cssi/SciSciGPT-SciSciNet huggingface dataset:
Distributional Structure

For the purposes of the present discussion, the term structure will be used in the following non-rigorous sense: A set of phonemes or a set of data is structured in respect to some feature, to the extent that we can form in terms of that feature some organized system of statements which describes the members of the set and their interrelations (at least up to some limit of complexity). In this sense, language can be structured in respect to various independent features. And whether it is structured (to more than a trivial extent) in respect to, say, regular historical change, social intercourse, meaning, or distribution - or to what extent it is structured in any of these respects - is a matter decidable by investigation. Here we will discuss how each language can be described in terms of a distributional structure, i.e. in terms of the occurrence of parts (ultimately sounds) relative to other parts, and how this description is complete without intrusion of other features such as history or meaning. It goes without saying that other studies of language - historical, psychological, etc.-are also possible, both in relation to distributional structure and independently of it.
Deriving Information Acquisition Criteria for Sequentially Inferring the Expected Value of a Black-Box Function

Bayesian optimal design of experiments (BODE) has been successful in acquiring information about a quantity of interest (QoI) which depends on a black-box function. BODE is characterized by sequentially querying the function at specific designs selected by an infill-sampling criterion. However, most current BODE methods operate in specific contexts like optimization, or learning a universal representation of the black-box function. The objective of this paper is to design a BODE for estimating the statistical expectation of a physical response surface. This QoI is omnipresent in uncertainty propagation and design under uncertainty problems. Our hypothesis is that an optimal BODE should be maximizing the expected information gain in the QoI. We represent the information gain from a hypothetical experiment as the Kullback-Liebler (KL) divergence between the prior and the posterior probability distributions of the QoI. The prior distribution of the QoI is conditioned on the observed data and the posterior distribution of the QoI is conditioned on the observed data and a hypothetical experiment. The main contribution of this paper is the derivation of a semi-analytic mathematical formula for the expected information gain about the statistical expectation of a physical response. The developed BODE is validated on synthetic functions with varying number of input-dimensions. We demonstrate the performance of the methodology on a steel wire manufacturing problem.
Role of Mitogen-Activated Protein Kinase in Cholinergic Stimulation of Conjunctival Goblet Cell Secretion

Conjunctival goblet cells are a primary source for the mucous layer of the tear film. We showed previously that conjunctival goblet cell mucin secretion is under neural control as activation of afferent sensory nerves in the cornea stimulates mucin secretion.1 This neural reflex is mediated either by the parasympathetic and sympathetic nerves that surround the goblet cells, or by antidromic stimulation of the sensory nerves in the conjunctiva and collateral sensory nerves from the cornea. Exogenous addition of the parasympathetic agonist carbachol or the parasympathetic neuropeptide VIP stimulated conjunctival goblet cell secretion.2,3 Cholinergic agonists released from parasympathetic nerves bind to and activate G protein linked- M2 and M3 muscarinic receptors. In most tissues, activation of these receptors stimulates phospholipase C to hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to specific receptors on the endoplasmic reticulum to increase intracellular Ca2+. The increased intracellular Ca2+ either directly, or in combination with Ca2+/calmodulin-dependent protein kinases, activates mucin secretion. DAG in turn stimulates protein kinase C (PKC). In many tissues, cholinergic agonists also activate the mitogen-activated protein kinase (MAPK) signaling pathway used by growth factor receptors, which usually regulate cell growth and proliferation. Activation of the MAPK pathway by cholinergic agonists can occur through several mechanisms. One such mechanism is through transactivation of the EGF receptor in an EGF-independent manner.4 The activated recepter then serves as a scaffold for recruitment of Grb2-SoS complex via tyrosine phosphorylation of Shc.
Financial Fraud Among Older Americans: Evidence and Implications

Objectives The consequences of poor financial capability at older ages are serious and include making mistakes with credit, spending retirement assets too quickly, and being defrauded by financial predators. Because older persons are at or past the peak of their wealth accumulation, they are often the targets of fraud. Methods Our project analyzes a module we developed and fielded on people aged 50 an older years in the 2016 Health and Retirement Study (HRS). Using this data set, we evaluated the incidence and prospective risk factors (measured in 2010) for investment fraud and prize/lottery fraud using logistic regression (N = 1,220). Results Relatively few HRS respondents mentioned any single form of fraud over the prior 5 years, but 5.0% reported at least one form of investment fraud and 4.4% recounted prize/lottery fraud. Greater wealth (nonhousing) was associated with investment fraud, whereas lower housing wealth and symptoms of depression were associated with prize/lottery fraud. Hispanics were significantly less likely to report either type of fraud. Other suspected risk factors-low social integration and financial literacy-were not significant. Discussion Fraud is a complex phenomenon and no single factor uniquely predicts victimization across different types, even within the category of investment fraud. Prevention programs should educate consumers about various types of fraud and increase awareness among financial services professionals.
Isolation and characterization of human goblet cells in vitro: regulation of proliferation and activation of mitogen-activated protein kinase by EGF and carbachol.

