cssi/SciSciGPT-SciSciNet huggingface dataset:
Comparison of β-Cell Function Between Overweight/Obese Adults and Adolescents Across the Spectrum of Glycemia

OBJECTIVE Type 2 diabetes is a growing health problem among both adults and adolescents. To better understand the differences in the pathogenesis of diabetes between these groups, we examined differences in β-cell function along the spectrum of glucose tolerance. RESEARCH DESIGN AND METHODS We evaluated 89 adults and 50 adolescents with normal glucose tolerance (NGT), dysglycemia, or type 2 diabetes. Oral glucose tolerance test results were used for C-peptide and insulin/glucose minimal modeling. Model-derived and direct measures of insulin secretion and insulin sensitivity were compared across glycemic stages and between age-groups at each stage. RESULTS In adolescents with dysglycemia, there was marked insulin resistance (insulin sensitivity index: adolescents, median [interquartile range] 1.8 [1.1–2.4] × 10−4; adults, 5.0 [2.3–9.9]; P = 0.01). The nature of β-cell dysfunction across stages of dysglycemia differed between the groups. We observed higher levels of secretion among adolescents than adults (total insulin secretion: NGT, 143 [103–284] × 10−9/min adolescent vs. 106 [71–127], P = 0.001); adults showed stepwise impairments in static insulin secretion (NGT, 7.5 [4.0–10.3] × 10−9/min; dysglycemia, 5.0 [2.3–9.9]; type 2 diabetes, 0.7 [0.1–2.45]; P = 0.003), whereas adolescents showed diabetes-related impairment in dynamic secretion (NGT, 1,905 [1,630–3,913] × 10−9; dysglycemia, 2,703 [1,323–3,637]; type 2 diabetes, 1,189 [269–1,410]; P = 0.001). CONCLUSIONS Adults and adolescents differ in the underlying defects leading to dysglycemia, and in the nature of β-cell dysfunction across stages of dysglycemia. These results may suggest different approaches to diabetes prevention in youths versus adults.
Precise positioning for near-bottom equipment using a relay transponder

The Marine Physical Laboratory of the Scripps Institution of Oceanography has developed an acoustic relay transponder for precise relative positioning of near-bottom instruments and geologic sampling devices. Although specifically designed to position equipment lowered on standard wire ropes without a need to maintain direct electrical contact with the surface ship, the relay transponder may be used to track free vehicles, such as deep submersibles, from the surface. The relay transponder is positioned relative to an array of bottom-anchored acoustic transponders. It is interrogated acoustically from the surface ship; it then sequentially interrogates the bottom transponders which, in turn, reply to the ship. From the measurement of the total travel time (ship to relay transponder to bottom transponder to ship) and assuming, or knowing, the sound velocity of the water, we obtain a relayed range measurement. These relayed ranges, used in conjunction with ship to bottom-transponder ranges, allow us to calculate the position of the relay transponder. A recent application of this technique is described in which several gravity core samples from the crest of the Horizon Guyot were positioned with respect to the detailed bathymetry and the geology within the area. The estimated error in positioning the samples is less than 20 m inside a navigational net extending over 100 km2.
Smoothed GMM for quantile models

Abstract We consider estimation of finite-dimensional parameters identified by general conditional quantile restrictions, including instrumental variables quantile regression. Within a generalized method of moments framework, moment functions are smoothed to aid both computation and precision. Consistency and asymptotic normality are established under weaker assumptions than previously seen in the literature, allowing dependent data and nonlinear structural models. Simulations illustrate the finite-sample properties. An in-depth empirical application estimates the consumption Euler equation derived from quantile utility maximization. Advantages of quantile Euler equations include robustness to fat tails, decoupling risk attitude from the elasticity of intertemporal substitution, and error-free log-linearization.
Hong Kong Liberals Are WEIRD: Analytic Thought Increases Support for Liberal Policies:

This study tests whether liberals and conservatives within the same society think as if they were from different cultures. I tested this by measuring the cultural thought style of social liberals and conservatives in Hong Kong (Study 1). Liberals tended to think more analytically (more "WEIRD"), and conservatives tended to think more holistically (more common in East Asia). In Study 2, I trained people to think analytically or holistically before they read articles on political issues. Analytic thought caused people to form more liberal opinions, and holistic thought caused people to form more conservative opinions. The thought training affected participants' responses to a social issue, but not an economic issue or whether they identified as liberal or conservative. This study replicates a previous U.S. finding in an East Asian culture and a different political environment, suggesting that the link between politics and thought style extends beyond the United States.
Racial Disparities in Drug Court Graduation Rates: The Role of Recovery Support Groups and Environments

There are more than 3,000 drug courts in the United States, and research has demonstrated that, in some drug courts, African American participants are less likely to graduate than their White count...
Improving Accuracy of Nuclei Segmentation by Reducing Histological Image Variability

