cssi/SciSciGPT-SciSciNet huggingface dataset:
A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux

Summary Endogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults/therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila "blood"-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends on a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires cyclically expressed gap junctions. Specifically, during nighttime, gap junctions reduce intracellular magnesium ([Mg 2+ ]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system.
Economic consequences of and resilience to a disruption of petroleum trade: The role of seaports in U.S. energy security

Abstract Despite increased domestic production, the U.S. is still importing more than one-third of its crude oil needs, the vast majority via ocean tankers. At the same time, there are increasing concerns about the vulnerability of ports and terminals to man-made and natural disasters. This paper advances a methodology for estimating the total economic consequences of and resilience to a disruption of crude oil and refined petroleum product trade at a major seaport. The methodology is able to estimate not only the direct impacts of such disruptions but also the supply-chain effects. It also estimates the effects of muting the impacts by various resilience tactics such as ship re-routing, drawing inventories from storage, accessing the Strategic Petroleum Reserve, geographic shifting of petroleum refining, and production rescheduling. We apply the methodology to a 90-day disruption of petroleum trade at the twin seaports of Beaumont and Port Arthur, Texas. The results indicate that port region and national economic activity could decline by billions of dollars, but that resilience can reduce these consequences significantly. We also conclude that factors associated with the recent surge in the extraction of shale and tight oil resources has significantly enhanced the potential effectiveness of some resilience tactics.
The Economics of Being Poor

Part 1 Most people are poor: Nobel lecture - the economics of being poor the economics of poverty in low income countries investing in poor people reflections on poverty within agriculture our welfare state and the welfare of farm people economic puzzles pertaining to proverty. Part 2 Investing in skills and knowledge: investment in human capital capital formation by education rates of return on education resources for higher education reckoning education as human capital equity and efficiency in college instruction are university scholars and scientists free agents? Adam Smith and human capital. Part 3 Effects of human capital: institutions and the rising economic value of man the increasing economic value of human time woman's new economic demands children - an economic perspective high value of human time population equilibrium investment in entrepreneurial ability a long view of increases in the value of human time.
Distributed Scheduling Algorithms for Optimizing Information Freshness in Wireless Networks

Age of Information (AoI), measures the time elapsed since the last received information packet was generated at the source. We consider the problem of AoI minimization for single-hop flows in a wireless network, under pairwise interference constraints and time varying channel. We consider simple, yet broad, class of distributed scheduling policies, in which a transmission is attempted over each link with a certain attempt probability. We obtain an interesting relation between the optimal attempt probability and the optimal AoI of the link, and its neighboring links. We then show that the optimal attempt probabilities can be computed by solving a convex optimization problem, which can be done distributively.
Combining High-Resolution and Exact Calibration To Boost Statistical Power: A Well-Calibrated Score Function for High-Resolution MS2 Data.

To achieve accurate assignment of peptide sequences to observed fragmentation spectra, a shotgun proteomics database search tool must make good use of the very high-resolution information produced by state-of-the-art mass spectrometers. However, making use of this information while also ensuring that the search engine’s scores are well calibrated, that is, that the score assigned to one spectrum can be meaningfully compared to the score assigned to a different spectrum, has proven to be challenging. Here we describe a database search score function, the “residue evidence” (res-ev) score, that achieves both of these goals simultaneously. We also demonstrate how to combine calibrated res-ev scores with calibrated XCorr scores to produce a “combined p value” score function. We provide a benchmark consisting of four mass spectrometry data sets, which we use to compare the combined p value to the score functions used by several existing search engines. Our results suggest that the combined p value achieves sta...
Outcomes From Lateral Eyelid Coupling for Facial Paralysis Using the Modified Tarsoconjunctival Flap.

ImportanceIn the setting of facial paralysis, inadequate eyelid closure and lower eyelid ectropion can lead to corneal exposure and impaired quality of life. Repair of paralytic ectropion is challe...
A Preliminary Statement of Principles of Planning and Control

Although this paper attempts to deal in a preliminary fashion only with a portion of the theory of management, it is essentially a plea for more attention to fundamentals in management, to principl...
Regulation of Cell-to-Cell Communication and Cell Wall Integrity by a Network of MAP Kinase Pathways and Transcription Factors in Neurospora crassa

