bluuebunny/crossref_metadata_2025 huggingface dataset:
Study on site selection for a cruise home port in the Yangtze River Delta region from the perspective of safety
Authors: Su Zhaoqian , Xiao Yingjie
Published: May 2022

To improve the safety of cruise tourism in the Yangtze River Delta region (YRD), a new cruise ship home port is needed. This paper studies the process for selection of a site for the new cruise home port. Through analysis of previous cases of cruise tourism safety accidents, it is found that the basic situation of the cruise port, such as the channel, the port, logistics support and scenic places to visit, is important to cruise operation safety. An index system of site selection for a cruise home port is established, and the optimal choice of location for a regional cruise home port – between Shanghai, Zhoushan and Nantong – is analysed by the analytic hierarchy process (AHP). The research shows that the order of preferred site for the cruise home port is Zhoushan, then Shanghai and, third, Nantong. This paper can provide a reference for the layout of the whole industry chain of the cruise economy in the YRD in the future. This will promote the integration of development of the YRD, and enhance the regional connectivity and policy system efficiency in the YRD.
New court, same division: The Bemba case as an illustration of the continued confusion regarding the command responsibility doctrine
Authors: O’Sullivan Carmel
Published: May 2022

Prosecutor v. Jean-Pierre Bemba Gombo was the International Criminal Court’s first case directly addressing the command responsibility doctrine. As the first permanent international criminal court who can exercise jurisdiction over a majority of the world’s nation states, its interpretation of the doctrine was potentially an important development in international criminal law and an opportunity to affirm the legal responsibility of commanders for their subordinates’ crimes. However, rather than providing a clear articulation of the doctrine and its scope, the Appeals Chamber was split. By a 3–2 majority, it reversed the Trial Chamber’s decision and the Appeals Chamber’s judges were sufficiently divided in their reasoning that they felt compelled to deliver separate opinions.

A key disagreement within the doctrine is whether command responsibility is a mode of liability or a separate offence of dereliction of duty. This disagreement feeds into further contestation about the doctrine’s core elements, including the standard of fault necessary under its actus reus or mens rea elements. This article examines the judges’ reasoning in Bemba to illustrate that, despite decades of jurisprudence and academic debate, there is still confusion on these foundational elements. Instead of being ‘settled law’, the debate on command responsibility is still live. The article maintains that the current law supports a mode of liability interpretation but proposes that reclassifying the doctrine as a separate offence could resolve many of its tensions while observing the culpability principle, satisfying its justifications, and facilitating an adequately wide scope of accountability.
Displaying the Magician's Art: Theatrical Illusion in Ingmar Bergman's The Magic Flute (1975)
Authors: Ibáñez-García Estela
Published: May 2022

Ingmar Bergman's The Magic Flute is a film that not only represents a performance of Mozart's opera but also reflects on the experience it generates in the theatrical audience. The opera becomes the means through which Bergman explores the magic of theatrical illusion by displaying the artifice behind it. I examine the film's take on the representation of theatrical illusion from two perspectives. First, with reference to the famous sequence of the overture, I demonstrate the crucial role of the audience's imaginative engagement. Second, I zero in on Bergman's role as omniscient director who not only uncovers the artificiality of the theatrical source but also plays tricks with the film audience. Yet our observing the ‘constructed naturalness’ of the magic flute and Papageno or the theatricality of the Queen of the Night's performance does not hinder the film's ability to engage us. Rather, witnessing the workings of illusion strengthens its grip on us.
FRIENDSHIP AND THE WISHES OF THE DEAD
Authors: Dorsey Dale
Published: May 2022

The wishes of the dead seem to have normative significance. We not only respect last wills and testaments, but we take seriously what the dead loved, what they valued, even after they have long escaped this mortal coil. But this presents a philosophical puzzle. Is this a normatively justified practice? Why should the fact that some dead person preferred state of affairs x to state of affairs y be a reason to bring about x rather than y—especially if there is otherwise reason to promote y rather than x? In this paper, I argue that extant solutions to this problem are inadequate and propose an alternative. I argue that the normative significance of the wishes of the dead is to be found not in the dead's well-being or interests, but instead in the relations of friendship we bear to the dead.
Terrorist campaigns and the growth of the Muslim population: a reply to Clara Egger and Raul Magni-Berton
Authors: Choi Seung-Whan
Published: May 2022

I am delighted to see that my study on the effect of terrorist campaigns on the growth of Muslim populations has intrigued Egger and Magni-Berton. After discussing potential theoretical and methodological shortcomings in my study, Egger and Magni-Berton conclude that there is no empirical support for the positive relationship between terror attacks and Muslim populations. Their approach of separating terrorism into Islamist and non-Islamist terrorism is an effort to advance the contemporary research on the nexus between terrorism and Islam. In this re-examination, I show that Egger and Magni-Berton's conclusion is based on two limitations: theoretically unfounded and empirically inadequate. After remedying these limitations step by step, I reconfirm that a series of terrorist activities collectively serve as an explanation for the growth of the worldwide Muslim population. Future research can offer additional evidence to understand whether there is a significant and positive relationship between Islamist terrorism and the growth of Muslim populations.
Drug-coated balloons in below-the-knee arteries
Authors: Stoll Felicitas , Uslu Reyhan , Blessing Erwin , Frey Norbert , Katus Hugo A. , Erbel Christian , Heilmeier Britta , Müller Oliver J.
Published: May 2022