Histological analyses of tissue biopsies is an essential component in the diagnosis of several diseases including cancer. In the past, evaluation of tissue samples was done manually, but to improve efficiency and ensure consistent quality, there has been a push to evaluate these algorithmically. One important task in histological analysis is the segmentation and evaluation of nuclei. Nuclear morphology is important to understand the grade and progression of disease. However, implementing automated methods at scale across histological datasets is challenging due to differences in stain, slide preparation and slide storage. This paper evaluates the impact of four stain normalization methods on the performance of nuclei segmentation algorithms. The goal is to highlight the critical role of stain normalization in improving the usability of learning-based models (such as convolutional neural networks (CNNs)) for this task. Using stain normalization, the baseline segmentation accuracy across distinct training and test datasets was improved by more than 50% of its base value as measured by the AUC and Recall. We believe this is the first study to perform a comparative analysis of four stain normalization approaches (histogram equalization, Reinhart, Macenko, spline mapping) on segmentation accuracy of CNNs.
SAT-based bit-flipping attack on logic encryptions

Logic encryption is a hardware security technique that uses extra key inputs to prevent unauthorized use of a circuit. With the discovery of the SAT-based attack, new encryption techniques such as SARLock and Anti-SAT are proposed, and further combined with traditional logic encryption techniques, to guarantee both high error rates and resilience to the SAT-based attack. In this paper, the SAT-based bit-flipping attack is presented. It first separates the two groups of keys via SAT-based bit-flippings, and then attacks the traditional encryption and the SAT-resilient encryption, by conventional SAT-based attack and by-passing attack, respectively. The experimental results show that the bit-flipping attack successfully returns a circuit with the correct functionality and significantly reduces the execution time compared with other advanced attacks.
How Long Does the Benefit of Biologics Last? An Update on Time to Relapse and Potential for Rebound of Biologic Agents for Psoriasis:

The biologic agents vary considerably in terms of their long-term duration of effect. Using the definitions provided by the National Psoriasis Foundation Medical Board, the objective of this review was to compare all biologic agents with respect to time to relapse and potential for rebound. Overall, alefacept had the longest off-treatment benefit (29.9 weeks in Psoriasis Area and Severity Index [PASI] 75 responders), followed by ustekinumab (22 weeks), infliximab (19.5 weeks), adalimumab (18 weeks), etanercept (12.1 weeks in PASI 50 responders), and lastly efalizumab (9.6 weeks). Rebound was reported commonly for efalizumab (14%) and extremely rarely for etanercept (0.002%).
Approaches to parental demand for non-established medical treatment: reflections on the Charlie Gard case.

The opinion of Mr. Justice Francis of the English High Court which denied the parents of Charlie Gard, who had been born with an extremely rare mutation of a genetic disease, the right to take their child to the United States for a proposed experimental treatment occasioned world wide attention including that of the Pope, President Trump, and the US Congress. The case raise anew a debate as old as the foundation of Western medicine on who should decide and on what standard when there is a conflict between a family and the treating physicians over a possible treatment. This paper will explore the different approaches of the British and American courts on the issue and the various proposals from that of John Rawls in his A Theory of Justice to a processed-based approach for resolving such disputes. As carefully crafted as the opinion of Mr Justice Nicholas Francis in the Gard case proved to be, it left commentators unsatisfied. A widespread criticism, captured in an article by Michael Dougherty in The National Review was for the state to ‘get out of the way of the parents trying to act in the best interests of the child’.1 Although he conceded the parents could be adding to the suffering of the child by taking Charlie to America for an experimental therapy and agreed that such a choice ‘may be the wrong decision,’ in Dougherty’s view, it should still be ‘their decision’. Dougherty’s stand was the popular response to the question of ‘Who should decide?’ It fails, however, to propose any rationale for the decision. It provided no norms, no standards and no guidelines for the parents. Their motive could equally well be indifference to the suffering of the child as concern for his well-being. Furthermore, even good, loving parents may …
Predict Vehicle Collision by TTC From Motion Using a Single Video Camera

The objective of this paper is the instantaneous computation of time-to-collision (TTC) for potential collision only from the motion information captured with a vehicle borne camera. The contribution is the detection of dangerous events and degree directly from motion divergence in the driving video, which is also a clue used by human drivers. Both horizontal and vertical motion divergence are analyzed simultaneously in several collision sensitive zones. The video data are condensed to the motion profiles both horizontally and vertically in the lower half of the video to show motion trajectories directly as edge traces. Stable motion traces of linear feature components are obtained through filtering in the motion profiles. As a result, this avoids object recognition and sophisticated depth sensing in prior. The fine velocity computation yields reasonable TTC accuracy so that a video camera can achieve collision avoidance alone from the size changes of visual patterns. We have tested the algorithm for various roads, environments, and traffic, and shown results by visualization in the motion profiles for overall evaluation.
Normal Breast-Derived Epithelial Cells with Luminal and Intrinsic Subtype-Enriched Gene Expression Document Interindividual Differences in Their Differentiation Cascade

