cssi/SciSciGPT-SciSciNet huggingface dataset:
Learning plannable representations with causal InfoGAN

In recent years, deep generative models have been shown to 'imagine' convincing high-dimensional observations such as images, audio, and even video, learning directly from raw data. In this work, we ask how to imagine goal-directed visual plans – a plausible sequence of observations that transition a dynamical system from its current configuration to a desired goal state, which can later be used as a reference trajectory for control. We focus on systems with high-dimensional observations, such as images, and propose an approach that naturally combines representation learning and planning. Our framework learns a generative model of sequential observations, where the generative process is induced by a transition in a low-dimensional planning model, and an additional noise. By maximizing the mutual information between the generated observations and the transition in the planning model, we obtain a low-dimensional representation that best explains the causal nature of the data. We structure the planning model to be compatible with efficient planning algorithms, and we propose several such models based on either discrete or continuous states. Finally, to generate a visual plan, we project the current and goal observations onto their respective states in the planning model, plan a trajectory, and then use the generative model to transform the trajectory to a sequence of observations. We demonstrate our method on imagining plausible visual plans of rope manipulation.
Phase Field Simulation of Dendritic Solidification of Ti-6Al-4V During Additive Manufacturing Process

In this study, the phase field method is applied to simulate the phase transformation of Ti-6Al-4V from liquid phase to solid phase during solidification. The simulated results show the dendritic arms grow along the direction of the heat flow. Droplets are found formed inside the dendrites. Solute enriches in the liquid near the dendritic tips and between the dendritic arms. The effects of various processing parameters, including local temperature gradient, scan speed, and cooling rate, on dendrites morphology and growth velocity are studied. The results show that the higher temperature gradient, scan speed, and cooling rate will result in smaller dendritic arm spacing and higher growth velocity. The simulated dendritic morphology and arm spacings are in good agreement with experimental data and theoretical predictions.
Building an Efficient Lattice Gadget Toolkit: Subgaussian Sampling and More

Many advanced lattice cryptography applications require efficient algorithms for inverting the so-called “gadget” matrices, which are used to formally describe a digit decomposition problem that produces an output with specific (statistical) properties. The common gadget inversion problems are the classical (often binary) digit decomposition, subgaussian decomposition, Learning with Errors (LWE) decoding, and discrete Gaussian sampling. In this work, we build and implement an efficient lattice gadget toolkit that provides a general treatment of gadget matrices and algorithms for their inversion/sampling. The main contribution of our work is a set of new gadget matrices and algorithms for efficient subgaussian sampling that have a number of major theoretical and practical advantages over previously known algorithms. Another contribution deals with efficient algorithms for LWE decoding and discrete Gaussian sampling in the Residue Number System (RNS) representation.
Unsupervised Image-to-Image Translation Using Domain-Specific Variational Information Bound

Unsupervised image-to-image translation is a class of computer vision problems which aims at modeling conditional distribution of images in the target domain, given a set of unpaired images in the source and target domains. An image in the source domain might have multiple representations in the target domain. Therefore, ambiguity in modeling of the conditional distribution arises, specially when the images in the source and target domains come from different modalities. Current approaches mostly rely on simplifying assumptions to map both domains into a shared-latent space. Consequently, they are only able to model the domain-invariant information between the two modalities. These approaches cannot model domain-specific information which has no representation in the target domain. In this work, we propose an unsupervised image-to-image translation framework which maximizes a domain-specific variational information bound and learns the target domain-invariant representation of the two domain. The proposed framework makes it possible to map a single source image into multiple images in the target domain, utilizing several target domain-specific codes sampled randomly from the prior distribution, or extracted from reference images.
Visual Memory for Robust Path Following

Humans routinely retrace a path in a novel environment both forwards and backwards despite uncertainty in their motion. In this paper, we present an approach for doing so. Given a demonstration of a path, a first network generates an abstraction of the path. Equipped with this abstraction, a second network then observes the world and decides how to act in order to retrace the path under noisy actuation and a changing environment. The two networks are optimized end-to-end at training time. We evaluate the method in two realistic simulators, performing path following both forwards and backwards. Our experiments show that our approach outperforms both a classical approach to solving this task as well as a number of other baselines.
The synthetic histone-binding regulator protein PcTF activates interferon genes in breast cancer cells

Mounting evidence from genome-wide studies of cancer shows that chromatin-mediated epigenetic silencing at large cohorts of genes is strongly linked to a poor prognosis. This mechanism is thought to prevent cell differentiation and enable evasion of the immune system. Drugging the cancer epigenome with small molecule inhibitors to release silenced genes from the repressed state has emerged as a powerful approach for cancer research and drug development. Targets of these inhibitors include chromatin-modifying enzymes that can acquire drug-resistant mutations. In order to directly target a generally conserved feature, elevated trimethyl-lysine 27 on histone H3 (H3K27me3), we developed the Polycomb-based Transcription Factor (PcTF), a fusion activator that targets methyl-histone marks via its N-terminal H3K27me3-binding motif, and co-regulates sets of silenced genes. Here, we report transcriptome profiling analyses of PcTF-treated breast cancer model cell lines. We identified a set of 19 PcTF-upregulated genes, or PUGs, that were consistent across three distinct breast cancer cell lines. These genes are associated with the interferon response pathway. Our results demonstrate for the first time a chromatin-mediated interferon-related transcriptional response driven by an engineered fusion protein that physically links repressive histone marks with active transcription.
Finding crash-consistency bugs with bounded black-box crash testing