Maintenance of cell integrity and cell-to-cell communication are fundamental biological processes. Filamentous fungi, such as Neurospora crassa, depend on communication to locate compatible cells, coordinate cell fusion, and establish a robust hyphal network. Two MAP kinase (MAPK) pathways are essential for communication and cell fusion in N. crassa: the cell wall integrity/MAK-1 pathway and the MAK-2 (signal response) pathway. Previous studies have demonstrated several points of cross-talk between the MAK-1 and MAK-2 pathways, which is likely necessary for coordinating chemotropic growth toward an extracellular signal, and then mediating cell fusion. Canonical MAPK pathways begin with signal reception and end with a transcriptional response. Two transcription factors, ADV-1 and PP-1, are essential for communication and cell fusion. PP-1 is the conserved target of MAK-2, but it is unclear what targets ADV-1. We did RNA sequencing on Δadv-1, Δpp-1, and wild-type cells and found that ADV-1 and PP-1 have a shared regulon including many genes required for communication, cell fusion, growth, development, and stress response. We identified ADV-1 and PP-1 binding sites across the genome by adapting the in vitro method of DNA-affinity purification sequencing for N. crassa To elucidate the regulatory network, we misexpressed each transcription factor in each upstream MAPK deletion mutant. Misexpression of adv-1 was sufficient to fully suppress the phenotype of the Δpp-1 mutant and partially suppress the phenotype of the Δmak-1 mutant. Collectively, our data demonstrate that the MAK-1/ADV-1 and MAK-2/PP-1 pathways form a tight regulatory network that maintains cell integrity and mediates communication and cell fusion.
Using a mathematical model of motivation, volition, and performance to examine students’ e-text learning experiences

This empirical study used Keller’s (Technol Instr Cogn Learn 16:79–104, 2008b) motivation, volition, and performance (MVP) theory to develop and statistically evaluate a mathematical MVP model that can serve as a research and policy tool for evaluating students’ learning experiences in digital environments. Specifically, it explored undergraduate biology students’ learning and attitudes toward e-texts using a MVP mathematical model in two different e-text environments. A data set (N = 1334) that included student motivation and e-text information processing, frustration with using e-texts, and student ability variables was used to evaluate e-text satisfaction. A regression analysis of these variables revealed a significant model that explained 77% of the variation in student e-text satisfaction in both e-text learning environments. Student motivation and intrinsic cognitive load were positive predictors of student satisfaction, while extraneous cognitive load and student prior knowledge and background variables were negative predictors. Practical implications for e-text learning and generalizability of a mathematical MVP model are discussed.
Planning, Inference and Pragmatics in Sequential Language Games

We study sequential language games in which two players, each with private information, communicate to achieve a common goal. In such games, a successful player must (i) infer the partner’s private...
Ising ferromagnet to valence bond solid transition in a one-dimensional spin chain: Analogies to deconfined quantum critical points

We study a one-dimensional (1D) system that shows many analogies to proposed two-dimensional (2D) deconfined quantum critical points (DQCP). Our system is a translationally invariant spin-$\frac{1}{2}$ chain with onsite ${Z}_{2}\ifmmode\times\else\texttimes\fi{}{Z}_{2}$ symmetry and time-reversal symmetry. It undergoes a direct continuous transition from a ferromagnet (FM), where one of the ${Z}_{2}$ symmetries and the time reversal are broken, to a valence bond solid (VBS), where all onsite symmetries are restored while the translation symmetry is broken. The other ${Z}_{2}$ symmetry remains unbroken throughout, but its presence is crucial for both the direct transition (via specific Berry phase effect on topological defects, also related to a Lieb-Schultz-Mattis--type theorem) and the precise characterization of the VBS phase (which has crystalline-symmetry-protected-topological--like property). The transition has a description in terms of either two domain-wall species that ``fractionalize'' the VBS order parameter or in terms of two partons that ``fractionalize'' the FM order parameter, with each picture having its own ${Z}_{2}$ gauge theory structure. The two descriptions are dual to each other and, at long wavelengths, take the form of a self-dual gauged Ashkin-Teller model, reminiscent of the self-dual easy-plane noncompact ${\mathrm{CP}}^{1}$ model that arises in the description of the 2D easy-plane DQCP. We also find an exact reformulation of the transition that leads to a simple field-theory description that explicitly unifies the FM and VBS order parameters; this reformulation can be interpreted as a new parton approach that does not attempt to fractionalize either of the FM and VBS order parameters but instead encodes them in instanton operators. Aside from providing explicit realizations of many ideas proposed in the context of the 2D DQCP, here in the simpler and fully tractable 1D setting with continuous transition, our study also suggests a possible line of approach to the 2D DQCP.
The Accuracy of the Demographic Inferences Shown on Google's Ad Settings

Google's Ad Settings shows the gender and age that Google has inferred about a web user. We compare the inferred values to the self-reported values of 501 survey participants. We find that Google often does not show an inference, but when it does, it is typically correct. We explore which usage characteristics, such as using privacy enhancing technologies, are associated with Google's accuracy, but found no significant results.
Does Climate Change Bolster the Case for Fishery Reform in Asia

I examine the estimated economic, ecological, and food security effects of future fishery management reform in Asia. Without climate change, most Asian fisheries stand to gain substantially from re...
State of knowledge: Four decades of victim-offender mediation research and practice: The evidence

