bluuebunny/crossref_metadata_2025 huggingface dataset:
A methodology for multilayer networks analysis in the context of open and private data: biological application
Authors: Malek Maria , Zorzan Simone , Ghoniem Mohammad
Published: July 2020

Recently, an increasing body of work investigates networks with multiple types of links. Variants of such systems have been examined decades ago in disciplines such as sociology and engineering, but only recently have they been unified within the framework of multilayer networks. In parallel, many aspects of real systems are increasingly and routinely sensed, measured and described, resulting in many private, but also open data sets. In many domains publicly available repositories of open data sets constitute a great opportunity for domain experts to contextualise their privately generated data compared to publicly available data in their domain. We propose in this paper a methodology for multilayer network analysis in order to provide domain experts with measures and methods to understand, evaluate and complete their private data by comparing and/or combining them with open data when both are modelled as multilayer networks. We illustrate our methodology through a biological application where interactions between molecules are extracted from open databases and modelled by a multilayer network and where private data are collected experimentally. This methodology helps biologists to compare their private networks with the open data, to assess the connectivity between the molecules across layers and to compute the distribution of the identified molecules in the open network. In addition, the shortest paths which are biologically meaningful are also analysed and classified.
Antwort auf „Ungleiche Grundschulen und die meritokratische Fiktion im deutschen Schulsystem“ von Georg Breidenstein
Authors: Helbig Marcel
Published: July 2020

Der vorliegende Beitrag setzt sich mit dem Beitrag von Georg Breidenstein „Ungleiche Grundschulen und die meritokratische Fiktion im deutschen Schulsystem“ auseinander. Dabei werden viele Aspekte von Breidenstein unterstrichen. Allerdings wiederspricht der Beitrag in einem zentralen Punkt, dass die soziale Ungleichverteilung von Schülerinnen und Schülern auf den Grundschulen dem meritokratischen Prinzip widerspricht. Vielmehr ist der Blick auf soziale Ungleichheiten zu richten, die aus den familiären Kontexten entstehen. Diese wiedersprechen Breidensteins Logik folgend dem meritokratischen Prinzip deutlich stärker als die soziale Ungleichverteilung in Grundschulen. Insgesamt ergänzt der vorliegende Beitrag Breidensteins Argumentation um eine gesamtgesellschaftliche Perspektive auf Bildungsungleichheiten. Denn die Fokussierung auf das, was Grundschulen leisten können, um soziale Ungleichheiten abzumildern, verkennt die eigentlichen Treiber von sozial ungleichen Grundschulen: Wohnungsbaupolitik, Einkommensungleichheit und sozial ungleiche Zuwanderung. Im Ergebnis führen diese Aspekte zu steigender sozialer Segregation in unseren Städten und zu einer massiven Ballung armer Kinder in einzelnen Grundschulen. Bildungspolitik, Schulen und Lehrer allein können diesen Ungleichheiten kaum entgegenwirken, weil sie nicht an den wahren Gründen von Ungleichheit ansetzen.
Sozialräumliche Segregation und Bildungsungleichheiten in der Grundschule – eine Bestandsaufnahme
Authors: Parade Ralf , Heinzel Friederike
Published: July 2020

Während bundesweit das 100-jährige Bestehen der Grundschule zelebriert und dabei häufig an das Gründungsversprechen erinnert wird, es handele sich um eine „Schule für alle“, wird im Beitrag auf Basis eines Überblicks empirischer Studien zu sozialräumlicher Segregation in Deutschland und damit zusammenhängenden Bildungsungleichheiten in der Grundschule geprüft, inwiefern jenes Credo der aktuellen empirischen Befundlage standhält. In der Folge wird argumentiert, dass sich künftig die Grundschulpädagogik vermehrt der Problematik anzunehmen hat, um dafür Sorge zu tragen, dass sich die Grundschule dem annähert, was sie seit jeher zu sein beansprucht.
Fatigue analysis of a bridge deck using the peaks-over-threshold approach with application to the Millau viaduct
Authors: Nesterova Mariia , Schmidt Franziska , Soize Christian
Published: July 2020

Usually, to estimate the fatigue life of structural details in existing bridges, fatigue damage assessed with monitoring data is extrapolated linearly in time. In this study, a methodology is proposed for predicting the numbers of fatigue cycles with the peaks-over-threshold approach. On the other side, this POT approach, which is based on extreme values, is, as usually, also used to predict the load effects of extreme amplitude. This provides an innovative method to predict fatigue damage, which considers the initial distribution of numbers of cycles over time. It may account for traffic growth in volume and mass. This paper shows the comparison between reliability indexes assessed with the proposed method and the linear extrapolation.
Innovation in the Mining Industry: Technological Trends and a Case Study of the Challenges of Disruptive Innovation
Authors: Sánchez Felipe , Hartlieb Philipp
Published: July 2020

Innovation plays a critical role in the mining industry as a tool to improve the efficiency of its processes, to reduce costs, but also to meet the increasing social and environmental concerns among communities and authorities. Technological progress has also been crucial to allow the exploitation of new deposits in more complex scenarios: lower ore grades, extreme weather conditions, deeper deposits, harder rock mass, and high-stress environments. This paper discusses the importance of innovation for the mining industry and describes the mechanisms by which it is carried out. It includes a review of the drivers and actors involved and current trends. The digital transformation process that the industry is going through is analyzed, along with other relevant trends that are likely to shape the mining of the future. Additionally, a case study is presented to illustrate the technical and economic implications of developing a disruptive innovation project.
Assessment of the Association of Cannabis on Female Sexual Function With the Female Sexual Function Index
Authors: Kasman Alex M. , Bhambhvani Hriday P. , Wilson-King Genester , Eisenberg Michael L.
Published: July 2020

Introduction

Cannabis use has increased in the last decade, and the impact of cannabis on female sexual function remains unclear.