We present a new approach to testing file-system crash consistency: bounded black-box crash testing (B3). B3 tests the file system in a black-box manner using workloads of file-system operations. Since the space of possible workloads is infinite, B3 bounds this space based on parameters such as the number of file-system operations or which operations to include, and exhaustively generates workloads within this bounded space. Each workload is tested on the target file system by simulating power-loss crashes while the workload is being executed, and checking if the file system recovers to a correct state after each crash. B3 builds upon insights derived from our study of crash-consistency bugs reported in Linux file systems in the last five years. We observed that most reported bugs can be reproduced using small workloads of three or fewer file-system operations on a newly-created file system, and that all reported bugs result from crashes after fsync() related system calls. We build two tools, CRASHMONKEY and ACE, to demonstrate the effectiveness of this approach. Our tools are able to find 24 out of the 26 crash-consistency bugs reported in the last five years. Our tools also revealed 10 new crash-consistency bugs in widely-used, mature Linux file systems, seven of which existed in the kernel since 2014. The new bugs result in severe consequences like broken rename atomicity and loss of persisted files.
Time-varying predatory behavior is primary predictor of fine-scale movement of wildland-urban cougars.

While many species have suffered from the detrimental impacts of increasing human population growth, some species, such as cougars (Puma concolor), have been observed using human-modified landscapes. However, human-modified habitat can be a source of both increased risk and increased food availability, particularly for large carnivores. Assessing preferential use of the landscape is important for managing wildlife and can be particularly useful in transitional habitats, such as at the wildland-urban interface. Preferential use is often evaluated using resource selection functions (RSFs), which are focused on quantifying habitat preference using either a temporally static framework or researcher-defined temporal delineations. Many applications of RSFs do not incorporate time-varying landscape availability or temporally-varying behavior, which may mask conflict and avoidance behavior. Contemporary approaches to incorporate landscape availability into the assessment of habitat selection include spatio-temporal point process models, step selection functions, and continuous-time Markov chain (CTMC) models; in contrast with the other methods, the CTMC model allows for explicit inference on animal movement in continuous-time. We used a hierarchical version of the CTMC framework to model speed and directionality of fine-scale movement by a population of cougars inhabiting the Front Range of Colorado, U.S.A., an area exhibiting rapid population growth and increased recreational use, as a function of individual variation and time-varying responses to landscape covariates. We found evidence for individual- and daily temporal-variability in cougar response to landscape characteristics. Distance to nearest kill site emerged as the most important driver of movement at a population-level. We also detected seasonal differences in average response to elevation, heat loading, and distance to roads. Motility was also a function of amount of development, with cougars moving faster in developed areas than in undeveloped areas. The time-varying framework allowed us to detect temporal variability that would be masked in a generalized linear model, and improved the within-sample predictive ability of the model. The high degree of individual variation suggests that, if agencies want to minimize human-wildlife conflict management options should be varied and flexible. However, due to the effect of recursive behavior on cougar movement, likely related to the location and timing of potential kill-sites, kill-site identification tools may be useful for identifying areas of potential conflict.
Unrequited: Asymmetry in interorganizational trust:

Many studies of interorganizational relationships assume that trust between organizations is symmetric. In this essay, we explore the origins of this assumption and examine relevant quantitative an...
Simultaneous innovation and the cyclicality of R&D

Abstract There is ample evidence that R&D investment is mildly pro-cyclical. Whereas the existing literature can explain the positive correlation between investment in R&D and output, the moderate strength of the relationship remains under-explored. This paper develops a stochastic expanding-variety endogenous growth model that accounts for the observed mild pro-cyclicality of R&D. In the model, several firms may simultaneously make the same innovation. Innovations made by many firms simultaneously are of higher quality, on average, and contribute relatively more to the expansion of the knowledge stock in the economy. This delivers an endogenous mechanism that breaks the otherwise perfect correlation between R&D and output. A calibration of our model closely matches the cyclical properties of R&D.
Population genomics perspectives on convergent adaptation.