The epithelium of the conjunctiva is a non-keratinizing stratified squamous epithelium1 Goblet cells, highly specialized epithelial cells, are located in the apical surface of the conjunctiva between the layers of stratified epithelium.2 These cells are primarily responsible for the secretion of the inner mucous layer of the tear film, thereby providing a physical and chemical barrier that hydrates the conjunctiva and protects it from exposure to other injurious agents. Abnormal mucin secretion (either overproduction or underproduction) by goblet cells can eventually lead to deterioration of the ocular surface.
Controlling Light Transmission Through Highly Scattering Media Using Semi-Definite Programming as a Phase Retrieval Computation Method

Complex Semi-Definite Programming (SDP) is introduced as a novel approach to phase retrieval enabled control of monochromatic light transmission through highly scattering media. In a simple optical setup, a spatial light modulator is used to generate a random sequence of phase-modulated wavefronts, and the resulting intensity speckle patterns in the transmitted light are acquired on a camera. The SDP algorithm allows computation of the complex transmission matrix of the system from this sequence of intensity-only measurements, without need for a reference beam. Once the transmission matrix is determined, optimal wavefronts are computed that focus the incident beam to any position or sequence of positions on the far side of the scattering medium, without the need for any subsequent measurements or wavefront shaping iterations. The number of measurements required and the degree of enhancement of the intensity at focus is determined by the number of pixels controlled by the spatial light modulator.
The Effect of e-Book Vocabulary Instruction on Spanish–English Speaking Children

Purpose This study aimed to examine the effect of an intensive vocabulary intervention embedded in e-books on the vocabulary skills of young Spanish–English speaking English learners (ELs) from low...
Hierarchical clustering better than average-linkage

Hierarchical Clustering (HC) is a widely studied problem in exploratory data analysis, usually tackled by simple agglomerative procedures like average-linkage, single-linkage or complete-linkage. In this paper we focus on two objectives, introduced recently to give insight into the performance of average-linkage clustering: a similarity based HC objective proposed by [21] and a dissimilarity based HC objective proposed by [9]. In both cases, we present tight counterexamples showing that average-linkage cannot obtain better than 1/3 and 2/3 approximations respectively (in the worst-case), settling an open question raised in [21]. This matches the approximation ratio of a random solution, raising a natural question: can we beat average-linkage for these objectives? We answer this in the affirmative, giving two new algorithms based on semidefinite programming with provably better guarantees.
Vitamin E Has Reduced Affinity for a Polyunsaturated Phospholipid: An Umbrella Sampling Molecular Dynamics Simulations Study

Vitamin E is an essential micronutrient. The primary function of this lipid-soluble antioxidant is to protect membrane phospholipids from oxidation. Whether vitamin E preferentially interacts with polyunsaturated phospholipids to optimize protection of the lipid species most vulnerable to oxidative attack has been an unanswered question for a long time. In this work, we compared the binding of α-tocopherol (αtoc), the form of vitamin E retained by the human body, in bilayers composed of polyunsaturated 1-stearoyl-2-docosahexaenoylphosphatidylcholine (SDPC, 18:0-22:6PC) and, as a control, monounsaturated 1-stearoyl-2-oleoylphosphatidylcholine (SOPC, 18:0-18:1PC) by umbrella sampling molecular dynamics simulations. From the potential of mean force as a function depth within the bilayer, we find that the binding energy of αtoc is less in SDPC (Δ Gbind = 16.7 ± 0.3 kcal/mol) than that in SOPC (Δ Gbind = 18.3 ± 0.4 kcal/mol). The lower value in SDPC is ascribed to the high disorder of polyunsaturated fatty acids that produces a less tightly packed arrangement. Deformation of the bilayer is observed during desorption, indicating that phosphatidylcholine (PC)-PC and αtoc-PC interactions contribute to the binding energy. Our results do not support the proposal that vitamin E interacts more favorably with polyunsaturated phospholipids.
Anomaly constraint on massless QCD and the role of Skyrmions in chiral symmetry breaking

We discuss consequences of the ’t Hooft anomaly matching condition for Quantum Chromodynamics (QCD) with massless fundamental quarks. We derive the new discrete ’t Hooft anomaly of massless QCD for generic numbers of color Nc and flavor Nf , and an exotic chiral-symmetry broken phase without quark-bilinear condensate is ruled out from possible QCD vacua. We show that the U(1)B baryon number symmetry is anomalously broken when the $$ {\left({\mathrm{\mathbb{Z}}}_{2{N}_{\mathrm{f}}}\right)}_{\mathrm{A}} $$ discrete axial symmetry and the flavor symmetry are gauged. In the ordinary chiral symmetry breaking, the Skyrmion current turns out to reproduce this ’t Hooft anomaly of massless QCD. In the exotic chiral symmetry breaking, however, the anomalous breaking of U(1)B does not take the correct form, and it is inconsistent with anomaly matching. This no-go theorem is based only on symmetries and anomalies, and thus has a wider range of applicability to the QCD phase diagram than the previous one obtained by QCD inequalities. Lastly, as another application, we check that duality of $$ \mathcal{N}=1 $$ supersymmetric QCD with Nf ≥Nc + 1 satisfies the new anomaly matching.
High-Tc Hydrides: Interplay of Optical and Acoustic Modes and Comments Regarding the Upper Limit of Tc