Summary: Background: The search for an optimal interventional treatment strategy in infrapopliteal peripheral artery disease remains in the focus of interest. Whether drug-coated balloons (DCB) might enhance interventional outcomes after crural interventions is a matter of debate, as studies yielded conflicting results on DCB safety and efficacy. Patients and methods: We analyzed a retrospective cohort of 75 infrapopliteal DCB interventions performed at our institution in 68 patients with peripheral artery disease in Rutherford category 3 to 6. Results: Despite a high rate of long complex lesions and multi-vessel disease, freedom from clinically driven target lesions revascularization (TLR) after 365 days was 68%. After six months, healing or significant improvement of the ischemic ulcer was observed in 78% of cases. Accordingly, freedom from major amputation and death after 365 days was 82%. Freedom from major amputation and death was 76.2% of cases in patients with diabetes mellitus as opposed to 91.5% in patients without diabetes mellitus (p=0.049). Conclusions: With this real-world analysis we would like to contribute to the ongoing discussion on the benefit and safety of DCB treatment in below-the-knee interventions.
Emotion Recognition, Empathy, or ToM? The Influence of Social Cognition on Communication in Traumatic Brain Injury
Authors: Quinting Jana , Jonas Kristina , Kuhn Charlotte , Stenneken Prisca
Published: May 2022

Abstract: Communication disorders following traumatic brain injury have been attributed to social-cognitive dysfunctions. However, this relationship is not always clearly demonstrated in empirical research. This systematic review seeks to clarify the relationship by considering different subcomponents of social cognition and communication. The results show that, for the social-cognitive subcomponents of emotion recognition and empathy, evidence is available mainly for a relationship to global communication abilities. However, we did find a systematic relationship between Theory of Mind and individual aspects of pragmatics (i. e., the processing of irony/sarcasm, insincerity, indirect speech acts). To strengthen the evidence for the role of social-cognitive subcomponents concerning communication, future research could implement a core outcome set based on the present findings.
Prävention von chronischen Krankheiten
Authors: Mattig Thomas
Published: May 2022

Dieses Buch gibt einen umfassenden Überblick zu Strategien und Maßnahmen zur Prävention nichtübertragbarer Krankheiten. In diesem Bereich engagieren sich eine Vielzahl von staatlichen und nicht-staatlichen Organisationen, von denen zahlreiche im vorliegenden Werk zu Wort kommen. Die Beiträge wurden koordiniert von Gesundheitsförderung Schweiz und dessen Direktor Thomas Mattig. Gesundheitsförderung Schweiz ist eine privatrechtliche Stiftung, die von Kantonen und Versicherern getragen wird. Mit gesetzlichem Auftrag initiiert, koordiniert und evaluiert sie Maßnahmen zur Förderung der Gesundheit. Gesunde Lebensverhältnisse und ein gesunder Lebensstil können chronische Krankheiten vermindern oder dafür sorgen, dass sie gar nicht erst auftreten. Verschiedene Akteure (z.B. BAG, Bundesamt für Statistik; Krankenversicherer, Rheumaliga, CardioVasc Suisse; Krebsliga, Swiss-Screening, e-health Suisse, u.a.) beschreiben in mehr als 30 verschiedenen mehrsprachigen Beiträgen, was in der Schweiz in der Prävention aktiv und erfolgreich praktiziert wird und welche Strategien umgesetzt werden.
Kinder spielerisch auf die Schule vorbereiten
Authors: Wirth Astrd , Birtwistle Efsun , Mues Anna , Niklas Frank
Published: May 2022

Wissenschaftliche Hintergründe und Praxistipps für die Schulvorbereitung Die Autorinnen und Autoren zeigen Ihnen Wege auf, wie Sie die Entwicklung Ihrer Kinder im Vorschulalter spielerisch im familiären und im Kindergartenalltag unterstützen können - ganz ohne exklusive Hilfsmittel! Einen Schwerpunkt bildet die (Schrift-)Sprachentwicklung sowie die mathematische Entwicklung, um Ihr Kind optimal auf die beiden Schulfächer Deutsch und Mathematik vorzubereiten. Darüber hinaus erhalten Sie Informationen und Tipps zur Förderung der kognitiven, sozial-emotionalen und der Persönlichkeitsentwicklung: •Wie lernen Kinder logisches Denken? •Wie können Kinder soziale Fähigkeiten ausbilden? ? •Welche Aspekte gilt es beim Thema Kinderbücher zu beachten? ? •Wie wirkt sich die Raumgestaltung auf die Konzentration und Aufmerksamkeit von Vorschulkindern aus? ? In diesem Buch erhalten Sie Antworten auf diese und viele weitere Fragen zur Kompetenzentwicklung Ihrer Kinder. Vier Expertinnen und Experten auf dem Gebiet der pädagogischen Psychologie nehmen Sie mit in die spannende Welt der psychologischen und pädagogischen Wissenschaft und geben Ihnen wertvolle Einblicke in die ganzheitliche kindliche Kompetenzentwicklung. Darauf aufbauend erhalten Sie viele Praxistipps zur spielerischen Förderung - kindgerecht und mit viel Freude am Lernen für Sie und Ihr Kind!
Wohlfühlgärtnern
Authors: Niepel Andreas
Published: May 2022

