Long-standing Effort Research Articles

Characterization of the slow extraction frequency response

The main physics program of the CERN Super Proton Synchrotron (SPS) is dedicated to the fixed target physics experiments hosted in the North experimental Area (NA). Protons are delivered to the NA via third-integer resonant slow extraction over an almost 5 s flattop. In order to maximize the usable intensity delivered to the experiments, the flux of extracted particles should be kept as constant as possible. This is a very general requirement for fixed target experiments served by synchrotrons. Power supply ripples are a well-known issue in resonant slow extraction, affecting the quality of the spill. A long-standing effort is ongoing at CERN to characterize the SPS slow extraction frequency response to its main power supplies. In this paper, beam dynamics simulations are employed to understand and characterize the process, combined with dedicated beam based measurements.

SHOULD ASEAN ANTITRUST LAWS EMULATE EUROPEAN COMPETITION POLICY?

Recent years have seen the Association of Southeast Asian Nations (ASEAN) members embark upon various initiatives that seek to harmonize their competition regimes. These ongoing efforts to modernize and harmonize ASEAN competition laws take place amid a longstanding effort by both the European Union (EU) and the United States (US) to export their respective competition laws throughout the world. This raises a critical question: Should the ASEAN countries attempt to mimic the competition regimes of other developed nations, notably those that are in force in the EU and the US? And, if so, which one of these regimes should they draw more inspiration from? This paper seeks to dispel the myth that the European model of competition enforcement would necessarily provide a superior blueprint. To the contrary, it shows that the evolutionary, common-law-like regime that has emerged in the US has many strengths that are often overlooked by contemporary competition policy scholarship, and which might provide a particularly good fit for the economic and political realities of the ASEAN member states. The paper proceeds as follows. Section 2 analyzes the high-level differences between the American and European approaches to competition policy. Section 3 shows that the US and Europe also differ substantially in terms of the conduct that may constitute an infringement of competition law — the EU system being significantly more restrictive. Section 4 turns to the thorny problem of digital platforms, in particular, and argues that while the European model might more readily facilitate intervention against digital platforms, the resulting cases may be detrimental to consumers and the economy more broadly. Section 5 posits that reducing economic concentration — sometimes cited as a byproduct of European-style competition enforcement — should not be a self-standing goal of antitrust policy. Finally, Section 6 argues that many of the economic and political characteristics of the ASEAN economy cut in favor of using the US model of competition enforcement as a blueprint for further development and harmonization of ASEAN competition law.

Detecting variability: A study on the application of bayesian multilevel modelling to archaeological data. Evidence from the Neolithic Adriatic and the Bronze Age Aegean

The detection and interpretation of variability in archaeological data has been a long-standing effort in the field. This paper aims to introduce the application of Bayesian multilevel modelling as a tool for the detection of variability at levels within nested archaeological data. Model structure, ways of construction, and the potential of using variability information to enhance archaeological interpretations is presented. This is demonstrated through the analysis of two case study datasets: Neolithic pottery finds from Mala (Nova) Pećina cave excavations in Croatia and stone finds from the Bronze Age site of Akrotiri, Thera, Greece. This is followed by a discussion of the multilevel model results and the possible interpretations that can be derived from them. Finally, propositions are made on how these and other models can be extended.

Should ASEAN Antitrust Laws Emulate European Competition Policy?

