cssi/SciSciGPT-SciSciNet huggingface dataset:
Constructionist steps towards an autonomously empathetic system

Prior efforts to create an autonomous computer system capable of predicting what a human being is thinking or feeling from facial expression data have been largely based on outdated, inaccurate models of how emotions work that rely on many scientifically questionable assumptions. In our research, we are creating an empathetic system that incorporates the latest provable scientific understanding of emotions: that they are constructs of the human mind, rather than universal expressions of distinct internal states. Thus, our system uses a user-dependent method of analysis and relies heavily on contextual information to make predictions about what subjects are experiencing. Our system's accuracy and therefore usefulness are built on provable ground truths that prohibit the drawing of inaccurate conclusions that other systems could too easily make.
Factors affecting the Affordable Care Act Marketplace stand-alone pediatric dental plan premiums.

Background Children from lower income families have inadequate dental insurance coverage and poorer dental health in the United States. The Affordable Care Act (ACA) created Health Insurance Exchange Marketplaces to increase competition among health insurers and to provide low-income families with less costly health plans. The study examined Marketplace pediatric stand-alone dental plans (SADPs) and factors that affect their premiums. Methods The data used were 2016 Federal-Facilitated and State-Partnership Marketplace pediatric SADP data. Ordinary least squares regressions were applied to estimate contributing factors' effects on SADP premiums. Results Great premium variation was found among low and high coverage level SADPs, respectively. Premiums of Health Maintenance Organization (HMO) SADPs were significantly less expensive than Preferred Provider Organization (PPO) SADPs. SADPs charged significantly higher premiums for more types of services covered. SADPs also charged higher premiums in states where there are larger proportions of low-income people who report poor dental health, more dentists per capita, or higher dentists' wages. The number of insurance companies offering pediatric SADPs in a Marketplace was negatively associated with premiums. Conclusion The current Marketplace pediatric SADPs may have limited effects on increasing economically disadvantaged children's access to quality dental care. Marketplaces can promote competition among its pediatric dental insurers on providing lower-cost pediatric SADPs.
Protein–protein binding pathways and calculations of rate constants using fully-continuous, explicit-solvent simulations

A grand challenge in the field of biophysics has been the complete characterization of protein–protein binding processes at atomic resolution. This characterization requires the direct simulation of binding pathways starting from the initial, unbound state and proceeding through states that are too transient to be captured by experiment. Here, we applied the weighted ensemble path sampling strategy to orchestrate atomistic simulation of protein–protein binding pathways. Our simulation generated 203 fully-continuous and independent pathways along with rate constants for the binding process involving the barnase and barstar proteins. Results reveal multiple binding pathways along a “funnel-like” free energy landscape in which the formation of the “encounter complex” intermediate is rate-limiting followed by a relatively rapid rearrangement of the encounter complex to the bound state. Among all diffusional collisions, only ∼11% were productive. In the most probable binding pathways, the proteins rotated to a large extent (likely via electrostatic steering) in order to collide productively followed by “rolling” of the proteins along each other's binding interfaces to reach the bound state. Consistent with experiment, R59 was identified as the most kinetically important barnase residue for the binding process. Furthermore, protein desolvation occurs late in the binding process during the rearrangement of the encounter complex to the bound state. Notably, the positions of crystallographic water molecules that bridge hydrogen bonds between barnase and barstar are occupied in the bound-state ensemble. Our simulation was completed in a month using 1600 CPU cores at a time, demonstrating that it is now practical to carry out atomistic simulations of protein–protein binding.
Tensor Matched Kronecker-structured Subspace Detection for Missing Information

We consider the problem of detecting whether a tensor signal having many missing entities lies within a given low dimensional Kronecker-Structured (KS) subspace. This is a matched subspace detection problem. Tensor matched subspace detection problem is more challenging because of the intertwined signal dimensions. We solve this problem by projecting the signal onto the KS subspace, which is a Kronecker product of different subspaces corresponding to each signal dimension. Under this framework, we define the KS subspaces and the orthogonal projection of the signal onto the KS subspace. We prove that reliable detection is possible as long as the cardinality of the missing signal is greater than the dimensions of the KS subspace by bounding the residual energy of the sampling signal with high probability.
Loss of embryonic neural crest derived cardiomyocytes causes adult onset hypertrophic cardiomyopathy in zebrafish

Neural crest cells migrate to the embryonic heart and transform into a small number of cardiomyocytes, but their functions in the developing and adult heart are unknown. Here, we show that neural crest derived cardiomyocytes (NC-Cms) in the zebrafish ventricle express Notch ligand jag2b, are adjacent to Notch responding cells, and persist throughout life. Genetic ablation of NC-Cms during embryogenesis results in diminished jag2b, altered Notch signaling and aberrant trabeculation patterns, but is not detrimental to early heart function or survival to adulthood. However, embryonic NC-Cm ablation results in adult fish that show severe hypertrophic cardiomyopathy (HCM), altered cardiomyocyte size, diminished adult heart capacity and heart failure in cardiac stress tests. Adult jag2b mutants have similar cardiomyopathy. Thus, we identify a cardiomyocyte population and genetic pathway that are required to prevent adult onset HCM and provide a zebrafish model of adult-onset HCM and heart failure.
The Small β-Barrel Domain: A Survey-Based Structural Analysis