This paper provides an overview of 40 years of victim‐offender mediation evaluation research. This research demonstrates that victims and offenders are more satisfied with the process and outcomes than with the courts, they are more likely to draft and complete restitution agreements, they derive psychosocial benefits, the process is less expensive, crime victims are more likely to receive apologies from offenders, and offenders are less likely to recidivate. These benefits are not necessarily uniformly distributed. This “first wave” research provides a platform for the second wave, currently underway. To contextualize these findings, current and future victim‐offender mediation practices are outlined.
Molecules and the Eigenstate Thermalization Hypothesis

We review a theory that predicts the onset of thermalization in a quantum mechanical coupled non-linear oscillator system, which models the vibrational degrees of freedom of a molecule. A system of N non-linear oscillators perturbed by cubic anharmonic interactions exhibits a many-body localization (MBL) transition in the vibrational state space (VSS) of the molecule. This transition can occur at rather high energy in a sizable molecule because the density of states coupled by cubic anharmonic terms scales as N3, in marked contrast to the total density of states, which scales as exp(aN), where a is a constant. The emergence of a MBL transition in the VSS is seen by analysis of a random matrix ensemble that captures the locality of coupling in the VSS, referred to as local random matrix theory (LRMT). Upon introducing higher order anharmonicity, the location of the MBL transition of even a sizable molecule, such as an organic molecule with tens of atoms, still lies at an energy that may exceed the energy to surmount a barrier to reaction, such as a barrier to conformational change. Illustrative calculations are provided, and some recent work on the influence of thermalization on thermal conduction in molecular junctions is also discussed.
Beyond Social Contagion: Associative Diffusion and the Emergence of Cultural Variation:

Network models of diffusion predominantly think about cultural variation as a product of social contagion. But culture does not spread like a virus. We propose an alternative explanation we call as...
Privacy-Preserving Multiparty Learning for Logistic Regression

In recent years, machine learning techniques are widely used in numerous applications, such as weather forecast, financial data analysis, spam filtering, and medical prediction. In the meantime, massive data generated from multiple sources further improve the performance of machine learning tools. However, data sharing from multiple sources brings privacy issues for those sources since sensitive information may be leaked in this process. In this paper, we propose a framework enabling multiple parties to collaboratively and accurately train a learning model over distributed datasets while guaranteeing the privacy of data sources. Specifically, we consider logistic regression model for data training and propose two approaches for perturbing the objective function to preserve \( \epsilon \)-differential privacy. The proposed solutions are tested on real datasets, including Bank Marketing and Credit Card Default prediction. Experimental results demonstrate that the proposed multiparty learning framework is highly efficient and accurate.
Where Does the Minimum Wage Bite Hardest in California

This study uses employment data on California county-industry pairs (CIPs) between 1990 and 2016 to test whether minimum wage increases caused employment growth to slow most in the CIPs with a large share of low wage workers. Evidence supports the hypothesis, and we use the estimates to simulate the effect of a 10% increase in the minimum wage. The simulations suggest that a 10% increase could cause a 3.4% employment loss in the average CIP in California. The job loss is projected to be concentrated in two industries: accommodation and food services, and retail. While the most populated counties of California are expected to incur the largest employment loss in terms of the number of workers, the smaller counties generally experience a larger percentage point loss in employment due to the lower wages and the greater number of workers that would be affected by the minimum wage hike. Moreover, there is substantial variation across counties in terms of the percentage of jobs lost within a given industry.
Participation Incentives on a Wireless Random Access Erasure Collision Channel

Random medium access on wireless channels has two key characteristics: heterogeneous channel quality across users (due to the variable wireless channel conditions with the access point across users) and packet collisions (due to random access) at the access point. The design of optimal channel contention probabilities is nontrivial on account of the need to balance between under-utilization (no transmission attempts) and over-utilization (channel collisions) of the wireless channel. The wireless random access erasure collision channel presented in this paper is a parsimonious abstraction of these phenomena. We consider a scenario wherein the base station provides a reward to users in proportion to the rate of successfully received packets, and users incur a cost in proportion to their contention probability. The objective is to select a reward such that the sum-user delivered rate in the equilibrium of the induced game is (approximately) optimal, i.e., such that only higher quality users are incentivized to contend the channel. We use the price of anarchy (PoA) measure and study the extent to which appropriate reward mechanisms can yield good PoA bounds.
Modeling fundamentals the importance of validation for all simulations

Model Validation Suggestions •When attempting to validate a model, these suggestions may be helpful to follow — Keep the problem simple — Choose applications that can be validated — Keep in mind, inaccurate models provide useful data
Distinct activity-gated pathways mediate attraction and aversion to CO 2 in Drosophila