The phonon spectrum of many superconducting compounds and, especially, high-Tc hydrides, is broad and rather complicated, because of the presence of high-frequency optical modes. In order to analyze an interplay of optical and acoustic phonon branches, it is convenient to introduce two coupling constants, $\lambda _{\text {opt.}}$ and $\lambda _{\text {ac.}}$ , along with characteristic frequencies. The correlation between the value of Tc and this interplay is demonstrated for the family of tantal hydrides (TaH2/TaH4/TaH6). The problem of the upper limit of Tc is discussed. The phenomenon of room temperature superconductivity can be provided by the electron-phonon interaction and is described by the strong coupling theory.
Auditing DBMSes through Forensic Analysis

The pervasive use of databases for the storage of critical and sensitive information in many organizations has led to an increase in the rate at which databases are exploited in computer crimes. While there are several techniques and tools available for database forensics, they mostly assume apriori database preparation, such as relying on tamper-detection software to already be in place or use of detailed logging. Alternatively, investigators need forensic tools and techniques that work on poorly-con?gured databases and make no assumptions about the extent of damage in a database. In this paper, we present our database forensics methods, which are capable of examining database content from a database image without using any log or system metadata. We describe how these methods can be used to detect security breaches in untrusted environments where the security threat arose from a privileged user (or someone who has obtained such privileges).
Theoretical Linear Convergence of Unfolded ISTA and Its Practical Weights and Thresholds

In recent years, unfolding iterative algorithms as neural networks has become an empirical success in solving sparse recovery problems. However, its theoretical understanding is still immature, which prevents us from fully utilizing the power of neural networks. In this work, we study unfolded ISTA (Iterative Shrinkage Thresholding Algorithm) for sparse signal recovery. We introduce a weight structure that is necessary for asymptotic convergence to the true sparse signal. With this structure, unfolded ISTA can attain a linear convergence, which is better than the sublinear convergence of ISTA/FISTA in general cases. Furthermore, we propose to incorporate thresholding in the network to perform support selection, which is easy to implement and able to boost the convergence rate both theoretically and empirically. Extensive simulations, including sparse vector recovery and a compressive sensing experiment on real image data, corroborate our theoretical results and demonstrate their practical usefulness. We have made our codes publicly available: https://github.com/xchen-tamu/linear-lista-cpss.
Financial Statement Footnote Readability and Corporate Audit Outcomes

SUMMARY We examine whether the readability of financial statement footnotes in the annual report is informative about audit engagement risk. Using various readability measures, we predict and find ...
Sequential Detection of Regime Changes in Neural Data

The problem of detecting changes in firing patterns in neural data is studied. The problem is formulated as a quickest change detection (QCD) problem. Important algorithms from the literature are reviewed. A new algorithmic technique is discussed to detect deviations from learned baseline behavior. The algorithms studied can be applied to both spike and local field potential data. The algorithms are applied to mice spike data to verify the presence of behavioral learning.
Quantum optomechanics of a two-dimensional atomic array

Two mutually exclusive characteristics of traditional optomechanical systems based on bulk mirrors or membranes are combined: The ability to strongly scatter light and the one to attain very large mechanical susceptibility. The proposed platform, a two-dimensional atomic array, exhibits rich multimode phenomena and the reported results suggest that the regime of few-photon quantum optomechanics is closer to reach.
Lon recognition of the replication initiator DnaA requires a bipartite degron

DnaA initiates chromosome replication in bacteria. In Caulobacter crescentus, the Lon protease degrades DnaA to coordinate replication with nutrient availability and to halt the cell cycle during acute stress. Here, we characterize the mechanism of DnaA recognition by Lon. We find that the folded state of DnaA appears crucial for its degradation, in contrast to the well-known role of Lon in degrading misfolded proteins. We fail to identify a single degradation motif (degron) sufficient for DnaA degradation, rather we show that both the ATPase domain and a species-specific N-terminal motif are important for productive Lon degradation of full-length DnaA. Mutations in either of these determinants disrupt DnaA degradation in vitro and in vivo. However, analysis of truncation products reveals that appending other extensions to the ATPase domain is sufficient to trigger degradation, suggesting plasticity in Lon recognition. Our final working model is that Lon engages DnaA through at least two elements, one of which anchors DnaA to Lon and the other acting as an initiation site for degradation.
Green's function for higher-order boundary value problems involving a Nabla Caputo fractional operator

ABSTRACTWe consider the discrete, fractional operator (Laνx)(t):=∇[p(t)∇a∗νx(t)]+q(t)x(t−1) involving the nabla Caputo fractional difference, which can be thought of as an analogue to the self-adjo...
Smart Inverter Volt-Watt Control Design in High PV-Penetrated Distribution Systems

Advanced control techniques such as volt-watt and volt-VAR control have been developed for high integration of distributed renewable energy, such as photovoltaic (PV) resources, on an electric distribution system. However, designing these control parameters, which yields the best results in the system, is complicated and depends on feeder conditions. This paper proposes a method to properly design the volt-watt control parameters in smart PV inverters to increase the benefit of their control action. The intention of this control design is to mitigate the voltage violations in a high PV-penetrated distribution feeder, while evenly distributing the weight of energy curtailment among all PV systems. Test results are provided from simulation-only scenarios and a hardware-in-the-loop test platform.
Home Away from Home? A Case Study of Student Transitions to an International Branch Campus.