Immer mehr und immer jüngere Menschen und Familien haben in den zurückliegenden Jahren nach einem eigenen Garten Ausschau gehalten. Dieser Trend wurde durch die Coronapandemie noch verstärkt. Diente das Gärtnern früher primär zur Selbstversorgung, so ist der Gedanke der Gesundheitsförderung zuletzt in den Vordergrund gerückt. Der bekannte Gartentherapeut Andreas Niepel geht mit seinem Werk auf die neuen jungen Gärtner*innen zu. Er beschreibt anschaulich und locker, wie Gärtnern positive Emotionen des Genusses, der Lebensfreude, des besseren Selbstwertgefühls, der sozialen Integration, der Naturverbundenheit, des Wohlbefindens, des Sicherheits- und Kontrollgefühls und der Entspannung fördert. Verständig geht er auf die unterschiedlichen Bedürfnisse der neuen Gärtner*innen ein und beschreibt, wie man und frau typengerecht glücklich und zufrieden im eigenen Garten werden können. Mit Beispielen aus seinem Konzept «POSITIV GÄRTNERN» verbindet er Theoretisches aus der Gartentherapie, wichtige Gesundheitsaspekte und Gartenspaß mit Beispielen aus dem alltäglichen Leben. Humorvoll hält er «eingefahrenen Denkern» ein wenig den Spiegel vor - frei nach dem Motto: Fangen Sie etwas Neues an! Denken Sie wohlwollend über sich, Ihren Alltag und Ihre Einstellungen nach. Werden Sie kreativ und identifizieren Sie Ihre persönlichen Gartenvorlieben passend zu Ihrer Persönlichkeit. Gehen Sie Gärtnern richtig und durchdacht an. Nichts ist falsch, vieles richtig, solange es Gartenfreund*innen gut tut.
Das Memo–Training
Authors: Everts Regula , Ritter Barbara
Published: May 2022

Memo ist ein Zirkuselefant und lebt in der Schweiz. Weil es ihm dort zu kalt ist, will er zurück in seine Heimat Botswana reisen. Doch Memo ist leider sehr vergesslich. Wie gut, dass er im Zirkus eine Menge Freunde hat, die ihm dabei helfen, die abenteuerliche Reise nach Botswana mit schlauen Gedächtnistricks zu meistern.
Das neurowissenschaftlich begründete Gedächtnistraining mit dem Elefanten Memo wurde an der Universitätsklinik für Kinderheilkunde in Bern entwickelt, angewendet und auf seine Wirkung hin untersucht. Das Training vermittelt Gedächtnisstrategien und stärkt das Arbeitsgedächtnis. Es verhilft Kindern ab sieben Jahren durch sechs einfache Lektionen erwiesenermaßen und nachhaltig zu mehr Lernerfolg. Die einfache Handhabung, die kindgerecht gestalteten Übungen und die kunterbunten Geschichten machen das MEMO-Training zu einem gelungenen Lernerlebnis sowohl für die Kinder als auch für die Trainerinnen und Trainer. Das MEMO-Training wird seit der Erstausgabe im Jahr 2013 von Eltern und Fachpersonen mit Begeisterung und Erfolg angewendet.
Für die dritte., aktualisierte Auflage wurden der Trainings- und der Theorieteil aktualisiert und auf den neuesten Erkenntnisstand gebracht.
The Web-Based Assessment of Mental Speed
Authors: Gnambs Timo
Published: May 2022

Abstract: Although web-based cognitive assessments have gained increasing attention in recent decades, it is still debated whether unstandardized test settings allow for comparable measurements as compared to proctored testing, particularly for speeded cognitive tests. Therefore, two within-subject experiments ( N = 73 and N = 72) compared differences in means, criterion correlations with measures of intelligence, and subjective test quality perceptions of a trail-making test between a proctored paper-based, a proctored computerized, and an unproctored web-based administration mode. The results in both samples showed equivalent means between the two computerized modes, equivalent criterion correlations between the three modes, and no differential item functioning. However, the web-based tests were rated as having an inferior measurement quality as compared to the proctored assessments. Thus, web-based testing allows for comparable measurements of mental speed as compared to traditional computerized tests, although it is still regarded as a lower quality medium by test takers.
Alternate Histories: Synthetic Large Ensembles of Sea‐Air CO2 Flux
Authors: Olivarez Holly C. , Lovenduski Nicole S. , Brady Riley X. , Fay Amanda R. , Gehlen Marion , Gregor Luke , Landschützer Peter , McKinley Galen A. , McKinnon Karen A. , Munro David R.
Published: May 2022