Recent years have seen the ASEAN members embark upon various initiatives that seek to harmonize their competition regimes. These ongoing efforts to modernize and harmonize ASEAN competition laws take place amid a longstanding effort by both the European Union and the United States to export their respective competition laws throughout the world. This raises a critical question: should the ASEAN countries attempt to mimic the competition re-gimes of other developed nations, notably those that are in force in the EU and the US? And, if so, which one of these regimes should they draw more inspiration from? This paper seeks to dispel the myth that the European model of competition enforcement would necessarily provide a superior blueprint. To the contrary, it shows that the evolutionary, common-law-like regime that has emerged in the US has many strengths that are often overlooked by con-temporary competition policy scholarship, and which might provide a particularly good fit for the economic and political realities of the ASEAN member states. The paper proceeds as follows. Section I analyzes the high-level differences between the American and European approaches to competition policy. Section II shows that the US and Europe also differ substantially in terms of the conduct that may constitute an infringement of competition law — the EU system being significantly more restrictive. Section III turns to the thorny problem of digital platforms, in particular, and argues that while the European model might more readily facilitate intervention against digital platforms, the resulting cases may be detrimental to consumers and the economy more broadly. Section IV posits that reducing economic concentration — sometimes cited as a byproduct of European-style competition enforcement — should not be a self-standing goal of antitrust policy. Finally, Section V argues that many of the economic and political characteristics of the ASEAN economy cut in favor of using the US model of competition enforcement as a blueprint for further development and harmonization of ASEAN competition law.

Solar-assisted icephobicity down to −60°C with superhydrophobic selective surfaces

Engineering icephobic surfaces has been a long-standing effort to address the challenges of ice prevention and removal in our daily life and industrial applications. Superhydrophobic surfaces and photothermal effect have shown their distinct merits in anti-icing and deicing. It is highly desirable to exploit their mutual benefits to realize passive, durable, and sustainable icephobicity even at extremely low temperatures. We report on a superhydrophobic selective surface constructed with a hierarchical architecture to enable stable superhydrophobicity and high-efficiency solar-thermal conversion. The surface spectral selectivity is deliberately designed to maximize solar harvesting while minimizing the thermal re-radiation loss. The boosted solar-thermal conversion empowers remarkable anti-icing of a sessile droplet at a record-low temperature of −60°C under 1-sun illumination. The synergy of solar-thermal conversion and superhydrophobicity endows the surface with superior and durable icephobicity. Moreover, the presented icephobic surface shows great potential and broad impacts, owing to its all-solution-based scalable fabrication method. Spectral selectivity and superhydrophobicity are integrated into an icephobic surface Anti-icing of a sessile droplet at −60°C Highly durable deicing or defrosting in repeated cycles in frigid conditions Facile, low-cost, all-solution-based process suitable for scalable manufacturing Ma et al. develop a photothermal icephobic surface that combines spectral selectivity and superhydrophobicity by trapping plasmonic TiN nanoparticles into hierarchical structures on an aluminum substrate. The synergy of solar-thermal conversion and superhydrophobicity endows the surface with superior and durable icephobicity at extremely low temperatures.

Lebanon’s October 2019 Revolution

In a world dominated by neoliberalism, there is renewed attention to labor organizing and radical forms of action outside the institutional framework. In Lebanon, the October 2019 Revolution brought to the forefront the capacity of labor to recompose its power in the face of the long-standing capitalist effort to decompose it. This essay first examines the outbreak of social unrest in 2019 that accompanied the failure of neoliberal policies. Second, it explains the absence and silence of the labor movement amid the 2019 revolution by state interference and at the service of a long-standing laissez-faire economy. Finally, it concludes by examining recent attempts of professionals to organize from within the October Revolution and the challenges they currently grapple with.

Are climate risks encouraging cover crop adoption among farmers in the southern Wabash River Basin?