Cell-type origin is one of the factors that determine molecular features of tumors, but resources to validate this concept are scarce because of technical difficulties in propagating major cell types of adult organs. Previous attempts to generate such resources to study breast cancer have yielded predominantly basal-type cell lines. We have created a panel of immortalized cell lines from core breast biopsies of ancestry-mapped healthy women that form ductal structures similar to normal breast in 3D cultures and expressed markers of major cell types, including the luminal-differentiated cell-enriched ERα-FOXA1-GATA3 transcription factor network. We have also created cell lines from PROCR (CD201)+/EpCAM- cells that are likely the "normal" counterpart of the claudin-low subtype of breast cancers. RNA-seq and PAM50-intrinsic subtype clustering identified these cell lines as the "normal" counterparts of luminal A, basal, and normal-like subtypes and validated via immunostaining with basal-enriched KRT14 and luminal-enriched KRT19. We further characterized these cell lines by flow cytometry for distribution patterns of stem/basal, luminal-progenitor, mature/differentiated, multipotent PROCR+ cells, and organogenesis-enriched epithelial/mesenchymal hybrid cells using CD44/CD24, CD49f/EpCAM, CD271/EpCAM, CD201/EpCAM, and ALDEFLUOR assays and E-cadherin/vimentin double staining. These cell lines showed interindividual heterogeneity in stemness/differentiation capabilities and baseline activity of signaling molecules such as NF-κB, AKT2, pERK, and BRD4. These resources can be used to test the emerging concept that genetic variations in regulatory regions contribute to widespread differences in gene expression in "normal" conditions among the general population and can delineate the impact of cell-type origin on tumor progression.Significance: In addition to providing a valuable resource for the breast cancer research community to investigate cell-type origin of different subtypes of breast cancer, this study highlights interindividual differences in normal breast, emphasizing the need to use "normal" cells from multiple sources as controls to decipher the effects of cancer-specific genomic aberrations. Cancer Res; 78(17); 5107-23. ©2018 AACR.
Web-Based Support for Data-Based Decision Making: Effect of Intervention Implementation on Infant–Toddler Communication:

Programs serving infants and toddlers are expected to use child data to inform decisions about intervention services; however, few tools exist to support these efforts. The Making Online Decisions ...
Device-directed Utterance Detection

In this work, we propose a classifier for distinguishing device-directed queries from background speech in the context of interactions with voice assistants. Applications include rejection of false wake-ups or unintended interactions as well as enabling wake-word free follow-up queries. Consider the example interaction: $"Computer,~play~music", "Computer,~reduce~the~volume"$. In this interaction, the user needs to repeat the wake-word ($Computer$) for the second query. To allow for more natural interactions, the device could immediately re-enter listening state after the first query (without wake-word repetition) and accept or reject a potential follow-up as device-directed or background speech. The proposed model consists of two long short-term memory (LSTM) neural networks trained on acoustic features and automatic speech recognition (ASR) 1-best hypotheses, respectively. A feed-forward deep neural network (DNN) is then trained to combine the acoustic and 1-best embeddings, derived from the LSTMs, with features from the ASR decoder. Experimental results show that ASR decoder, acoustic embeddings, and 1-best embeddings yield an equal-error-rate (EER) of $9.3~\%$, $10.9~\%$ and $20.1~\%$, respectively. Combination of the features resulted in a $44~\%$ relative improvement and a final EER of $5.2~\%$.
Perform better, or else: Academic probation, public praise, and students decision-making

Abstract This paper examines how college initiatives that ascribe public recognition or written reprimand to a set standard of academic performance impact students’ decision-making. Many colleges utilize programs such as the Dean’s list and academic probation policies as mediums to encourage student success. These policies impose a cost on affected students through the potential loss of acquired benefits or the threat of expulsion for failing to perform above the established standard in future semesters. Using the regression discontinuity design, I find that students who are named to the Dean’s list or put on academic probation during their first year improved their subsequent academic performance. To achieve this improvement, students on the Dean’s list are induced into selecting courses and instructors that are more likely to result in higher letter grades and those bounded by the academic probation policy are likely to switch majors and employ a maximin strategy for expected grades when choosing courses.
Improved time bounds for linearizable implementations of abstract data types

Abstract Linearizability is a well-known consistency condition for shared objects in concurrent systems. We focus on the problem of implementing linearizable objects of arbitrary data types in message-passing systems with bounded, but uncertain, message delay and bounded, but non-zero, clock skew. We present an algorithm that exploits axiomatic properties of different operations to reduce the running time of each operation below that obtainable with previously known algorithms. We also prove lower bounds on the time complexity of various kinds of operations, specified by the axioms they satisfy, resulting in reduced gaps in some cases and tight bounds in others.
A multiple motives theory of church and missionary relationships

This grounded theory study examines the motives for relationships between local churches and missionaries: What motivates churches to enter into a relationship with a missionary, to continue this r...
Back to the Future? The Fallopian Tube, Precursor Escape and a Dualistic Model of High-Grade Serous Carcinogenesis