We use a statistical emulation technique to construct synthetic ensembles of global and regional sea‐air carbon dioxide (CO2) flux from four observation‐based products over 1985–2014. Much like ensembles of Earth system models that are constructed by perturbing their initial conditions, our synthetic ensemble members exhibit different phasing of internal variability and a common externally forced signal. Our synthetic ensembles illustrate an important role for internal variability in the temporal evolution of global and regional CO2 flux and produce a wide range of possible trends over 1990–1999 and 2000–2009. We assume a specific externally forced signal and calculate the rank of the observed trends within the distribution of statistically modeled synthetic trends during these periods. Over the decade 1990–1999, three of four observation‐based products exhibit small negative trends in globally integrated sea‐air CO2 flux (i.e., enhanced ocean CO2 absorption with time) that are within one standard deviation of the mean in their respective synthetic ensembles. Over the decade 2000–2009, however, three products show large negative trends in globally integrated sea‐air CO2 flux that have a low rate of occurrence in their synthetic ensembles. The largest positive trends in global and Southern Ocean flux over 1990–1999 and the largest negative trends over 2000–2009 fall nearly two standard deviations away from the mean in their ensembles. Our approach provides a new perspective on the important role of internal variability in sea‐air CO2 flux trends, and furthers understanding of the role of internal and external processes in driving observed sea‐air CO2 flux variability.
On the Occurrence of Magnetic Reconnection Along the Terrestrial Magnetopause, Using Magnetospheric Multiscale (MMS) Observations in Proximity to the Reconnection Site
Authors: Petrinec S. M. , Burch J. L. , Fuselier S. A. , Trattner K. J. , Giles B. L. , Strangeway R. J.
Published: May 2022

Observations at the reconnection site from the Magnetospheric Multiscale mission are used to examine the occurrence of magnetic reconnection along the magnetopause in relation to both the upstream interplanetary magnetic field (IMF) orientation and local magnetosheath variations. While there is a statistically larger number of reconnection intervals observed downstream of the quasi‐parallel bow shock than is accounted for based on the histogram of overall IMF orientations, it is surmised that increased fluctuations downstream of the quasi‐parallel bow shock cause greater large‐scale motion of the magnetopause surface; but do not preferentially enhance the occurrence of steady magnetic reconnection. An examination of the locations of observed reconnection sites relative to model predictions also suggest that enhanced magnetosheath fluctuations do not result in steady reconnection occurring at random locations at the magnetopause.
Wind‐Induced Hypolimnetic Upwelling Between the Multi‐Depth Basins of Lake Geneva During Winter: An Overlooked Deepwater Renewal Mechanism?
Authors: Reiss Rafael S. , Lemmin U. , Barry D. A.
Published: May 2022

Combining field observations, 3D hydrodynamic modeling, and particle tracking, we investigated wind‐induced interbasin exchange between the Petit Lac (PL) (depth 75 m) and Grand Lac (GL) (depth 309 m) basins of Lake Geneva in early winter. Following a strong 2.5‐day wind event, a two‐layer flow field developed, where the downwind surface drift into the GL was balanced by counterflowing hypolimnetic currents into the PL. Velocities in both layers exceeded 20 cm s−1, with the highest values (27 cm s−1) found near the bottom. For 3.5 days, hypolimnetic temperatures at the confluence decreased to values found in the deep GL hypolimnion at 180‐m depth. Approximately 1.5 days after the wind event ceased, currents reversed and upwelled waters returned into the deep GL hypolimnion. The Coriolis force strongly modified the interbasin exchange dynamics, which were well represented by the model. Particle tracking revealed a “current loop,” that is, water from below 150‐m depth first upwelled into the PL, intruded approximately 10 km (half its length), and then descended back into the GL hypolimnion. Model results showed that the PL hypolimnetic volume doubled during the upwelling. Low model‐based gradient Richardson numbers and temperature inversions in CTD profiles indicated turbulent mixing between the upwelled GL and surrounding PL waters. Our findings demonstrate that hypolimnetic upwelling between the two basins frequently occurs during winter and could potentially be an important, but as yet overlooked mechanism for hypolimnetic‐epilimnetic exchange and deepwater renewal in Lake Geneva, and probably in other multi‐depth basin lakes under similar wind conditions.
Tracking Global Patterns of Drought‐Induced Productivity Loss Along Severity Gradient
Authors: Wang Yiheng , Fu Zheng , Hu Zhongmin , Niu Shuli
Published: May 2022

Droughts significantly impact land carbon uptake by reducing the gross primary productivity (GPP). Projections suggest an increase in severe and extreme droughts in the twenty‐first century. Despite the importance of droughts on carbon uptakes, it remains unclear about the GPP responses under different drought severity and its changes under current climate changes. Using four state‐of‐the‐science GPP products, we showed that moderate (−1 ≤ SPEI < −1.5), severe (−1.5 ≤ SPEI < −2), and extreme (SPEI < −2) droughts caused on average 5%, 7%, and 9% GPP reductions, respectively, across the globe during the recent decades. Although the mean reductions varied among GPP products, we observed similar spatial patterns. The reductions increased significantly along the severity gradient, while the sharpest increases were observed in semi‐arid and grassland ecosystems. On a biome level, we found that the reductions increased nonlinearly with increasing drought severities for almost all vegetation types, but the trends and slopes varied significantly. In addition, we found that the mean drought‐induced GPP reductions had increased in dry ecosystems but decreased in humid ecosystems from 2001–2008 to 2009–2016. The result highlights the potential increase of drought‐induced land carbon sink loss responding to more extreme climates and offers new perspectives to improve the prediction of global carbon fluxes in a changing climate.
A Hybrid Statistical Downscaling Framework Based on Nonstationary Time Series Decomposition and Machine Learning
Authors: Li Xintong , Zhang Xiaodong , Wang Shuguang
Published: May 2022

