs: xTMEM16A and X. laevis bestrophin 2A (xBEST2A). By exogenously expressing xTMEM16A and xBEST2A in axolotl cells lacking endogenous Ca2+-activated currents, we characterize the effect of inhibitors on currents mediated by these channels. None of the inhibitors tested block xBEST2A currents specifically. However, 2-(4-chloro-2-methylphenoxy)-N-[(2-methoxyphenyl)methylideneamino]-acetamide (Ani9) and N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid (MONNA) each reduce xTMEM16A currents by more than 70% while only nominally inhibiting those generated by xBEST2A. Using whole-cell recordings during fertilization, we find that Ani9 and MONNA effectively diminish fertilization-evoked depolarizations. Additionally, these inhibitors lead to increased polyspermy in X. laevis embryos. These results indicate that fertilization activates TMEM16A channels in X. laevis eggs and induces the earliest known event triggered by fertilization: the fast block to polyspermy.
The current status of isomer enumeration of useful benzenoids and a new topological paradigm

The enumeration and development of conceptual tools for understanding the chemical properties of practical benzenoid hydrocarbons is stressed. Currently known isomer numbers for benzenoids having up to 60 carbons are summarized. Although there are well over 2 million isomers in this range, only approximately 500 benzenoid hydrocarbons have been characterized.
Nitromethyl benzoate annulation reactions: a rapid construction of the stealthin skeleton

Abstract The annulation of 2-(nitromethyl)benzoates with enones gave 4-nitro-1-naphthols in good yields. The carbocyclic framework of the stealthins was synthesized.
The stereochemical course of intramolecular vinylogous Mannich reactions

Abstract Substituted furans 8a-d underwent cyclizations via vinylogous Mannich reactions to give the threo-adducts 9a-d as the major products (1.3 - 20:1); the effects of solvent, Lewis acid and temperature were examined.
DIELS-ALDER REACTIONS OF 2- AND 3-VINYL-1-(PHENYLSULFONYL) PYRROLES

Regioselectively produced 2- and 3-acetyl-1-(phenylsulfonyl)pyrroles can be reduced to the corresponding alcohols and subsequently dehydrated to afford N-protected vinylpyrroles. These remarkably stable vinylpyrroles can then serve as heterodienes in [4 + 2] cycloaddition reactions with electron deficient dienophiles to afford tetrahydroindole derivatives.
TOTAL SYNTHESIS OF ()-PHOSPHONOTHRIXIN

Abstract Synthesis of the novel natural product Phosphonothrixin has been accomplished in 6 steps and 24% overall yield from the commercially available Baylis-Hillman adduct derived from acetaldehyde and methyl vinyl ketone. The synthesis features use of a trisubstituted olefin as a latent a-hydroxyketone, which formally reverses the oxidation states of the hydroxyl and carbonyl functionalities. This alleviates some of the difficulties encountered in alternative syntheses which proceed through metastable intermediates.
Geographic cline analysis as a tool for studying genome-wide variation: a case study of pollinator-mediated divergence in a monkeyflower.

A major goal of speciation research is to reveal the genomic signatures that accompany the speciation process. Genome scans are routinely used to explore genome-wide variation and identify highly differentiated loci that may contribute to ecological divergence, but they do not incorporate spatial, phenotypic or environmental data that might enhance outlier detection. Geographic cline analysis provides a potential framework for integrating diverse forms of data in a spatially explicit framework, but has not been used to study genome-wide patterns of divergence. Aided by a first-draft genome assembly, we combined an FCT scan and geographic cline analysis to characterize patterns of genome-wide divergence between divergent pollination ecotypes of Mimulus aurantiacus. FCT analysis of 58 872 SNPs generated via RAD-seq revealed little ecotypic differentiation (mean FCT = 0.041), although a small number of loci were moderately-to-highly diverged. Consistent with our previous results from the gene MaMyb2, which contributes to differences in flower colour, 130 loci have cline shapes that recapitulate the spatial pattern of trait divergence, suggesting that they may reside in or near the genomic regions that contribute to pollinator isolation. In the narrow hybrid zone between the ecotypes, extensive admixture among individuals and low linkage disequilibrium between markers indicate that most outlier loci are scattered throughout the genome, rather than being restricted to one or a few divergent regions. In addition to revealing the genomic consequences of ecological divergence in this system, we discuss how geographic cline analysis is a powerful but under-utilized framework for studying genome-wide patterns of divergence.
Predicting Carriers of Ongoing Selective Sweeps without Knowledge of the Favored Allele