Aim

To assess the impact of frequency of use, chemovar (tetrahydrocannabinol, cannabinol, or both) type, and method of consumption on female sexual function among cannabis users.

Methods

Adults who visited a single-partner cannabis dispensary’s locations were invited to participate in an uncompensated, anonymous online survey October 20, 2019 and March 12, 2020. The survey assessed baseline demographics, health status, cannabis use habits as well as used the validated Female Sexual Function Index (FSFI) to assess sexual function.

Main Outcome Measure

The main outcomes of this study are the total FSFI score (sexual dysfunction cutoff <26.55) and subdomain scores including desire, arousal, lubrication, orgasm, satisfaction, and pain.

Results

A total of 452 women responded with the majority between the ages of 30–49 years (54.7%) and in a relationship or married (81.6%). Of them,72.8% reported using cannabis more than 6 times per week, usually through smoking flower (46.7%). Women who reported more cannabis use, reported higher FSFI scores (29.0 vs 26.7 for lowest vs highest frequencies of reported use, P = .003). Moreover, an increase in cannabis use frequency by one additional use per week was associated with an increase in total FSFI (β = 0.61, P = .0004) and subdomains including desire domain (P = .02), arousal domain (P = .0002), orgasm domain (P = .002), and satisfaction domain (P = .003). For each additional step of cannabis use intensity (ie, times per week), the odds of reporting female sexual dysfunction declined by 21% (odds ratio: 0.79, 95% confidence interval: 0.68–0.92, P = .002). Method of consumption of cannabis and chemovar type did not consistently impact FSFI scores or odds of sexual dysfunction.

Conclusion

Increased frequency of marijuana use is associated with improved sexual function among female users, whereas chemovar type, method of consumption, and reason for use does not impact outcomes.
Development of SC‐10: A psychometrically equivalent Singapore Mandarin disyllabic word list for clinical speech audiometry use
Authors: Lee Gary Jek Chong , Lee Steven Lock Hey
Published: July 2020

Objective

The aim of this study is to develop and evaluate a set of psychometrically equivalent disyllabic wordlist (SC‐10) in Singapore Mandarin for clinical use.

Study design

A preliminary set of 1000 words were obtained from a dictionary of frequently used words by Singapore students. Ten native judges rate the familiarity level of each word. This is followed by a face‐to‐face public survey to rank the shortlisted word set from most to least familiar. The final 108 disyllabic words were recorded by a native female talker. 20 normal hearing subjects were used to obtain the percentage of correct word recognition at 24 intensity levels (−10 dB HL to 26 dB HL in 2 dB increment). Psychometric function slopes were calculated for each word. 100 words were eventually chosen and assigned into ten 10‐word lists based on a psychometric balancing protocol. Minor digital adjustments were made to the intensity of each wordlist to improve their auditory homogeneity.

The developed SC‐10 wordlists were validated by a separate group of 25 normal hearing subjects. Test‐retest reliability was carried out on 20 out of 25 participants at the selected intensity levels (SRT‐5, SRT, SRT+5).

Results

The calculated regression slopes in the psychometric functions for the ten lists are between 8.0 and 9.8%/dB. Single factor ANOVA analysis showed no significant difference in both the mean intensity required to obtain 50% recognition score (f = 0.109,df = 9,p = 0.999) and the slopes of the psychometric functions (f = 0.078,df = 9,p = 0.999) between the ten word lists. List validation on 25 normal hearing participants (PTA = 11.0 dB HL,SD = 4.3) showed a mean speech recognition threshold (SRT) of 9.3 dB HL (SD = 3.5)and regression slope of 8.395%/dB. Quadratic regression analysis showed a positive correlation (r2 = 0.923) between presentation level and word recognition score (WRS). The difference between PTA and SRT of each subject all fall within the clinically acceptable difference of 10 dB HL. Test‐retest reliability, carried out on 20 subjects at three levels (SRT‐5, SRT, and SRT+5 dB), showed no significance difference between word recognition score when the same participant is tested again at the same intensity level using a different wordlist.

Conclusion

All in all, it shows that the SC‐10 speech materials are valid for clinical use for Mandarin speech audiometry in Singapore.
Snow-ice contribution to the structure of sea ice in the Amundsen Sea, Antarctica
Authors: Tian Lijun , Gao Yongli , Weissling Blake , Ackley Stephen F.
Published: July 2020