Beginning with the discovery of the BRCA-associated ovarian cancer susceptibility genes and subsequent detailed examination of risk-reducing salpingo-oophorectomy (RRSO) specimens, a new paradigm of ovarian carcinogenesis has unfolded with attention to the distal fallopian tube. The primary focus has been an early cancer or neoplasm in the fallopian tube which is seen in virtually all incidentally discovered high-grade serous cancers in asymptomatic women. This high-frequency of tubal involvement in early serous neoplasm (usually in the form of serous tubal intraepithelial carcinoma-STIC) has galvanized attention to this organ as a primary source of this disease. However, an enduring mystery has been the relatively low frequency of STIC in the fallopian tubes of women with advanced malignancy. This paradox, a high frequency of tubal involvement early on and a low frequency of involvement later in the disease process, has spurred interest in other potential sources, such as the ovarian surface epithelium or cortical inclusions and the secondary Mullerian system. However, because essentially all high-grade serous carcinomas are linked by TP53 mutations, and because fallopian tubes frequently contain early serous proliferations (ESPs) with these mutations, attention has turned to the possibility that the nonmalignant but TP53 mutated tubal epithelium could be responsible for an eventual malignancy. Recent data have shown evidence of a lineage continuity between ESPs and concurrent serous carcinomas prompting the concept of "precursor escape". This creates a second component of the paradigm by which cells from early precursors are shed from the tube and undergo subsequent malignant transformation, emerging suddenly as widespread intraperitoneal malignancy. This dualistic model thus provides a unique pathway by which the future outcome (wide spread high-grade serous carcinomas-HGSC) is ultimately explained by going back in time to an early serous proliferation. This paradigm also brings the peritoneal cavity into focus, raising new questions about the potential co-variables or exposures that might facilitate the occasional malignant transformation of an ESP in the peritoneal cavity or on the peritoneal surface.
The UN’s Development Function: Time for Renewal

The United Nations’ development function is vital to its purpose. Although the UN has many outstanding development achievements to its credit, its development-related organizations do not meet their full potential. They often do not work together, choose priorities that are well funded over those that have strategic potential, and fail to challenge or to shape development priorities and ways of thinking defined elsewhere. The UN should focus on activities to which its unique characteristics make it best suited and undertake changes that enable it better to act boldly, for example by acting as a convener of unruly but productive debates and by being a truthteller rather than a score keeper. The current process of reforming the governance of the UN’s development function holds promise, even in the present difficult political conditions, but is a mere beginning.
Synthesis and initial in vitro characterization of a new P2X7R radioligand [18F]IUR-1602.

Abstract The overexpression of P2X7R is associated with neuroinflammation and plays an important role in various neurodegenerative diseases. The [18F]fluoropropyl derivative of GSK1482160, [18F]IUR-1602, has been first prepared and examined as a new potential P2X7R radioligand. The reference standard IUR-1602 was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoropropylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 13% in three steps. The target tracer [18F]IUR-1602 was synthesized from desmethyl-GSK1482160 with 3-[18F]fluoropropyl tosylate, prepared from propane-1,3-diyl bis(4-methylbenzenesulfonate) and K[18F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 2–7% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74–370 GBq/μmol. The potency of IUR-1602 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for IUR-1602 and GSK1482160 are 23.6 and 3.07 nM, respectively. The initial in vitro evaluation results, 8-fold less potency of [18F]IUR-1602 compared to [11C]GSK1482160, prevent further in vivo evaluation of [18F]IUR-1602 in animals and human.
Observation of twist-induced geometric phases and inhibition of optical tunneling via Aharonov-Bohm effects

Geometric phases appear ubiquitously in many and diverse areas of the physical sciences, ranging from classical and molecular dynamics to quantum mechanics and solid-state physics. In the realm of optics, similar phenomena are known to emerge in the form of a Pancharatnam-Berry phase whenever the polarization state traces a closed contour on the Poincare sphere. While this class of geometric phases has been extensively investigated in both free-space and guided wave systems, the observation of similar effects in photon tunneling arrangements has so far remained largely unexplored. Here, we experimentally demonstrate that the tunneling or coupling process in a twisted multicore fiber system can display a chiral geometric phase accumulation, analogous to the Aharonov-Bohm effect. In our experiments, the tunneling geometric phase is manifested through the interference of the corresponding supermodes. Our work provides the first observation of Aharonov-Bohm suppression of tunneling in an optical setting.
Teachers as curators: Curating authentic online content for beginning and intermediate CFL learners

An abundance of authentic materials is available online for language learning. To locate appropriate materials is challenging for even the most motivated learners. This requires teachers to curate authentic online content to enhance and supplement learners' learning. Content curation is the process of collecting, organizing and displaying information. This article describes the procedure and strategies one may use in curating authentic content materials for Chinese language learning online. Teachers as curators need to collect the content with the consideration of difficulty level for different learners. In addition, they should put a lot of thought into content categorization based on the learners' language levels, interests, and their language skills they would like to practice so as to make it conveniently accessible to learners. Necessary pedagogical supports should be provided with the collection.
Quantum measurements and contextuality

In quantum physics, the term contextual can be used in more than one way. One usage, here called Bell contextual since the idea goes back to Bell, is that if A, B and C are three quantum observable...
Forests and Wetlands

Forests and wetlands are landscape features that play integral roles in the hydrological cycle. Within the landscape, forests and wetlands are inextricably linked. Wetlands may exist within forest ecosystems, or wetland ecosystems can be characterized as “forested.” This article will outline the characteristics of both forests and wetlands and some implications for water resource management. Keywords: forest hydrology; interception; transpiration; stemflow; infiltration; riparian wetland; swamp; hydrological storage; biogeochemical cycling
Implications of the Holocaust for Social Work