This phenomenological case study explored the transition experience of undergraduate students attending an international branch campus in South Korea. Findings revealed pre-transition experiences and personal characteristics, peer support, and a connection between the home and international branch campus greatly impacted the transition experience, including a participant’s ability to cope with the transition. Findings have both positive and negative considerations that institutions establishing or operating a new international branch campus will find particularly useful in practice.
STEM Performance and Supply: Assessing the Evidence for Education Policy

The relationship between education policy and workforce policy has long been uneasy. It is widely believed in many quarters of American society that the U.S. education system is in decline and, what’s more, that it bears significant responsibility for a wide range of social ills, including stagnant wages, increasing inequality, high unemployment, and overall economic lethargy. However, as analyzed in this paper, the preponderance of evidence suggests that the U.S. education system has produced ample supplies of students to respond to STEM labor market demand. The “pipeline” of STEM-potential students is similarly strong and expanding.
Estimating Position Bias without Intrusive Interventions

Presentation bias is one of the key challenges when learning from implicit feedback in search engines, as it confounds the relevance signal. While it was recently shown how counterfactual learning-to-rank (LTR) approaches \citeJoachims/etal/17a can provably overcome presentation bias when observation propensities are known, it remains to show how to effectively estimate these propensities. In this paper, we propose the first method for producing consistent propensity estimates without manual relevance judgments, disruptive interventions, or restrictive relevance modeling assumptions. First, we show how to harvest a specific type of intervention data from historic feedback logs of multiple different ranking functions, and show that this data is sufficient for consistent propensity estimation in the position-based model. Second, we propose a new extremum estimator that makes effective use of this data. In an empirical evaluation, we find that the new estimator provides superior propensity estimates in two real-world systems -- Arxiv Full-text Search and Google Drive Search. Beyond these two points, we find that the method is robust to a wide range of settings in simulation studies.
Ship Classification from Overhead Imagery using Synthetic Data and Domain Adaptation

In this paper, we revisit the problem of classifying ships (maritime vessels) detected from overhead imagery. Despite the last decade of research on this very important and pertinent problem, it remains largely unsolved. One of the major issues with the detection and classification of ships and other objects in the maritime domain is the lack of substantial ground truth data needed to train state-of-the-art machine learning algorithms. We address this issue by building a large (200k) synthetic image dataset using the Unity gaming engine and 3D ship models. We demonstrate that with the use of synthetic data, classification performance increases dramatically, particularly when there are very few annotated images used in training.
Proceedings of the 4th international workshop on End-user software engineering

Welcome to the Fourth Workshop on End-User Software Engineering. WEUSE IV is a one-day workshop aimed at challenges faced in helping end users develop dependable software. WEUSE IV is structured around four themes. Each of the twenty short papers accepted to the workshop has overlap with one or more of the following themes: Empirical Evaluation in End-User Software Engineering Learning from End Users Software Engineering for End Users End-User Tools for Creating Dependable Software Each theme will be introduced by a session lead who will set forth his or her vision in the theme area, taking into account relevant papers. Following each presentation, there will be ample time for discussion.
Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan

Accumulation of mutations in somatic cells has been implicated as a cause of aging since the 1950s. However, attempts to establish a causal relationship between somatic mutations and aging have been constrained by the lack of methods to directly identify mutational events in primary human tissues. Here we provide genome-wide mutation frequencies and spectra of human B lymphocytes from healthy individuals across the entire human lifespan using a highly accurate single-cell whole-genome sequencing method. We found that the number of somatic mutations increases from 3,000 per cell in centenarians. We discovered mutational hotspot regions, some of which, as expected, were located at Ig genes associated with somatic hypermutation (SHM). B cell–specific mutation signatures associated with development, aging, or SHM were found. The SHM signature strongly correlated with the signature found in human B cell tumors, indicating that potential cancer-causing events are already present even in B cells of healthy individuals. We also identified multiple mutations in sequence features relevant to cellular function (i.e., transcribed genes and gene regulatory regions). Such mutations increased significantly during aging, but only at approximately one-half the rate of the genome average, indicating selection against mutations that impact B cell function. This full characterization of the landscape of somatic mutations in human B lymphocytes indicates that spontaneous somatic mutations accumulating with age can be deleterious and may contribute to both the increased risk for leukemia and the functional decline of B lymphocytes in the elderly.
Controllable Dispersion of Domain-Wall Movement in Antiferromagnetic Thin Films at Finite Temperatures