Downscaling techniques are effective to bridge the scale gap between global circulation models and regional studies. Statistical downscaling methods are prevalent due to their advantages in high computational efficiency and accuracy. However, an implicit assumption of most statistical techniques is that time series should be relatively stationary after certain function transformations. Otherwise, statistics of nonstationary time series may be meaningless for describing future behavior. In this study, a hybrid statistical downscaling framework was developed through integrating bivariate empirical mode decomposition (BEMD) and a machine learning method to extract multi‐timescale features from nonstationary data to enhance downscaling performance. The proposed framework can reduce the effects of non‐stationarity in data‐driven models by using the BEMD method, which can decompose time series into independent and stationary components at multiple time‐frequency resolutions. It was applied to downscale monthly precipitation and temperature of Canadian Earth System Model in multiple stations with different climate types in the Central Valley of California, USA, to verify its accuracy and generalization ability. The performance of downscaling maximum and minimum temperatures (R2 > 0.9) was more accurate than that of precipitation. The potential reason is that precipitation is more sensitive to transient weather phenomena, which can only be extracted from data with higher temporal resolution. The proposed model was further compared with models based on discrete wavelet transform and models without time series decomposition. The results showed that a decomposition strategy of the proposed framework can improve the downscaling accuracy, potentially providing a viable option to deal with the nonstationary of data in statistical downscaling models.
Simultaneous Observations of a Polar Cap Sporadic‐E Layer by Twin Incoherent Scatter Radars at Resolute
Authors: Wang Yong , Themens David R. , Wang Cheng , Ma Yu‐Zhang , Reimer Ashton , Varney Roger , Gilies Robert , Xing Zan‐Yang , Zhang Qing‐He , Jayachandran P. T.
Published: May 2022

At high latitudes, the Sporadic‐E layer (Es layer) is a common phenomenon but is still poorly understood due to sparse measurements and the difficulty of conventional mechanisms to operate. In this study, an interesting case of polar cap Es layer is first studied by using the twin incoherent scatter radars (northward‐looking face of Resolute Incoherent‐Scatter Radar and Resolute Incoherent‐Scatter Radar‐Canada), a Canadian Advanced Digital Ionosonde, and a Magnetometer, all at Resolute, Canada. From several electron density profiles of the twin radars, the horizontal scale of the polar cap Es layer is found to be greater than 350 km. Moreover, the polar cap Es layer is determined to be drifting from the bottom F region (>150 km) to the lower E region. Furthermore, a unique appearance of double polar cap Es layers is observed. As a result, these peculiar signatures inspire a newly proposed process that involves the combination of localized electric fields and gravity waves.
Topologically tuned terahertz confinement in a nonlinear photonic chip
Authors: Wang Jiayi , Xia Shiqi , Wang Ride , Ma Ruobin , Lu Yao , Zhang Xinzheng , Song Daohong , Wu Qiang , Morandotti Roberto , Xu Jingjun , Chen Zhigang
Published: May 2022

Compact terahertz (THz) functional devices are greatly sought after for high-speed wireless communication, biochemical sensing, and non-destructive inspection. However, controlled THz generation, along with transport and detection, has remained a challenge especially for chip-scale devices due to low-coupling efficiency and unavoidable absorption losses. Here, based on the topological protection of electromagnetic waves, we demonstrate nonlinear generation and topologically tuned confinement of THz waves in an engineered lithium niobate chip forming a wedge-shaped Su–Schrieffer–Heeger lattice. Experimentally measured band structures provide direct visualization of the THz localization in the momentum space, while robustness of the confined mode against chiral perturbations is also analyzed and compared for both topologically trivial and nontrivial regimes. Such topological control of THz waves may bring about new possibilities in the realization of THz integrated circuits, promising for advanced photonic applications.
Scalable high-repetition-rate sub-half-cycle terahertz pulses from spatially indirect interband transitions
Authors: Meineke Christian , Prager Michael , Hayes Johannes , Wen Qiannan , Kastner Lukas Zheyi , Schuh Dieter , Fritsch Kilian , Pronin Oleg , Stein Markus , Schäfer Felix , Chatterjee Sangam , Kira Mackillo , Huber Rupert , Bougeard Dominique
Published: May 2022