Cover crops represent a potential win-win opportunity to promote climate resilience by helping farmers adapt to climate risks while simultaneously mitigating multiple environmental impacts from agriculture. However, cover crop adoption rates are increasing slowly and cover less than 5% of U.S. croplands. In contrast, several Indiana counties in the southern Wabash River Basin have cover crops on more than 20 % of farmland. This qualitative study draws on 33 semi-structured interviews with farmers to understand whether climate risks are driving the above-average rates of adoption in this area. Our purposive sample of farmers was guided by whether they farmed flood-prone areas along the White and Wabash Rivers, thus making them especially sensitive to increasing flood risks from climate change. We found that while climate risks, particularly intensifying rainfall events, were a factor in some cases, most adoption was a longstanding effort to control wind-erosion on hilly areas with sandy soils. We also found that farmers experienced challenges with adoption following successful establishment of cover crops tied to climate-driven ecosystem responses. Greater spring precipitation delayed cash crop planting because of moisture retention and intensified pest pressures from increased habitat has caused replanting of cash crop seeds. Responses indicate that climate risks have mixed effects that may either discourage or encourage cover crop adoption depending on whether future outreach and policy interventions can help farmers overcome the adoption challenges they encounter.

Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation.

The aberrant function of chromatin regulatory networks (epigenetics) is a hallmark of cancer promoting oncogenic gene expression. A growing body of evidence suggests that the disruption of specific chromatin-associated protein complexes has therapeutic potential in malignant conditions, particularly those that are driven by aberrant chromatin modifiers. Of note, a number of enzymatic inhibitors that block the catalytic function of histone modifying enzymes have been established and entered clinical trials. Unfortunately, many of these molecules do not have potent single-agent activity. One potential explanation for this phenomenon is the fact that those drugs do not profoundly disrupt the integrity of the aberrant network of multiprotein complexes on chromatin. Recent advances in drug development have led to the establishment of novel inhibitors of protein–protein interactions as well as targeted protein degraders that may provide inroads to longstanding effort to physically disrupt oncogenic multiprotein complexes on chromatin. In this review, we summarize some of the current concepts on the role epigenetic modifiers in malignant chromatin states with a specific focus on myeloid malignancies and recent advances in early-phase clinical trials.

DARPP-32 40 years later.

DARPP-32 (dopamine- and cAMP-regulated phosphoprotein with an apparent Mr of 32,000), now also known as phosphoprotein phosphatase 1 regulatory subunit 1B (PPP1R1B), is a potent inhibitor of protein phosphatase 1 (PP1, also known as PPP1) when phosphorylated at Thr34 by cAMP-dependent protein kinase (PKA). DARPP-32 exhibits a remarkable regional distribution in brain, roughly similar to that of dopamine innervation. Its discovery was a culmination of the long-standing effort of Paul Greengard to understand the mechanisms through which neurotransmitters such as dopamine exert their effects on target neurons. DARPP-32 is particularly enriched in striatal projection neurons where it is regulated by numerous signals through which it integrates and amplifies responses to many stimuli. Molecular studies of DARPP-32 have revealed that its regulation and function are more complex than anticipated. It is phosphorylated on multiple sites by several protein kinases that modulate DARPP-32 properties. Primarily, when phosphorylated at Thr34 DARPP-32 is a potent inhibitor of PP1, whereas when phosphorylated at Thr75 by Cdk5 it inhibits PKA. Phosphorylation at serine residues by CK1 and CK2 modulates its intracellular localization and its sensitivity to kinases or phosphatases. Modeling studies provide evidence that the signaling pathways including DARPP-32 are endowed of strong robustness and bistable properties favoring switch-like responses. Thus DARPP-32 combined with a set of other distinct signaling molecules enriched in striatal projection neurons plays a key role in the characteristic properties and physiological function of these neurons.

Effectual selling in service ecosystems

This research draws on effectuation theory and service dominant logic to develop the concept of effectual selling. Effectual selling is focused on resource integration, stakeholder interaction, and value co-creation under environmental uncertainty. The effectual selling perspective developed here is consistent with the emerging service ecosystem view. As such, it is holistic and dynamic. Broadly, this investigation represents the longstanding and continuous effort to understand and articulate the important and evolving role of the salesperson. Several testable propositions are developed to facilitate further study of effectual selling behavior. Guided by the motivation, opportunity, ability (MOA) framework, the propositions suggest different salesperson characteristics, sales manager leader behaviors, and firm-level characteristics that will drive effectual selling behavior.