The widespread occurrence of snow-ice formation on the pack ice plays a critical role in the mass balance of Antarctic sea ice. The stable isotope composition, ice texture and salinity of eight ice cores, obtained from the Amundsen Sea during the Oden Southern Ocean 2010/11 expedition from late December 2010 to January 2011, were investigated to illustrate the snow-ice growth process and its contribution to sea-ice development. Most previous research has utilized δ18O as an index tracer to determine the percentages of core length that contain meteoric water, i.e. snow ice. However, this standard practice of snow-ice identification might be biased due to normally low-resolution isotopic measurements and mixing/diffusion processes between the snow ice and underlying ice layers. Snow-ice contributions in these ice cores based instead on an updated isotope mixing model are also presented. Depth profiles of ice texture and salinity are described to serve as representations of the structures of these ice cores. Our isotope mixing model produced an average of 15.9% snow-ice contribution for pack ice in the Amundsen Sea, and meteoric water occupying 40% of snow-ice mass for all ice stations. These results are compared to previous investigations of snow-ice occurrence around Antarctica.
Early Impact of the COVID-19 Pandemic on Acute Stroke Treatment Delays
Authors: Neves Briard Joel , Ducroux Célina , Jacquin Grégory , Alesefir Walid , Boisseau William , Daneault Nicole , Deschaintre Yan , Eneling Johanna , Gioia Laura C. , Iancu Dana , Odier Céline , Raymond Jean , Roy Daniel , Stapf Christian , Weill Alain , Poppe Alexandre Y.
Published: July 2020

This is an observational cohort study comparing 156 patients evaluated for acute stroke between March 30 and May 31, 2020 at a comprehensive stroke center with 138 patients evaluated during the corresponding time period in 2019. During the pandemic, the proportion of COVID-19 positive patients was low (3%), the time from symptom onset to hospital presentation was significantly longer, and a smaller proportion of patients underwent reperfusion therapy. Among patients directly evaluated at our institution, door-to-needle and door-to-recanalization metrics were significantly longer. Our findings support concerns that the current pandemic may have a negative impact on the management of acute stroke.
Introduction to the Special Issue on Best Papers, International Competition of Young Criminologists 2019
Authors: Viano Emilio C.
Published: July 2020

An international competition was held in 2019 in conjunction with the 19th World Congress of Criminology. It was co-sponsored by the Education for Justice (E4J) Programme of the United Nations Office on Drugs and Crime (UNODC) and the International Society of Criminology. Ten papers were selected as winners by an international jury. Their authors received financial support to attend, be recognized and present their work at the Congress. This editorial piece presents details about the competition and the winning papers.
The South African Cash-In-Transit Heist Enterprise: Managing its Wellspring and Concatenation
Authors: Thobane Mahlogonolo Stephina
Published: July 2020

South African cash-in-transit (CIT) robberies appear to be in a state of flux. According to the Minister of Police, Mr Bheki Cele, the incidence of these crimes has steadily decreased due to rapid response by the police in arresting more than 200 suspects between June and November 2018. Given the rhizomatic, eclectic nature of this crime type – and possible mechanical linkages and/or linear causality within the genesis of the crime – it is debatable whether arrests and incarceration offer a long-term solution. CIT robbers interviewed for this study reported that they were career criminals, less likely to be rehabilitated and that incarceration was only an interruption to their career. These findings were backed by life-course theories. This article contends that if the South African Criminal Justice System wants to curb CIT robberies, an investigation into proactive methods for combating the crime should be developed and risk reduction strategies crafted. After investigating possible causes of CIT robberies, this research made recommendations based on holistic measures involving the public, family, and various government and non-governmental departments. The research was conducted for a Master of Arts degree in Criminology. A mixed-method approach was followed and 40 incarcerated offenders who committed robbery with aggravating circumstances participated in the study.
RETHINKING ASSIGNABILITY
Authors: MacMahon Paul
Published: July 2020

When should a contractual right be assignable to a non-party? English law's answer to this question is complex, and many of its rules are difficult to justify. In some respects, the law appears unreasonably pro-assignment, whereas sometimes it denies assignability to rights that should be assignable. This article contends that, in developing the law of assignability, the judiciary and Parliament have relied on a series of dubious ideas that deviate from the law's usual approach to contracts, and the current law rests partly on intuitive policy rationales that do not withstand scrutiny. The main aim of the article is to propose a new framework for thinking about the law of assignability that is more closely aligned with general ideas about contract law.
Dorsolateral prefrontal cortex and amygdala function during cognitive reappraisal predicts weight restoration and emotion regulation impairment in anorexia nervosa
Authors: Steward Trevor , Martínez-Zalacaín Ignacio , Mestre-Bach Gemma , Sánchez Isabel , Riesco Nadine , Jiménez-Murcia Susana , Fernández-Formoso Jose A , Veciana de las Heras Misericordia , Custal Nuria , Menchón Jose M , Soriano-Mas Carles , Fernandez-Aranda Fernando
Published: July 2020

Background

Although deficits in affective processing are a core component of anorexia nervosa (AN), we lack a detailed characterization of the neurobiological underpinnings of emotion regulation impairment in AN. Moreover, it remains unclear whether these neural correlates scale with clinical outcomes.

Methods

We investigated the neural correlates of negative emotion regulation in a sample of young women receiving day-hospital treatment for AN (n= 21) and healthy controls (n= 21). We aimed to determine whether aberrant brain activation patterns during emotion regulation predicted weight gain following treatment in AN patients and were linked to AN severity. To achieve this, participants completed a cognitive reappraisal paradigm during functional magnetic resonance imaging. Skin conductance response, as well as subjective distress ratings, were recorded to corroborate task engagement.

Results

Compared to controls, patients with AN showed reduced activation in the dorsolateral prefrontal cortex (dlPFC) during cognitive reappraisal [pFWE<0.05, threshold-free cluster enhancement (TFCE) corrected]. Importantly, psycho–physiological interaction analysis revealed reduced functional connectivity between the dlPFC and the amygdala in AN patients during emotion regulation (pFWE<0.05, TFCE corrected), and dlPFC-amygdala uncoupling was associated with emotion regulation deficits (r= −0.511,p= 0.018) and eating disorder severity (r= −0.565,p= .008) in the AN group. Finally, dlPFC activity positively correlated with increases in body mass index (r= 0.471,p= 0.042) and in body fat mass percentage (r= 0.605,p= 0.008) following 12 weeks of treatment.