Fluctuating thermal fields in antiferromagnets are seen as a potential means to realize a probabilistic distribution in an output signal that can also be tailored by electrical control. To this end, the dynamics of a 90-degree domain wall driven by spin-orbit torque are theoretically examined in an antiferromagnetic structure at finite temperatures. The calculations clearly illustrate that both the average displacement of the domain wall and its thermally induced dispersion can be electrically modulated, or ``trained'', by tuning the driving spin-orbit torque. This unusual functionality could provide a key component in probabilistic computing and machine learning.
A randomized efficacy trial of the second step early learning (SSEL) curriculum

Abstract A classroom randomized efficacy trial conducted over four years in 7 community-based preschool and 6 Head Start programs investigated effects of the Second Step Early Learning (SSEL) curriculum on end of preschool executive functioning (EF) and social-emotional (SE) skills in low-income children. Outcomes are reported for n = 770 four-year-olds independently assessed for EF and SE by study staff in fall and spring of the prekindergarten year. Main outcomes were analyzed using two, three- level hierarchical linear models, one each for EF and SE skills. A significant effect (effect size of 0.15) for EF and a nonsignificant effect for SE were found. Secondary analyses found no significant differences on pre-academic skills. SSEL appears to have a meaningful impact on at-risk children's EF skills that supports its continued dissemination.
Deciphering the Role of a SLOG Superfamily Protein YpsA in Gram-Positive Bacteria

Bacteria adapt to different environments by regulating cell division and several conditions that modulate cell division have been documented. Understanding how bacteria transduce environmental signals to control cell division is critical in understanding the global network of cell division regulation. In this article we describe a role for Bacillus subtilis YpsA, an uncharacterized protein of the SLOG superfamily of nucleotide and ligand-binding proteins, in cell division. We observed that YpsA provides protection against oxidative stress as cells lacking ypsA show increased susceptibility to hydrogen peroxide treatment. We found that the increased expression of ypsA leads to filamentation and disruption of the assembly of FtsZ, the tubulin-like essential protein that marks the sites of cell division in B. subtilis. We also showed that YpsA-mediated filamentation is linked to the growth rate. Using site-directed mutagenesis, we targeted several conserved residues and generated YpsA variants that are no longer able to inhibit cell division. Finally, we show that the role of YpsA is possibly conserved in Firmicutes, as overproduction of YpsA in Staphylococcus aureus also impairs cell division.
fMRI replicability depends upon sufficient individual-level data.

Abstract The replicability of findings drawn from functional magnetic resonance imaging (fMRI) data have increasingly been called into question. Concerns have been raised that historically, sample sizes have been insufficient to produce adequate power, leading to unreliable results. Recently, Turner and colleagues demonstrated that even with large sample sizes, the replicability of fMRI can be worryingly low. However, their datasets featured low amounts of data at the individual-level. Here, I demonstrate that replicability depends critically on sufficient individual-level sampling. I show that fMRI can have strong replicability even at modest sample sizes when individuals are adequately sampled, but that inadequate individual-level sampling leads to poor replicability. These data indicate that fMRI replicability cannot be judged solely on sample size, and that adequate sampling at the individual-level is a critical design consideration.
“Good Orthodoxy” and the Legacy Of Barnette

This Essay applies the much-revered case of West Virginia Board of Education v. Barnette, which held that public school students may not be forced to stand and salute the American flag, to what I call the “good orthodoxy” context. In so doing, I hope to build a bridge between partisans on issues of free speech. In good orthodoxy cases, the individual claiming a right against compelled speech seeks to overturn a law or policy that was designed to remedy the harms committed against or to otherwise benefit historically marginalized groups. These good orthodoxy cases are both similar to and different from Barnette, where the Supreme Court held that the state cannot compel “unanimity of opinion” in support of patriotism or nationalism. Using examples such as public accommodations laws that compel production of expressive goods, union dues for public sector unions, and diversity statements at public law schools, I will demonstrate how new groups of dissenters are created in response to policies designed to protect historically marginalized or disadvantaged groups — instead of laws designed to compel respect for authority. Because of the differences between Barnette and the good orthodoxy cases, I argue that courts should be cautious before holding that the modern cases implicate pure speech, as opposed to expressive conduct or unprotected conduct. However, when pure speech is implicated, these laws or policies should be generally overturned as failing to satisfy strict scrutiny. Specifically, dignitary interests designed to protect individuals’ sense of acceptance in the community should generally not be considered sufficient to compel unanimity of opinion, and indeed, dignitary interests often indicate that what is being imposed is conformity to particular values.
The fiscal roots of inflation

