bluuebunny/crossref_metadata_2025 huggingface dataset:
Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study
Authors: Grachev Igor D. , Meyer Philipp M. , Becker Georg A. , Bronzel Marcus , Marsteller Doug , Pastino Gina , Voges Ole , Rabinovich Laura , Knebel Helena , Zientek Franziska , Rullmann Michael , Sattler Bernhard , Patt Marianne , Gerhards Thilo , Strauss Maria , Kluge Andreas , Brust Peter , Savola Juha-Matti , Gordon Mark F. , Geva Michal , Hesse Swen , Barthel Henryk , Hayden Michael R. , Sabri Osama
Published: September 2020

Purpose

Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD.

Methods

Using [18F] fluspidine PET (300 MBq, 0–90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [18F] fallypride PET (200 MBq, 0–210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot.

Results

S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%).

Conclusions

Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine’s mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders.

Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.
Newly diagnosed glioblastoma in geriatric (65 +) patients: impact of patients frailty, comorbidity burden and obesity on overall survival
Authors: Schneider Matthias , Potthoff Anna-Laura , Scharnböck Elisa , Heimann Muriel , Schäfer Niklas , Weller Johannes , Schaub Christina , Jacobs Andreas H. , Güresir Erdem , Herrlinger Ulrich , Vatter Hartmut , Schuss Patrick
Published: September 2020

Object

Increasing age is a known negative prognostic factor for glioblastoma. However, a multifactorial approach is necessary to achieve optimal neuro-oncological treatment. It remains unclear to what extent frailty, comorbidity burden, and obesity might exert influence on survival in geriatric glioblastoma patients. We have therefore reviewed our institutional database to assess the prognostic value of these factors in elderly glioblastoma patients.

Methods

Between 2012 and 2018, patients aged ≥ 65 years with newly diagnosed glioblastoma were included in this retrospective analysis. Patients frailty was analyzed using the modified frailty index (mFI), while patients comorbidity burden was assessed according to the Charlson comorbidity index (CCI). Body mass index (BMI) was used as categorized variable.

Results

A total of 110 geriatric patients with newly diagnosed glioblastoma were identified. Geriatric patients categorized as least-frail achieved a median overall survival (mOS) of 17 months, whereas most frail patients achieved a mOS of 8 months (p = 0.003). Patients with a CCI > 2 had a lower mOS of 6 months compared to patients with a lower comorbidity burden (12 months; p = 0.03). Multivariate analysis identified “subtotal resection” (p = 0.02), “unmethylated MGMT promoter status” (p = 0.03), “BMI < 30” (p = 0.04), and “frail patient (mFI ≥ 0.27)” (p = 0.03) as significant and independent predictors of 1-year mortality in geriatric patients with surgical treatment of glioblastoma (Nagelkerke's R2 0.31).

Conclusions

The present study concludes that both increased frailty and comorbidity burden are significantly associated with poor OS in geriatric patients with glioblastoma. Further, the present series suggests an obesity paradox in geriatric glioblastoma patients.
Medicines use review service in community pharmacies in Spain: REVISA project
Authors: García-Agua Soler Nuria , Gómez-Bermúdez Eugenia , Baixauli-Fernández Vicente J. , Bellver-Beltrán Sara , Velasco-Martínez Javier , García Ruiz Antonio J. , Jódar-Sánchez Francisco
Published: September 2020

Background Community pharmacy services play an important role in controlling some factors related to medicine use and patients can benefit from these services to improve the adherence and knowledge of their medications, besides to reduce medicine-related problems. Objective The aim of the REVISA project is to carry out a study on preliminary implementation of the medicines use review service in Spanish community pharmacies. Setting Sixty-four community pharmacies from all regions of Spain. Method A preliminary implementation, cross-sectional multicentre study was conducted using a convenience sample of voluntary community pharmacies. A structured interview enabled to pharmacists to obtain a better understanding of patient’s medicines use. Main outcome measure Medicines use review-related time and cost, satisfaction and willingness to pay. Results A total of 495 patients were enrolled. The mean age of the patients was 66.1 years, with the majority females (56.4%) and a mean consumption of 5.7 medicines. A total of 2811 medicines were evaluated and 550 referral recommendations were made (29.8% to Primary Care). The mean time employed by the pharmacists in the medicines use review service was 52.8 min (medicines use review-related cost of €17.27). Most patients expressed a high level of satisfaction with this service (98.5%) and a willingness to pay for it (84%). Conclusion Medicines use review service in community pharmacies in Spain can be delivered, that it appears to be acceptable to patients and that most patients said they would be willing to pay for it. This service may offer an opportunity to promote inter-professional collaboration between pharmacists and general practitioners.
Association of Clinical Assessments of Hand Function and Quantitative Ultrasound Metrics in First Carpometacarpal Osteoarthritis
Authors: Nwawka O. Kenechi , Weinstock-Zlotnick Gwen , Lin Bin , Ko Lydia M.
Published: September 2020

Background

Thumb carpometacarpal (CMC) osteoarthritis (OA), a degenerative condition affecting hand use, is typically evaluated through radiographs and clinical examination. Although this can determine treatment, it is difficult to evaluate functional limitations. Shear wave elastography (SWE) is a quantitative ultrasound technique that characterizes tissue stiffness.