Convergent adaptation is the independent evolution of similar traits conferring a fitness advantage in two or more lineages. Cases of convergent adaptation inform our ideas about the ecological and...
Backing Despots? Foreign Aid and the Survival of Autocratic Regimes

What is the effect of foreign aid on the survival of autocratic regimes? Extant work about the effect of foreign aid on the recipient’s political regime has come to contradictory conclusions. Curre...
Reliability based hardware Trojan design using physics-based electromigration models

Abstract In recent years the concern over Hardware Trojans has come to the forefront of hardware security research as these types of attacks pose a real and dangerous threat to both commercial and mission-critical systems. One interesting threat model utilizes semiconductor physics, specifically aging effects such as Electromigration (EM). However, existing methods for EM-based Trojans rely on empirical Black's models can easily lead to performance degradation and less accuracy in Trojan activation time prediction. In this article, we study the EM-based Trojan attacks based on recently developed physics-based EM models. We propose novel EM attack techniques in which the EM-induced hydrostatic stress increase in a wire is caused by wire structure or layer changes without changing the current density of the wires. The proposed techniques consist of sink/reservoir insertion or sizing and layer switching techniques based on the early and late failure modes of EM wear-out effects. As a result, the proposed techniques can have minimal impact on circuit performance, which is in contrast with existing current-density-based EM attacks. The proposed techniques can serve as a trigger for the EM attack on power/ground networks and signal and clock networks. Furthermore, we also present two potential EM attack mitigation techniques, namely, the split fabrication and burn-in testing.
Fuchs' problem for p-groups

Abstract Which groups can be the group of units in a ring? This open question, posed by Laszlo Fuchs in 1960, has been studied by the authors and others with a variety of restrictions on either the class of groups or the class of rings under consideration. In the present work, we investigate Fuchs' problem for the class of p-groups. Ditor provided a solution in the finite, odd-primary case in 1970. Our first main result is that a finite 2-group G is the group of units of a ring of odd characteristic if and only if G is of the form C 8 t × ∏ i = 1 k C 2 n i s i , where t and s i are non-negative integers and 2 n i + 1 is a Fermat prime for all i. We also determine the finite abelian 2-groups of rank at most 2 that are realizable over the class of rings of characteristic 2, and we give some results concerning the realizability of 2-groups in characteristic 0 and 2 n . Finally, we show that the only almost cyclic 2-groups which appear as the group of units in a ring are C 2 , C 4 , C 8 , C q − 1 (q a Fermat prime), C 2 × C 2 n ( n ≥ 1 ) , D 8 , and Q 8 . From this list we obtain the p-groups with periodic cohomology which arise as the group of units in a ring.
State Pension Accounting Estimates and Strong Public Unions

Concerns are commonly raised that strong public unions extract generous pension benefits from state governments and are the cause of states’ burdensome pension obligations. Prior research (Anzia and Moe 2015) finds evidence supporting such concerns. Consistent with incentives to minimize such perceptions, our findings suggest that state pension plans with stronger public unions select higher discount rates to improve reported funding levels. While riskier asset allocations are used to support the higher discount rates (which equal the expected return on the plan assets), most of the higher rates appear opportunistic. In addition, consistent with a desire to avoid drawing attention to persistent plan underfunding, our evidence indicates that stronger union plans are less likely to select longer amortization periods to recognize pension deficits when underfunding is larger. We do not, however, find evidence for asset smoothing periods being used to delay the recognition of investment losses on plan assets. Together, our findings suggest that stronger union plans take steps to make their pension obligations look less burdensome to the public.
Vasculitis of the Nervous System.

Purpose of reviewVasculitis refers to heterogenous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. When unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability making this a disorder of paramount impo
Atrial-Esophageal Fistula After Catheter Ablation: Diagnosing and Managing a Rare Complication of a Common Procedure

BACKGROUND Atrial fibrillation is considered the most common cardiac arrhythmias in the United States with rate and rhythm control strategies traditionally used for management. If patients are intolerant to class I or class III anti-arrhythmic medications, catheter ablation may be used as a rhythm control strategy. As catheter ablation becomes more commonplace, so too do the procedure-related complications, which include tamponade, total arterio-venous fistula, pulmonary vein stenosis, and atrial-esophageal fistula. CASE REPORT A 67-year-old male underwent catheter ablation for atrial fibrillation and subsequently presented with complaints of fever and chills. Initial workup for a source of infection included a computed tomography (CT) scan and transesophageal echocardiogram which did not reveal any abnormalities. Antibiotic therapy was initiated, and multiple CT scans were performed; eventually patient was found to have an atrial-esophageal fistula, secondary to thermal injury. The patient underwent thoracotomy and full thickness necrosis of the posterior left atrium and pericardium near the base of the left inferior pulmonary vein was visualized, with a roughly nickel sized orifice, which was repaired. The patient had an uneventful recovery and was doing well on follow-up. CONCLUSIONS Atrial-esophageal fistula is a rare but lethal complication of atrial fibrillation ablation. While imaging modalities have improved and can detect the condition, they can also yield ambivalent findings which can challenge patient care. It is important for clinicians to maintain a heightened awareness of this complication in post-ablation patients and utilize clinical history and not rely solely on imaging to diagnose and treat this complication.
Ribozyme-mediated, multiplex CRISPR gene editing and CRISPR interference (CRISPRi) in rodent-infectious Plasmodium yoelii