Abstract Unexpected inflation devalues nominal government bonds. It must therefore correspond to a decline in expected future surpluses, or a rise in their discount rates, so that the real value of debt equals the present value of surpluses. I measure each component using a vector autoregression, via responses to inflation, recession, surplus and discount rate shocks. Discount rates account for much inflation variation, for the cyclical pattern of inflation, and why persistent deficits often do not cause inflation. Long-term debt is important. In response to a fiscal shock, smooth inflation slowly devalues outstanding long-term bonds.
An image-based assay to quantify changes in proliferation and viability upon drug treatment in 3D microenvironments

Every biological experiment requires a choice of throughput balanced against physiological relevance. Most primary drug screens neglect critical parameters such as microenvironmental conditions, cell-cell heterogeneity, and specific readouts of cell fate for the sake of throughput. Here we describe a methodology to quantify proliferation and viability of single cells in 3D culture conditions by leveraging automated microscopy and image analysis to facilitate reliable and high-throughput measurements. We detail experimental conditions that can be adjusted to increase either throughput or robustness of the assay, and we provide a stand alone image analysis program for users who wish to implement this 3D drug screening assay in high throughput. We demonstrate this approach by evaluating a combination of RAF and MEK inhibitors on melanoma cells, showing that cells cultured in 3D collagen-based matrices are more sensitive than cells grown in 2D culture, and that cell proliferation is much more sensitive than cell viability. We also find that cells grown in 3D cultured spheroids exhibit equivalent sensitivity to single cells grown in 3D collagen, suggesting that for the case of melanoma, a 3D single cell model may be equally effective for drug identification as 3D spheroids models. The single cell resolution of this approach enables stratification of heterogeneous populations of cells into differentially responsive subtypes upon drug treatment, which we demonstrate by determining the effect of RAK/MEK inhibition on melanoma cells co-cultured with fibroblasts. Furthermore, we show that spheroids grown from single cells exhibit dramatic heterogeneity to drug response, suggesting that heritable drug resistance can arise stochastically in single cells but be retained by subsequent generations. In summary, image-based analysis renders cell fate detection robust, sensitive, and high-throughput, enabling cell fate evaluation of single cells in more complex microenvironmental conditions.
Enantioselective Synthesis of Bridged- or Fused-Ring Bicyclic Ketones by a Catalytic Asymmetric Michael Addition Pathway

Efficient methodology has been developed for the conjugate addition of ketene acetals to cyclic α,β-enones. The chiral adducts allow access to fused- or bridged-ring structures such as those shown.
Highly enantioselective catalytic Diels-Alder addition promoted by a chiral bis(oxazoline)-magnesium complex

Abstract The new chiral bis(oxazoline) ligand 8 has been synthesized from (S)-phenylglycine and has been shown to form effective catalysts for enantioselective Diels-Alder addition in combination with ferric iodide, magnesium iodide or magnesium tetraphenylborate. Catalytic activation of the dienophile, 3-acryloyl-1,3-oxazolidine-2-one ( 4 ), in the magnesiwn system is proposed to involve tetrahedrally coordinated magnesium in a dipositive complex ( 10 ).
One- and two-dimensional silver and zinc uranyl phosphates containing bipyridyl ligands.

The reaction of AgCN with UO2, 4,4‘-bipy, and phosphoric acid in water at 160 °C under autogeneously generated pressure results in the formation of [Ag(4,4‘-bipy)]2[(UO2)2H3(PO4)3] (AgUP-1). Ag(2,2...
Pd-NHC Catalyzed Cyclopentannulation of Diazabicyclic Alkenes with ortho-aryl halides

Pd-NHC catalyzed cyclopentannulation of diazabicyclic alkenes with ortho- functionalized aryl halides is described. In all the reactions, a single diastereomer of the cyclopentannulated product is ...
Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16

Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, however, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy that leverages broadly reactive, cysteine-directed electrophilic fragments coupled to selective ligands for intracellular proteins (for example, SLF for FKBP12, JQ1 for BRD4) to screen for heterobifunctional degrader compounds (or proteolysis targeting chimeras, PROTACs) that operate by covalent adduction of E3 ligases. This approach identified DCAF16-a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases-as a target of electrophilic PROTACs that promote the nuclear-restricted degradation of proteins. We find that only a modest fraction (~10-40%) of DCAF16 needs to be modified to support protein degradation, pointing to the potential for electrophilic PROTACs to induce neosubstrate degradation without substantially perturbing the function of the participating E3 ligase.
A New Arrangement for the Anticancer Antibiotics Tallysomycin and Bleomycin When Bound to Zinc: An Assessment of Metal and Ligand Chirality by NMR and Molecular Dynamics

Bleomycin A2 (BLMA2, a clinically used drug) and tallysomycin A (TLMA) are two closely related anticancer antibiotics activated by O2 reaction with their Fe(II) complexes. Fe(II) can be modeled by Zn(II). Evidence obtained that the disaccharide and metal-binding domains of ZnTLMA and ZnBLMA2 are superimposable includes the following very similar NMR features: the 1H and 13C NMR chemical shifts, the 1H and 13C chemical shift changes upon Zn(II) binding, and the NOESY spectra. We evaluated several ZnTLMA structural models with four and five ligating donor atoms from TLMA by using 2D NMR, NOESY back-calculation methods, and restrained molecular mechanics/molecular dynamics calculations. Our results are most consistent with ligation by five N donors, the β-aminoalanine (ALA) amines (NC2 and NC3), the pyrimidinylpropionamide (PRO) pyrimidine (NC10), and the β-hydroxyhistidine amide (NC12) and imidazole (NC29). Metal complexation to TLMA or BLMA2 creates newly stable chiral centers (the metal and the ALA secon...
Computational prediction of the tolerance to amino-acid deletion in green-fluorescent protein