Intense phase-locked terahertz (THz) pulses are the bedrock of THz lightwave electronics, where the carrier field creates a transient bias to control electrons on sub-cycle time scales. Key applications such as THz scanning tunnelling microscopy or electronic devices operating at optical clock rates call for ultimately short, almost unipolar waveforms, at megahertz (MHz) repetition rates. Here, we present a flexible and scalable scheme for the generation of strong phase-locked THz pulses based on shift currents in type-II-aligned epitaxial semiconductor heterostructures. The measured THz waveforms exhibit only 0.45 optical cycles at their centre frequency within the full width at half maximum of the intensity envelope, peak fields above 1.1 kV cm−1 and spectral components up to the mid-infrared, at a repetition rate of 4 MHz. The only positive half-cycle of this waveform exceeds all negative half-cycles by almost four times, which is unexpected from shift currents alone. Our detailed analysis reveals that local charging dynamics induces the pronounced positive THz-emission peak as electrons and holes approach charge neutrality after separation by the optical pump pulse, also enabling ultrabroadband operation. Our unipolar emitters mark a milestone for flexibly scalable, next-generation high-repetition-rate sources of intense and strongly asymmetric electric field transients.
Personalised selection of experimental treatment in patients with advanced solid cancer is feasible using whole-genome sequencing
Authors: Pruis Melinda A. , Groenendijk Floris H. , Badloe K. Sangeeta , van Puffelen Andrea , Robbrecht Debbie , Dinjens Winand N. M. , Sleijfer Stefan , Dingemans Anne-Marie C. , von der Thüsen Jan H. , Roepman Paul , Lolkema Martijn P.
Published: May 2022

Background

Biomarker-guided therapy in an experimental setting has been suggested to improve patient outcomes. However, trial-specific pre-screening tests are time and tissue consuming and complicate the personalised treatment of patients eligible for early-phase clinical trials. In this study the feasibility of whole-genome sequencing (WGS) as a one-test-for-all for guided inclusion in early-phase trials was investigated.

Methods

Phase I Molecular Tumor Board (MTB) at the Erasmus MC Cancer Institute reviewed patients with advanced cancer without standard-of-care treatment (SOC) options for a ‘fresh-frozen’ (FF) tumour biopsy for WGS based on clinical-pathological features. Clinical grade WGS was performed by Hartwig Medical Foundation. MTB matched the patient with a trial, if available.

Results

From September 2019–March 2021, 31 patients with highly diverse tumour types underwent a tumour biopsy for WGS. The median turnaround time (TAT) was 15 days [10–42 days]. At least one actionable event was found in 84% of the patients (26/31). One-third of the patients (11/31) received matched experimental treatment.

Conclusions

WGS on fresh FF biopsies is a feasible tool for the selection of personalised experimental therapy in patients with advanced cancer without SOC options. WGS is now possible in an acceptable TAT and thus could fulfil the role of a universal genomic pre-screening test.
Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy
Authors: van Beijnum Judy R. , Huijbers Elisabeth J. M. , van Loon Karlijn , Blanas Athanasios , Akbari Parvin , Roos Arno , Wong Tse J. , Denisov Stepan S. , Hackeng Tilman M. , Jimenez Connie R. , Nowak-Sliwinska Patrycja , Griffioen Arjan W.
Published: May 2022

Anti-angiogenic cancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional secretion mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions. Antibody targeting of extracellular vimentin shows inhibition of angiogenesis in vitro and in vivo. Effective and safe inhibition of angiogenesis and tumor growth in several preclinical and clinical studies is demonstrated using a vaccination strategy against extracellular vimentin. Targeting vimentin induces a pro-inflammatory condition in the tumor, exemplified by induction of the endothelial adhesion molecule ICAM1, suppression of PD-L1, and altered immune cell profiles. Our findings show that extracellular vimentin contributes to immune suppression and functions as a vascular immune checkpoint molecule. Targeting of extracellular vimentin presents therefore an anti-angiogenic immunotherapy strategy against cancer.
Synthesis and macrocyclization-induced emission enhancement of benzothiadiazole-based macrocycle
Authors: Li Shuo , Liu Kun , Feng Xue-Chen , Li Zhao-Xian , Zhang Zhi-Yuan , Wang Bin , Li Minjie , Bai Yue-Ling , Cui Lei , Li Chunju
Published: May 2022

We presented an effective and universal strategy for the improvement of luminophore’s solid-state emission, i.e., macrocyclization-induced emission enhancement (MIEE), by linking luminophores through C(sp3) bridges to give a macrocycle. Benzothiadiazole-based macrocycle (BT-LC) has been synthesized by a one-step condensation of the monomer 4,7-bis(2,4-dimethoxyphenyl)−2,1,3-benzothiadiazole (BT-M) with paraformaldehyde, catalyzed by Lewis acid. In comparison with the monomer, macrocycle BT-LC produces much more intense fluorescence in the solid state (ΦPL = 99%) and exhibits better device performance in the application of OLEDs. Single-crystal analysis and theoretical simulations reveal that the monomer can return to the ground state through a minimum energy crossing point (MECPS1/S0), resulting in the decrease of fluorescence efficiency. For the macrocycle, its inherent structural rigidity prohibits this non-radiative relaxation process and promotes the radiative relaxation, therefore emitting intense fluorescence. More significantly, MIEE strategy has good universality that several macrocycles with different luminophores also display emission improvement.
Band conductivity oscillations in a gate-tunable graphene superlattice
Authors: Huber Robin , Steffen Max-Niklas , Drienovsky Martin , Sandner Andreas , Watanabe Kenji , Taniguchi Takashi , Pfannkuche Daniela , Weiss Dieter , Eroms Jonathan
Published: May 2022