Conclusions

Taken together, our findings indicate that individuals with AN present altered fronto-amygdalar response during cognitive reappraisal and that this response may serve as a predictor of response to treatment and be linked to clinical severity.
“Reconsidering the 1918–19 Influenza Pandemic in the Age of COVID-19”
Authors: Nichols Christopher McKnight , Bristow Nancy , Ewing E. Thomas , Gabriel Joseph M. , Montoya Benjamin C. , Outka Elizabeth
Published: July 2020

For many us who have studied, researched, written, and taught about the influenza pandemic of 1918–19, the current period of the global viral pandemic is eerily and unpleasantly familiar. Today, the rapid global spread of a virus has prompted policies calling for widespread closures, social distancing, constant handwashing, and public mask wearing in additional to other non-pharmaceutical interventions (NPIs). We have also seen pushback and resistance to these directives as well as substantial mismanagement of resources and a flood of misinformation. Much health policy has been inconsistently set at the local rather than federal level. These responses to our current pandemic closely mirror those to the pandemic 102 years ago.
Time of Emergence and Large Ensemble Intercomparison for Ocean Biogeochemical Trends
Authors: Schlunegger Sarah , Rodgers Keith B. , Sarmiento Jorge L. , Ilyina Tatiana , Dunne John P. , Takano Yohei , Christian James R. , Long Matthew C. , Frölicher Thomas L. , Slater Richard , Lehner Flavio
Published: July 2020

Anthropogenically forced changes in ocean biogeochemistry are underway and critical for the ocean carbon sink and marine habitat. Detecting such changes in ocean biogeochemistry will require quantification of the magnitude of the change (anthropogenic signal) and the natural variability inherent to the climate system (noise). Here we use Large Ensemble (LE) experiments from four Earth system models (ESMs) with multiple emissions scenarios to estimate Time of Emergence (ToE) and partition projection uncertainty for anthropogenic signals in five biogeochemically important upper‐ocean variables. We find ToEs are robust across ESMs for sea surface temperature and the invasion of anthropogenic carbon; emergence time scales are 20–30 yr. For the biological carbon pump, and sea surface chlorophyll and salinity, emergence time scales are longer (50+ yr), less robust across the ESMs, and more sensitive to the forcing scenario considered. We find internal variability uncertainty, and model differences in the internal variability uncertainty, can be consequential sources of uncertainty for projecting regional changes in ocean biogeochemistry over the coming decades. In combining structural, scenario, and internal variability uncertainty, this study represents the most comprehensive characterization of biogeochemical emergence time scales and uncertainty to date. Our findings delineate critical spatial and duration requirements for marine observing systems to robustly detect anthropogenic change.
Uncertainties in Turbulent Statistics and Fluxes of CO2 Associated With Density Effect Corrections
Authors: Gao Zhongming , Liu Heping , Arntzen Evan , Mcfarland Douglas P. , Chen Xingyuan , Huang Maoyi
Published: July 2020

Density effect corrections (DECs) are applied to adjust raw CO2 fluxes measured by eddy covariance (EC) systems with open‐path gas analyzers. DEC is also required for adjusting the measured CO2 concentration fluctuations to obtain the adjusted CO2 concentrations for analyzing turbulent statistics or quantifying fluxes. However, our data show that the power spectra of the DEC‐adjusted CO2 concentrations are distorted in the high‐frequency range, as compared with the corresponding spectra of temperature and water vapor density. This contradicts the similarity behavior of scalars, as suggested by Monin‐Obukhov similarity theory. It is demonstrated that such a distortion is caused by the DEC‐induced spikes in the DEC‐adjusted CO2, altering turbulent statistics of CO2 and scalar similarity between CO2 and other scalars. Our results suggest that CO2 fluxes are overestimated by applying DEC especially under high Bowen ratio conditions, potentially leading to substantial uncertainties in long‐term ecosystem carbon exchange in dry regions.
Improving Wind Forecasts in the Lower Stratosphere by Distilling an Analog Ensemble Into a Deep Neural Network
Authors: Candido Salvatore , Singh Aakanksha , Delle Monache Luca
Published: July 2020

We discuss improving forecasts of winds in the lower stratosphere using machine learning to postprocess the output of the European Centre for Medium‐Range Weather Forecasts (ECMWF) Integrated Forecast System. We postprocess global three‐dimensional predictions and demonstrate distilling the analog ensemble (AnEn) method into a deep neural network, which reduces postprocessing latency to near zero maintaining increased forecast skill. This approach reduces the error with respect to ECMWF high‐resolution deterministic prediction between 2–15% for wind speed and 15–25% for direction and is on par with ECMWF ensemble (ENS) forecast skill to hour 60. Verifying with Loon data from stratospheric balloons, AnEn has 20% lower error than ENS for wind speed and 15% for wind direction, despite significantly lower real‐time computational cost to ENS. Similar performance patterns are reported for probabilistic predictions, with larger improvements of AnEn with respect to ENS. We also demonstrate that AnEn generates a calibrated probabilistic forecast.
Determination of the Configurations of Boundaries in Space
Authors: Shen Chao , Zeng Gang , Zhang Chi , Rong Zhaojin , Dunlop M. , Russell C. T. , Escoubet C. Philippe , Ren Nian
Published: July 2020

