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Plasma cleaning is a technique that can be applied in superconducting radio-frequency cavities in situ in cryomodules to decrease their level of field emission (FE). We developed the technique for Linac Coherent Light Source II (LCLS-II) cavities and we present in this paper the full development and application of plasma processing to the LCLS-II High Energy verification cryomodule (vCM). We validated our plasma processing procedure on the vCM, fully processing four out of eight cavities of this CM, demonstrating that cavity performance was preserved in terms of both accelerating field and quality factor. Applying plasma processing to this clean, record breaking cryomodule also showed that no contaminants were introduced in the string, maintaining the vCM FE-free up to the maximum field reached by each cavity. We also found that plasma processing eliminates multipacting (MP)-induced quenches that are frequently observed within the MP band field range. This suggests that plasma processing could be employed in situ in CMs to mitigate both FE and MP, significantly decreasing the testing time of cryomodules, the linac commissioning time and cost, and increasing the accelerator reliability.

An eight-cavity, 1.3 GHz, SLAC linac coherent light source II High Energy cryomodule was assembled and tested at Fermilab to verify performance before the start of production. Its cavities were processed with a novel nitrogen doping treatment to improve gradient performance. The cryomodule was tested with a modified protocol to process sporadic quenches, which were observed in Linac Coherent Light Source II production cryomodules and are attributed to multipacting. Dedicated vertical test experiments support the attribution to multipacting. The verification cryomodule achieved an acceleration voltage of 200 MV in continuous wave mode, corresponding to an average accelerating gradient of 24.1 MV/m, significantly exceeding the specification of 173 MV. The average Q_{0} (3.0×10^{10}) also exceeded its specification (2.7×10^{10}). After processing, no field emission was observed up to the maximum gradient of each cavity. This paper reviews the cryomodule performance and discusses operational issues and mitigations implemented during the several month program.

GaN device is a potential alternative to SiC as a wide band gap device. At present, there are almost no high-voltage GaN devices above 650 V, which makes an inverter design difficult for three-phase input using the standard two-level (2L) inverters. Therefore, at present, a three-level (3L) inverter is an obvious choice for the GaN inverter for three-phase 400/480 V input applications. Moreover, a 2L inverter suffers from drawbacks like increased filtering efforts, high dv/dt and limited switching frequency due to the effect of power loss on semiconductors. Therefore, at the medium-to-high-power level, a hard switched GaN inverter with a 2L structure is still questionable. To address some of the challenges, this study brings in a 700 V dc-link-based three-phase, 3L inverter with GaN and SiC diodes. This study discusses multiple aspects of the design such as (a) advantages over the 2L design at a higher power, (b) filters designs, (c) power losses in the devices and (d) design challenges of the inverter through comprehensive simulation models and experimental investigations. The study claims that the GaN inverter for the medium-to-high-power level makes more sense with a 3L design.

Development of superconducting undulators (SCUs) continues at the Advanced Photon Source (APS). Several planar SCUs were designed and built, and two of them are currently in operation at the APS. In January 2018 a new helical SCU (HSCU) was installed on the storage ring at the APS. It has a 1.2 m-long magnet with bifilar winding that generates on its axis a single harmonic of about 6 keV x-rays. The magnet is housed in the newly designed compact cryostat equipped with four cryocoolers. The HSCU was extensively tested prior to its installation on the APS storage ring, and it demonstrated cryogenic and magnetic performance in accordance with the design specifications. The HSCU was rapidly and successfully commissioned, and in February 2018 it was transferred to user operations. Its performance as an x-ray radiation source has been studied and spectral characteristics confirmed. The HSCU is currently used to support unique scientific program at the APS.

Development of superconducting undulators continues at the Advanced Photon Source (APS). Two years after successful installation and commissioning of the first relatively short superconducting undulator “SCU0” in Sector 6 of the APS storage ring, the second 1.1-m-long superconducting undulator “SCU1” was installed in Sector 1 of the APS. The device has been in user operation since its commissioning in May 2015. This paper describes the magnetic and cryogenic design of the SCU1 together with the results of stand-alone cold tests. The SCU1’s magnetic and cryogenic performance as well as its operating experience in the APS storage ring are also presented.