The small β-barrel (SBB) is an ancient protein structural domain characterized by extremes: it features a broad range of structural varieties, a deeply intricate evolutionary history, and it is associated with a bewildering array of cellular pathways. Here, we present a thorough, survey-based analysis of the structural properties of SBBs. We first consider the defining properties of the SBB, including various systems of nomenclature used to describe it, and we introduce the unifying concept of an "urfold." To begin elucidating how vast functional diversity can be achieved by a relatively simple domain, we explore the anatomy of the SBB and its representative structural variants. Many SBB proteins assemble into cyclic oligomers as the biologically functional units; these oligomers often bind RNA, and typically exhibit great quaternary structural plasticity (homomeric and heteromeric rings, variable subunit stoichiometries, etc.). We conclude with three themes that emerge from the rich structure ↔ function versatility of the SBB.
Public Health Implications of Google Searches for Sunscreen, Sunburn, Skin Cancer, and Melanoma in the United States.

Purpose Google Trends (GT) offers insights into public interests and behaviors and holds potential for guiding public health campaigns. We evaluated trends in US searches for sunscreen, sunburn, skin cancer, and melanoma and their relationships with melanoma outcomes. Design Google Trends was queried for US search volumes from 2004 to 2017. Time-matched search term data were correlated with melanoma outcomes data from Surveillance Epidemiology and End Results Program and United States Cancer Statistics databases (2004-2014 and 2010-2014, respectively). Setting Users of the Google search engine in the United States. Participants Google search engine users in the United States. This represents approximately 65% of the population. Measures Search volumes, melanoma outcomes. Analysis Pearson correlations between search term volumes, time, and national melanoma outcomes. Spearman correlations between state-level search data and melanoma outcomes. Results The terms "sunscreen," "sunburn," "skin cancer," and "melanoma" were all highly correlated ( P Conclusions We conclude that online skin cancer prevention campaigns should focus on the search terms "sunburn" and "sunscreen," given the decreasing online searches for skin cancer and melanoma. This is reinforced by the finding that sunscreen searches are higher in areas with higher melanoma incidence.
Household investment in durable appliances and outcomes for children: Evidence from China

Abstract Does the ownership of time-saving household appliances have a positive impact on children’s outcomes? I use micro-level data from the China Health and Nutrition Survey from 1989 through 2011 to infer that ownership of time-saving household appliances results in a decrease in time allocated to household work, increase in school enrollment rates, and decrease in labor force participation rates for children aged 12 to 18. When the sample is partitioned on the basis of gender, these outcomes are more pronounced among females. To deal with endogeneity of household durable goods, I instrument household ownership of time-saving appliances by average ownership rate among households with no children living in the same community and two family-specific time-using household assets. With gender equality and women’s empowerment being a top priority among developing countries according to the United Nations, the results presented in this paper suggest one effective way to increase girls’ school enrollment is to reduce their household obligations. Time-saving appliances are tools that can provide the requisite decrease in time dedicated to household work. This study is the first to estimate the effect of time-saving technologies on child outcomes.
Graduation and Academic Placement of Underrepresented Racial/Ethnic Minority Doctoral Recipients in Public Health Disciplines, United States, 2003-2015.

Objectives:Given public health’s emphasis on health disparities in underrepresented racial/ethnic minority communities, having a racially and ethnically diverse faculty is important to ensure adequ...
Generalizability of the FOURIER trial to routine clinical care: Do trial participants represent patients in everyday practice?

Background In the FOURIER trial, evolocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, reduced cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD). We aimed to examine how closely patients in routine practice resemble the FOURIER trial participants and to assess the observed cardiovascular risks based on trial eligibility and underrepresentativeness. Methods Using a large US administrative database with linked laboratory data, we identified adult patients with ASCVD between January 1, 2012, and December 31, 2016. We identified the excluded and underrepresented populations and examined the risk of cardiovascular events (a composite endpoint of myocardial infarction [MI], stroke, angina, and coronary revascularization) based on trial eligibility and underrepresentativeness. Results Only 15.2% of 233,977 patients met the FOURIER eligibility. Nearly 60% of the ineligible patients met at least 2 exclusion criteria. Among trial-eligible patients, elderly patients, women, minorities, and those without prior MI were underrepresented in FOURIER. Patients who would have been excluded from FOURIER had a diverse risk profile but, on average, had a lower cardiovascular risk than those who would have qualified (hazard ratio [HR] 0.84 [0.81-0.88], P Conclusions One in 7 ASCVD patients in practice would have qualified for FOURIER. The excluded and underrepresented populations were at a particularly low or high cardiovascular risk. Statin therapy was underused, and physicians may need to evaluate adherence before adding a proprotein convertase subtilisin-kexin type 9 inhibitor.
Gravitational wave denoising of binary black hole mergers with deep learning