Questions/Purposes

This pilot study aimed to establish data of the SWE findings in the thenar eminence muscles in patients with first CMC OA and correlate these findings with the clinical tests of hand function.

Methods

This cross-sectional study correlated the SWE stiffness of thenar eminence muscles to clinical tests of hand function in patients with first CMC OA and in asymptomatic control subjects, using Spearman's correlation coefficient. Mean SWE values of the thenar eminence muscles in patients were compared with those in control subjects. The study was performed in a non-profit tertiary care hospital setting. Patients and control subjects were recruited on a volunteer basis.

Results

SWE values in the abductor pollicis brevis and flexor pollicis brevis muscles showed moderate to very strong correlation with multiple measures of hand function. Mean SWE values of the thenar eminence muscles in first CMC OA patients were lower than those in asymptomatic control subjects.

Conclusions

Correlations between mean SWE values in the thenar eminence muscles and clinical measures of hand function suggest decreased function in subjects with less stiff thenar eminence muscles.
Abnormal brain activity patterns during spatial working memory task in patients with end-stage renal disease on maintenance hemodialysis: a fMRI study
Authors: Huang Jinzhuang , Xie Lei , Guo Ruiwei , Wang Jinhong , Lin Jinquan , Sun Zongbo , Duan Shouxing , Lin Zhirong , Li Hui , Ma Shuhua
Published: September 2020

Hemodialysis (HD) is associated with cognitive impairment in patients with end-stage renal disease (ESRD). However, the neural mechanism of spatial working memory (SWM) impairment in HD-ESRD patients remains unclear. We investigated the abnormal alterations in SWM-associated brain activity patterns in HD-ESRD patients using blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) technique during n-back tasks. Twenty-two HD-ESRD patients and 22 well-matched controls underwent an fMRI scan while undergoing a three-load n-back tasks with different difficulty levels. Cognitive and mental states were assessed using a battery of neuropsychologic tests. The HD-ESRD patients exhibited worse memory abilities than controls. Compared with the control group, the HD-ESRD patient group showed lower accuracy and longer response time under the n-back tasks, especially in the 2-back task. The patterns of brain activation changed under different working memory loads in the HD-ESRD patients, showing decreased activity in the right medial frontal gyrus and inferior frontal gyrus under 0-back and 1-back task, while more decreased activation in the bilateral frontal cortex, parietal lobule, anterior/posterior cingulate cortex and insula cortex under 2-back task. With the increase of task difficulty, the activation degree of the frontal and parietal cortex decreased. More importantly, we found that lower activation in frontal cortex and parietal lobule was associated with worse cognitive function in the HD-ESRD patients. These results demonstrate that the abnormal brain activity patterns of frontal cortex and parietal lobule may reflect the neural mediation of SWM impairment.
Social and competitive threat as situational factors moderating relationships between moral judgments and different components of authoritarian ideology
Authors: Radkiewicz Piotr
Published: September 2020

This paper presents research on the complexity of moral judgments underlying two components of authoritarian ideology: right-wing authoritarianism (RWA) and social dominance orientation (SDO). Based on previous research, it was expected that people who were high on moral intuitions of Ingroup/loyalty and Authority/respect (Ethics of Community) should be high on RWA, whereas people who were high on moral intuitions of Care/harm and Fairness/reciprocity (Ethics of Autonomy) should be low on SDO. In more detailed hypotheses it was assumed that such general relationships would be moderated by situational factors - threat to social order and competitive threat, respectively. Two experimental studies were conducted: the first with manipulation of the threat to social order, and the second with manipulation of the competitive threat (N = 180 and 150, respectively). Both studies showed that Ethics of Community predicted clear increase in RWA, while the Ethics of Autonomy predicted considerable decrease in SDO. However positive relationships between Ingroup/loyalty and RWA as well as between Authority/respect and RWA were strongly reinforced by threat to social order, whereas the negative relationships between Care/harm and SDO as well as between Fairness/reciprocity and SDO diminished under situationally induced aggressive ‘Darwinian’ competition. The Ethics of Community appears as a moral basis for development of right-wing authoritarianism, and this relationship is especially strong when the social order is perceived as threatened. On the other hand, the Ethics of Autonomy can be seen as a moral basis for inhibition of social dominance orientation, but it loses the moral relevance in strongly competitive social environment.
Walking in My Shoes: Imagined Synchrony Improves Attitudes Towards Out-groups
Authors: Atherton Gray , Cross Liam
Published: September 2020