Carbon dioxide is produced by many organic processes and is a convenient volatile cue for insects1 that are searching for blood hosts2, flowers3, communal nests4, fruit5 and wildfires6. Although Drosophila melanogaster feed on yeast that produce CO2 and ethanol during fermentation, laboratory experiments7-12 suggest that walking flies avoid CO2. Here we resolve this paradox by showing that both flying and walking Drosophila find CO2 attractive, but only when they are in an active state associated with foraging. Their aversion to CO2 at low-activity levels may be an adaptation to avoid parasites that seek CO2, or to avoid succumbing to respiratory acidosis in the presence of high concentrations of CO2 that exist in nature13,14. In contrast to CO2, flies are attracted to ethanol in all behavioural states, and invest twice the time searching near ethanol compared to CO2. These behavioural differences reflect the fact that ethanol is a unique signature of yeast fermentation, whereas CO2 is generated by many natural processes. Using genetic tools, we determined that the evolutionarily conserved ionotropic co-receptor IR25a is required for CO2 attraction, and that the receptors necessary for CO2 avoidance are not involved in this attraction. Our study lays the foundation for future research to determine the neural circuits that underlie both state- and odorant-dependent decision-making in Drosophila.
"I Believe in Cusk": The Effect of Explicit Belief Statements on Children's Reality Status Judgments and Beliefs about Consensus.

ABSTRACTChildren learn about the world through others’ testimony, and much of this knowledge likely comes from parents. Furthermore, parents may sometimes want children to share their beliefs about topics on which there is no universal consensus. In discussing such topics, parents may use explicit belief statements (e.g., “Evolution is real”) or implicit belief statements (e.g., “Evolution happened over millions of years”). But little research has investigated how such statements affect children’s beliefs. In the current study, 4- to 7-year-olds (N = 102) were shown videos of their parent providing either Explicit (“Cusk is real”) or Implicit (“I know about cusk”) belief testimony about novel entities. Then, children heard another speaker provide either Denial (“Cusk isn’t real”) or Neutral (“I’ve heard of cusk”) testimony. Children made reality status judgments and consensus judgments (i.e., whether people agree about the entity’s existence). Results showed that explicit and implicit belief statements di...
Molecular Crowding Tunes Material States of Ribonucleoprotein Condensates.

Ribonucleoprotein (RNP) granules are membraneless liquid condensates that dynamically form, dissolve, and mature into a gel-like state in response to a changing cellular environment. RNP condensation is largely governed by promiscuous attractive inter-chain interactions mediated by low-complexity domains (LCDs). Using an archetypal disordered RNP, fused in sarcoma (FUS), here we study how molecular crowding impacts the RNP liquid condensation. We observe that the liquid–liquid coexistence boundary of FUS is lowered by polymer crowders, consistent with an excluded volume model. With increasing bulk crowder concentration, the RNP partition increases and the diffusion rate decreases in the condensed phase. Furthermore, we show that RNP condensates undergo substantial hardening wherein protein-dense droplets transition from viscous fluid to viscoelastic gel-like states in a crowder concentration-dependent manner. Utilizing two distinct LCDs that broadly represent commonly occurring sequence motifs driving RNP phase transitions, we reveal that the impact of crowding is largely independent of LCD charge and sequence patterns. These results are consistent with a thermodynamic model of crowder-mediated depletion interaction, which suggests that inter-RNP attraction is enhanced by molecular crowding. The depletion force is likely to play a key role in tuning the physical properties of RNP condensates within the crowded cellular space.
Addressing cross-national generalizability in educational impact evaluation

Abstract Evaluation of educational programs has accelerated dramatically in the past quarter century. With this expansion has come clear methodological improvement involving randomized control studies and other approaches for establishing causation that considerably strengthen their internal validity. Such studies are, however, conducted within individual countries with the institutional structure of the schools and the national labor markets, and they are seldom replicated either within or across countries. A natural question is whether the results of an individual high-quality educational evaluation in one country can be reasonably applied in other countries. This paper focuses on existing research into differences across countries that, while generally impossible to incorporate into program evaluations, potentially have direct effects on key elements of policy and on the outcomes that can be expected. In particular, available cross-national studies on a variety of topics suggest using caution when generalizing evaluation results across countries, because student results are likely to vary systematically with a number of fundamental country-level institutional characteristics that are not explicitly considered in within-country evaluation analyses. Unfortunately, there is currently too little replication of basic research studies to provide explicit guidance on when and where cross-national generalizations are possible.
Monte Carlo Simulation in Finance

Monte Carlo simulation has become an essential tool for pricing and risk estimation in financial applications. It allows finance professionals to incorporate uncertainty in financial models, and to consider additional layers of complexity that are difficult to incorporate in analytical models. The main idea of Monte Carlo simulation is to represent the uncertainty in market variables through scenarios, and to evaluate parameters of interest that depend on these market variables in complex ways. The advantage of such an approach is that it can easily capture the dynamics of underlying processes and the otherwise complex effects of interactions among market variables. A substantial amount of research in recent years has been dedicated to making scenario generation more accurate and efficient, and a number of sophisticated computational techniques are now available to the financial modeler. Keywords: simulation; pricing; risk management; random number generation; variance reduction; antithetic variables; stratified sampling; importance sampling; low discrepancy sequences
Different mechanisms drive the maintenance of polymorphism at loci subject to strong versus weak fluctuating selection