Studying the Holocaust teaches moral and behavioral lessons and helps social workers understand and respond to the special needs of Holocaust survivors and their children. This activity has implica...
A note on Sobolev type inequalities on graphs with polynomial volume growth

We prove the generalized $$L^p$$ -Poincare inequalities and Sobolev type inequalities on graphs with polynomial volume growth. They are optimal on Vicsek graphs.
Emotional Intelligence in Medical Laboratory Science

OBJECTIVE: Explore the role of emotional intelligence (EI) among medical laboratory scientists as perceived by clinical laboratory administrators. DESIGN: A detailed survey was designed to assess the importance laboratory administrators placed on EI related skills as well as to gauge their satisfaction with EI among currently practicing medical laboratory scientists (MLSs). Other survey questions solicited information about the responsibility individuals and college-based programs should assume for EI training as well as what is currently being done in clinical laboratories to promote the development of soft skills. Quantitative and qualitative information from 413 completed surveys was compiled and analyzed. SETTING: Surveys were collected from clinical laboratory administrators from 42 states. CONCLUSION: Laboratory administrators indicated that EI related skills were very important for successful job performance in the clinical laboratory. They expressed overall satisfaction with EI among currently practicing MLSs, but indicated room for improvement. ABBREVIATIONS:EI - Emotional intelligence, MLS - medical laboratory scientist, ANOVA - analysis of variance, LSD - least squared difference.
Metagenome-assembled genomes provide new insight into the microbial diversity of two thermal pools in Kamchatka, Russia

Culture-independent methods have contributed substantially to our understanding of global microbial diversity. Recently developed algorithms to construct whole genomes from environmental samples have further refined, corrected and revolutionized understanding of the tree of life. Here, we assembled draft metagenome-assembled genomes (MAGs) from environmental DNA extracted from two hot springs within an active volcanic ecosystem on the Kamchatka peninsula, Russia. This hydrothermal system has been intensively studied previously with regard to geochemistry, chemoautotrophy, microbial isolation, and microbial diversity. We assembled genomes of bacteria and archaea using DNA that had previously been characterized via 16S rRNA gene clone libraries. We recovered 36 MAGs, 29 of medium to high quality, and inferred their placement in a phylogenetic tree consisting of 3,240 publicly available microbial genomes. We highlight MAGs that were taxonomically assigned to groups previously underrepresented in available genome data. This includes several archaea (Korarchaeota, Bathyarchaeota and Aciduliprofundum) and one potentially new species within the bacterial genus Sulfurihydrogenibium. Putative functions in both pools were compared and are discussed in the context of their diverging geochemistry. This study adds comprehensive information about phylogenetic diversity and functional potential within two hot springs in the caldera of Kamchatka.
Design of Variable Magnetization Pattern Machines for Dynamic Changes in the Back EMF Waveform

Variable magnetization pattern permanent magnet synchronous machines (VMP-PMSMs) capable of dynamic changes in the magnetization spatial distribution are discussed in this paper. VMP-PMSMs are able to change the harmonic components in the air gap magnetic flux density due to the magnet by intentional demagnetization; hence, they can effectively manipulate the torque ripples and losses according to the required operating points. The objective of this paper is to provide a procedure to design VMP-PMSMs that can have both the sinusoidal and the trapezoidal back EMF waveforms by switching magnetization pattern. The performance of the designed VMP-PMSM following the reported procedure is confirmed through experiments as well as finite element analysis (FEA) simulations in terms of the back EMF shaping, torque ripple reduction, and loss reduction. Loss analysis of VMP-PMSMs is also given as contrasting with variable flux permanent magnet machines (VF-PMSMs), showing that VMP-PMSMs can reduce more losses than VF-PMSMs with the same torque density.
Shift in seasonal climate patterns likely to impact residential energy consumption in the United States

This paper presents an ensemble of climate simulations and empirical relationships between weather and household energy consumption to provide detailed estimates for potential climate-driven changes in the United States residential energy demand.
Synthesis of benzyl and tert‐butyl 3‐(2‐methoxycarbonylethyl)‐4‐methylpyrrole‐2‐carboxylates from methyl 4‐oxobutanoate

Condensation of methyl 4-oxobutanoate with nitroethane in the presence of 4-dimethylaminopyridine, followed by treatment with acetic anhydride, afforded a nitroacetoxyester 10b. Subsequent reaction with isocyanoacetate esters and DBU in refluxing tetrahydrofuran gave the synthetically valuable pyrroles 1a and 1b.
Biological coordination chemistry of magnesium, sodium, and potassium ions. Protein and nucleotide binding sites