Boosting Free-Energy Perturbation Calculations with GPU-Accelerated NAMD.

Harnessing the power of graphics processing units (GPUs) to accelerate molecular dynamics (MD) simulations in the context of free-energy calculations has been a longstanding effort toward the development of versatile, high-performance MD engines. We report a new GPU-based implementation in NAMD of free-energy perturbation (FEP), one of the oldest, most popular importance-sampling approaches for the determination of free-energy differences that underlie alchemical transformations. Compared to the CPU implementation available since 2001 in NAMD, our benchmarks indicate that the new implementation of FEP in traditional GPU code is about four times faster, without any noticeable loss of accuracy, thereby paving the way toward more affordable free-energy calculations on large biological objects. Moreover, we have extended this new FEP implementation to a code path highly optimized for a single-GPU node, which proves to be up to nearly 30 times faster than the CPU implementation. Through optimized GPU performance, the present developments provide the community with a cost-effective solution for conducting FEP calculations. The new FEP-enabled code has been released with NAMD 3.0.

Phenotypic Associations Among Cell Cycle Genes in Saccharomyces cerevisiae.

A long-standing effort in biology is to precisely define and group phenotypes that characterize a biological process, and the genes that underpin them. In Saccharomyces cerevisiae and other organisms, functional screens have generated rich lists of phenotypes associated with individual genes. However, it is often challenging to identify sets of phenotypes and genes that are most closely associated with a given biological process. Here, we focused on the 166 phenotypes arising from loss-of-function and the 86 phenotypes from gain-of-function mutations in 571 genes currently assigned to cell cycle-related ontologies in S. cerevisiae. To reduce this complexity, we applied unbiased, computational approaches of correspondence analysis to identify a minimum set of phenotypic variables that accounts for as much of the variability in the data as possible. Loss-of-function phenotypes can be reduced to 20 dimensions, while gain-of-function ones to 14 dimensions. We also pinpoint the contributions of phenotypes and genes in each set. The approach we describe not only simplifies the categorization of phenotypes associated with cell cycle progression but might also potentially serve as a discovery tool for gene function.

An organic approach to low energy memory and brain inspired electronics

Brain inspired electronics with organic memristors could offer a functionally promising and cost-effective platform for flexible, wearable, and personalized computing technologies. While there are different material approaches (viz. oxides, nitrides, 2D, organic) to realize memristors, organic materials are characteristically unique, as they could, in principle, offer spatially uniform switching, tunable molecular functionalities, and ultra-low switching energies approaching atto joules that are highly desirable but elusive with other material systems. However, despite a long-standing effort spanning almost 2 decades, the performance and mechanistic understanding in organic memristors are quite far from a translational stage and even a single suitable candidate is yet to emerge. Almost all the reported organic memristors lack reproducibility, endurance, stability, uniformity, scalability, and speed that are needed for an industrial application. In this review, we analyze the root cause of the prolonged failures of organic memory devices and discuss a new family of organic memristors, made of transition metal complexes of redox active organic ligands (RAL), that satisfy and go beyond the requirements specified in the 2015 ITRS roadmap for RRAM devices. These devices exhibit cyclability > 1012, retention of several months, on/off ratio > 103, switching voltage approaching 100 mV, rise time less than 30 ns, and switching energy <1 fJ, offering a quantum leap in organic memristor technology. This could give birth to a new generation of organic memristors that are industrially competitive with ample scopes for functional tunability by molecular engineering, such as variation of the metal center and ligands as well as the counterions. A combination of molecular and device engineering may enable this material system to be an ideal candidate for brain inspired electronics.

Talkin' Toxins: From Coley's to Modern Cancer Immunotherapy.