Malaria remains a major global health issue, affecting millions and killing hundreds of thousands of people annually. Efforts to break the transmission cycle of the causal Plasmodium parasite, and to cure those that are afflicted, rely upon functional characterization of genes essential to the parasite's growth and development. These studies are often based upon manipulations of the parasite genome to disrupt or modify a gene of interest to understand its importance and function. However, these approaches can be limited by the availability of selectable markers and the time required to generate transgenic parasites. Moreover, there also is a risk of disrupting native gene regulatory elements with the introduction of exogenous sequences. To address these limitations, we have developed CRISPR-RGR, a Streptococcus pyogenes (Sp)Cas9-based gene editing system for Plasmodium that utilizes a ribozyme-guide-ribozyme (RGR) single guide RNA (sgRNA) expression strategy with RNA polymerase II promoters. Using rodent-infectious Plasmodium yoelii, we demonstrate that both gene disruptions and coding sequence insertions are efficiently generated, producing marker-free parasites with homology arms as short as 80-100 bp. Additionally, we find that the common practice of using one sgRNA can produce both unintended plasmid integration and desired locus replacement editing events, whereas the use of two sgRNAs results in only locus replacement editing. Lastly, we show that CRISPR-RGR can be used for CRISPR interference (CRISPRi) by binding catalytically dead SpCas9 (dSpCas9) to the region upstream of a gene of interest, resulting in a position-dependent, but strand-independent reduction in gene expression. This robust and flexible system facilitates efficient genetic characterizations of rodent-infectious Plasmodium species.
On the indirect elicitability of the mode and modal interval

Scoring functions are commonly used to evaluate a point forecast of a particular statistical functional. This scoring function should be consistent, meaning the correct value of the functional is the Bayes act, in which case we say the scoring function elicits the functional. Recent results show that the mode functional is not elicitable. In this work, we ask whether it is at least possible to indirectly elicit the mode, wherein one elicits a low-dimensional functional from which the mode can be computed. We show that this cannot be done: Neither the mode nor a modal interval is indirectly elicitable with respect to the class of identifiable functionals.
A SAT-Based System for Consistent Query Answering

An inconsistent database is a database that violates one or more integrity constraints, such as functional dependencies. Consistent Query Answering is a rigorous and principled approach to the semantics of queries posed against inconsistent databases. The consistent answers to a query on an inconsistent database is the intersection of the answers to the query on every repair, i.e., on every consistent database that differs from the given inconsistent one in a minimal way. Computing the consistent answers of a fixed conjunctive query on a given inconsistent database can be a coNP-hard problem, even though every fixed conjunctive query is efficiently computable on a given consistent database.
Session details: Posters

SPLASH Posters provide an excellent forum for authors to present their work in an informal and interactive setting. Posters are ideal to showcase speculative, late-breaking results or to introduce interesting, innovative work. Posters sessions are highly interactive. They allow authors and interested participants to connect to each other and to engage in discussions about the work presented. Posters provide authors with a unique opportunity to draw attention to their work during the conference. Authors in other SPLASH technical tracks therefore are strongly encouraged to complement their submission with a poster about their work.After its remarkable success in previous years, SPLASH is again hosting an ACM SIGPLAN Student Research Competition. The competition, sponsored by Microsoft Research, is an internationally recognized venue that enables undergraduate and graduate students to experience the research world, share their research results with other students and SPLASH attendees, and compete for prizes. The ACM SIGPLAN Student Research Competition shares the Poster session's goal to facilitate students' interaction with researchers and industry practitioners, providing both sides with the opportunity to learn about ongoing research. Additionally, the ACM SIGPLAN Student Research Competition affords students with experience in both formal presentations and evaluations.On the following pages, you will find the SPLASH Poster and ACM SIGPLAN Student Research Competition abstracts that cover an interesting mix of topics from the domains of systems, applications, and programming languages. It is worth noting that students participating in the ACM SIGPLAN Student Research Competition submit their abstract as sole author. You can use the abstracts to receive a brief introduction to posters from both the SPLASH Posters and ACM SIGPLAN Student Research Competition on display during the poster session, or to find further information about the authors and their work. The ACM SIGPLAN Student Research Competition abstracts can also be used to get a general overview of what the student will be presenting during their formal presentation at the second round of the competition.
Asymptotic improvements to quantum circuits via qutrits

Quantum computation is traditionally expressed in terms of quantum bits, or qubits. In this work, we instead consider three-level qutrits. Past work with qutrits has demonstrated only constant factor improvements, owing to the $\log_{2}$ (3) binary-to-ternary compression factor. We present a novel technique using qutrits to achieve a logarithmic depth (runtime) decomposition of the Generalized Toffoli gate using no ancilla-a significant improvement over linear depth for the best qubit-only equivalent. Our circuit construction also features a 70x improvement in two-qudit gate count over the qubit-only equivalent decomposition. This results in circuit cost reductions for important algorithms like quantum neurons and Grover search. We develop an open-source circuit simulator for qutrits, along with realistic near-term noise models which account for the cost of operating qutrits. Simulation results for these noise models indicate over 90% mean reliability (fidelity) for our circuit construction, versus under 30% for the qubit-only baseline. These results suggest that qutrits offer a promising path towards scaling quantum computation.
Intrinsically disordered regions regulate both catalytic and non-catalytic activities of the MutLα mismatch repair complex