Abstract In this article, we review the structural chemistry of the alkali and alkaline earth metal cations (Mg2+, Na+, and K+) with three classes of biological macromolecule (proteins, nucleic acids, and membrane lipids). Emphasis is placed on crystallographically well-characterized examples that illustrate the characteristic features of ligand type and coordination geometry that define the binding specificity and functional role (structural or catalytic) of these co-factors. Reflecting the availability of literature data, the focus of the review is directed toward magnesium chemistry. Four classes of magnesium coordination site (A-D) are defined according to whether the co-factor interacts predominantly with the protein or substrate, and serves either a structural or catalytic role. The distinction between inner and outer coordination modes is made. There is an apparent tendency for magnesium to bind to nucleic acids by extensive hydrogen bonding from waters of hydration to heteroatoms on bases and the ribose-phosphate backbone, while inner-sphere binding to proteins is promoted by the well-defined chelating pockets defined by protein residues. With regard to the functional role of the metal, the lability of these metal cofactors must be considered in the context of enzyme mechanism, inasmuch as the most stable structural configuration is not necessarily the competent coordination state for enzyme turnover. Oxygen ligation (from carboxylates, hydroxyl, water, or phosphate functionality) is common, although coordination by N-7 of guanosine is frequently observed in metal nucleotide structures in the solid state. In contrast to calcium-binding proteins, no general binding motifs have been clearly identified for magnesium sites in proteins.
Homoleptic Tetrahydrometalate Anions MH4- (M = Sc, Y, La). Matrix Infrared Spectra and DFT Calculations

Laser-ablated Sc, Y, and La atoms react with molecular hydrogen upon condensation in excess argon, neon, and deuterium to produce the metal dihydride molecules and dihydrogen complexes MH2 and (H2)MH2. The homoleptic tetrahydrometalate anions ScH4-, YH4-, and LaH4- are formed by electron capture and identified by isotopic substitution (D2, HD, and H2 + D2 mixtures). Doping with CCl4 to serve as an electron trap virtually eliminates the anion bands, and further supports the anion identifications. The observed vibrational frequencies are in agreement with the results of density functional theory calculations, which predict electron affinities in the 2.8−2.4 eV range for the (H2)ScH2, (H2)YH2, and (H2)LaH2 complexes, and indicate high stability for the MH4- (M = Sc, La, Y) anions and suggest the promise of synthesis on a larger scale for use as reducing agents.
cis-2,5-Disubstituted tetrahydrofurans from pyranosides: A novel example of remote stereocontrol by the aglycone

Abstract A stereoselective methodology, based on neighboring group participation by the acetal ring oxygen, is described for the preparation of highly functionalizable cis-2,5-disubstituted tetrahydrofurans from C6 alkenyl branched pyranosides.
The Nature of [Ar III]-Bright Knots in the Crab Nebula

The kinematic and morphological properties of a string of [Ar III]-bright knots in the Crab Nebula are examined using 1994–1999 Hubble Space Telescope (HST) Wide Field Planetary Camera 2 images of the remnant. We find that five southern [Ar III]-bright knots exhibit ordinary radial motions away from the nebula's center of expansion with magnitudes consistent with their projected radial displacements. This result does not support the suggestion by MacAlpine et al. (published in 1994) that these knots might be moving rapidly away from the Crab pulsar because of a collimated wind. The HST images also do not show that the [Ar III] knots have unusual morphologies relative to other features in the remnant. Our proper-motion results, when combined with radial velocity estimates, suggest these knots have relatively small space velocities, implying locations relatively close to the central source of ionizing radiation. This might lead to higher knot gas temperatures and thereby explain the knots' unusual line emission strengths as MacAlpine et al. suspected.
Design and Optimization of New Phosphine Oxazoline Ligands via High-Throughput Catalyst Screening

This paper uses the phosphine oxazoline ligands 1 and an allylation transformation (reaction 1) to illustrate the value of divergent ligand syntheses and high-throughput screening in catalyst discovery and optimization. Thus, a diverse set of ligands 1 (Table 1) was prepared via a divergent synthesis involving the pivotal intermediate, phosphine-substituted amino alcohol 7 (Scheme 1). Single-crystal X-ray crystallographic data was obtained for a nickel complex 8 (Figure 3) of the phenyl-substituted ligand 1i. This analysis illustrated some structural features of the ligand systems 1 that may be conducive to asymmetric catalysis. High-throughput screens were then used to correlate the ligand 1 R-substituents with asymmetric induction in the allylation reaction 1, and it emerged that the pseudo-spherical adamantyl substituent was superior to other R-substituents. Other parameters in the catalyst systems were also varied, sometimes in “two-dimensional” screens. No pronounced solvent effects were identified. ...
Expression and biological significance of tissue inhibitors of metalloproteinases

Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent proteases that are involved in degrading extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) are naturally occurring proteins that inhibit MMP activity by binding noncovalently with the active forms of MMPs at molar equivalence. Of the four TIMPs characterized so far, TIMP-1 and TIMP-2 participate in the inhibition of tumor growth, invasion, and metastasis. They also promote growth, inhibit angiogenesis, and modulate cell morphology. TIMP-3 is unique among the TIMPs in being a component of the ECM itself and in suppressing tumor cell growth. TIMP-4, the most recently discovered TIMP, has its gene allocated to human chromosome 3p25 and is perhaps the most tissue-specific of the TIMPs being expressed largely in the heart. Synthetic low-molecular-weight MMP inhibitors with a hydroxamate structure that mimics collagen have reduced the tumor burden and altered the growth of primary tumors in animal models. Understanding the biological significance of TIMPs and their involvement in tumorigenicity will be valuable for the development of effective novel therapeutic strategies for controlling tumor growth and metastasis. This chapter provides a brief review of the four TIMPs characterized thus far, focuses on their roles in tumorigenesis and angiogenesis and concludes with a brief look at the use of synthetic MMP inhibitors in cancer treatment.
ATX-2, the C. elegans Ortholog of Human Ataxin-2, Regulates Centrosome Size and Microtubule Dynamics