The long-running debate about the role of selection in maintaining genetic variation has been given new impetus by the discovery of hundreds of seasonally oscillating polymorphisms in wild Drosophila, possibly stabilized by an alternating summer-winter selection regime. Historically, there has been skepticism about the potential of temporal variation to balance polymorphism, because selection must be strong to have a meaningful stabilizing effect-unless dominance also varies over time ("reversal of dominance"). Here, we develop a simplified model of seasonally variable selection that simultaneously incorporates four different stabilizing mechanisms, including two genetic mechanisms ("cumulative overdominance" and reversal of dominance), as well as ecological "storage" ("protection from selection" and boom-bust demography). We use our model to compare the stabilizing effects of these mechanisms. Although reversal of dominance has by far the greatest stabilizing effect, we argue that the three other mechanisms could also stabilize polymorphism under plausible conditions, particularly when all three are present. With many loci subject to diminishing returns epistasis, reversal of dominance stabilizes many alleles of small effect. This makes the combination of the other three mechanisms, which are incapable of stabilizing small effect alleles, a better candidate for stabilizing the detectable frequency oscillations of large effect alleles.
Pretrial negotiations under optimism

We develop a tractable and versatile model of pretrial negotiation in which the negotiating parties are optimistic about the judge's decision and anticipate the possible arrival of public information about the case prior to the trial date. The parties will settle immediately upon the arrival of information. However, they may also agree to settle prior to an arrival. We derive the settlement dynamics prior to an arrival: negotiations result in either immediate agreement, a weak deadline effect—settling at a particular date before the deadline, a strong deadline effect—settling at the deadline, or impasse, depending on the level of optimism. Our findings match stylized facts.
What signals matter for social startups? It depends: The influence of gender role congruity on social impact accelerator selection decisions

Abstract Social impact accelerators (SIAs) seek to select startups with the potential to generate financial returns and social impact. Through the lenses of signaling theory and gender role congruity theory, we examine 2324 social startups that applied to 123 SIAs globally in 2016 and 2017 and find that SIAs are more likely to accept startups that signal their economic and social credibility. Moreover, while we find that the influence of these signals is strongest when they are congruent with the stereotypes associated with the lead founder's gender, men seem to experience better outcomes from gender incongruity than women.
Optical Properties of Manganese Doped Amorphous and Crystalline Aluminum Nitride Films

An aluminum nitride (AlN) film deposited on silicon (100) was used as the substrate for growing manganese (Mn) doped AlN film by metal organic chemical vapor deposition (MOVCD). The (15.78 µm) under layer of AlN was grown at 615°C at a pressure of 10−4 Torr. The (2.1 µm) top layer of Mn-AlN was grown at the same temperature and pressure but doped with pulse valve introduction of the manganese decacarbonyl (100 ms on, 100 ms off). The film was then characterized ex situ with IR reflectance microscopy, X-ray diffraction, scanning electron microscopy imaging, cathodoluminescence, and X-ray fluorescence. The IR reflectance measurements showed a strong (A1) LO mode for AlN at 920 cm−1 and 900 cm−1 with a shoulder at 849 cm−1. X-ray Diffraction yielded three diffraction peaks at a 2θ position of 33, 36 and 38 degrees corresponding to 100, 002, and 101 lattice planes respectively. Cathodoluminescence results show strong visible emitted light from incorporated manganese. The relative percentage of manganese to aluminum was below the detection limit (0.01 %) of the X-ray fluorescence spectrometer. Amorphous Mn doped AlN films have also been grown using a low temperature atomically abrupt sputter epitaxial system. The amorphous Mn doped AlN showed no cathodoluminescence.
The limits of forward guidance

Abstract The viability of forward guidance as a monetary policy tool depends on the horizon over which it can be communicated and its influence on expectations over that horizon. This paper develops and estimates a model of imperfect central bank communications and uses it to measure how effectively the Fed has managed expectations about future interest rates and the influence of its communications on macroeconomic outcomes. Standard models assume central banks have perfect control over expectations about the policy rate up to an arbitrarily long horizon, and this is the source of the so-called “forward guidance puzzle.” Our estimated model suggests that the Fed has limited ability to affect expectations at horizons that are sufficiently long to give rise to the forward guidance puzzle. Additionally, imperfect communication has a significant impact on the propagation of forward guidance. Finally, we develop a novel decomposition of the response of the economy to forward guidance. The decomposition shows that empirically plausible imperfect forward guidance has a quantitatively important role bringing forward the effects of future rate changes and that poor communications have been a source of macroeconomic volatility.
Similarity of Neural Network Representations Revisited