Intrinsically disordered regions (IDRs) are present in at least 30% of the eukaryotic proteome and are enriched in chromatin-associated proteins. Using a combination of genetics, biochemistry and single-molecule biophysics, we characterize how IDRs regulate the functions of the yeast MutLα (Mlh1-Pms1) mismatch repair (MMR) complex. Shortening or scrambling the IDRs in both subunits ablates MMR in vivo. Mlh1-Pms1 complexes with shorter IDRs that disrupt MMR retain wild-type DNA binding affinity but are impaired for diffusion on both naked and nucleosome-coated DNA. Moreover, the IDRs also regulate the adenosine triphosphate hydrolysis and nuclease activities that are encoded in the structured N- and C-terminal domains of the complex. This combination of phenotypes underlies the catastrophic MMR defect seen with the mutant MutLα in vivo. More broadly, this work highlights an unanticipated multi-functional role for IDRs in regulating both facilitated diffusion on chromatin and nucleolytic processing of a DNA substrate.
What do we know about the acidity of solid acids

With a proper understanding of the nature of solid acidity, zeolites and other solid acids have great potential for replacing homogeneous acids in a wide range of catalytic applications. This paper describes results from our laboratory on the characterization and description of the acid sites in high‐silica zeolites, especially H‐MFI. A crucial observation from this work is the identification of stoichiometric adsorption complexes, one molecule per framework Al, for a wide range of adsorbates, including amines, alcohols, nitriles, ketones, and thiols. Examples are given in which temperature‐programmed desorption is used to identify these complexes and characterize their initial chemistries. Calorimetric measurements on the 1:1 complexes have been used to compare the enthalpies of protonation in the zeolite to enthalpies of protonation in the gas phase and in aqueous phase and to demonstrate that a gas‐phase basis provides better predictive capabilities. The issue of carbenium‐ion stabilities is discussed, as well as the unusual catalytic properties of acid sites formed by framework substitution of Fe. The effect of sorption and cavity size on reactions is described. Finally, the problems associated with trying to define or characterize solid acids by using ammonia TPD or 13C NMR isotropic shifts of ketones without proper consideration of the complicated nature of these techniques are discussed.
Systematic Functional Annotation and Visualization of Biological Networks

Large-scale biological networks represent relationships between genes, but our understanding of how networks are functionally organized is limited. Here, I describe spatial analysis of functional enrichment (SAFE), a systematic method for annotating biological networks and examining their functional organization. SAFE visualizes the network in 2D space and measures the continuous distribution of functional enrichment across local neighborhoods, producing a list of the associated functions and a map of their relative positioning. I applied SAFE to annotate the Saccharomyces cerevisiae genetic interaction similarity network and protein-protein interaction network with gene ontology terms. SAFE annotations of the genetic network matched manually derived annotations, while taking less than 1% of the time, and proved robust to noise and sensitive to biological signal. Integration of genetic interaction and chemical genomics data using SAFE revealed a link between vesicle-mediate transport and resistance to the anti-cancer drug bortezomib. These results demonstrate the utility of SAFE for examining biological networks and understanding their functional organization.
Molecular Engineering of Supported Vanadium Oxide Catalysts Through Support Modification

Highly dispersed, multilayered surface metal oxide catalysts (V2O5/MO x /SiO2, M = Ti(IV), Zr(IV) or Al(III)) were successfully synthesized by taking into account various factors that govern the maximum dispersion of metal oxide species on silica. The characterization results revealed that the molecular structures of the surface vanadium oxide species on the modified supports are a strong function of environmental conditions. The surface vanadium oxide species under dehydrated conditions are predominantly isolated VO4 units, similar to the dehydrated V2O5/SiO2 catalysts. Upon hydration, the surface vanadium oxide species on the modified supports consist of polymerized VO5/VO6 units and/or less polymerized (VO3) n species, which depend on the vanadia content and the specific second metal oxide loading. The surface V cations are found to preferentially interact with the surface metal (Ti, Zr or Al) oxide species on silica. The V(V) cations in the dehydrated state appear to possess both oxygenated ligands of Si(IV)–O− and M–O−. Consequently, the reducibility and catalytic properties of the surface vanadium oxide species are significantly altered. The turnover frequencies of the surface VO4 species on these modified supports for methanol oxidation to redox products (predominantly formaldehyde) increase by more than an order of magnitude relative to the unmodified V2O5/SiO2 catalysts. These reactivity enhancements are associated with the substitution of Si(IV)–O− oxygenated ligands by less electronegative M–O− ligands in the O=V(–O–support)3 structure, which strongly suggests that the bridging V–O–support bonds play a key role in determining the reactivity of the surface vanadium oxide species on oxide supports.
Studies directed toward the synthesis of viridenomycin. Route 2: a second generation approach

Abstract A second generation approach toward the synthesis of viridenomycin is described. Three key fragments of the molecule have been synthesized in stereochemically pure form. Initial studies toward the coupling of these fragments with the aim of assembling the macrocycle are detailed. Final efforts to reach the title compound are documented.
Reduced Repertoire of Cortical Microstates and Neuronal Ensembles in Medically Induced Loss of Consciousness.