Abstract Gravitational wave detection requires an in-depth understanding of the physical properties of gravitational wave signals, and the noise from which they are extracted. Understanding the statistical properties of noise is a complex endeavor, particularly in realistic detection scenarios. In this article we demonstrate that deep learning can handle the non-Gaussian and non-stationary nature of gravitational wave data, and showcase its application to denoise the gravitational wave signals generated by the binary black hole mergers GW150914, GW170104, GW170608 and GW170814 from advanced LIGO noise. To exhibit the accuracy of this methodology, we compute the overlap between the time-series signals produced by our denoising algorithm, and the numerical relativity templates that are expected to describe these gravitational wave sources, finding overlaps O ≳ 0.99 . We also show that our deep learning algorithm is capable of removing noise anomalies from numerical relativity signals that we inject in real advanced LIGO data. We discuss the implications of these results for the characterization of gravitational wave signals.
Nonrivalry and the Economics of Data

Data is nonrival: a person's location history, medical records, and driving data can be used by any number of firms simultaneously. Nonrivalry leads to increasing returns and implies an important role for market structure and property rights. Who should own data? What restrictions should apply to the use of data? We show that in equilibrium, firms may not adequately respect the privacy of consumers. But nonrivalry leads to other consequences that are less obvious. Because of nonrivalry, there may be large social gains to data being used broadly across firms, even in the presence of privacy considerations. Fearing creative destruction, firms may choose to hoard data they own, leading to the inefficient use of nonrival data. Instead, giving the data property rights to consumers can generate allocations that are close to optimal. Consumers balance their concerns for privacy against the economic gains that come from selling data to all interested parties.
Bayesian Exploration with Heterogeneous Agents

It is common in recommendation systems that users both consume and produce information as they make strategic choices under uncertainty. While a social planner would balance “exploration” and “exploitation” using a multi-armed bandit algorithm, users' incentives may tilt this balance in favor of exploitation. We consider Bayesian Exploration: a simple model in which the recommendation system (the “principal”) controls the information flow to the users (the “agents”) and strives to incentivize exploration via information asymmetry. A single round of this model is a version of a well-known “Bayesian Persuasion game” from [24]. We allow heterogeneous users, relaxing a major assumption from prior work that users have the same preferences from one time step to another. The goal is now to learn the best personalized recommendations. One particular challenge is that it may be impossible to incentivize some of the user types to take some of the actions, no matter what the principal does or how much time she has. We consider several versions of the model, depending on whether and when the user types are reported to the principal, and design a near-optimal “recommendation policy” for each version. We also investigate how the model choice and the diversity of user types impact the set of actions that can possibly be “explored” by each type.
Noise, Low-Frequency

Low-frequency noise, containing fluctuations of current or voltage with frequency components below 10 kHz, is mainly fundamental 1/f noise and sometimes nonfundamental 1/f noise. In addition, shot noise, generation–recombination (GR) noise, and thermal noise, which are important at higher frequencies, also extend to the low-frequency domain. All theses forms of electronic noise, are characterized by the mean squared current fluctuation ((δI)2) [or ((δV)2≡RMS δV)2 for voltage], measured in series with (or across) the device or sample under test, when a constant voltage (current) is applied, except for thermal noise, which is present even in thermal equilibrium, with no bias applied. Keywords: shot noise; generation-recombination noise; thermal noise; low-frequency noise; modulation noise; semiconductor
Big Picture, Bad Outcomes: When Visual Perspectives Harm Health Goal Pursuit

People often fail to achieve health goals, which compromises their well-being. Prior research suggests that seeing events through an observer’s eyes (i.e., adopting a third-person perspective) should facilitate goal pursuit. However, we find that third-person perspectives discourage goal-consistent intentions and behavior for health goals when goal centrality is low (i.e., the goal is peripheral to one’s self-concept). In Experiment 1, people who adopted a third-person perspective chose more sugary foods if they considered a healthy eating goal to be more peripheral to the self. Experiment 2 examines why a third-person perspective can hinder goal pursuit; it encourages a breakdown in implemental thinking which, in turn, increases negative self-conscious emotions. While high goal centrality buffers people from negative effects on goal intentions, low centrality does not. Experiment 3 demonstrates that this effect is robust when goal centrality is manipulated. We recommend that consumers pursuing health goals (and individuals who support them) exercise caution when employing perspective-based strategies, as they may backfire for people at greatest risk of goal abandonment.
Chapter 12 – Structuring the Deal: Tax and Accounting Considerations

This chapter focuses on the implications of tax and accounting considerations for the deal-structuring process. When and why certain alternative taxable and nontaxable structures are used is discussed in detail, as well as how purchase accounting is applied in business combinations and its implications for financial reporting.
Medical imaging