The ability of the immune system to precisely target and eliminate aberrant or infected cells has long been studied in the field of infectious diseases. Attempts to define and exploit these potent immunological processes in the fight against cancer has been a longstanding effort dating back over 100 years to when Dr. William Coley purposefully infected cancer patients with a cocktail of heat-killed bacteria to stimulate anti-cancer immune processes. Although the field of cancer immunotherapy has been dotted with skepticism at times, the success of immune checkpoint inhibitors and recent FDA approvals of autologous cell therapies have pivoted immunotherapy to center stage as one of the most promising strategies to treat cancer. This review aims to summarize historic milestones throughout the field of cancer immunotherapy as well as highlight current and promising immunotherapies in development.

High level of fetal-globin reactivation by designed transcriptional activator-like effector

AbstractThe fetal-to-adult hemoglobin switch has been a focus of a long-standing effort to potentially treat sickle cell disease and β thalassemia by induction of fetal hemoglobin. In a continuation of this effort, we designed specific transcriptional activator-like effectors (TALEs) to target both the Gγ and Aγ-globin promoters. We fused the TALEs to a LIM domain binding protein (Ldb1) dimerization domain, followed by a T2A green fluorescent protein (GFP) cassette, which were assembled into a lentiviral vector. To prevent deletions caused by the repeats of TALEs during the lentivirus packing process, we changed the TALE encoding DNA by codon optimization. Intriguingly, 5 of 14 TALEs showed forced reactivation of fetal-globin expression in human umbilical cord blood-derived erythroid progenitor (HUDEP-2) cells, with a significant increase in the γ-globin mRNA level by more than 70-fold. We also observed a more than 50% reduction of β-globin mRNA. High-performance liquid chromatography analysis revealed more than 30% fetal globin in TALE-induced cells compared with the control of 2%. Among several promoters studied, the β-globin gene promoter with the locus control region (LCR) enhancer showed the highest TALE expression during CD34 erythroid differentiation. At day 19 of differentiation, 2 TALEs increased fetal-globin expression more than 40-fold in the mRNA level and up to 70% of the total globin protein. These TALEs have potential for clinical translation.

The Hybrid-Scan Estimators: Exploiting WSR-88D Split Cuts to Improve the Quality of Polarimetric-Variable Estimates

AbstractSince the dual-polarization upgrade of the Weather Surveillance Radar-1988 Doppler (WSR-88D), the polarimetric variables have become a fundamental tool for better interpretation and forecasting of hazardous weather events. Thus, improving their quality has been an important long-standing effort. In this paper, we introduce the hybrid-scan estimators (HSE), which use the available data in split cuts of operational volume coverage patterns (VCP) to provide better estimates of differential reflectivity, differential phase, and correlation coefficient. The HSE are designed to choose between the data provided by either one of the two scans in split cuts based on their expected statistical performance, resulting in the same or better data quality compared to the conventional estimators. The performance improvement realized with the HSE is characterized with simulations and illustrated with data from WSR-88D. While relatively simple, an operational implementation of the HSE could bring improvements to forecasters’ data interpretation and algorithm performance, both of which rely on dual-polarization radar data.

Catalysis of material surface defects: Multiscale modeling of methanol synthesis by CO2 reduction on copper

The effect of the structure of copper catalyst surface on CO2 conversion has been a long-standing research effort, both theoretically and experimentally. In this paper, flat Cu(111) and stepped Cu(533) surfaces are theoretically studied for catalytic CO2 hydrogenation to methanol, an important carbon utilization process for tackling modern environmental pollution problems. First-principles multiscale modeling using density functional theory (DFT) and mesoscopic kinetic Monte Carlo (kMC) is employed to simulate the complex reaction pathway, focusing on the role of surface defects on the overall catalytic selectivity and activity at laboratory operating conditions. The contribution of the electronic (interaction energy) and geometric (distortion energy) effect to the adsorbates binding energy is evaluated and discussed. The results show that a stepped Cu(533) surface enhances the selectivity and activity of the methanol synthesis, with selectivity up to 84% and turn-over frequency (TOF) up to 10−4 s−1, which is over 4 orders of magnitude better than a flat Cu(111) surface. It is found that the surface defect, compared to the Cu(111) surface and other Cu/metal oxide alloys, promotes the H2COH hydrogenation pathway, resulting in higher total CH3OH yields. The study provides an insight into surface defects engineering, serving as a step towards the rational design of multifaceted copper catalysts.