Summary Medically induced loss of consciousness (mLOC) during anesthesia is associated with a macroscale breakdown of brain connectivity, yet the neural microcircuit correlates of mLOC remain unknown. To explore this, we applied different analytical approaches (t-SNE/watershed segmentation, affinity propagation clustering, PCA, and LZW complexity) to two-photon calcium imaging of neocortical and hippocampal microcircuit activity and local field potential (LFP) measurements across different anesthetic depths in mice, and to micro-electrode array recordings in human subjects. We find that in both cases, mLOC disrupts population activity patterns by generating (1) fewer discriminable network microstates and (2) fewer neuronal ensembles. Our results indicate that local neuronal ensemble dynamics could causally contribute to the emergence of conscious states.
CTD-dependent and -independent mechanisms govern co-transcriptional capping of Pol II transcripts

Co-transcriptional capping of RNA polymerase II (Pol II) transcripts by capping enzyme proceeds orders of magnitude more efficiently than capping of free RNA. Previous studies brought to light a role for the phosphorylated Pol II carboxyl-terminal domain (CTD) in activation of co-transcriptional capping; however, CTD phosphorylation alone could not account for the observed magnitude of activation. Here, we exploit a defined Pol II transcription system that supports both CTD phosphorylation and robust activation of capping to dissect the mechanism of co-transcriptional capping. Taken together, our findings identify a CTD-independent, but Pol II-mediated, mechanism that functions in parallel with CTD-dependent processes to ensure optimal capping, and they support a "tethering" model for the mechanism of activation.
Pollen Contaminated With Field-Relevant Levels of Cyhalothrin Affects Honey Bee Survival, Nutritional Physiology, and Pollen Consumption Behavior.

Honey bees are exposed to a variety of environmental factors that impact their health, including nutritional stress, pathogens, and pesticides. In particular, there has been increasing evidence that sublethal exposure to pesticides can cause subtle, yet important effects on honey bee health and behavior. Here, we add to this body of knowledge by presenting data on bee-collected pollen containing sublethal levels of cyhalothrin, a pyrethroid insecticide, which, when fed to young honey bees, resulted in significant changes in lifespan, nutritional physiology, and behavior. For the first time, we show that when young, nest-aged bees are presented with pollen containing field-relevant levels of cyhalothrin, they reduce their consumption of contaminated pollen. This indicates that, at least for some chemicals, young bees are able to detect contamination in pollen and change their behavioral response, even if the contamination levels do not prevent foraging honey bees from collecting the contaminated pollen.
Mapping the Ligand Binding Landscape.

Abstract The interaction between a ligand and a protein involves a multitude of conformational states. To achieve a particular deeply bound pose, the ligand must search across a rough free-energy landscape with many metastable minima. Creating maps of the ligand binding landscape is a great challenge, as binding and release events typically occur on timescales that are beyond the reach of molecular simulation. The WExplore enhanced sampling method is well suited to build these maps because it is designed to broadly explore free-energy landscapes and is capable of simulating ligand release pathways that occur on timescales as long as minutes. WExplore also uses only unbiased trajectory segments, allowing for the construction of Markov state models (MSMs) and conformation space networks that combine the results of multiple simulations. Here, we use WExplore to study two bromodomain-inhibitor systems using multiple docked starting poses (Brd4-MS436 and Baz2B-ICR7) and synthesize our results using a series of MSMs using time-lagged independent component analysis. Ranking the starting poses by exit rate agrees with the crystal structure pose in both cases. We also predict the most stable pose using the equilibrium populations from the MSM but find that the prediction is not robust as a function of MSM parameters. The simulated trajectories are synthesized into network models that visualize the entire binding landscape for each system, and we examine transition paths between deeply bound stable states. We find that, on average, transitions between deeply bound states convert through the unbound state 81% of the time, implying a trial-and-error approach to ligand binding. We conclude with a discussion of the implications of this result for both kinetics-based drug discovery and virtual screening pipelines that incorporate molecular dynamics.
A direct conversion of carboxylic acids to methylthiomethyl esters using a microwave-assisted pummerer rearrangement with dimethylsulfoxide

Abstract A simple microwave-assisted method for the conversion of carboxylic acids to MTM esters is presented. This new process allows for rapid introduction of an MTM ester protecting group to a variety of carboxylic acids including alkyl, electron-rich aromatic, and long chain unsaturated carboxylic acids. The products isolated from this reaction are very pure after a simple extraction, which eliminates the need for further purification. The reaction has also been carried out on 1.50 g without deterioration of product yields or purity.
Molecularly distinct models of zebrafish Myc-induced B cell leukemia.