Medical imaging is the study of human functions and anatomy through pictorial information. In order to generate this pictorial information, multidisciplinary knowledge, including biology, anatomy, physiology, chemistry, computer science, optical science, radiological science, electrical engineering, mathematics, and physics is required. Generally speaking, medical imaging studies the methods and procedures of:
4 – Exponents and Polynomials

Publisher Summary This chapter discusses the concept of exponents and polynomials. A shorthand notation is defined to represent repeated multiplications. It deals with developing properties associated with the new notation and then applying these properties to other situation. The rule for multiplication of real numbers is developed to use the fact that multiplication with whole numbers can be thought of as repeated addition. Multiplication by a whole number is shorthand notation for repeated addition. A similar relationship exists between what are called exponents and repeated multiplication. An exponent is a number written just above and to the right of another number, which is called the base. In the expression 52, for example, the exponent is 2 and the base is 5. There are two basic steps involved in the multiplication of monomials. First, one rewrites the products using the commutative and associative properties. Then, simplify by multiplying coefficients and adding exponents of like bases.
Learning to Groove with Inverse Sequence Transformations

We explore models for translating abstract musical ideas (scores, rhythms) into expressive performances using Seq2Seq and recurrent Variational Information Bottleneck (VIB) models. Though Seq2Seq models usually require painstakingly aligned corpora, we show that it is possible to adapt an approach from the Generative Adversarial Network (GAN) literature (e.g. Pix2Pix (Isola et al., 2017) and Vid2Vid (Wang et al. 2018a)) to sequences, creating large volumes of paired data by performing simple transformations and training generative models to plausibly invert these transformations. Music, and drumming in particular, provides a strong test case for this approach because many common transformations (quantization, removing voices) have clear semantics, and models for learning to invert them have real-world applications. Focusing on the case of drum set players, we create and release a new dataset for this purpose, containing over 13 hours of recordings by professional drummers aligned with fine-grained timing and dynamics information. We also explore some of the creative potential of these models, including demonstrating improvements on state-of-the-art methods for Humanization (instantiating a performance from a musical score).
Hybrid Metallocene–Phosphazene Polymers

The incorporation of η6-arene, ferrocene, and ruthenocene side groups into phosphazene high polymers generates properties such as high melting behavior and electronic conductivity, and provides insights into reaction mechanisms and ring–polymer equilibria. The design and synthesis of these polymers is facilitated by model compound studies using small molecule cyclic phosphazenes.
Design and Preparation of Heterogeneous Catalysts by Controlled Chemical Reactions with Oxygen and Hydrogen

Chemical reactions of metals and strongly interacting alloys such as Cu-Mn, Ni-Ti, Ni-Hf and Ni-Zr with oxygen and hydrogen play important roles in the preparation, activation, and regeneration of many important heterogeneous catalytic systems involving supported and unsupported metals and alloys. Recent advances in the understanding of metal and alloy oxidation is bringing new insight into the reactive design and activation of bi- and multi-metallic catalysts. By surface studies of oxidation, thermal annealing and reduction of selected alloys and their thin films and reaction layers and products we have been able to delineate the factors which are most important to the oxide formation processes and the oxide reduction processes. Reaction models developed from these results are permitting the design of new catalyst systems and providing long sought understanding to explain specific aspects of well established metallic catalysts.
Inverse-Electron-Demand Hetero-Diels−Alder Reaction of β,γ-Unsaturated α-Ketophosphonates Catalyzed by Prolinal Dithioacetals†

Some novel prolinal dithioacetal derivatives were studied as catalysts for the inverse-electron-demand hetero-Diels−Alder reaction of enolizable aldehydes and β,γ-unsaturated α-ketophosphonates. The corresponding 5,6-dihydro-4H-pyran-2-ylphosphonates were obtained in good ee values (up to 94% ee).
Signaling Dynamics Control Cell Fate in the Early Drosophila Embryo.

Summary The Erk mitogen-activated protein kinase plays diverse roles in animal development. Its widespread reuse raises a conundrum: when a single kinase like Erk is activated, how does a developing cell know which fate to adopt? We combine optogenetic control with genetic perturbations to dissect Erk-dependent fates in the early Drosophila embryo. We find that Erk activity is sufficient to “posteriorize” 88% of the embryo, inducing gut endoderm-like gene expression and morphogenetic movements in all cells within this region. Gut endoderm fate adoption requires at least 1 h of signaling, whereas a 30-min Erk pulse specifies a distinct ectodermal cell type, intermediate neuroblasts. We find that the endoderm-ectoderm cell fate switch is controlled by the cumulative load of Erk activity, not the duration of a single pulse. The fly embryo thus harbors a classic example of dynamic control, where the temporal profile of Erk signaling selects between distinct physiological outcomes.
Choosing Transfer Languages for Cross-Lingual Learning.