Large-eddy simulation of turbulent natural-bed flow

The turbulent flow in natural rough beds is a complex subject, still poorly understood despite the longstanding effort of several researchers. In the present work, a turbulent open-channel flow experiment, with a pebble bed at Reynolds and Froude numbers, respectively, Re = 4.65 × 104 and Fr = 0.186, has been simulated using the Large-Eddy Simulation (LES) technique, in which the wall-adapting local eddy viscosity subgrid scale closure model is used and in the presence of an air-water interface to take into account the effects of the interface deformation in the flow turbulence statistics under a low relative submergence condition. The simulations have been compared with a companion experiment, where the channel bottom is constituted by four pebble layers. For the simulations, the pebble-bed surface has been captured with a high-resolution three-dimensional laser scanner and used to morphologically characterize the numerical channel bottom. Results are presented in terms of turbulence statistics and turbulent laws, showing a good agreement with those obtained in the experiment. Since a good convergence between simulation and experimental results was obtained, the LES dataset was used to compute the Turbulent Kinetic Energy (TKE) dissipation rate across the water depth. The mesh resolution allows showing a detailed TKE dissipation rate distribution across the water depth. Moreover, the equilibrium between TKE production and dissipation was checked to verify the overlap layer existence under low relative submergence condition. Finally, a new procedure for vortex-visualization is implemented, based on the relationship between the vorticity and the TKE dissipation rate.

In the shadow of empire: Global Britain and the UK business school

In this essay, I scrutinize the ‘Global Britain’ project championed by the UK government since the Brexit vote and reflect on the role played by business schools in it. My argument is twofold. First, I contend the project is bound up with British imperialism, being at once the expression of a melancholic attachment to the colonial Empire of yesteryear and part of a long-standing effort to renew Britain’s imperial greatness in the so-called ‘postcolonial’ era. Second, I maintain that business schools, while notionally anti-Brexit, are complicit in the Global Britain project by virtue of propagating elements of its imperialist discourse. I conclude with some reflections on our role as scholars and educators in fostering debate on this project and challenging its imperialist underbelly.

Drug delivery systems designed to overcome antimicrobial resistance.

Antimicrobial resistance has emerged as a huge challenge to the effective treatment of infectious diseases. Aside from a modest number of novel anti-infective agents, very few new classes of antibiotics have been successfully developed for therapeutic use. Despite the research efforts of numerous scientists, the fight against antimicrobial (ATB) resistance has been a longstanding continued effort, as pathogens rapidly adapt and evolve through various strategies, to escape the action of ATBs. Among other mechanisms of resistance to antibiotics, the sophisticated envelopes surrounding microbes especially form a major barrier for almost all anti-infective agents. In addition, the mammalian cell membrane presents another obstacle to the ATBs that target intracellular pathogens. To negotiate these biological membranes, scientists have developed drug delivery systems to help drugs traverse the cell wall; these are called "Trojan horse" strategies. Within these delivery systems, ATB molecules can be conjugated with one of many different types of carriers. These carriers could include any of the following: siderophores, antimicrobial peptides, cell-penetrating peptides, antibodies, or even nanoparticles. In recent years, the Trojan horse-inspired delivery systems have been increasingly reported as efficient strategies to expand the arsenal of therapeutic solutions and/or reinforce the effectiveness of conventional ATBs against drug-resistant microbes, while also minimizing the side effects of these drugs. In this paper, we aim to review and report on the recent progress made in these newly prevalent ATB delivery strategies, within the current context of increasing ATB resistance.