Recent work has sought to understand the behavior of neural networks by comparing representations between layers and between different trained models. We examine methods for comparing neural network representations based on canonical correlation analysis (CCA). We show that CCA belongs to a family of statistics for measuring multivariate similarity, but that neither CCA nor any other statistic that is invariant to invertible linear transformation can measure meaningful similarities between representations of higher dimension than the number of data points. We introduce a similarity index that measures the relationship between representational similarity matrices and does not suffer from this limitation. This similarity index is equivalent to centered kernel alignment (CKA) and is also closely connected to CCA. Unlike CCA, CKA can reliably identify correspondences between representations in networks trained from different initializations.
CaMKK2 Signaling in Metabolism and Skeletal Disease: a New Axis with Therapeutic Potential

Age and metabolic disorders result in the accumulation of advanced glycation endproducts (AGEs), oxidative stress, and inflammation, which cumulatively cause a decline in skeletal health. Bone becomes increasingly vulnerable to fractures and its regenerative capacity diminishes under such conditions. With a rapidly aging population in the USA and the global increase in diabetes, efficacious, multi-dimensional therapies that can treat or prevent skeletal diseases associated with metabolic dysfunction and inflammatory disorders are acutely needed. Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of nutrient intake, glucose metabolism, insulin production, and adipogenesis. Recent studies suggest a pivotal role for CaMKK2 in bone metabolism, fracture healing, and inflammation. Aside from rekindling previous concepts of CaMKK2 as a potent regulator of whole-body energy homeostasis, this review emphasizes CaMKK2 as a potential therapeutic target to treat skeletal diseases that underlie metabolic conditions and inflammation.
Do Antibiotic Intramedullary Dowels Assist in Eradicating Infection in Two-Stage Resection for Septic Total Knee Arthroplasty?

Abstract Background Evidence suggests approximately 40% of intramedullary (IM) canals are culture positive at resection for infected knee arthroplasty. While commonly utilized, no clinical data on the efficacy of antibiotic-eluding IM dowels exist. We quantified treatment success with and without the use of antibiotic-eluding IM dowels in two-stage treatment of periprosthetic knee infection using static and articulating antibiotic cement spacers. Methods 109 consecutive patients who underwent two-stage treatment for periprosthetic knee infection were reviewed. Treatment failure, defined as repeat resection before reimplantation or recurrent infection within 6 months of reimplantation, was evaluated based on spacer type and use of IM dowels, accounting for infection type and systemic host and local extremity grade. Results After exclusions for confounds, articulating spacers without IM dowels were used in 49 (57.7%) cases, articulating spacers with IM dowels in 14 cases (16.5%), and static spacers with IM dowels in 22 (25.9%) cases. Treatment success regardless of infection classification was 85.7% for articulating spacers with IM dowels, 89.8% for articulating spacers without IM dowels, and 68.2% for static spacers with IM dowels (P = .074). In chronically infected poor hosts with compromised extremities, treatment success remained highest in patients with articulating spacers with (90.9%) or without (92.9%) IM dowels compared with static spacers with IM dowels (68.4%) (P = .061). Conclusion Findings suggest that the use of IM dowels did not enhance infection eradication above and beyond that observed for articulating spacers alone, including in the worst cases involving chronically infected poor hosts with compromised extremities.
The Family as a Stronghold of State Stability: Two Contradictions in China’s Anti-Domestic Violence Efforts

China’s first Anti-Domestic Violence Law that took effect in March 2016 is widely praised as progress against the malfunction of public power in the area of domestic violence allegations in an ingrained patriarchal society. However, empirical research points to the first contradiction in judicial practices, namely, the informal and flexible mechanism of judicial mediation that is the norm in domestic violence cases. The victims’ rights and safety are harmed under the political requirement of ‘saving and repairing the marital relationship’ or ‘maintaining social harmony.’ Facing this weakness of the judiciary and public power, Chinese civil society has been increasingly engaging in various forms of anti-domestic violence advocacy and has achieved considerable success inside and outside the courtroom. Nevertheless, in this context, the authorities have escalated repression and suppression of the anti-domestic violence advocacy amid its efforts of further suppressing civil society in general. Based on the analysis of these two contradictions, this article argues that the apparent contradictions reflect the inherent coherence of deploying law as an instrument serving for political ends in an authoritarian context. Alongside the intensifying tension in these two contradictions is the further setback to reform and the shrinking of the space for civil society activism.
Recent applications of 2,4,6-trichloro-1,3,5-triazine and its derivatives in organic synthesis

A new recently published application of 2,4,6-trichloro-1,3,5-triazine (CC) and its derivatives in organic synthesis are reviewed <div class=" textboxdefault "> Figure options Download full-size image Download as PowerPoint slide
Non-Malleable Encryption: Equivalence between Two Notions, and an Indistinguishability-based Characterization.