People are prone to dividing others into the categories of ‘us’ and ‘them’. This can be particularly detrimental to minorities who may experience social exclusion, prejudice, and reduced access to equal opportunities. One method of improving intergroup relations is to create opportunities for contact. Common contact interventions have members of different groups meet and engage in conversation. There are also non-verbal embodied intergroup activities that produce the same effects. Previous work has shown that the pro-social effects of coordination may be linked to whether co-actors are classed as in or out-group members. The current study explored whether imagining walking in synchrony with in- or out-group members changed majority members’ attitudes towards those individuals. Imagining walking in synchrony fostered greater increases in empathy and decreases in negative attitudes only towards minority group members following imagined coordination (not in-groups). Implications and future directions are discussed.
Fibre optic sensing of ageing railway infrastructure enhanced with statistical shape analysis
Authors: Alexakis Haris , Lau F. Din-Houn , DeJong Matthew J.
Published: September 2020

Developing early-warning sensor-based maintenance systems for ageing railway infrastructure, such as masonry arch bridges, can be a challenging task due to the difficulty of identifying degradation/damage as the source of small, gradual changes in sensor data, as opposed to other environmental and loading effects. This paper offers a new method of applying statistical modelling and machine learning to enhance the interpretation of fibre optic sensing data, and, therefore, improve deterioration monitoring of railway infrastructure. Dynamic strain and temperature monitoring data between 2016 and 2019 from a fibre Bragg grating (FBG) network installed in a Victorian railway viaduct are first presented. The statistical shape analysis adopted in this study is modified to track changes in the shape of FBG signals directly linked to train speed and dynamic strain amplitudes. The method is complemented by a support vector machine, which is trained to identify different classes of trains. After distinguishing train types, dynamic strain was found to be clearly correlated to temperature, verifying previous findings. No correlation with train speed was observed. The integrated system is then able to compensate for changes in the structural performance due to variations in train loading and ambient temperature, and identify changes in dynamic deformation caused by degradation, in an order comparable to the signal noise (± 2 micro-strain). As a result, the new procedure is shown to be capable of detecting small magnitudes of local degradation well before this degradation manifests itself in typical global measures of response.
The application of deep learning for the classification of correct and incorrect SNP genotypes from whole-genome DNA sequencing pipelines
Authors: Kotlarz Krzysztof , Mielczarek Magda , Suchocki Tomasz , Czech Bartosz , Guldbrandtsen Bernt , Szyda Joanna
Published: September 2020

A downside of next-generation sequencing technology is the high technical error rate. We built a tool, which uses array-based genotype information to classify next-generation sequencing–based SNPs into the correct and the incorrect calls. The deep learning algorithms were implemented via Keras. Several algorithms were tested: (i) the basic, naïve algorithm, (ii) the naïve algorithm modified by pre-imposing different weights on incorrect and correct SNP class in calculating the loss metric and (iii)–(v) the naïve algorithm modified by random re-sampling (with replacement) of the incorrect SNPs to match 30%/60%/100% of the number of correct SNPs. The training data set was composed of data from three bulls and consisted of 2,227,995 correct (97.94%) and 46,920 incorrect SNPs, while the validation data set consisted of data from one bull with 749,506 correct (98.05%) and 14,908 incorrect SNPs. The results showed that for a rare event classification problem, like incorrect SNP detection in NGS data, the most parsimonious naïve model and a model with the weighting of SNP classes provided the best results for the classification of the validation data set. Both classified 19% of truly incorrect SNPs as incorrect and 99% of truly correct SNPs as correct and resulted in the F1 score of 0.21 — the highest among the compared algorithms. We conclude the basic models were less adapted to the specificity of a training data set and thus resulted in better classification of the independent, validation data set, than the other tested models.
Beyond VoF: alternative OpenFOAM solvers for numerical wave tanks
Authors: Schmitt Pál , Windt Christian , Davidson Josh , Ringwood John V. , Whittaker Trevor
Published: September 2020

The vast majority of numerical wave tank applications are solved using finite volume-based, volume of fluid methods. One popular numerical modelling framework is OpenFOAM and its two phase solvers, interFoam and interIsoFoam, enabling the simulation of a broad range of marine hydrodynamic phenomena. However, in many applications, certain aspects of the entire set of possible hydrodynamic phenomena are not of interest and the reduced complexity could allow the use of simpler, more computationally efficient solvers. One barrier for the application of such alternative solvers is the lack of suitable wavemaking and absorption capabilities, which this paper aims to address. A wavemaking and absorption methodology is presented, which can be applied to different solvers using the same fundamental concept. The implementation is presented for interFoam and interIsoFoam, as well as two other solvers whose use as numerical wave tanks has not previously been reported in the literature, shallowWaterFoam and potentialFreeSurfaceFoam. Parameter studies are performed to guide the user in the use of the methods. Example applications for two industrially relevant test cases are demonstrated; a multi-frequency wave packet focused at one position over flat bottom and regular waves propagating over a submerged shoal. All solvers yielded useful results, but some complex wave transformations in the shoal case were only resolved by the VoF methods. Alternative methods beyond the already well established VoF methods seem worth considering because potential for significant reductions in computational effort exist.
Autonomous dry stone
Authors: Johns Ryan Luke , Wermelinger Martin , Mascaro Ruben , Jud Dominic , Gramazio Fabio , Kohler Matthias , Chli Margarita , Hutter Marco
Published: September 2020