Centrosomes are critical sites for orchestrating microtubule dynamics, and exhibit dynamic changes in size during the cell cycle. As cells progress to mitosis, centrosomes recruit more microtubules (MT) to form mitotic bipolar spindles that ensure proper chromosome segregation. We report a new role for ATX-2, a C. elegans ortholog of Human Ataxin-2, in regulating centrosome size and MT dynamics. ATX-2, an RNA-binding protein, forms a complex with SZY-20 in an RNA-independent fashion. Depleting ATX-2 results in embryonic lethality and cytokinesis failure, and restores centrosome duplication to zyg-1 mutants. In this pathway, SZY-20 promotes ATX-2 abundance, which inversely correlates with centrosome size. Centrosomes depleted of ATX-2 exhibit elevated levels of centrosome factors (ZYG-1, SPD-5, γ-Tubulin), increasing MT nucleating activity but impeding MT growth. We show that ATX-2 influences MT behavior through γ-Tubulin at the centrosome. Our data suggest that RNA-binding proteins play an active role in controlling MT dynamics and provide insight into the control of proper centrosome size and MT dynamics.
Studies on the synthesis of the core structures of the antitumor agents neocarzinostatin, kedarcidin, C-1027 and maduropeptin

Abstract The bicyclo[7.3.0]dodecadiyne core structure of the antitumor agents neocarzinostatin, kedarcidin, C-1027 and maduropeptin can be readily constructed by an intramolecular aldol reaction to form the C -8 C -9 bond only if the C-6,7 triple bond is complexed as its η 2 Co 2 (CO) 6 -acetylene adduct.
The Trust Triangle: Laws, Reputation, and Culture in Empirical Finance Research

We propose a construct, the Trust Triangle, that highlights three primary mechanisms that provide ex post accountability for opportunistic behavior and motivate ex ante trust in economic relationships. The mechanisms are (i) a society’s legal and regulatory framework, (ii) market-based discipline and reputational capital, and (iii) culture, including individual ethics and social norms. The Trust Triangle provides a framework to conceptualize the relationships between trust, corporate accountability, legal liability, reputation, and culture. We use the Trust Triangle to summarize recent developments in the empirical finance literature that examine how trust is formed and how trust, or its absence, affects financial markets, firm performance, and the incidence of financial fraud. To date, most studies examine only one leg of the Trust Triangle in isolation. The evidence, however, indicates that all three legs of the Trust Triangle have first-order effects on a wide range of financial outcomes and that they are interrelated. Attempts to model trust and trustworthiness that do not incorporate all three aspects of the Trust Triangle will therefore miss essential aspects of the basic economic problem of how counterparties overcome the risks of moral hazard, asymmetric information, and opportunism to engage in mutually beneficial exchange and production activities. We focus especially on culture-related mechanisms, a recently developed area in empirical finance research that has potential to influence the more established research on laws and reputation.
Synthesis and Structure of Ag6[(UO2)3O(MoO4)5]: A Novel Sheet of Triuranyl Clusters and MoO4 Tetrahedra

The new uranyl molybdate Ag6[(UO2)3O(MoO4)5] (1) with an unprecedented uranyl molybdate sheet has been synthesized at 650 °C. The structure (monoclinic, C2/c, a = 16.4508(14) A, b = 11.3236(14) A, c = 12.4718(13) A, β = 100.014(4)o, V = 2337.4(4) A3, Z = 4) contains [(UO2)3O(MoO4)5] sheets composed of triuranyl [(UO2)3O] clusters that are connected by MoO4 tetrahedra. The topology of the uranyl molybdate sheet in 1 represents a major departure from sheets observed in other uranyl compounds. Of the ∼120 known inorganic uranyl compounds containing sheets of polyhedra, 1 is the only structure that contains trimers of uranyl pentagonal bipyramids that are connected only by the sharing of vertexes with other polyhedra. The sheets are parallel to (001) and are linked by Ag cations.
Development of a continuous process for enol esters of fatty acids

A continuous process for the production of iso-propenyl stearate from stearic acid and propyne was developed. The reaction proceeds at elevated pres-sures and temperatures (∼550 psig and 400 F, respec-tively) in about l0 min. A slower, second reaction produces stearic anhydride from the isopropenyl stearate. A recovery section was devised, wherein the liquid product stream is chilled, recovered as flakes, and extracted with a solvent, e.g. Skelly B. Reaction studies were scaled-up from 10 to 40 lb feed/hr using triple pressed stearic acid and MAPP® gas (AIRCO, Inc., Montvale, NJ), a commercially available gas con-taining a nominal 1/3 propyne, 1/3 propadiene, and 1/3 stabilizing, saturated hydrocarbons. The acid and propyne are reacted in the presence of zinc stearate in a continuous stirred tank reactor (CSTR). The reac-tion is “finished” in a short tubular reactor. Data are presented on the effect of pressure, temperature, catalyst level, dwell in the reactors, and solvent ratio during extraction. The product is about 92% iso-propenyl ester, contaminated with unconverted stearic acid and by-product stearic anhydride.
Short Synthesis of α-Nitrile Sulfones

Abstract A short synthesis of α-(4-tolylsulfonyl)arylacetonitriles from the reaction of phenyl tosylate and α-lithiated nitriles is described.
Synthesis of S-linked glycosyl amino acids in aqueous solution with unprotected carbohydrates.