We prove the equivalence of two definitions of non-malleable encryption, one based on the simulation approach of Dolev, Dwork and Naor [6] and the other based on the comparison approach of Bellare, Desai, Pointcheval and Rogaway [2]. Our definitions are slightly stronger than the original ones. The equivalence relies on a new characterization of non-malleable encryption in terms of the standard notion of indistinguishability of Goldwasser and Micali. We show that non-malleability is equivalent to indistinguishability under a “parallel chosen ciphertext attack,” this being a new kind of chosen ciphertext attack we introduce, in which the adversary’s decryption queries are not allowed to depend on answers to previous queries, but must be made all at once. This characterization simplifies both the notion of non-malleable encryption and its usage, and enables one to see more easily how it compares with other notions of encryption. The results here apply to non-malleable encryption under any form of attack, whether chosen-plaintext, chosen-ciphertext, or adaptive chosen-ciphertext.
Synthesis of Racemic 6,7,8,9-Tetrahydro-3-hydroxy-1H-1-benzazepine-2,5-diones as Antagonists of N-Methyl-d-aspartate (NMDA) and α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid (AMPA) Receptors

The synthesis and pharmacological properties of several racemic 6,7,8,9-tetrahydro-3-hydroxy-1H-1-benzazepine-2,5-diones (THHBADs) are described. Synthesis was accomplished via a Schmidt reaction with 5,6,7,8-tetrahydro-2-methoxynaphthalene-1,4-diones (THMNDs) followed by demethylation. THMNDs were prepared via a Diels−Alder reaction with 2-methoxybenzoquinone (5) or 2-bromo-5-methoxybenzoquinone (14) and substituted 1,3-butadienes. The pharmacology of THHBADs was characterized by electrical recordings in Xenopus oocytes expressing rat brain NMDA and AMPA receptors. THHBADs are antagonists of NMDA and AMPA receptors with functional potency being dependent upon the substitution pattern on the tetrahydrobenzene moiety. The 7,8-dichloro-6-methyl (18a) and 7,8-dichloro-6-ethyl (18b) analogs are the most potent THHBADs prepared and have apparent antagonist dissociation constants (Kb values) of 0.0041 and 0.0028 μM, respectively, for NMDA receptors and 0.51 and 0.72 μM, respectively, for AMPA receptors.
The stereospecific cyclopropanation of diarylcarbene cation radicals

Abstract Catalytic chemical oxidation of p , p ′-dimethyldiphenyldiazomethane, 1 , using tris-(4-methylphenyl)aminium hexafluoroantimonate, Ar 3 N +· , in the presence of excess alkene in CH 2 Cl 2 yields substituted cyclopropanes, 3 , in high yield. Experiments show that cyclopropanation is stereospecific and probably proceeds via the initial formation of a 1,3 cation radical intermediate which undergoes ring closure.
An efficient synthesis of 4(5),11(12)-taxadiene derivatives and microbial mediated 20-hydroxylation of taxoids

4(20),11(12)-Taxadiene 1 is specifically converted into 4(5),11(12)-taxadiene 5 via Claisen-like rearrangement and Barton radical desulfurization (cleavage of C–S bond) in high yield. Taxoid 5 and its deoxygenated derivatives are potential biosynthetic precursors of paclitaxel and other taxoids. 20-Hydroxylated metabolite 8 is one major product from microbially mediated hydroxylation of 5.
Selective conversion of O-succinimidyl carbamates to N-(O-carbamoyl)-succinmonoamides and ureas

N-Monoalkyl-O-succinimidyl carbamates reacted with primary and secondary amines to produce ureas. However, N,N-dialkyl-O-succinimidyl carbamates reacted with primary and secondary amines, via succinimide ring opening, to afford N-(O-carbamoyl)-succinmonoamide derivatives. This ring-opening trend was also true with hydroxy and alkoxy nucleophiles. Herein, general methods for the synthesis and NMR characterization of N-(O-carbamoyl)-succinmonoamides are reported.
P(MeNCH2CH2)3N: An efficient nonionic superbase for Wittig and Wittig-Horner reactions

The strong non-ionic base P(MeNCH2CH2)3N 1 is an efficient base for conversion of [RCH2PPh3]X and RCH2P(O)(OEt)2 to their corresponding ylides under mild conditions. Reaction of the ylides (generated in situ) with benzaldehyde give the corresponding alkenes in high yield. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9: 687–689, 1998
Synthesis of conformationally restricted substance P antagonists

Reaction of CP-99,994 (1) with benzyl chloromethyl ether under basic conditions produced the novel 1,6-diazabicyclo[3.2.1]octane system in good yield; analogs containing this nucleus display high binding affinity for substance P receptors. The ethylene homologue of 1a, diamine 7, shows enhanced inhibitory activity and may more closely approximate the binding conformation of 1a at the NK1 receptor.
Atomically flat reconstructed rutile TiO2(001) surfaces for oxide film growth