Proteins evolve through two primary mechanisms: substitution, where mutations alter a protein's amino-acid sequence, and insertions and deletions (indels), where amino acids are either added to or removed from the sequence. Protein structure has been shown to influence the rate at which substitutions accumulate across sites in proteins, but whether structure similarly constrains the occurrence of indels has not been rigorously studied. Here, we investigate the extent to which structural properties known to covary with protein evolutionary rates might also predict protein tolerance to indels. Specifically, we analyze a publicly available dataset of single-amino-acid deletion mutations in enhanced green fluorescent protein (eGFP) to assess how well the functional effect of deletions can be predicted from protein structure. We find that weighted contact number (WCN), which measures how densely packed a residue is within the protein's three-dimensional structure, provides the best single predictor for whether eGFP will tolerate a given deletion. We additionally find that using protein design to explicitly model deletions results in improved predictions of functional status when combined with other structural predictors. Our work suggests that structure plays fundamental role in constraining deletions at sites in proteins, and further that similar biophysical constraints influence both substitutions and deletions. This study therefore provides a solid foundation for future work to examine how protein structure influences tolerance of more complex indel events, such as insertions or large deletions.
(+)-trans-camphenesulfonamide: A novel enantiomerically pure primary sulfonamide

Abstract (+)- trans -Camphenesulfonamide ( 3 ) is prepared in two steps (54%) from camphorsulfonamide 1 , via a acid catalyzed rearrangement of the corresponding carbinol 2a .
Light Guided In-vivo Activation of Innate Immune Cells with Photocaged TLR 2/6 Agonist

The complexity of the immune system creates challenges in exploring its importance and robustness. To date, there have been few techniques developed to manipulate individual components of the immune system in an in vivo environment. Here we show a light-based dendritic cell (DC) activation allowing spatial and temporal control of immune activation in vivo. Additionally, we show time dependent changes in RNA profiles of the draining lymph node, suggesting a change in cell profile following DC migration and indicating that the cells migrating have been activated towards antigen presentation.
Advances in geometric techniques for analyzing blebbing in chemotaxing Dictyostelium cells

We present a technical platform that allows us to monitor and measure cortex and membrane dynamics during bleb-based chemotaxis. Using D. discoideum cells expressing LifeAct-GFP and crawling under agarose containing RITC-dextran, we were able to simultaneously visualize the actin cortex and the cell membrane throughout bleb formation. Using these images, we then applied edge detect to generate points on the cell boundary with coordinates in a coordinate plane. Then we fitted these points to a curve with known x and y coordinate functions. The result was to parameterize the cell outline. With the parameterization, we demonstrate how to compute data for geometric features such as cell area, bleb area and edge curvature. This allows us to collect vital data for the analysis of blebbing.
Concise synthesis of (±)-rhazinilam

Abstract 2-Piperidone has been converted into (±)-rhazinilam in nine steps in 8% overall yield. The key transformation involves the conversion of the lactam 5 into the annulated pyrrole derivative 3 via the thiophenyl imine 8 .
Preparation and properties of antitubercular 1‐piperidino‐3‐arylthioureas

1-Piperidino-3-arylthioureas, of interest in the investigation of novel heterocyclic structures for their anti-tubercular activity, may be conveniently prepared in good yield and purity by the reaction of 1-arninopiperi-dine with aryl isothiocyanates in ethanol. The reaction takes place readily without the complication of thiourethane contaminants, and the products may be suitably identified by significant characteristics in the infrared spectra and the hydrogen and carbon magnetic resonance spectra.
Controlling for Confounding Effects in Single Cell RNA Sequencing Studies Using both Control and Target Genes

Single cell RNA sequencing (scRNAseq) technique is becoming increasingly popular for unbiased and high-resolutional transcriptome analysis of heterogeneous cell populations. Despite its many advantages, scRNAseq, like any other genomic sequencing technique, is susceptible to the influence of confounding effects. Controlling for confounding effects in scRNAseq data is a crucial step for accurate downstream analysis. Here, we present a novel statistical method, which we refer to as scPLS (single cell partial least squares), for robust and accurate inference of confounding effects. scPLS takes advantage of the fact that genes in a scRNAseq study often can be naturally classified into two sets: a control set of genes that are free of effects of the predictor variables and a target set of genes that are of primary interest. By modeling the two sets of genes jointly using the partial least squares regression, scPLS is capable of making full use of the data to improve the inference of confounding effects. With extensive simulations and comparisons with other methods, we demonstrate the effectiveness of scPLS. Finally, we apply scPLS to analyze two scRNAseq data sets to illustrate its benefits in removing technical confounding effects as well as for removing cell cycle effects.
Dynorphin Counteracts Orexin in the Paraventricular Nucleus of the Thalamus: Cellular and Behavioral Evidence