This research aims to determine the geometrical configurations of boundary surfaces in the space environment, based on multiple spacecraft measurements. To achieve this, the Normal Field Analysis (NFA) method is presented here. With multipoint observations, the three‐dimensional gradient of the normal of boundary layers can be obtained, and the principal curvatures and principal directions of the surfaces can be deduced. The correctness of the method is then verified. Two initial applications have been carried out. The first is to determine the geometrical features of the Earth's bow shock where it is found that, with a one‐dimensional approximation, the surface of the bow shock has a rotational conicoid shape with eccentricity about 0.82, consistent with previous studies. Second, the method is also used to analyze two magnetotail dipolarization fronts showing that the dipolarization fronts are hyperbolic paraboloids or saddle surfaces with negative Gaussian curvatures. The south‐north scale of the dipolarization fronts is about 0.835–3.98 RE, and the dawn‐dusk/azimuthal scale is about 1.58–1.92 RE, confirming previous studies. The method presented can also be applied to investigate the geometries of the magnetopause, plasmapause, and other boundaries.
Groundwater Flow to Gale Crater in an Episodically Warm Climate
Authors: Baum Mark , Wordsworth Robin
Published: July 2020

Orbiter and rover data have revealed a complex and intermittent hydrological history in Gale Crater on Mars, where habitable environments appear to have endured for at least thousands of years. The intermittency may be the result of a dominantly cold climate punctuated by geologically brief periods of warmth and active hydrology. However, the time required to establish an integrated hydrological cycle in a warming climate is difficult to ascertain and has not been thoroughly investigated. Here we model the transient evolution of groundwater flow and subsurface temperature, the slowest evolving components of the hydrological cycle, during a warm departure from cold conditions. We find that tens of thousands of years are likely required before groundwater could be a meaningful source for large lakes in Gale. With highly favorable conditions, primarily high permeability, significant flow might develop in thousands of years. This implies that surface water dominates during the beginning of a warm phase. Annual mean surface temperatures in Gale below 290 K would likely leave the nearby highlands frozen at the surface. In that case, deep aquifers beneath a highlands permafrost layer could deliver water to Gale, where low temperatures would have reduced evaporation.
Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis
Authors: Kato Masaki , Hori Hikaru , Inoue Takeshi , Iga Junichi , Iwata Masaaki , Inagaki Takahiko , Shinohara Kiyomi , Imai Hissei , Murata Atsunobu , Mishima Kazuo , Tajika Aran
Published: July 2020

A significant clinical issue encountered after a successful acute major depressive disorder (MDD) treatment is the relapse of depressive symptoms. Although continuing maintenance therapy with antidepressants is generally recommended, there is no established protocol on whether or not it is necessary to prescribe the antidepressant used to achieve remission. In this meta-analysis, the risk of relapse and treatment failure when either continuing with the same drug used to achieved remission or switching to a placebo was assessed in several clinically significant subgroups. The pooled odds ratio (OR) (±95% confidence intervals (CI)) was calculated using a random effects model. Across 40 studies (n = 8890), the relapse rate was significantly lower in the antidepressant group than the placebo group by about 20% (OR = 0.38, CI: 0.33–0.43, p < 0.00001; 20.9% vs 39.7%). The difference in the relapse rate between the antidepressant and placebo groups was greater for tricyclics (25.3%; OR = 0.30, CI: 0.17–0.50, p < 0.00001), SSRIs (21.8%; OR = 0.33, CI: 0.28–0.38, p < 0.00001), and other newer agents (16.0%; OR = 0.44, CI: 0.36–0.54, p < 0.00001) in that order, while the effect size of acceptability was greater for SSRIs than for other antidepressants. A flexible dose schedule (OR = 0.30, CI: 0.23–0.48, p < 0.00001) had a greater effect size than a fixed dose (OR = 0.41, CI: 0.36–0.48, p < 0.00001) in comparison to placebo. Even in studies assigned after continuous treatment for more than 6 months after remission, the continued use of antidepressants had a lower relapse rate than the use of a placebo (OR = 0.40, CI: 0.29–0.55, p < 0.00001; 20.2% vs 37.2%). The difference in relapse rate was similar from a maintenance period of 6 months (OR = 0.41, CI: 0.35–0.48, p < 0.00001; 19.6% vs 37.6%) to over 1 year (OR = 0.35, CI: 0.29–0.41, p < 0.00001; 19.9% vs 39.8%). The all-cause dropout of antidepressant and placebo groups was 43% and 58%, respectively, (OR = 0.47, CI: 0.40–0.55, p < 0.00001). The tolerability rate was ~4% for both groups. The rate of relapse (OR = 0.32, CI: 0.18–0.64, p = 0.0010, 41.0% vs 66.7%) and all-cause dropout among adolescents was higher than in adults. To prevent relapse and treatment failure, maintenance therapy, and careful attention for at least 6 months after remission is recommended. SSRIs are well-balanced agents, and flexible dose adjustments are more effective for relapse prevention.
ALDH2 contributes to melatonin-induced protection against APP/PS1 mutation-prompted cardiac anomalies through cGAS-STING-TBK1-mediated regulation of mitophagy
Authors: Wang Shuyi , Wang Lin , Qin Xing , Turdi Subat , Sun Dongdong , Culver Bruce , Reiter Russel J. , Wang Xiaoming , Zhou Hao , Ren Jun
Published: July 2020

Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease (AD), although neither precise etiology nor effective treatment is available. This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice, along with circulating levels of melatonin, mitochondrial aldehyde dehydrogenase (ALDH2) and autophagy. AD patients and APP/PS1 mice displayed cognitive and myocardial deficits, low levels of circulating melatonin, ALDH2 activity, and autophagy, ultrastructural, geometric (cardiac atrophy and interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies, mitochondrial injury, cytosolic mtDNA buildup, apoptosis, and suppressed autophagy and mitophagy. APP/PS1 mutation downregulated cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) levels and TBK1 phosphorylation, while promoting Aβ accumulation. Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function, apoptosis, mitochondrial integrity, cytosolic mtDNA accumulation (using both immunocytochemistry and qPCR), mitophagy, and cGAS-STING-TBK1 signaling, although these benefits were absent in APP/PS1/ALDH2−/− mice. In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function, and the effect was negated by the nonselective melatonin receptor blocker luzindole, inhibitors or RNA interference of cGAS, STING, TBK1, and autophagy. Our data collectively established a correlation among cardiac dysfunction, low levels of melatonin, ALDH2 activity, and autophagy in AD patients, with compelling support in APP/PS1 mice, in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.
Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages
Authors: Nasser Hesham , Adhikary Partho , Abdel-Daim Amira , Noyori Osamu , Panaampon Jutatip , Kariya Ryusho , Okada Seiji , Ma Wenjuan , Baba Masaya , Takizawa Hitoshi , Yamane Mariko , Niwa Hitoshi , Suzu Shinya
Published: July 2020

Recent studies have revealed that tissue macrophages are derived from yolk sac precursors or fetal liver monocytes, in addition to bone marrow monocytes. The relative contribution of these cells to the tissue macrophage pool is not fully understood, but embryo-derived cells are supposed to be more important because of their capacity to self-renew. Here, we show the presence of adult bone marrow-derived macrophages that retain self-renewing capacity. The self-renewing macrophages were readily obtained by long-term culture of mouse bone marrow cells with macrophage colony-stimulating factor (M-CSF), a key cytokine for macrophage development. They were non-tumorigenic and proliferated in the presence of M-CSF in unlimited numbers. Despite several differences from non-proliferating macrophages, they retained many features of cells of the monocytic lineage, including the differentiation into dendritic cells or osteoclasts. Among the transcription factors involved in the self-renewal of embryonic stem cells, Krüppel-like factor 2 (KLF2) was strongly upregulated upon M-CSF stimulation in the self-renewing macrophages, which was accompanied by the downregulation of MafB, a transcription factor that suppresses KLF2 expression. Indeed, knockdown of KLF2 led to cell cycle arrest and diminished cell proliferation in the self-renewing macrophages. Our new cell model would be useful to unravel differences in phenotype, function, and molecular mechanism of proliferation among self-renewing macrophages with different origins.
Machine-learned interatomic potentials by active learning: amorphous and liquid hafnium dioxide
Authors: Sivaraman Ganesh , Krishnamoorthy Anand Narayanan , Baur Matthias , Holm Christian , Stan Marius , Csányi Gábor , Benmore Chris , Vázquez-Mayagoitia Álvaro
Published: July 2020

We propose an active learning scheme for automatically sampling a minimum number of uncorrelated configurations for fitting the Gaussian Approximation Potential (GAP). Our active learning scheme consists of an unsupervised machine learning (ML) scheme coupled with a Bayesian optimization technique that evaluates the GAP model. We apply this scheme to a Hafnium dioxide (HfO2) dataset generated from a “melt-quench” ab initio molecular dynamics (AIMD) protocol. Our results show that the active learning scheme, with no prior knowledge of the dataset, is able to extract a configuration that reaches the required energy fit tolerance. Further, molecular dynamics (MD) simulations performed using this active learned GAP model on 6144 atom systems of amorphous and liquid state elucidate the structural properties of HfO2 with near ab initio precision and quench rates (i.e., 1.0 K/ps) not accessible via AIMD. The melt and amorphous X-ray structural factors generated from our simulation are in good agreement with experiment. In addition, the calculated diffusion constants are in good agreement with previous ab initio studies.
Specific targeting of IL-1β activity to CD8+ T cells allows for safe use as a vaccine adjuvant
Authors: Van Den Eeckhout Bram , Van Hoecke Lien , Burg Elianne , Van Lint Sandra , Peelman Frank , Kley Niko , Uzé Gilles , Saelens Xavier , Tavernier Jan , Gerlo Sarah
Published: July 2020

Annual administration and reformulation of influenza vaccines is required for protection against seasonal infections. However, the induction of strong and long-lasting T cells is critical to reach broad and potentially lifelong antiviral immunity. The NLRP3 inflammasome and its product interleukin-1β (IL-1β) are pivotal mediators of cellular immune responses to influenza, yet, overactivation of these systems leads to side effects, which hamper clinical applications. Here, we present a bypass around these toxicities by targeting the activity of IL-1β to CD8+ T cells. Using this approach, we demonstrate safe inclusion of IL-1β as an adjuvant in vaccination strategies, leading to full protection of mice against a high influenza virus challenge dose by raising potent T cell responses. In conclusion, this paper proposes a class of IL-1β-based vaccine adjuvants and also provides further insight in the mechanics of cellular immune responses driven by IL-1β.
MAGPEL: an autoMated pipeline for inferring vAriant-driven Gene PanEls from the full-length biomedical literature
Authors: Saberian Nafiseh , Shafi Adib , Peyvandipour Azam , Draghici Sorin
Published: July 2020