The availability of low-index rutile TiO2 single crystal substrates with atomically flat surfaces is essential for enabling epitaxialgrowth of rutile transition metal oxide films. The high surface energy of the rutile (001) surface often leads to surface faceting, which precludes the sputter and annealing treatment commonly used for the preparation of clean and atomically flat TiO2(110) substrate surfaces. In this work, we reveal that stable and atomically flat rutile TiO2(001) surfaces can be prepared with an atomically ordered reconstructedsurface already during a furnace annealing treatment in air. We tentatively ascribe this result to the decrease in surface energy associated with the surface reconstruction, which removes the driving force for faceting. Despite the narrow temperature window where this morphology can initially be formed, we demonstrate that it persists in homoepitaxialgrowth of TiO2(001) thin films. The stabilization of surface reconstructions that prevent faceting of high-surface-energy crystal faces may offer a promising avenue towards the realization of a wider range of high quality epitaxial transition metal oxide heterostructures.
Relationship between MEG global dynamic functional network connectivity measures and symptoms in schizophrenia

An investigation of differences in dynamic functional network connectivity (dFNC) of healthy controls (HC) versus that of schizophrenia patients (SP) was completed, using eyes-open resting state MEG data. The MEG analysis utilized a source-space activity estimate (MNE/dSPM) whose result was the input to a group spatial independent component analysis (ICA), on which the networks of our MEG dFNC analysis were based. We have previously reported that our MEG dFNC revealed that SP change between brain meta-states (repeating patterns of network correlations which are allowed to overlap in time) significantly more often and to states which are more different, relative to HC. Here, we extend our previous work to investigate the relationship between symptomology in SP and four meta-state metrics. We found a significant correlation between positive symptoms and the two meta-state metrics which showed significant differences between HC and SP. These two statistics quantified 1) how often individuals change state and 2) the total distance traveled within the state-space. We additionally found that a clustering of the meta-state metrics divides SP into groups which vary in symptomology. These results indicate specific relationships between symptomology and brain function for SP.
Total Synthesis of Bryostatin 2

The total synthesis of the marine macrolide bryostatin 2 is described. The synthesis plan relies on aldol and directed reduction steps in order to construct the anti-1,3-diol array present in each of the principal subunits (A, B, and C). These fragments were coupled using a Julia olefination and subsequent sulfone alkylation. A series of functionalization reactions provided a bryopyran seco acid, which was macrolactonized under Yamaguchi conditions. Installation of the two enoate moieties took advantage of asymmetric phosphonate and aldol condensation strategies. Reduction of the C20 ketone and simple protecting group operations then completed the synthesis of bryostatin 2. This flexible approach should provide access to a series of new analogues of this clinically important marine natural product.
Mixed Oxide Surfaces: Ultrathin Films of CaxMg(1-x)O

Nonstochiometric mixed oxides are often of interest for their novel catalytic or material properties yet are often difficult to synthesize in easily characterizable forms. We report on the use of low-temperature epitaxy of Ca and Mg under oxidizing conditions to yield mixed thin film oxides. Low-energy electron diffraction showed that the mixed oxides grew as single crystals over a wide range of compositions. We compare the water adsorption characteristics of the mixed oxide to that of CaO and MgO and find that the mixed oxide behavior is not a linear combination of the two pure oxide systems. The thermal stability of the mixed oxide film was checked by Auger electron ratios for an oxide−oxide “sandwich” after various “flash” anneals. This and water adsorption results suggest intimate atomic-scale mixing exists until flashed above 1100 K.
Facile preparation of allenic hydroxyketones via rearrangement of propargylic alcohols.

Treatment of tertiary propargylic alcohols 13 with 3-diazo-2-butanone 6 and catalytic dirhodium tetraacetate in benzene gave good yields of the diastereomeric allenic hydroxyketones 14, with, in some cases, good diastereocontrol. These products are presumably formed via the [2,3]-sigmatropic rearrangement of an α-propargyloxy enol derivative. This reaction has been extended to the preparation of homoallylic hydroxyketones from allylic alcohols by reaction with 6 and the rhodium catalyst.
Synthesis and oxidation of Ti2InC, Zr2InC, (Ti0.5,Zr0.5)2InC and (Ti0.5,Hf0.5)2InC in air

Abstract In this paper, we report on the synthesis and oxidation behavior of Ti 2 InC, Zr 2 InC, (Ti 0.5 ,Hf 0.5 ) 2 InC and (Ti 0.5 ,Zr 0.5 ) 2 InC. The oxidation kinetics were studied thermogravimetrically in air in the 400–700 °C temperature range. With the exception of Ti 2 InC, the oxide layers formed failed to offer any oxidation resistance at 400 °C or higher temperatures. The reaction products are In 2 O 3 , in which some transition metal ions are probably dissolved, and the transition metal oxides. The latter are either amorphous or nanocrystalline. In the case of Ti 2 InC, a protective oxide was formed at 500 °C. However, at higher temperatures, after an incubation period, catastrophic oxidation ensued. In all cases, the oxidation occurred by the inward diffusion of oxygen.