Zebrafish models of T cell acute lymphoblastic leukemia (T-ALL) have been studied for over a decade, but curiously, robust zebrafish B cell ALL (B-ALL) models had not been described. Recently, our laboratories reported two seemingly closely-related models of zebrafish B-ALL. In these genetic lines, the primary difference is expression of either murine or human transgenic c-MYC, each controlled by the zebrafish rag2 promoter. Here, we compare ALL gene expression in both models. Surprisingly, we find that B-ALL arise in different B cell lineages, with ighm+ vs. ighz+ B-ALL driven by murine Myc vs. human MYC, respectively. Moreover, these B-ALL types exhibit signatures of distinct molecular pathways, further unexpected dissimilarity. Thus, despite sharing analogous genetic makeup, the ALL types in each model are markedly different, proving subtle genetic changes can profoundly impact model organism phenotypes. Investigating the mechanistic differences between mouse and human c-MYC in these contexts may reveal key functional aspects governing MYC-driven oncogenesis in human malignancies.
Glycosidase Inhibitors: Synthesis of Enantiomerically Pure Aza-Sugars from Schiff Base Amino Esters via Tandem Reduction-Alkenylation and Osmylation

Nitrogen-in-the-ring “aza-sugars” have been synthesized in enantiomerically pure form from the amino acid l-alanine in excellent overall yield. The O'Donnell's Schiff base of l-alanine methyl ester 9a was converted to aza-sugar l-fuco-1-deoxy-nojirimycin, 18, and to the epimer l-gulo-1-deoxy-nojirimycin, 20, in eight steps. The overall yields were 20 and 29%, respectively. The methodology for the efficient generation of silyl- and benzyl-protected (E)-3-lithio-2-propen-1-ols, and the use of these alkenyllithiums with iBu5Al2H as nucleophiles in the threo-selective tandem reduction−alkenylation of the Schiff base esters is described. Osmium-catalyzed cis-oxygenation of the resulting olefin products was selective for the galacto (fuco) amino polyols in all cases for the acyclic olefins, and was gulo-selective for the cyclic D-4,5-dihydropyridine pivalate, 17c. TEMPO-NaOCl was selective for oxidation of the primary position of the acyclic Schiff bases, and allowed for minimal protection/deprotection of the i...
Bioorganic chemistry of cyclic ADP-ribose (cADPR)

The objective of this brief review is to present an overview of the bioorganic chemistry of cyclic-ADP-ribose (cADPR) with special emphasis on the methodology used for the synthesis of analogues of cADPR. New structural analogues of cADPR can be prepared using either the biomimetic method or ADP-ribosyl cyclase from Aplysia californica. For the most part, both procedures give similar product profiles, but higher yields are generally obtained with the enzymatic method. These synthetic methodologies have allowed the transformation of a variety of structurally modified analogues of NAD+ into their corresponding cyclic nucleotides. Several of these novel analogues are more potent than cADPR in inducing calcium release and are also more stable towards degradative enzymes. They could serve as valuable affinity probes for the isolation of cADPR-binding proteins.
Synthesis of a novel pyrene-containing nucleoside and its incorporation into oligonucleotides

Abstract The synthesis of the aryl nucleoside analogue β -2′-deoxy-D-ribofuranosyl-1′- N -pyrenly-carboxamide ( 4 ) is described. This compound can be converted into a phosphoramidite reagent and used in solid phase oligonucleotide synthesis.
Exact Adaptive Confidence Intervals for Small Areas

In the analysis of survey data it is of interest to estimate and quantify uncertainty about means or totals for each of several non-overlapping subpopulations, or areas. When the sample size for a given area is small, standard confidence intervals based on data only from that area can be unacceptably wide. In order to reduce interval width, practitioners often utilize multilevel models in order to borrow information across areas, resulting in intervals centered around shrinkage estimators. However, such intervals only have the nominal coverage rate on average across areas under the assumed model for across-area heterogeneity. The coverage rate for a given area depends on the actual value of the area mean, and can be nearly zero for areas with means that are far from the across-group average. As such, the use of uncertainty intervals centered around shrinkage estimators are inappropriate when area-specific coverage rates are desired. In this article, we propose an alternative confidence interval procedure for area means and totals under normally distributed sampling errors. This procedure not only has constant $1-\alpha$ frequentist coverage for all values of the target quantity, but also uses auxiliary information to borrow information across areas. Because of this, the corresponding intervals have shorter expected lengths than standard confidence intervals centered on the unbiased direct estimator. Importantly, the coverage of the procedure does not depend on the assumed model for across-area heterogeneity. Rather, improvements to the model for across-area heterogeneity result in reduced expected interval width.
The synthesis of novel nonclassical reversed bridge quinazoline antifolates as inhibitors of thymidylate synthase