Cross-lingual transfer, where a high-resource transfer language is used to improve the accuracy of a low-resource task language, is now an invaluable tool for improving performance of natural language processing (NLP) on low-resource languages. However, given a particular task language, it is not clear which language to transfer from, and the standard strategy is to select languages based on ad hoc criteria, usually the intuition of the experimenter. Since a large number of features contribute to the success of cross-lingual transfer (including phylogenetic similarity, typological properties, lexical overlap, or size of available data), even the most enlightened experimenter rarely considers all these factors for the particular task at hand. In this paper, we consider this task of automatically selecting optimal transfer languages as a ranking problem, and build models that consider the aforementioned features to perform this prediction. In experiments on representative NLP tasks, we demonstrate that our model predicts good transfer languages much better than ad hoc baselines considering single features in isolation, and glean insights on what features are most informative for each different NLP tasks, which may inform future ad hoc selection even without use of our method.
Substitution and Remote Protecting Group Influence on the Oxidation/Addition of α-Substituted 1,2-Anhydroglycosides: A Novel Entry into C-Ketosides

C-Ketosides are valuable intermediates in chemical synthesis and as glycoside mimics. This manuscript describes the efficient generation of these substrates from α-alkyl-substituted glycals and an ...
Alterations in striato-thalamo-pallidal intrinsic functional connectivity as a prodrome of Parkinson’s disease

Although the diagnosis of Parkinson's disease (PD) remains anchored around the cardinal motor symptoms of bradykinesia, rest tremor, rigidity and postural instability, it is becoming increasingly clear that the clinical phase of the disease is preceded by a long period of neurodegeneration, which is not readily evident in terms of motor dysfunction. The neurobiological mechanisms that underpin this prodromal phase of PD remain poorly understood. Based on converging evidence of basal ganglia (BG) dysfunction in early PD, we set out to establish whether the prodromal phase of the disease is characterized by alterations in functional communication within the input and output structures of the BG. We analyzed resting-state functional MRI data collected from patients with REM sleep behavior disorder (RBD) and/or hyposmia, two of the strongest markers of prodromal PD, in comparison to age-matched controls. Relative to controls, subjects in the prodromal group showed reduced intra- and interhemispheric functional connectivity in a striato-thalamo-pallidal network. Functional connectivity alterations were restricted to the BG and did not extend to functional connections with the cortex. The data suggest that local interactions between input and output BG structures may be disrupted already in the prodromal phase of PD.
Enantioselective organocatalytic epoxidation using hypervalent iodine reagents

Abstract A rare example of a hypervalent iodine reagent participating in a 1,4-heteroconjugate addition reaction is reported for the organocatalytic, asymmetric epoxidation of α,β-unsaturated aldehydes using imidazolidinone catalyst 1. Development of an ‘internal syringe pump’ effect via the slow release of iodosobenzene from an iminoiodinane source provides high levels of reaction efficiency and enantiomeric control in the asymmetric epoxidation of electron-deficient olefins. 15N NMR studies were conducted to elucidate the reaction pathways that lead to catalyst depletion in the presence of prototypical oxidants. These NMR studies also provided the mechanistic foundation for the application of iminoiodinanes as an internal slow release oxidant to circumvent these catalyst depletion pathways.
COLLAGEN AND COLLAGEN-GLYCOSAMINOGLYCAN MATRICES AS CARRIERS FOR GROWTH FACTORS

Tissue engineering is an emerging interdisciplinary field that applies the principles of engineering to the life sciences, with the aim of developing biological substitutes that restore, maintain or improve tissue function. In this process, extracellular matrix, cells and regulatory signals are important in guiding, modulating and facilitating regenerative events.
The synthesis of new 2,4‐diaminofuro[2,3‐d]pyrimidines with 5‐biphenyl, phenoxyphenyl and tricyclic substitutions as dihydrofolate reductase inhibitors

Nonclassical 2,4-diamino-5-substituted furo[2,3-d]pyrimidines 4a-i, 5a-b and 7a-f were synthesized as extended aromatic ring appended analogs of previously reported antifolates 1a-b. The extended aromatic system was designed to better interact with a phenylalanine residue (Phe69) of dihydrofolate reductase from the opportunistic pathogen Pneumocystis carinii to afford potent and selective inhibitors of Pneumocystis carinii dihydrofolate reductase. The target compounds were synthesized by nucleophilic displacement of 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine 3 with the appropriate aromatic amine or thiol. The compounds were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii, and their selectivity was determined using rat liver dihydrofolate reductase as the mammalian reference. In the C8-N9 bridged series, compound 4e, with a 3-(2-methoxydibenzofuran)- side chain, exhibited greatest potency and was more than 3 times as selective for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase. Compounds 4b and 4c also exhibited selectivity. Compounds in the C8-S9 bridged series showed comparable potencies, and each showed higher selectivity for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase.
Knoevenagel condensations of β-hemiacetyl esters

Abstract The intermolecular Knoevenagel condensation of β-hemiacetyl ester proceeds by an in situ unmasking of a reactive ω-hydroxy-β-keto ester giving unsaturated ω-hydroxy-β-keto esters 6–12 which accommodate acetal formation.
Differential mast cell outcomes are sensitive to FcεRI-Syk binding kinetics.