A decade-long effort at the Advanced Photon Source (APS) of Argonne National Laboratory (ANL) on development of superconducting undulators culminated in December 2012 with the installation of the first superconducting undulator “SCU0” into Sector 6 of the APS storage ring. The device was commissioned in January 2013 and has been in user operation since. This paper presents the magnetic and cryogenic design of the SCU0 together with the results of stand-alone cold tests. The initial commissioning and characterization of SCU0 as well as its operating experience in the APS storage ring are described.

PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.

Amorphous Solid Dispersion (ASD) based formulations have been frequently used to improve the bioavailability of poorly water soluble drugs, however, common processes to produce ASDs are not feasible for Absorption, Distribution, Metabolism and Excretion (ADME) studies with radio-labeled Active Pharmaceutical Ingredients (API) due to the complications associated with radioactive material handling. Liquid formulations are routinely used to support the ADME studies, though bridging the bioperformance between a liquid formulation to the amorphous dosage form for poorly soluble compounds has not been well studied, and can be challenging due to the potentially rapid in vitro and in vivo recrystallization and precipitation. Here we report the development of a fit for purpose liquid formulation that could accommodate the radioactive API and provide comparable bioavailability relative to the amorphous formulation without the need for dose adjustment. A number of formulation approaches were explored and the prototype formulations were evaluated by dissolution and preclinical pharmacokinetic studies. A PolyEthylene Glycol 400 (PEG 400) based solution formulation impregnated with a polymer, HydroxyPropyl MethylCellulose Acetate Succinate-L (HPMCAS-L), was identified as the lead formulation. It was found that the bioavailability of the formulation can be compromised by the presence of undissolved crystalline seeds, and the inclusion of HPMCAS-L can mitigate this effect, as well as potentially facilitate the nanoparticle formation. During the study, it is also noted that although dissolution test is instrumental in the formulation development, the in vitro study over predicted the extent of in vivo precipitation for PEG 400 formulation containing no crystalline seeds., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: The deviation and spread of values measured by tensile strength tests should be significantly reduced by optimized axially pull-off-device., Material and Methods: Factors like geometry, roughness, surface texture and fit of the specimens, the luting procedure (mixing ratio, compacting pressure) were standardized and the precision of the axially load transmission during the tensile force application optimized. Copings of CoCr-alloy were luted using a provisional zinc-oxide eugenol and a glass-ionomer cement (n = 20 per group each) on 4°, respectively 8° titanium implant abutment analogs. 24 h after luting the copings were pulled off with the improved (IPD) and the previous non improved device (NIPD). Means, std. dev. and t-tests were calculated., Results: The stress- strain curves produced by the IPD showed a clear and linear relationship between stress and strain. The curves of the NIPD were ragged and chaotic. For both luting agents the means of the retentive force were considerable higher (p > 0.000) with IPD. However, the standard deviation was unimproved for the zinc oxide eugenol cement: IPD: 27%; NIPD: 27%, but significantly improved with glass ionomer: IPD: 16%, NIPD: 28%., Conclusion: The results from luting agents, which react like a solid body, may benefit from the optimized pull-off-device. Despite the fact that many factors in this investigation have been controlled, unknown flow characteristics of non-Newtonian-fluids like luting agents may have a considerable influence on the standard deviation of pull-off tests., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

An article's keywords are distinct because they represent what authors feel are the most important words in their papers. Combined, they can even shed light on which research topics in a field are popular (or less so). Here we conducted bibliometric keyword analyses of articles published in the journal, Intelligence (2000-2016). The article set comprised 916 keyword-containing papers. First, we analyzed frequencies to determine which keywords were most/least popular. Second, we analyzed Web of Science (WOS) citation counts for the articles listing each keyword and we ran regression analyses to examine the effect of keyword categories on citation counts. Third, we looked at how citation counts varied across time. For the frequency analysis, "g factor", "psychometrics/statistics", and "education" emerged as the keywords with the highest counts. Conversely, the WOS citation analysis showed that papers with the keywords "spatial ability", "factor analysis", and "executive function" had the highest mean citation values. We offer tentative explanations for the discrepant results across frequencies and citations. The analysis across time revealed several keywords that increased (or decreased) in frequency over 17 years. We end by discussing how bibliometric keyword analysis can detect research trends in the field, both now and in the past.

Identification of ligands that selectively activate the M 1 muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M 1 muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease., Competing Interests: The authors declare the following competing financial interest(s): Authors are current or former employees of Merck & Co., Inc., Kenilworth, NJ, U.S., and potentially own stock and/or hold stock options in the Company.

Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)