2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one (3, AG337) a lipophilic thymidylate synthase inhibitor, is currently in clinical trials as an antitumor agent. On the basis of the crystal structure of 3 and the classical inhibitor 10-propargyl-5,8-dideazafolic acid (1, PDDF) with thymidylate synthase, we designed and synthesized a series of nonclassical 2-amino-6-substituted-3H-quinazolin-4-ones 4–13, with a variety of electron withdrawing groups in the side chain (with the exception of compound 4). Molecular modeling indicates that these reversed bridge (N9–C10) 6-substituted analogues orient their side chain C10-substituent such that it lies between that of 1 and 3. These compounds were obtained by reduc tive amination of 6-aminoquinazoline 16 and the appropriate aryl aldehyde 17 or aryl ketone 18. For ana logues 11–13, the yield depended on the substitutents on the aryl ketone 18 (comparison of 11 and 13). With the exception of analogue 13, all the compounds in the series were poor inhibitors of thymidylate synthase from Lactobacillus casei, Pneumocystis carinii and human sources.
Condensations of aryl trifluoromethyl ketones with arenes in acidic media

The chemistry of trifluoromethyl ketones has been studied. The work examines the condensation reactions of trifluoromethyl ketones with arenes in the superacid, including both synthetic and mechanistic aspects.
A cell penetrating peptide from SOCS-1 prevents ocular damage in experimental autoimmune uveitis.

Abstract We describe an immunosuppressive peptide corresponding to the kinase inhibitory region (KIR) of the intracellular checkpoint protein suppressor of cytokine signaling 1 (SOCS-1) that binds to the phospho-tyrosine containing regions of the tyrosine kinases JAK2 and TYK2 and the adaptor protein MAL, and thereby inhibits signaling downstream from these signaling mediators. The peptide, SOCS1-KIR, is thus capable of downregulating overactive JAK/STAT or NF-kB signaling in somatic cells, including those in many compartments of the eye. Attachment of poly-arginine to this peptide (R9-SOCS1-KIR) allows it to penetrate the plasma membrane in aqueous media. R9-SOCS1-KIR was tested in ARPE-19 cells and was found to attenuate mediators of inflammation by blocking the inflammatory effects of IFNγ, TNFα, or IL-17A. R9-SOCS1-KIR and also protected against TNFα or IL-17A mediated damage to the barrier properties of ARPE-19 cells, as evidenced by immunostaining with the tight junction protein, zona occludin 1 (ZO-1), and measurement of transepithelial electrical resistance (TEER). Experimental autoimmune uveitis (EAU) was generated in B10. RIII mice using a peptide of interphotoreceptor retinal binding protein (IRBP161−180) as immunogen. Topical administration of R9-SOCS1-KIR, 2 days before (prophylactic), or 7 days after immunization (therapeutic) protected ocular structure and function as seen by fundoscopy, optical coherence tomography (OCT), and electroretinography (ERG). The ability R9-SOCS1-KIR to suppress ocular inflammation and preserve barrier properties of retinal pigment epithelium makes it a potential candidate for treatment of autoimmune uveitis.
Labeling RNAs in Live Cells Using Malachite Green Aptamer Scaffolds as Fluorescent Probes

RNAs mediate many different processes that are central to cellular function. The ability to quantify or image RNAs in live cells is very useful in elucidating such functions of RNA. RNA aptamer–fluorogen systems have been increasingly used in labeling RNAs in live cells. Here, we use the malachite green aptamer (MGA), an RNA aptamer that can specifically bind to malachite green (MG) dye and induces it to emit far-red fluorescence signals. Previous studies on MGA showed a potential for the use of MGA for genetically tagging other RNA molecules in live cells. However, these studies also exhibited low fluorescence signals and high background noise. Here we constructed and tested RNA scaffolds containing multiple tandem repeats of MGA as a strategy to increase the brightness of the MGA aptamer-fluorogen system as well as to make the system fluoresce when tagging various RNA molecules, in live cells. We demonstrate that our MGA scaffolds can induce fluorescence signals by up to ∼20-fold compared to the basal l...
Materials for high temperature electrochemical NOx gas sensors

Abstract Solid electrolytes are well-suited for high-temperature electrochemical devices and thus have been used in sensors for monitoring exhaust gas concentrations. Oxygen content can be measured directly using a potentiometric sensor with an oxygen-ion conductor, such as yttria-stabilized zirconia, but sensors for other exhaust gases, including NO x , require more complicated approaches, such as auxiliary electrodes for equilibrium measurements or electrocatalytic electrodes for mixed potential non-equilibrium measurements. The successful development of these sensors depends critically on the identification of electrode materials with the appropriate thermodynamic and catalytic properties. In this paper, the materials used for electrochemical NO x gas sensors are reviewed with an emphasis on potentiometric sensors, but the materials used in other approaches, such as impedancemetric and amperometric sensors, are also discussed.