Methods for detecting the genomic signatures of natural selection have been heavily studied, and they have been successful in identifying many selective sweeps. For most of these sweeps, the favored allele remains unknown, making it difficult to distinguish carriers of the sweep from non-carriers. In an ongoing selective sweep, carriers of the favored allele are likely to contain a future most recent common ancestor. Therefore, identifying them may prove useful in predicting the evolutionary trajectory--for example, in contexts involving drug-resistant pathogen strains or cancer subclones. The main contribution of this paper is the development and analysis of a new statistic, the Haplotype Allele Frequency (HAF) score. The HAF score, assigned to individual haplotypes in a sample, naturally captures many of the properties shared by haplotypes carrying a favored allele. We provide a theoretical framework for computing expected HAF scores under different evolutionary scenarios, and we validate the theoretical predictions with simulations. As an application of HAF score computations, we develop an algorithm (PreCIOSS: Predicting Carriers of Ongoing Selective Sweeps) to identify carriers of the favored allele in selective sweeps, and we demonstrate its power on simulations of both hard and soft sweeps, as well as on data from well-known sweeps in human populations.
Structure determination of mycolactone C via total synthesis.

By total synthesis, mycolactone C has been established as an approximately 1:1 mixture of Z-Δ4‘5‘- and E-Δ4‘5‘-geometric isomers of C12‘-deoxymycolactones A and B.
Pr1.33Pt4Ga10: Superstructure and magnetism

Abstract Pr1.33Pt4Ga10 crystals were prepared by Ga-flux method. The superstructure of this compound was studied by single-crystal X-ray diffraction (XRD), transmission electron microscopy (TEM), and diffuse X-ray scattering. Pr1.33Pt4Ga10 adopts the P63/mmc space group with a=b=4.3227(5) A, c=16.485(3) A: the structure features Pr2Ga3 layers alternating with Pt2Ga4 layers along the c-axis. TEM studies and pair distribution function (PDF) analysis of X-ray total scattering data show that Pr2Ga3 layers possess an ordered superstructure (of dimension a ′ = a 3 ) in which Pr vacancies and Ga atoms are ordered within the ab-plane but disordered along the c-direction. PDF analysis also shows temperature-dependent structural features local to the Pr3+ ion. Magnetic measurements reveal that Pr3+ ions order ferrimagnetically below 12.5(2) K.
Polarizability versus mobility: atomistic force field for ionic liquids.

Based on classical molecular dynamics simulations, we discuss the impact of Coulombic interactions on a comprehensive set of properties of room temperature ionic liquids (RTILs) containing 1,3-dimethylimidazolium (MMIM+), N-butylpyridinium (BPY+), and bis(trifluoromethane sulfonyl)imide (TFSI−) ions. Ionic transport is found to be noticeably hindered by the excessive Coulombic energy, originating from the neglect of electronic polarization in the condensed phase of these RTILs. Starting from the models, recently suggested by Lopes and Padua, we show that realistic ionic dynamics can be achieved by the uniform scaling of electrostatic charges on all interaction sites. The original model systematically overestimates density and heat of vaporization of RTILs. Since density linearly depends on charge scaling, it is possible to use it as a convenient beacon to promptly derive a correct scaling factor. Based on the simulations of [BPY][TFSI] and [MMIM][TFSI] over a wide temperature range, we conclude that the suggested technique is feasible to greatly improve quality of the already existing non-polarizable FFs for RTILs.
Natural selection on MHC IIβ in parapatric lake and stream stickleback: Balancing, divergent, both or neither?