In spite of the efforts in developing and maintaining accurate variant databases, a large number of disease-associated variants are still hidden in the biomedical literature. Curation of the biomedical literature in an effort to extract this information is a challenging task due to: (i) the complexity of natural language processing, (ii) inconsistent use of standard recommendations for variant description, and (iii) the lack of clarity and consistency in describing the variant-genotype-phenotype associations in the biomedical literature. In this article, we employ text mining and word cloud analysis techniques to address these challenges. The proposed framework extracts the variant-gene-disease associations from the full-length biomedical literature and designs an evidence-based variant-driven gene panel for a given condition. We validate the identified genes by showing their diagnostic abilities to predict the patients’ clinical outcome on several independent validation cohorts. As representative examples, we present our results for acute myeloid leukemia (AML), breast cancer and prostate cancer. We compare these panels with other variant-driven gene panels obtained from Clinvar, Mastermind and others from literature, as well as with a panel identified with a classical differentially expressed genes (DEGs) approach. The results show that the panels obtained by the proposed framework yield better results than the other gene panels currently available in the literature.
Characterization of a novel STAT 2 knock-out hamster model of Crimean-Congo hemorrhagic fever virus pathogenesis
Authors: Ranadheera Charlene , Valcourt Emelissa J. , Warner Bryce M. , Poliquin Guillaume , Rosenke Kyle , Frost Kathy , Tierney Kevin , Saturday Greg , Miao Jinxin , Westover Jonna B. , Gowen Brian B. , Booth Stephanie , Feldmann Heinz , Wang Zhongde , Safronetz David
Published: July 2020

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen causing a febrile illness in humans, which can progress to hemorrhagic manifestations, multi-organ failure, and death. Current mouse models of CCHFV infection reliably succumb to virus challenge but vary in their ability to reflect signs of disease similar to humans. In this study, we established a signal transducer and activator of transcription 2 (STAT2) knockout hamster model to expand the repertoire of animal models of CCHFV pathogenesis that can be used for therapeutic development. These hamsters demonstrated a systemic and lethal disease in response to infection. Hallmarks of human disease were observed including petechial rash, blood coagulation dysfunction, and various biochemistry and blood cell count abnormalities. Furthermore, we also demonstrated the utility of this model for anti-CCHFV therapeutic evaluation. The STAT2 knock-out hamster model of CCHFV infection may provide some further insights into clinical disease, viral pathogenesis, and pave the way for testing of potential drug and vaccine candidates.
Prospective evaluation and classification of endoscopic findings for ureteral calculi
Authors: Hamamoto Shuzo , Okada Shinsuke , Inoue Takaaki , Sugino Teruaki , Unno Rei , Taguchi Kazumi , Ando Ryosuke , Okada Atsushi , Miura Hiroyasu , Matsuda Tadashi , Yasui Takahiro
Published: July 2020

Difficulty in performing ureteroscopic lithotripsy (URSL) depends on endoscopic findings surrounding calculi. In this multicentre prospective cohort study of 185 patients with a single ureteral stone who underwent ureteroscopic lithotripsy registered in the SMART study between January 2014 and February 2017, we established a classification of endoscopic findings and analysed risk factors for ureteral changes. We evaluated endoscopic findings (oedema, polyps, ureteral mucosa-stone adherence, and distal ureteric tightness) based on the SMART classification. Operative time and ureteral injuries were significantly correlated with endoscopic finding grades. Multivariate analyses revealed that mucosa-stone adherence (MSA) was strongly affected by hydronephrosis grade (odds ratio, 12.4; p = 0.022) and the interval before surgery (odds ratio, 1.10; p = 0.012). The cutoff value for MSA was 98 days, with a predictive accuracy of 0.78. Risk factors for distal ureteric tightness were age (odds ratio, 0.96; p = 0.004) and early intervention (odds ratio, 0.90; p = 0.023). The cutoff value was 34 days, with a predictive accuracy of 0.72. In conclusion, appropriate intervention around 34 days (limited to 98 days) after symptom onset is necessary for treating ureteral calculi. Even if intervention passed 98 days post-symptom onset, staged URSL, alternative procedures, and detailed informed consent should be planned in advance, assuming strong MSA.
Effects of prey trophic mode on the gross-growth efficiency of marine copepods: the case of mixoplankton
Authors: Traboni Claudia , Calbet Albert , Saiz Enric
Published: July 2020

Copepod reproductive success largely depends on food quality, which also reflects the prey trophic mode. As such, modelling simulations postulate a trophic enhancement to higher trophic levels when mixotrophy is accounted in planktonic trophodynamics. Here, we tested whether photo-phagotrophic protists (mixoplankton) could enhance copepod gross-growth efficiency by nutrient upgrading mechanisms compared to obligate autotrophs and heterotrophs. To validate the hypothesis, we compared physiological rates of the copepod Paracartia grani under the three functional nutrition types. Ingestion and egg production rates varied depending on prey size and species, regardless of the diet. The gross-growth efficiency was variable and not significantly different across nutritional treatments, ranging from 3 to 25% in the mixoplanktonic diet compared to autotrophic (11–36%) and heterotrophic (8–38%) nutrition. Egg hatching and egestion rates were generally unaffected by diet. Overall, P. grani physiological rates did not differ under the tested nutrition types due to the large species-specific variation within trophic mode. However, when we focused on a single species, Karlodinium veneficum, tested as prey under contrasting trophic modes, the actively feeding dinoflagellate boosted the egestion rate and decreased the copepod gross-growth efficiency compared to the autotrophic ones, suggesting possible involvement of toxins in modulating trophodynamics other than stoichiometric constraints.
DNA unchained: two assays to discover and study inhibitors of the DNA clustering function of barrier-to-autointegration factor
Authors: Burger Michael , Schmitt-Koopmann Caroline , Leroux Jean-Christophe
Published: July 2020