The cyclic sulfamidate 5 was synthesized in 60% overall yield from l-serine benzyl ester. Compound 5 reacted cleanly with the sodium thiolate salt of a variety of unprotected 1-thio sugars in aqueo...
Angular Ligand Constraint Yields an Improved Olefin Aziridination Catalyst

[reaction: see text] The use of a pyridinophane, a macrocycle composed of three pyridines linked, via all ortho positions through CH(2) or CH(2)CH(2) groups, bound to copper, gives good performance (rate and yield) catalyzing the conversion of substituted aliphatic olefins and PhINTs to aziridines. Advantages also derive from using CH(2)Cl(2) solvent and the weakly coordinating anions BAr(4)(-) (Ar = C(6)H(5) or 3,5-C(6)H(3)(CF(3))(2)). Reactions are complete in minutes at 20 degrees C, and yields are almost quantitative for olefins not bearing secondary allylic CH bonds; however, cis-cyclooctene gives only the aziridine despite the allylic hydrogens.
Synthesis and Study of A Molecular Fluorescent Chemosensor For Potassium

A potassium selective fluorescent chemosensor, 2, was designed and synthesized. The molecular sensor is weakly luminescent in acetonitrile solution, but exhibits a significant increase in intensity upon addition of K+. The luminescence intensity increases reach a plateau when the K+/2 ratio is 3:2. The sensor shows a linear fluorescent enhancement with the concentration of potassium ion in the presence of a large excess of sodium ion.
Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

Lipid droplets (LDs) are neutral lipid storage organelles that transfer lipids to various organelles including peroxisomes. Here, we show that the hereditary spastic paraplegia protein M1 Spastin, a membrane-bound AAA ATPase found on LDs, coordinates fatty acid (FA) trafficking from LDs to peroxisomes through two interrelated mechanisms. First, M1 Spastin forms a tethering complex with peroxisomal ABCD1 to promote LD–peroxisome contact formation. Second, M1 Spastin recruits the membrane-shaping ESCRT-III proteins IST1 and CHMP1B to LDs via its MIT domain to facilitate LD-to-peroxisome FA trafficking, possibly through IST1- and CHMP1B-dependent modifications in LD membrane morphology. Furthermore, LD-to-peroxisome FA trafficking mediated by M1 Spastin is required to relieve LDs of lipid peroxidation. M1 Spastin’s dual roles in tethering LDs to peroxisomes and in recruiting ESCRT-III components to LD–peroxisome contact sites for FA trafficking may underlie the pathogenesis of diseases associated with defective FA metabolism in LDs and peroxisomes.
A natural variant and engineered mutation in a GPCR promote DEET resistance in C. elegans

DEET (N,N-diethyl-meta-toluamide) is a synthetic chemical identified by the US Department of Agriculture in 1946 in a screen for repellents to protect soldiers from mosquito-borne diseases1,2. Since its discovery, DEET has become the world’s most widely used arthropod repellent and is effective against invertebrates separated by millions of years of evolution—including biting flies3, honeybees4, ticks5, and land leeches3. In insects, DEET acts on the olfactory system5–12 and requires the olfactory receptor co-receptor Orco7,9–12, but exactly how it works remains controversial13. Here we show that the nematode Caenorhabditis elegans is sensitive to DEET and use this genetically tractable animal to study the mechanism of action of this chemical. We found that DEET is not a volatile repellent, but instead interferes selectively with chemotaxis to a variety of attractant and repellent molecules. In a forward genetic screen for DEET-resistant worms, we identified a gene that encodes a single G protein-coupled receptor, str-217, which is expressed in a single pair of chemosensory neurons that are responsive to DEET, called ADL neurons. Mis-expression of str-217 in another chemosensory neuron conferred responses to DEET. Engineered str-217 mutants, and a wild isolate of C. elegans that carries a str-217 deletion, are resistant to DEET. We found that DEET can interfere with behaviour by inducing an increase in average pause length during locomotion, and show that this increase in pausing requires both str-217 and ADL neurons. Finally, we demonstrated that ADL neurons are activated by DEET and that optogenetic activation of ADL neurons increased average pause length. This is consistent with the ‘confusant’ hypothesis, which proposes that DEET is not a simple repellent but that it instead modulates multiple olfactory pathways to scramble behavioural responses10,11. Our results suggest a consistent motif in the effectiveness of DEET across widely divergent taxa: an effect on multiple chemosensory neurons that disrupts the pairing between odorant stimulus and behavioural response. DEET interferes selectively with chemotaxis of Caenorhabditis elegans nematodes, and mutations in the str-217 gene or silencing of the pair of chemosensory neurons that express it makes worms DEET-resistant.