Major histocompatibility (MHC) genes encode proteins that play a central role in vertebrates’ adaptive immunity to parasites. MHC loci are among the most polymorphic in vertebrates’ genomes, inspiring many studies to identify evolutionary processes driving MHC polymorphism within populations, and divergence between populations. Leading hypotheses include balancing selection favoring rare alleles within populations, and spatially divergent selection. These hypotheses do not always produce diagnosably distinct predictions, causing many studies of MHC to yield inconsistent or ambiguous results. We suggest a novel strategy to distinguish balancing versus divergent selection on MHC, taking advantage of natural admixture between parapatric populations. With divergent selection, individuals with immigrant alleles will be more infected and less fit because they are susceptible to novel parasites in their new habitat. With balancing selection, individuals with locally-rare immigrant alleles will be more fit (less infected). We tested these contrasting predictions using threespine stickleback from three replicate pairs of parapatric lake and stream habitats. We found numerous positive and negative associations between particular MHC IIβ alleles and particular parasite taxa. A few allele-parasite comparisons supported balancing selection, others supported divergent selection between habitats. But, there was no overall tendency for fish with immigrant MHC alleles to be more or less heavily infected. Instead, locally rare MHC alleles (not necessarily immigrants) were associated with heavier infections. Our results illustrate the complex relationship between MHC IIβ allelic variation and spatially varying multi-species parasite communities: different hypotheses may be concurrently true for different allele-parasite combinations. This article is protected by copyright. All rights reserved.
Delivery of GalNAc-Conjugated Splice-Switching ASOs to Non-hepatic Cells through Ectopic Expression of Asialoglycoprotein Receptor

Splice-switching antisense oligonucleotides (ASOs) are promising therapeutic tools to target various genetic diseases, including cancer. However, in vivo delivery of ASOs to orthotopic tumors in cancer mouse models or to certain target tissues remains challenging. A viable solution already in use is receptor-mediated uptake of ASOs via tissue-specific receptors. For example, the asialoglycoprotein receptor (ASGP-R) is exclusively expressed in hepatocytes. Triantennary N-acetylgalactosamine (GalNAc) (GN3)-conjugated ASOs bind to the receptor and are efficiently internalized by endocytosis, enhancing ASO potency in the liver. Here we explore the use of GalNAc-mediated targeting to deliver therapeutic splice-switching ASOs to cancer cells that ectopically express ASGP-R, both in vitro and in tumor mouse models. We found that ectopic expression of the major isoform ASGP-R1 H1a is sufficient to promote uptake and increase GN3-ASO potency to various degrees in four of five tested cancer cells. We show that cell-type-specific glycosylation of the receptor does not affect its activity. In vivo, GN3-conjugated ASOs specifically target subcutaneous xenograft tumors that ectopically express ASGP-R1, and modulate splicing significantly more strongly than unconjugated ASOs. Our work shows that GN3-targeting is a useful tool for proof-of-principle studies in orthotopic cancer models, until endogenous receptors are identified and exploited for efficiently targeting cancer cells.
Titanium-Mediated Alkylative Coupling of N-Acylpyrroles

Inter- and intramolecular titanium-mediated coupling reactions of N-acylpyrroles are reported for convenient functionalization of terminal olefins. Comparison with the Kulinkovich reaction of esters and other carboxylic acid derivatives is also included.
Eikonal methods applied to gravitational scattering amplitudes

We apply factorization and eikonal methods from gauge theories to scattering amplitudes in gravity. We hypothesize that these amplitudes factor into an IR-divergent soft function and an IR-finite hard function, with the former given by the expectation value of a product of gravitational Wilson line operators. Using this approach, we show that the IR-divergent part of the n-graviton scattering amplitude is given by the exponential of the one-loop IR divergence, as originally discovered by Weinberg, with no additional subleading IR-divergent contributions in dimensional regularization.
Rearrangements of N-alkyl-/aryl-nitrones derived from 4-oxo-4H-1-benzopyran-3-carboxaldehyde––a solvent-dependent process