The protein barrier-to-autointegration factor (BAF) and its interaction partners, the LEM (LAP2B, emerin, MAN1)-domain proteins, constitute a powerful cytoplasmic DNA defense mechanism. Invading DNA molecules are quickly bound by the BAF system and trapped in membrane compartments. This decreases the nuclear uptake of DNA from the cytoplasm. Inhibition of the BAF system is therefore expected to enhance the efficacy of non-viral DNA transfection agents. In this study, we introduced a protocol for the recombinant expression of soluble BAF and developed two ELISA-type assays to discover small molecule inhibitors of BAF-dependent DNA retention by high throughput screening (HTS). The proton pump inhibitor rabeprazole as well as three compounds of the Maybridge library were identified as inhibitors of the LEM-BAF-DNA interaction chain. The inhibition was based on adduct formation with BAF cysteine residues. An enhancing effect of the compounds on cell culture transfection, however, was not observed, which may be attributed to the reducing environment of the cytoplasm that prevents the adduct formation with BAF cysteine residues. The novel assays developed here can provide new tools to further study the biological functions of the BAF system, and may lead to the identification of suitable BAF inhibitors in future HTS campaigns.
Identification of potential biomarkers for predicting the early onset of diabetic cardiomyopathy in a mouse model
Authors: Johnson Rabia , Nxele Xolisa , Cour Martin , Sangweni Nonhlakanipho , Jooste Tracey , Hadebe Nkanyiso , Samodien Ebrahim , Benjeddou Mongi , Mazino Mikateko , Louw Johan , Lecour Sandrine
Published: July 2020

Type 2 diabetes (T2D) is characterized by metabolic derangements that cause a shift in substrate preference, inducing cardiac interstitial fibrosis. Interstitial fibrosis plays a key role in aggravating left ventricular diastolic dysfunction (LVDD), which has previously been associated with the asymptomatic onset of heart failure. The latter is responsible for 80% of deaths among diabetic patients and has been termed diabetic cardiomyopathy (DCM). Through in silico prediction and subsequent detection in a leptin receptor-deficient db/db mice model (db/db), we confirmed the presence of previously identified potential biomarkers to detect the early onset of DCM. Differential expression of Lysyl Oxidase Like 2 (LOXL2) and Electron Transfer Flavoprotein Beta Subunit (ETFβ), in both serum and heart tissue of 6–16-week-old db/db mice, correlated with a reduced left-ventricular diastolic dysfunction as assessed by high-resolution Doppler echocardiography. Principal component analysis of the combined biomarkers, LOXL2 and ETFβ, further displayed a significant difference between wild type and db/db mice from as early as 9 weeks of age. Knockdown in H9c2 cells, utilising siRNA of either LOXL2 or ETFβ, revealed a decrease in the expression of Collagen Type I Alpha1 (COL1A1), a marker known to contribute to enhanced myocardial fibrosis. Additionally, receiver-operating curve (ROC) analysis of the proposed diagnostic profile showed that the combination of LOXL2 and ETFβ resulted in an area under the curve (AUC) of 0.813, with a cut-off point of 0.824, thus suggesting the favorable positive predictive power of the model and further supporting the use of LOXL2 and ETFβ as possible early predictive DCM biomarkers.
Molecular malaria surveillance using a novel protocol for extraction and analysis of nucleic acids retained on used rapid diagnostic tests
Authors: Guirou Etienne A. , Schindler Tobias , Hosch Salome , Donfack Olivier Tresor , Yoboue Charlene Aya , Krähenbühl Silvan , Deal Anna , Cosi Glenda , Gondwe Linda , Mwangoka Grace , Masuki Heavenlight , Salim Nahya , Mpina Maxmillian , Said Jongo , Abdulla Salim , Hoffman Stephen L. , Nlavo Bonifacio Manguire , Maas Carl , Falla Carlos Cortes , Phiri Wonder P. , Garcia Guillermo A. , Tanner Marcel , Daubenberger Claudia
Published: July 2020

The use of malaria rapid diagnostic tests (RDTs) as a source for nucleic acids that can be analyzed via nucleic acid amplification techniques has several advantages, including minimal amounts of blood, sample collection, simplified storage and shipping conditions at room temperature. We have systematically developed and extensively evaluated a procedure to extract total nucleic acids from used malaria RDTs. The co-extraction of DNA and RNA molecules from small volumes of dried blood retained on the RDTs allows detection and quantification of P. falciparum parasites from asymptomatic patients with parasite densities as low as 1 Pf/µL blood using reverse transcription quantitative PCR. Based on the extraction protocol we have developed the ENAR (Extraction of Nucleic Acids from RDTs) approach; a complete workflow for large-scale molecular malaria surveillance. Using RDTs collected during a malaria indicator survey we demonstrated that ENAR provides a powerful tool to analyze nucleic acids from thousands of RDTs in a standardized and high-throughput manner. We found several, known and new, non-synonymous single nucleotide polymorphisms in the propeller region of the kelch 13 gene among isolates circulating on Bioko Island, Equatorial Guinea.