Cross-linking of immunoglobulin E-bound FceRI triggers multiple cellular responses, including degranulation and cytokine production. Signaling is dependent on recruitment of Syk via docking of its dual SH2 domains to phosphorylated tyrosines within the FceRI immunoreceptor tyrosine-based activation motifs. Using single-molecule imaging in live cells, we directly visualized and quantified the binding of individual mNeonGreen-tagged Syk molecules as they associated with the plasma membrane after FceRI activation. We found that Syk colocalizes transiently to FceRI and that Syk-FceRI binding dynamics are independent of receptor aggregate size. Substitution of glutamic acid for tyrosine between the Syk SH2 domains (Syk-Y130E) led to an increased Syk-FceRI off-rate, loss of site-specific Syk autophosphorylation, and impaired downstream signaling. Genome edited cells expressing only Syk-Y130E were deficient in antigen-stimulated calcium release, degranulation, and production of some cytokines (TNF-a, IL-3) but not others (MCP-1, IL-4). We propose that kinetic discrimination along the FceRI signaling pathway occurs at the level of Syk-FceRI interactions, with key outcomes dependent upon sufficiently long-lived Syk binding events.
Large-Scale, Quantitative Protein Assays on a High-Throughput DNA Sequencing Chip.

Summary High-throughput DNA sequencing techniques have enabled diverse approaches for linking DNA sequence to biochemical function. In contrast, assays of protein function have substantial limitations in terms of throughput, automation, and widespread availability. We have adapted an Illumina high-throughput sequencing chip to display an immense diversity of ribosomally translated proteins and peptides and then carried out fluorescence-based functional assays directly on this flow cell, demonstrating that a single, widely available high-throughput platform can perform both sequencing-by-synthesis and protein assays. We quantified the binding of the M2 anti-FLAG antibody to a library of 1.3 × 104 variant FLAG peptides, exploring non-additive effects of combinations of mutations and discovering a “superFLAG” epitope variant. We also measured the enzymatic activity of 1.56 × 105 molecular variants of full-length human O6-alkylguanine-DNA alkyltransferase (SNAP-tag). This comprehensive corpus of catalytic rates revealed amino acid interaction networks and cooperativity, linked positive cooperativity to structural proximity, and revealed ubiquitous positively cooperative interactions with histidine residues.
Strategies for the synthesis of N-(azacycloalkyl)bisindolylmaleimides: selective inhibitors of PKCβ

N-(Azacycloalkyl)bisindolylmaleimides 1 have been identified to be selective inhibitors of PKCβ. This manuscript will describe the synthetic approaches employed to prepare this class of compounds that resulted in development of efficient methods for preparation of N-(azacycloalkyl) indole 5, indole-3-acetamide 8 and indole-3-glyoxylate ester 4 derivatives.
Variation in Filamentous Growth and Response to Quorum-Sensing Compounds in Environmental Isolates of Saccharomyces cerevisiae

In fungi, filamentous growth is a major developmental transition that occurs in response to environmental cues. In diploid Saccharomyces cerevisiae, it is known as pseudohyphal growth and presumed to be a foraging mechanism. Rather than unicellular growth, multicellular filaments composed of elongated, attached cells spread over and into surfaces. This morphogenetic switch can be induced through quorum sensing with the aromatic alcohols phenylethanol and tryptophol. Most research investigating pseudohyphal growth has been conducted in a single lab background, Σ1278b. To investigate the natural variation in this phenotype and its induction, we assayed the diverse 100-genomes collection of environmental isolates. Using computational image analysis, we quantified the production of pseudohyphae and observed a large amount of variation. Population origin was significantly associated with pseudohyphal growth, with the West African population having the most. Surprisingly, most strains showed little or no response to exogenous phenylethanol or tryptophol. We also investigated the amount of natural genetic variation in pseudohyphal growth using a mapping population derived from a highly-heterozygous clinical isolate that contained as much phenotypic variation as the environmental panel. A bulk-segregant analysis uncovered five major peaks with candidate loci that have been implicated in the Σ1278b background. Our results indicate that the filamentous growth response is a generalized, highly variable phenotype in natural populations, while response to quorum sensing molecules is surprisingly rare. These findings highlight the importance of coupling studies in tractable lab strains with natural isolates in order to understand the relevance and distribution of well-studied traits.
Using machine learning to predict antimicrobial MICs and associated genomic features for nontyphoidal Salmonella

ABSTRACT Nontyphoidal Salmonella species are the leading bacterial cause of foodborne disease in the United States. Whole-genome sequences and paired antimicrobial susceptibility data are available for Salmonella strains because of surveillance efforts from public health agencies. In this study, a collection of 5,278 nontyphoidal Salmonella genomes, collected over 15 years in the United States, was used to generate extreme gradient boosting (XGBoost)-based machine learning models for predicting MICs for 15 antibiotics. The MIC prediction models had an overall average accuracy of 95% within ±1 2-fold dilution step (confidence interval, 95% to 95%), an average very major error rate of 2.7% (confidence interval, 2.4% to 3.0%), and an average major error rate of 0.1% (confidence interval, 0.1% to 0.2%). The model predicted MICs with no a priori information about the underlying gene content or resistance phenotypes of the strains. By selecting diverse genomes for the training sets, we show that highly accurate MIC prediction models can be generated with less than 500 genomes. We also show that our approach for predicting MICs is stable over time, despite annual fluctuations in antimicrobial resistance gene content in the sampled genomes. Finally, using feature selection, we explore the important genomic regions identified by the models for predicting MICs. To date, this is one of the largest MIC modeling studies to be published. Our strategy for developing whole-genome sequence-based models for surveillance and clinical diagnostics can be readily applied to other important human pathogens.
Plasmodium Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis.