Electrons exposed to a two-dimensional (2D) periodic potential and a uniform, perpendicular magnetic field exhibit a fractal, self-similar energy spectrum known as the Hofstadter butterfly. Recently, related high-temperature quantum oscillations (Brown-Zak oscillations) were discovered in graphene moiré systems, whose origin lies in the repetitive occurrence of extended minibands/magnetic Bloch states at rational fractions of magnetic flux per unit cell giving rise to an increase in band conductivity. In this work, we report on the experimental observation of band conductivity oscillations in an electrostatically defined and gate-tunable graphene superlattice, which are governed both by the internal structure of the Hofstadter butterfly (Brown-Zak oscillations) and by a commensurability relation between the cyclotron radius of electrons and the superlattice period (Weiss oscillations). We obtain a complete, unified description of band conductivity oscillations in two-dimensional superlattices, yielding a detailed match between theory and experiment.
p53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis
Authors: Solé Laura , Lobo-Jarne Teresa , Álvarez-Villanueva Daniel , Alonso-Marañón Josune , Guillén Yolanda , Guix Marta , Sangrador Irene , Rozalén Catalina , Vert Anna , Barbachano Antonio , Lop Joan , Salido Marta , Bellosillo Beatriz , García-Romero Raquel , Garrido Marta , González Jessica , Martínez-Iniesta María , López-Arribillaga Erika , Salazar Ramón , Montagut Clara , Torres Ferrán , Iglesias Mar , Celià-Terrassa Toni , Muñoz Alberto , Villanueva Alberto , Bigas Anna , Espinosa Lluís
Published: May 2022

Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy (CT) does not select previously resistant tumor populations but induces a quiescent state specifically to TP53 wildtype (WT) cancer cells, which is linked to the acquisition of a YAP1-dependent fetal phenotype. Cells displaying this phenotype exhibit high tumor-initiating and metastatic activity. Nuclear YAP1 and fetal traits are present in a proportion of tumors at diagnosis and predict poor prognosis in patients carrying TP53 WT CRC tumors. We provide data indicating the higher efficacy of CT together with YAP1 inhibitors for eradication of therapy resistant TP53 WT cancer cells. Together these results identify fetal conversion as a useful biomarker for patient prognosis and therapy prescription.
An electrochemically stable homogeneous glassy electrolyte formed at room temperature for all-solid-state sodium batteries
Authors: Chi Xiaowei , Zhang Ye , Hao Fang , Kmiec Steven , Dong Hui , Xu Rong , Zhao Kejie , Ai Qing , Terlier Tanguy , Wang Liang , Zhao Lihong , Guo Liqun , Lou Jun , Xin Huolin L. , Martin Steve W. , Yao Yan
Published: May 2022

All-solid-state sodium batteries (ASSSBs) are promising candidates for grid-scale energy storage. However, there are no commercialized ASSSBs yet, in part due to the lack of a low-cost, simple-to-fabricate solid electrolyte (SE) with electrochemical stability towards Na metal. In this work, we report a family of oxysulfide glass SEs (Na3PS4−xOx, where 0 < x ≤ 0.60) that not only exhibit the highest critical current density among all Na-ion conducting sulfide-based SEs, but also enable high-performance ambient-temperature sodium-sulfur batteries. By forming bridging oxygen units, the Na3PS4−xOx SEs undergo pressure-induced sintering at room temperature, resulting in a fully homogeneous glass structure with robust mechanical properties. Furthermore, the self-passivating solid electrolyte interphase at the Na|SE interface is critical for interface stabilization and reversible Na plating and stripping. The new structural and compositional design strategies presented here provide a new paradigm in the development of safe, low-cost, energy-dense, and long-lifetime ASSSBs.
The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands
Authors: Wang Jingjing , Wu Meng , Chen Zhangcheng , Wu Lijie , Wang Tian , Cao Dongmei , Wang Huan , Liu Shenhui , Xu Yueming , Li Fei , Liu Junlin , Chen Na , Zhao Suwen , Cheng Jianjun , Wang Sheng , Hua Tian
Published: May 2022

Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer’s disease and schizophrenia. However, the lack of understanding on M4R’s activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-Gi structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes.
Controllable multiple-step configuration transformations in a thermal/photoinduced reaction
Authors: Wang Meng-Fan , Mi Yan , Hu Fei-Long , Hirao Hajime , Niu Zheng , Braunstein Pierre , Lang Jian-Ping
Published: May 2022

Solid-state photochemical reactions of olefinic compounds have been demonstrated to represent powerful access to organic cyclic molecules with specific configurations. However, the precise control of the stereochemistry in these reactions remains challenging owing to complex and fleeting configuration transformations. Herein, we report a unique approach to control the regiospecific configurations of C = C groups and the intermediates by varying temperatures in multiple-step thermal/photoinduced reactions, thus successfully realizing reversible ring closing/opening changes using a single-crystal coordination polymer platform. All stereochemical transitions are observed by in situ single-crystal X-ray diffraction, powder X-ray diffraction and infrared spectroscopy. Density functional theory calculations allow us to rationalize the mechanism of the synergistic thermal/photoinduced transformations. This approach can be generalized to the analysis of the possible configuration transformations of functional groups and intermediates and unravel the detailed mechanism for any inorganic, organic and macromolecular reactions susceptible to incorporation into single-crystal coordination polymer platforms.
Multisensory task demands temporally extend the causal requirement for visual cortex in perception
Authors: Oude Lohuis Matthijs N. , Pie Jean L. , Marchesi Pietro , Montijn Jorrit S. , de Kock Christiaan P. J. , Pennartz Cyriel M. A. , Olcese Umberto
Published: May 2022