On-site robotic construction not only has the potential to enable architectural assemblies that exceed the size and complexity practical with laboratory-based prefabrication methods, but also offers the opportunity to leverage context-specific, locally sourced materials that are inexpensive, abundant, and low in embodied energy. We introduce a process for constructing dry stone walls in situ, facilitated by a customized autonomous hydraulic excavator. Cabin-mounted LiDAR sensors provide for terrain mapping, stone localization and digitization, and a planning algorithm determines the placement position of each stone. As the properties of the materials are unknown at the beginning of construction, and because error propagation can hinder the efficacy of pre-planned assemblies with non-uniform components, the structure is planned on-the-fly: the desired position of each stone is computed immediately before it is placed, and any settling or unexpected deviations are accounted for. We present the first result of this geometric- and motion-planning process: a 3-m-tall wall composed of 40 stones with an average weight of 760 kg.
Insubordinate Plasticity: Judith Butler and Catherine Malabou
Authors: Helberg Natalie
Published: September 2020

In this article, I explore the relationship betweenperformativity, as it appears in Judith Butler's work, andplasticity, as it appears in the work of Catherine Malabou. I argue that these concepts are isomorphic. Butler and Malabou both hold that resistance to contemporary forms of power, or “insubordination,” is contingent on a subject's ability to become other than what it is; Butler articulates this ability in terms of performativity, and Malabou articulates it in terms of plasticity. I reveal the social-constructivist dimension of Malabou's work while also making apparent the extent to which Butler's work, contrary to her own way of conceptualizing it, and hence surprisingly and uneasily, presupposes a biologically basic capacity for change. Plasticity is this biologically basic capacity. Both thinkers affirm the idea that insubordinate forms of transformation can be impeded by the discourse that conditions what a subject can think. I suggest that this is an insight that must be heeded, even as I seek to affirm a form of plasticity beyond discourse.
A Nation on Paper: Making a State in the Republic of Biafra
Authors: Daly Samuel Fury Childs
Published: September 2020

What role did law play in articulating sovereignty and citizenship in postcolonial Africa? Using legal records from the secessionist Republic of Biafra, this article analyzes the relationship between law and national identity in an extreme context—that of the Nigerian Civil War (1967–1970). Ideas about order, discipline, and legal process were at the heart of Biafra's sense of itself as a nation, and they served as the rhetorical justification for its secession from Nigeria. But they were not only rhetoric. In the turmoil of the ensuing civil war, Biafra's courts became the center of its national culture, and law became its most important administrative implement. In court, Biafrans argued over what behaviors were permissible in wartime, and judges used law to draw the boundaries of the new country's national identity. That law played this role in Biafra shows something broader about African politics: law, bureaucracy, and paperwork meant more to state-making than declensionist views of postcolonial Africa usually allow. Biafra failed as a political project, but it has important implications for the study of law in postcolonial Africa, and for the nation-state form in general.
Nationalist Spirits of Islamic Law after World War I: An Arab-Indian Battle of Fatwas over Alcohol, Purity, and Power
Authors: Halevi Leor
Published: September 2020

In 1922, one of the most famous Muslim scholars of modern times, the Syrian-Egyptian reformer Rashīd Riḍā, published in his journal a detailed fatwa in defense of alcohol. He did so in reaction to an obscure Indian jurist's fatwa that had warned Muslims not to use alcoholic products. On the surface, the authors of the fatwas appeared to be principally concerned with the right way to interpret sacred laws of purity and pollution. However, this article reveals that their disagreement had much to do with differing approaches to the politics of independence. Their divergence is intriguing because the cities where they lived, Cairo and Bombay, had just experienced the convulsions of anti-British consumer boycotts. And it emerged at a time when anti-imperial Muslim activists from the Middle East and South Asia were rallying together for a pan-Islamic cause—to prevent the final collapse of the caliphate. These movements swayed both Riḍā and his rival, who may well be described as Muslim nationalists. Yet they embraced radically different strategies for independence. One aimed for national purity, the other for national power. This discrepancy led to the battle of fatwas—a forgotten battle that is worth remembering because it suggests some of the difficulties that Muslim jurists of Arab or Indian ancestry faced during the interwar period when they tried to turn Islamic law into an effective nationalist discourse.
Overview of the SPARC tokamak
Authors: Creely A. J. , Greenwald M. J. , Ballinger S. B. , Brunner D. , Canik J. , Doody J. , Fülöp T. , Garnier D. T. , Granetz R. , Gray T. K. , Holland C. , Howard N. T. , Hughes J. W. , Irby J. H. , Izzo V. A. , Kramer G. J. , Kuang A. Q. , LaBombard B. , Lin Y. , Lipschultz B. , Logan N. C. , Lore J. D. , Marmar E. S. , Montes K. , Mumgaard R. T. , Paz-Soldan C. , Rea C. , Reinke M. L. , Rodriguez-Fernandez P. , Särkimäki K. , Sciortino F. , Scott S. D. , Snicker A. , Snyder P. B. , Sorbom B. N. , Sweeney R. , Tinguely R. A. , Tolman E. A. , Umansky M. , Vallhagen O. , Varje J. , Whyte D. G. , Wright J. C. , Wukitch S. J. , Zhu J. ,   the SPARC Team
Published: September 2020