C-(4-Oxo-4H-1-benzopyran-3-yl)-N-alkyl-/aryl-nitrones derived from 4-oxo-4H-1-benzopyran-3-carboxaldehyde, rearrange to 2-alkyl-/aryl-amino-3-formylchromone and/or 3-(alkyl-/aryl-aminomethylene)chroman-2,4-dione depending upon the reaction medium. 3-(Alkylaminomethylene)chroman-2,4-dione has been utilized in the synthesis of 1-benzopyrano[3,4-d]isoxazole-4-one.
ASYMMETRIC SYNTHESES OF N-BOC 2-SUBSTITUTED PYRROLIDINES AND PIPERIDINES BY INTRAMOLECULAR CYCLIZATION

Asymmetric lithiation-substitutions by n-BuLi/(−)-sparteine with the N-Boc-N-(3-halopropyl)allylamines 1−4 provide the N-Boc-2-alkenylpyrrolidines (S)-5, (S)-6, and (S)-7 in yields of 31−93% with enantiomeric ratios (ers) from 65:35 to 90:10. These reactions are shown to involve an initial asymmetric deprotonation, but the enantiodetermining step is a subsequent asymmetric cyclization under the influence of the chiral ligand. Extension to formation of a piperidine is illustrated by reaction of N-Boc-(4-chlorobutyl)cinnamylamine (9) to afford (S)-N-Boc-2-(trans-β-styryl)piperidine ((S)-10) in 68% yield with an enantiomeric ratio (er) of 84:16. Analogous reactions with epoxide ring openings of N-Boc-N-(oxaalkenyl)benzylamines 11 and 12 afford the corresponding N-Boc-2-phenyl-3-(hydroxymethyl)pyrrolidine (13) in 67% yield with a diastereomeric ratio (dr) of 50:50 and ers of 97:3 and 95:5 and the corresponding N-Boc-2-phenyl-3-(hydroxymethyl)piperidine (14) in 29% yield with a dr of 86:14 and ers of 81:19 and...
Noradrenergic Plasticity of Olfactory Sensory Neuron Inputs to the Main Olfactory Bulb

Sensory responses are modulated by internal factors including attention, experience, and brain state. This is partly due to fluctuations in neuromodulatory input from regions such as the noradrenergic locus ceruleus (LC) in the brainstem. LC activity changes with arousal and modulates sensory processing, cognition, and memory. The main olfactory bulb (MOB) is richly targeted by LC fibers and noradrenaline profoundly influences MOB circuitry and odor-guided behavior. Noradrenaline-dependent plasticity affects the output of the MOB; however. it is unclear whether noradrenergic plasticity also affects the input to the MOB from olfactory sensory neurons (OSNs) in the glomerular layer. Noradrenergic terminals are found in the glomerular layer, but noradrenaline receptors do not seem to acutely modulate OSN terminals in vitro. We investigated whether noradrenaline induces plasticity at the glomerulus. We used wide-field optical imaging to measure changes in odor responses following electrical stimulation of LC in anesthetized mice. Surprisingly, odor-evoked intrinsic optical signals at the glomerulus were persistently weakened after LC activation. Calcium imaging selectively from OSNs confirmed that this effect was due to suppression of presynaptic input and was prevented by noradrenergic antagonists. Finally, suppression of responses to an odor did not require precise coincidence of the odor with LC activation. However, suppression was intensified by LC activation in the absence of odors. We conclude that noradrenaline release from LC has persistent effects on odor processing already at the first synapse of the main olfactory system. This mechanism could contribute to arousal-dependent memories.
Base-catalyzed three-component direct Mannich reaction of enolizable ketones with high syn-selectivities

The three-component direct Mannich reaction between aldehydes, p-toluenesulfonamide, and enolizable ketones was achieved for the first time with organic bases as the catalysts. The corresponding N-tosylated β-aminoketones were obtained in high yields and good to excellent diastereoselectivities using TMG as the catalyst. Through reduction of the ketone group, the reaction product may be converted into β-aminol with excellent diastereoselectivity.
La9Sb16Br3 and Ce9Sb16Cl3: stars and stripes in rare earth halide and intermetallic compounds.

The title compounds were synthesized from Ln, LnX3 (Ln = La, Ce; X = Cl, Br), and Sb under an Ar atmosphere at 950 °C. They crystallize in the space group P63/m (No. 176) with lattice constants a =...