Primary sensory areas constitute crucial nodes during perceptual decision making. However, it remains unclear to what extent they mainly constitute a feedforward processing step, or rather are continuously involved in a recurrent network together with higher-order areas. We found that the temporal window in which primary visual cortex is required for the detection of identical visual stimuli was extended when task demands were increased via an additional sensory modality that had to be monitored. Late-onset optogenetic inactivation preserved bottom-up, early-onset responses which faithfully encoded stimulus features, and was effective in impairing detection only if it preceded a late, report-related phase of the cortical response. Increasing task demands were marked by longer reaction times and the effect of late optogenetic inactivation scaled with reaction time. Thus, independently of visual stimulus complexity, multisensory task demands determine the temporal requirement for ongoing sensory-related activity in V1, which overlaps with report-related activity.
STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity
Authors: Dane Eric L. , Belessiotis-Richards Alexis , Backlund Coralie , Wang Jianing , Hidaka Kousuke , Milling Lauren E. , Bhagchandani Sachin , Melo Mariane B. , Wu Shengwei , Li Na , Donahue Nathan , Ni Kaiyuan , Ma Leyuan , Okaniwa Masanori , Stevens Molly M. , Alexander-Katz Alfredo , Irvine Darrell J.
Published: May 2022

Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to PEGylated lipids (CDN-PEG-lipids; PEG, polyethylene glycol) via a cleavable linker and incorporated them into lipid nanodiscs (LNDs), which are discoid nanoparticles formed by self-assembly. Compared to state-of-the-art liposomes, intravenously administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumours, exposing the majority of tumour cells to STING agonist. A single dose of LND-CDNs induced rejection of established tumours, coincident with immune memory against tumour rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by cancer cells correlated with robust T-cell activation by promoting CDN and tumour antigen co-localization in dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumours, which can be exploited for enhanced immunotherapy.
A multisystem, cardio-renal investigation of post-COVID-19 illness
Authors: Morrow Andrew J. , Sykes Robert , McIntosh Alasdair , Kamdar Anna , Bagot Catherine , Bayes Hannah K. , Blyth Kevin G. , Briscoe Michael , Bulluck Heerajnarain , Carrick David , Church Colin , Corcoran David , Findlay Iain , Gibson Vivienne B. , Gillespie Lynsey , Grieve Douglas , Hall Barrientos Pauline , Ho Antonia , Lang Ninian N. , Lennie Vera , Lowe David J. , Macfarlane Peter W. , Mark Patrick B. , Mayne Kaitlin J. , McConnachie Alex , McGeoch Ross , McGinley Christopher , McKee Connor , Nordin Sabrina , Payne Alexander , Rankin Alastair J. , Robertson Keith E. , Roditi Giles , Ryan Nicola , Sattar Naveed , Allwood-Spiers Sarah , Stobo David , Touyz Rhian M. , Veldtman Gruschen , Watkins Stuart , Weeden Sarah , Weir Robin A. , Welsh Paul , Wereski Ryan ,   CISCO-19 Consortium, Basu Neil , Brown Ammani , Butler Elaine , Dobbin Stephen J. H. , Dougherty Andrew , Dymock Laura , Fallon Kirsty , Gilmour Lesley , Hopkins Tracey , Lees Jennifer S. , McInnes Iain B , McLennan Evonne , Savage Fiona , Siebert Stefan , Tynan Nicola , Woodward Rosemary , Mangion Kenneth , Berry Colin
Published: May 2022

The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov IDNCT04403607). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28–60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28–60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was ‘very likely’ in 21 (13%) patients, ‘probable’ in 65 (41%) patients, ‘unlikely’ in 56 (35%) patients and ‘not present’ in 17 (11%) patients. At 28–60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (allP < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.
Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging
Authors: Wang Chaoyue , Martins-Bach Aurea B. , Alfaro-Almagro Fidel , Douaud Gwenaëlle , Klein Johannes C. , Llera Alberto , Fiscone Cristiana , Bowtell Richard , Elliott Lloyd T. , Smith Stephen M. , Tendler Benjamin C. , Miller Karla L.
Published: May 2022

A key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging magnetic resonance imaging technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We present an open resource of QSM-based imaging measures of multiple brain structures in 35,273 individuals from the UK Biobank prospective epidemiological study. We identify statistically significant associations of 251 phenotypes with magnetic susceptibility that include body iron, disease, diet and alcohol consumption. Genome-wide associations relate magnetic susceptibility to 76 replicating clusters of genetic variants with biological functions involving iron, calcium, myelin and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* signal decay time measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers worldwide, creating the potential to discover new, non-invasive markers of brain health.