The SPARC tokamak is a critical next step towards commercial fusion energy. SPARC is designed as a high-field ($B_0 = 12.2$T), compact ($R_0 = 1.85$m,$a = 0.57$m), superconducting, D-T tokamak with the goal of producing fusion gain$Q>2$from a magnetically confined fusion plasma for the first time. Currently under design, SPARC will continue the high-field path of the Alcator series of tokamaks, utilizing new magnets based on rare earth barium copper oxide high-temperature superconductors to achieve high performance in a compact device. The goal of$Q>2$is achievable with conservative physics assumptions ($H_{98,y2} = 0.7$) and, with the nominal assumption of$H_{98,y2} = 1$, SPARC is projected to attain$Q \approx 11$and$P_{\textrm {fusion}} \approx 140$MW. SPARC will therefore constitute a unique platform for burning plasma physics research with high density ($\langle n_{e} \rangle \approx 3 \times 10^{20}\ \textrm {m}^{-3}$), high temperature ($\langle T_e \rangle \approx 7$keV) and high power density ($P_{\textrm {fusion}}/V_{\textrm {plasma}} \approx 7\ \textrm {MW}\,\textrm {m}^{-3}$) relevant to fusion power plants. SPARC's place in the path to commercial fusion energy, its parameters and the current status of SPARC design work are presented. This work also describes the basis for global performance projections and summarizes some of the physics analysis that is presented in greater detail in the companion articles of this collection.
Physics basis for the ICRF system of the SPARC tokamak
Authors: Lin Y. , Wright J. C. , Wukitch S. J.
Published: September 2020

Ion cyclotron range of frequencies (ICRF) heating will be the sole auxiliary heating method on SPARC for both full-field (Bt0 ~ 12 T) D–T operation and reduced field (Bt0 ~ 8 T) D–D operation. Using the fast wave at ~120 MHz, good wave penetration and strong single-pass absorption is expected for D–T(3He), D(3He), D(H) and4He(H) heating scenarios. The dependences of wave absorption on${k_\parallel }$,3He concentration, resonance location, antenna poloidal location and losses on alpha particles and ash have been studied. The antenna loading has been assessed by comparison with the Alcator C-Mod antennae. An antenna spectrum of${k_\parallel }\sim 15\text{--}18\,{\textrm{m}^{ - 1}}$is shown to be good for both core absorption and edge coupling. For the control of impurity sources, the antenna straps are rotated ~10° to be perpendicular to the B field and the straps can run with different power levels in order to optimize the antenna spectrum and to minimize the image current on the antenna frame. Combining the physics constraints with the SPARC port design, maintenance requirement and contingency against antenna failure during D–T operation, we plan to mount on the inner wall of the vacuum vessel a total of 12 4-strap antennae in 6 ports while keeping 3-strap antennae that are insertable and removable on port plugs as the backup option.
Pearson and Reid Receive 2019 Norman L. Bowen Awards
Authors:   AGU
Published: September 2020

Graham Pearson and Mary R. Reid received the 2019 Norman L. Bowen Award at AGU’s Fall Meeting 2019, held 9–13 December in San Francisco, Calif. The award recognizes “outstanding contributions to the fields of volcanology, geochemistry, and petrology.”
On the Linkage Between Rossby Wave Phase Speed, Atmospheric Blocking, and Arctic Amplification
Authors: Riboldi Jacopo , Lott François , D'Andrea Fabio , Rivière Gwendal
Published: September 2020