Plasmodium parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Niemann-Pick Type C1-Related protein, NCR1). We isolated parasites with resistance-conferring mutations in Plasmodium falciparum NCR1 (PfNCR1) during selections with three diverse small-molecule antimalarial compounds and show that the mutations are causative for compound resistance. PfNCR1 protein knockdown results in severely attenuated growth and confers hypersensitivity to the compounds. Compound treatment or protein knockdown leads to increased sensitivity of the parasite plasma membrane (PPM) to the amphipathic glycoside saponin and engenders digestive vacuoles (DVs) that are small and malformed. Immuno-electron microscopy and split-GFP experiments localize PfNCR1 to the PPM. Our experiments show that PfNCR1 activity is critically important for the composition of the PPM and is required for DV biogenesis, suggesting PfNCR1 as a novel antimalarial drug target. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
Synthesis of carbacyclins via palladium-promoted, tandem alkene insertion

Abstract Carbacyclins 7 and 8 are readily prepared by the palladium-promoted, tandem alkene insertion of enol silane 3 with 1-octen-3-one and subsequent elaboration involving the stereoselective reduction of an enone in the presence of a ketone.
Synthesis and analysis of compounds having the skeleton of ergot alkaloids with the nitrogen atom in the D‐ring transposed

Alkylation-amination of the enamine 2 in the presence of ethyl α,α-bis(dibromomethyl)acetate, triethyl-amine, and methylamine lead to the construction of the aza-transposed ergoline 3. Sequential reduction, hydrolysis, reesterification, and indolization of 3, produced three diastereomers of 6. The structure of these three diastereomers was assigned on the basis of nmr and ir spectral analysis to be (α-cis) syn, (β-cis) anti, and (α-trans) syn. The isomer (β-cis) anti was reduced with lithium aluminum hydride to the corresponding alcohol.
Nitric oxide and carbon monoxide adsorption on lanthana-supported platinum and rhodium catalysts

Abstract We have examined the adsorption of carbon monoxide and nitric oxide on model Rh/lanthana and Pt/lanthana catalysts using temperature-programmed desorption (TPD). First, the surface of lanthana can be reduced in carbon monoxide by forming the carbonate which decomposes above 650 K. Reduced lanthana adsorbs significant amounts of carbon monoxide and nitric oxide, both of which desorb in a similar temperature region to that found for rhodium and platinum. Substantial amounts of the nitric oxide on reduced lanthana react to form nitrogen and nitrous oxide. The addition of rhodium and platinum significantly promotes the reduction of lanthana, and a significant fraction of the carbon monoxide adsorbed on freshly deposited metal films forms carbon dioxide. Based on suppressed adsorption of nitric oxide on thin metal films, it appears that the metals are oxidized and the lanthana reduced immediately following deposition. The TPD curves on the reduced Rh/lanthana and Pt/lanthana appear to be a simple sum of the desorption from reduced lanthana and small metal particles, so that there is no evidence for new adsorption states which might indicate changes in the metal properties due to the presence of lanthana.
Prolonged ocular exposure leads to retinal lesions in mice.

Abstract Retinal lesions in the posterior pole of laboratory mice occur due to native, developmental abnormalities or as a consequence of environmental or experimental conditions. In this study, we investigated the rate and extent of retinal lesions as a result of prolonged ocular exposure following general anesthesia. Following experimental preparation induction procedures (EPIP) involving general anesthesia, mydriasis/cycloplegia, and topical anesthesia to the cornea, two ocular recovery conditions (protected and unprotected) were tested within two different animal recovery chambers (open or closed). The anterior and posterior poles were evaluated for the development of retinal lesions using digital color photography, scanning laser ophthalmoscopy, and spectral-domain optical coherence during anesthesia recovery and up to 2.5 months thereafter. In some mice, electroretinograms, histological and immunohistological evaluations were performed to assess functional and structural changes that accompanied the retinal lesions detected by in vivo imaging. Our data suggests that prolonged ocular surface exposure to circulating ambient room air leads to significant anterior and posterior segment ocular complications. The most abundant, semi-reversible complication observed was the development of lesions in the outer retina, which had a 90% probability of occurring after 45 min of exposure. The lesions mostly resolved short-term, but functional and imaging evidence suggest that some perturbations to the outer retina may persist one or more months following initial development.
Matrix Linear Models for High-Throughput Chemical Genetic Screens