The orexin (Orx) system plays a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orx and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Previous studies suggested that OrxA transmission in the posterior paraventricular nucleus of the thalamus (pPVT) participates in cocaine-seeking behavior. This study determined whether Orx and Dyn interact in the pPVT. Using the brain slice preparation for cellular recordings, superfusion of DynA onto pPVT neurons decreased the frequency of spontaneous and miniature excitatory postsynaptic currents (s/mEPSCs). OrxA increased the frequency of sEPSCs but had no effect on mEPSCs, suggesting a network-driven effect of OrxA. The amplitudes of s/mEPSCs were unaffected by the peptides, indicating a presynaptic action on glutamate release. Augmentation of OrxA-induced glutamate release was reversed by DynA. Utilizing a behavioral approach, separate groups of male Wistar rats were trained to self-administer cocaine or sweetened condensed milk (SCM). After extinction, rats received intra-pPVT administration of OrxA±DynA±the κ-opioid receptor antagonist nor-binaltorphimine (NorBNI) under extinction conditions. OrxA reinstated cocaine- and SCM-seeking behavior, with a greater effect in cocaine animals. DynA blocked OrxA-induced cocaine seeking but not SCM seeking. NorBNI did not induce or potentiate cocaine-seeking behavior induced by OrxA but reversed DynA effect. This indicates that the κ-opioid system in the pPVT counteracts OrxA-induced cocaine seeking, suggesting a novel therapeutic target to prevent cocaine relapse.
The gravitational-wave memory effect

The nonlinear memory effect is a slowly growing, non-oscillatory contribution to the gravitational-wave amplitude. It originates from gravitational waves that are sourced by the previously emitted waves. In an ideal gravitational-wave interferometer a gravitational wave with memory causes a permanent displacement of the test masses that persists after the wave has passed. Surprisingly, the nonlinear memory affects the signal amplitude starting at leading (Newtonian-quadrupole) order. Despite this fact, the nonlinear memory is not easily extracted from current numerical relativity simulations. After reviewing the linear and nonlinear memory I summarize some recent work, including (1) computations of the memory contribution to the inspiral waveform amplitude (thus completing the waveform to third post-Newtonian order); (2) the first calculations of the nonlinear memory that include all phases of binary black hole coalescence (inspiral, merger, ringdown); and (3) realistic estimates of the detectability of the memory with LISA.
Effect of Rhodium Carbenoid Structure on Cyclopropanation Chemoselectivity

Abstract Rhodium-stabilized carbenoids derived from aryldiazoacetates and vinyldiazoacetates undergo highly chemoselective intermolecular cyclopropanations, and this selectivity has been quantified by a Hammett study. These donor/acceptor substituted carbenoids are much more chemoselective than the traditional carbenoids derived from alkyl diazoacetates.
Transition Metal Catalyzed Decarboxylative Additions of Enolates

Transition metal catalyzed decarboxylation of β-keto acids and esters provides a convenient route for the regiospecific generation of enolates under neutral conditions. Enolates generated by decarboxylation have been utilized in aldol and Michael additions as well as allylic alkylations. The scope and mechanisms of these transformations are discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
A contribution to the confusion surrounding the reaction of ketenes with imines to produce β-lactams. A comparison of stereoselectivity dependence on the method of ketene generation : acid chloride/triethylamine vs photolysis of chromium-carbene complexes

The stereoselectivity of the reaction of imines of benzaldehyde and cinnamaldehyde with ketenes generated by the reaction of optically active oxazolidinone acid chlorides with triethylamine and complexed ketenes generated by photolysis of optically active oxazolidine ― and oxazolidinone-chromium-carbene complexes in the presence and absence of added triethylamine was compared. The absolute stereochemistry was determined primarily by the structure of the chiral auxiliary. The relative (cis-trans) stereochemistry was determined primarily by the structure of the imine and the free or bound character of the ketene. Triethylamine addition to reactions of carbene complexes afforded results that closely paralleled that of acid chloride generated ketenes. A mechanistic scheme accounting for these results and the general trends observed in other ketene/imine cyclizations is provided
Alternatives to 1-H-tetrazole in the preparation of phosphonate diesters and phosphonamidates from phosphonyl dichlorides

Abstract 5-Ethylthio-1- H -tetrazole (SET) and 4,5-dicyanoimidazole (DCI) were examined as alternatives to 1- H -tetrazole to mediate the synthesis of phosphonate diesters and phosphonamidates from phosphonyl dichlorides through a two-step one-pot reaction in various organic solvents. SET and DCI were comparable to 1- H -tetrazole for catalyzing these reactions. SET afforded slightly greater yields than DCI while benzene was universally the best solvent for this reaction.