It has been hypothesized that enhanced Arctic warming with respect to midlatitudes, known as Arctic amplification, had led to a deceleration of eastward propagating Rossby waves, more frequent atmospheric blocking, and extreme weather in recent decades. We employ a novel, daily climatology of Rossby wave phase speed between March 1979 and November 2018, based on upper‐level wind data, to test this hypothesis and describe phase speed variability. The diagnostic distinguishes between periods of enhanced or reduced eastward wave propagation and is related to the occurrence of blocking and extreme temperatures over midlatitudes. While remaining tied to the upper‐level geopotential gradient, decadal trends in phase speed did not accompany the observed reduction in the low‐level temperature gradient. These results confirm the link between low phase speeds and extreme temperature events, but indicate that Arctic amplification did not play a decisive role in modulating phase speed variability in recent decades.
Modeling Fluid Reinjection Into an Enhanced Geothermal System
Authors: Parisio Francesco , Yoshioka Keita
Published: September 2020

The manuscript analyzes the stimulation for an Enhanced Geothermal System development in Acoculco, Mexico. Using an analytical penny‐shaped hydraulic fracture model covering different propagation regimes, we computed the final fracture length and width by varying fluid properties with temperature. Our analysis indicates that for the given scenario, the fluid viscosity plays a minor role and instead flow rate and time of the stimulation are the controlling variables. We computed the fracture reopening as a consequence of water reinjection in the second stage of the stimulation through numerical computations based on the enriched discontinuity method. The computation shows that a single isolated fracture will not provide sufficient permeability, as the continuous injection will quickly fill and pressurize the crack. We demonstrate that the fracture needs to be connected to a permeable network to avoid excessive pressurization and achieve a commercially exploitable reservoir for Enhanced Geothermal System.
Year‐Round Measurements of the Irminger Current: Variability of a Two‐Core Current System Observed in 2014–2016
Authors: de Jong M. F. , de Steur L. , Fried N. , Bol R. , Kritsotalakis S.
Published: September 2020

The Irminger Current (IC), flowing northeastward along the western flank of the Reykjanes Ridge, is an important component in the overturning of the North Atlantic subpolar gyre. A 2‐year (2014–2016) time series from moored observations shows that the IC consists of two highly variable current cores. A subsampling experiment, using an ocean reanalysis, showed that this current's variability is adequately captured by the array. The two current cores contribute nearly equally to the mean volume transport. The total 2‐year mean transport was found to be 10.6 Sv with a standard deviation of daily (monthly) values of 9.2 Sv (4.4 Sv) and a standard error of 1.4 Sv. Mean heat and freshwater transport were 0.21 PW and −22.5 mSv, respectively (Sref = 34.92). The volume transport is strongest in spring, and the average over the first year (8.6 Sv) was lower than that of the second year (12.4 Sv), coinciding with an increase in the density gradient over the array in the second year. The variability of the total transport is dominated by variations in the western core, while the warmer, saltier eastern core contributes more to the heat and (negative) freshwater transport. During the two observed winters, which were marked by exceptional deep convection in the central Irminger Sea, mixed layer deepening down to 400 m depth and outcropping of the 27.7 kg m3 isopycnal were observed within the IC.
Nociceptive behavioural assessments in mouse models of temporomandibular joint disorders
Authors: Li Jun , Ma Kaige , Yi Dan , Oh Chun-do , Chen Di
Published: September 2020

Orofacial pain or tenderness is a primary symptom associated with temporomandibular joint (TMJ) disorders (TMDs). To understand the pathological mechanisms underlying TMDs, several mouse models have been developed, including mechanical stimulus-induced TMD and genetic mouse models. However, a lack of feasible approaches for assessing TMD-related nociceptive behaviours in the orofacial region of mice has hindered the in-depth study of TMD-associated mechanisms. This study aimed to explore modifications of three existing methods to analyse nociceptive behaviours using two TMD mouse models: (1) mechanical allodynia was tested using von Frey filaments in the mouse TMJ region by placing mice in specially designed chambers; (2) bite force was measured using the Economical Load and Force (ELF) system; and (3) spontaneous feeding behaviour tests, including eating duration and frequency, were analysed using the Laboratory Animal Behaviour Observation Registration and Analysis System (LABORAS). We successfully assessed changes in nociceptive behaviours in two TMD mouse models, a unilateral anterior crossbite (UAC)-induced TMD mouse model and a β-catenin conditional activation mouse model. We found that the UAC model and β-catenin conditional activation mouse model were significantly associated with signs of increased mechanical allodynia, lower bite force, and decreased spontaneous feeding behaviour, indicating manifestations of TMD. These behavioural changes were consistent with the cartilage degradation phenotype observed in these mouse models. Our studies have shown reliable methods to analyse nociceptive behaviours in mice and may indicate that these methods are valid to assess signs of TMD in mice.
Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease
Authors: Tesi Niccolò , van der Lee Sven J. , Hulsman Marc , Jansen Iris E. , Stringa Najada , van Schoor Natasja M. , Scheltens Philip , van der Flier Wiesje M. , Huisman Martijn , Reinders Marcel J. T. , Holstege Henne
Published: September 2020

Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.
Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer
Authors: Mout Lisanne , Moll Jan M. , Chen Mingqing , de Morrée Eleonora S. , de Ridder Corrina M. A. , Gibson Alice , Stuurman Debra , Aghai Ashraf , Erkens-Schulze Sigrun , Mathijssen Ron H. J. , Sparreboom Alex , de Wit Ronald , Lolkema Martijn P. , van Weerden Wytske M.
Published: September 2020

Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.
Human-like driving behaviour emerges from a risk-based driver model
Authors: Kolekar Sarvesh , de Winter Joost , Abbink David
Published: September 2020

Current driving behaviour models are designed for specific scenarios, such as curve driving, obstacle avoidance, car-following, or overtaking. However, humans can drive in diverse scenarios. Can we find an underlying principle from which driving behaviour in different scenarios emerges? We propose the Driver’s Risk Field (DRF), a two-dimensional field that represents the driver’s belief about the probability of an event occurring. The DRF, when multiplied with the consequence of the event, provides an estimate of the driver’s perceived risk. Through human-in-the-loop and computer simulations, we show that human-like driving behaviour emerges when the DRF is coupled to a controller that maintains the perceived risk below a threshold-level. The DRF model predictions concur with driving behaviour reported in literature for seven different scenarios (curve radii, lane widths, obstacle avoidance, roadside furniture, car-following, overtaking, oncoming traffic). We conclude that our generalizable DRF model is scientifically satisfying and has applications in automated vehicles.
Visible-light-driven amino acids production from biomass-based feedstocks over ultrathin CdS nanosheets
Authors: Song Song , Qu Jiafu , Han Peijie , Hülsey Max J. , Zhang Guping , Wang Yunzhu , Wang Shuai , Chen Dongyun , Lu Jianmei , Yan Ning
Published: September 2020

Chemical synthesis of amino acids from renewable sources is an alternative route to the current processes based on fermentation. Here, we report visible-light-driven amination of biomass-derived α-hydroxyl acids and glucose into amino acids using NH3 at 50 °C. Ultrathin CdS nanosheets are identified as an efficient and stable catalyst, exhibiting an order of magnitude higher activity towards alanine production from lactic acid compared to commercial CdS as well as CdS nanoobjects bearing other morphologies. Its unique catalytic property is attributed mainly to the preferential formation of oxygen-centered radicals to promote α-hydroxyl acids conversion to α-keto acids, and partially to the poor H2 evolution which is an undesired side reaction. Encouragingly, a number of amino acids are prepared using the current protocol, and one-pot photocatalytic conversion of glucose to alanine is also achieved. This work offers an effective catalytic system for amino acid synthesis from biomass feedstocks under mild conditions.
Strain localisation and failure at twin-boundary complexions in nickel-based superalloys
Authors: Zhang Zhenbo , Yang Zhibiao , Lu Song , Harte Allan , Morana Roberto , Preuss Michael
Published: September 2020

Twin boundaries (TBs) in Ni-based superalloys are vulnerable sites for failure in demanding environments, and a current lack of mechanistic understanding hampers the reliable lifetime prediction and performance optimisation of these alloys. Here we report the discovery of an unexpected γ″ precipitation mechanism at TBs that takes the responsibility for alloy failure in demanding environments. Using multiscale microstructural and mechanical characterisations (from millimetre down to atomic level) and DFT calculations, we demonstrate that abnormal γ″ precipitation along TBs accounts for the premature dislocation activities and pronounced strain localisation associated with TBs during mechanical loading, which serves as a precursor for crack initiation. We clarify the physical origin of the TBs-related cracking at the atomic level of γ″-strengthened Ni-based superalloys in a hydrogen containing environment, and provide practical methods to mitigate the adverse effect of TBs on the performance of these alloys.
Flexopiezoelectricity at ferroelastic domain walls in WO3 films
Authors: Yun Shinhee , Song Kyung , Chu Kanghyun , Hwang Soo-Yoon , Kim Gi-Yeop , Seo Jeongdae , Woo Chang-Su , Choi Si-Young , Yang Chan-Ho
Published: September 2020

The emergence of a domain wall property that is forbidden by symmetry in bulk can offer unforeseen opportunities for nanoscale low-dimensional functionalities in ferroic materials. Here, we report that the piezoelectric response is greatly enhanced in the ferroelastic domain walls of centrosymmetric tungsten trioxide thin films due to a large strain gradient of 106 m−1, which exists over a rather wide width (~20 nm) of the wall. The interrelationship between the strain gradient, electric polarity, and the electromechanical property is scrutinized by detecting of the lattice distortion using atomic scale strain analysis, and also by detecting the depolarized electric field using differential phase contrast technique. We further demonstrate that the domain walls can be manipulated and aligned in specific directions deterministically using a scanning tip, which produces a surficial strain gradient. Our findings provide the comprehensive observation of a flexopiezoelectric phenomenon that is artificially controlled by externally induced strain gradients.
Examining the impact of inducible ischemia on myocardial fibrosis and exercise capacity in hypertrophic cardiomyopathy
Authors: Malahfji Maan , Senapati Alpana , Debs Dany , Angulo Clara , Zhan Yang , Nagueh Sherif F. , Shah Dipan J.
Published: September 2020