We develop a flexible and computationally efficient approach for analyzing high-throughput chemical genetic screens. In such screens, a library of genetic mutants is phenotyped in a large number of stresses. Typically, interactions between genes and stresses are detected by grouping the mutants and stresses into categories, and performing modified t-tests for each combination. This approach does not have a natural extension if mutants or stresses have quantitative or nonoverlapping annotations (e.g., if conditions have doses or a mutant falls into more than one category simultaneously). We develop a matrix linear model (MLM) framework that allows us to model relationships between mutants and conditions in a simple, yet flexible, multivariate framework. It encodes both categorical and continuous relationships to enhance detection of associations. We develop a fast estimation algorithm that takes advantage of the structure of MLMs. We evaluate our method’s performance in simulations and in an Escherichia coli chemical genetic screen, comparing it with an existing univariate approach based on modified t-tests. We show that MLMs perform slightly better than the univariate approach when mutants and conditions are classified in nonoverlapping categories, and substantially better when conditions can be ordered in dosage categories. Therefore, it is an attractive alternative to current methods, and provides a computationally scalable framework for larger and complex chemical genetic screens. A Julia language implementation of MLMs and the code used for this paper are available at https://github.com/janewliang/GeneticScreen.jl and https://bitbucket.org/jwliang/mlm_gs_supplement, respectively.
The local entropy along Ricci flow Part A: the no-local-collapsing theorems

We localize the entropy functionals of G. Perelman and generalize his no-local-collapsing theorem and pseudo-locality theorem. Our generalization is technically inspired by further development of Li-Yau estimate along the Ricci flow. It can be used to show the Gromov-Hausdorff convergence of the Kahler Ricci flow on each minimal projective manifold of general type.
Socles of Buchsbaum modules, complexes and posets

Abstract The socle of a graded Buchsbaum module is studied and is related to its local cohomology modules. This algebraic result is then applied to face enumeration of Buchsbaum simplicial complexes and posets. In particular, new necessary conditions on face numbers and Betti numbers of such complexes and posets are established. These conditions are used to settle in the affirmative Kuhnel's conjecture for the maximum value of the Euler characteristic of a 2k-dimensional simplicial manifold on n vertices as well as Kalai's conjecture providing a lower bound on the number of edges of a simplicial manifold in terms of its dimension, number of vertices, and the first Betti number.
On an extension of the universal monodromy representation for $\mathbb{P}^1 \backslash \{ 0, 1,\infty \}$

The Chen series map giving the universal monodromy representation of $\mathbb{P}^1\backslash\{0,1,\infty\}$ is extended to an injective 1-cocycle of $PSL(2, \mathbb{Z})$ into power series with complex coefficients in two non-commuting variables, twisted by an action of $S_3.$ The definition of the 1-cocycle is effected by parallel transport of flat sections of the bundle, also with an $S_3$ twisting, along paths in $\mathbb{P}^1\backslash\{0,1,\infty\}$ which are explicitly associated to elements of $PSL(2, \mathbb{Z})$. The resulting action of the modular group on the polylogarithm generating function is shown to yield a family of proofs of the analytic continuation and functional equation of the Riemann zeta function.
Critical branching Brownian motion with killing

We obtain sharp asymptotic estimates for hitting probabilities of a critical branching Brownian motion in one dimension with killing at 0. We also obtain sharp asymptotic formulas for the tail probabilities of the number of particles killed at 0. In the special case of double-or-nothing branching, we give exact formulas for both the hitting probabilities, in terms of elliptic functions, and the distribution of the number of killed particles.
Virtual covers of links

We use virtual knot theory to detect the non-invertibility of some classical links in &#x1d54a;3. These links appear in the study of virtual covers. Briefly, a virtual cover associates a virtual knot υ to a knot K in a 3-manifold N, under certain hypotheses on K and N. Virtual covers of links in &#x1d54a;3 come from taking K to be in the complement N of a fibered link J. If J ⊔ K is invertible and K is “close to” a fiber of J, then υ satisfies a symmetry condition to which some virtual knot polynomials are sensitive. We also discuss virtual covers of links J ⊔ K, where J is not fibered, but is virtually fibered (in the sense of W. Thurston).
RF energy harvesting enabled power sharing in relay networks

Through simultaneous energy and information transfer, radio frequency (RF) energy harvesting (EH) reduces the energy consumption of the wireless networks. It also provides a new approach for the wireless devices to share each other’s energy storage, without relying on the power grid or traffic offloading. In this paper, we study RF energy harvesting enabled power balancing within the decode-and-forward (DF) relaying-enhanced cooperative wireless system. An optimal power allocation policy is proposed for the scenario where both source and relay nodes can draw power from the radio frequency signals transmitted by each other. To maximize the overall throughput while meeting the energy constraints imposed by the RF sources, an optimization problem is formulated and solved. Based on different harvesting efficiency and channel condition, closed form solutions for optimal joint source and relay power allocation are derived.