Myocardial ischemia in hypertrophic cardiomyopathy (HCM) is associated with poor outcomes. Vasodilator stress cardiac magnetic resonance (CMR) can detect and quantitate inducible ischemia in HCM patients. We hypothesized that myocardial ischemia assessed by CMR is associated with myocardial fibrosis and reduced exercise capacity in HCM. In 105 consecutive HCM patients, we performed quantitative assessment of left ventricular volume and mass, wall thickness, segmental wall thickening percent, segmental late Gadolinium enhancement (LGE), and extracellular volume fraction (ECV). Time-signal intensity curves of first pass perfusion sequences were generated for each segment at stress and rest. A myocardial perfusion reserve index (MPRI) (stress/rest slope) was calculated. Patients who underwent an echocardiographic (n = 73) and cardiopulmonary exercise test (n = 37) within 30 days were included. The mean age was 53.2 ± 15.4 years; 60% were male, and 82 patients had asymmetric hypertrophy. Segments with end diastolic thickness ≥ 1.2 cm had a higher burden of LGE (4.1% vs 0.5% per segment), reduced MPRI (2.6 ± 1.5 vs 3.1 ± 1.8) and reduced thickening percent (48.9 ± 41.7% vs. 105.3 ± 59.5%), (P < 0.0001 for all comparisons). Patients with ischemia (any segment with MPRI < 2) were more likely to have dynamic left ventricular outflow tract (LVOT) obstruction (63.3% vs 36.7%, P = 0.01), to be smokers (17% vs 6.9%, P = 0.04), and had a higher ECV (30% vs 28%, P = 0.04). The total LGE burden was similar between the two groups (P = 0.47). Increasing ischemia burden (number of segments with MPRI < 2) was associated with worsened ventilatory efficiency (VE/VCO2) (P < 0.001) but not peak oxygen consumption or anerobic threshold (P > 0.2). In a patient-level multivariable logistic regression model, only LVOT obstruction remained a significant predictor of ischemia burden (P = 0.03). Myocardial ischemia by CMR is associated with myocardial segmental dysfunction and interstitial fibrosis, as assessed by ECV, in HCM patients, even in segments free of LGE. Conversely, quantitative ischemia burden was not associated with replacement fibrosis as assessed by total LGE burden. Patients with ischemia had greater prevalence of dynamic LVOT obstruction; and in a subset of patients with cardiopulmonary exercise testing, ischemia burden was associated with worsened ventilatory efficiency.
Safety and functional enrichment of gut microbiome in healthy subjects consuming a multi-strain fermented milk product: a randomised controlled trial
Authors: Alvarez Anne-Sophie , Tap Julien , Chambaud Isabelle , Cools-Portier Stéphanie , Quinquis Laurent , Bourlioux Pierre , Marteau Philippe , Guillemard Eric , Schrezenmeir Juergen , Derrien Muriel
Published: September 2020

Many clinical studies have evaluated the effect of probiotics, but only a few have assessed their dose effects on gut microbiota and host. We conducted a randomized, double-blind, controlled intervention clinical trial to assess the safety (primary endpoint) of and gut microbiota response (secondary endpoint) to the daily ingestion for 4 weeks of two doses (1 or 3 bottles/day) of a fermented milk product (Test) in 96 healthy adults. The Test product is a multi-strain fermented milk product, combining yogurt strains and probiotic candidate strains Lactobacillus paracasei subsp. paracasei CNCM I-1518 and CNCM I-3689 and Lactobacillus rhamnosus CNCM I-3690. We assessed the safety of the Test product on the following parameters: adverse events, vital signs, hematological and metabolic profile, hepatic, kidney or thyroid function, inflammatory markers, bowel habits and digestive symptoms. We explored the longitudinal gut microbiota response to product consumption and dose, by 16S rRNA gene sequencing and functional contribution by shotgun metagenomics. Safety results did not show any significant difference between the Test and Control products whatever the parameters assessed, at the two doses ingested daily over a 4-week-period. Probiotic candidate strains were detected only during consumption period, and at a significantly higher level for the three strains in subjects who consumed 3 products bottles/day. The global structure of the gut microbiota as assessed by alpha and beta-diversity, was not altered by consumption of the product for four weeks. A zero-inflated beta regression model with random effects (ZIBR) identified a few bacterial genera with differential responses to test product consumption dose compared to control. Shotgun metagenomics analysis revealed a functional contribution to the gut microbiome of probiotic candidates.