bluuebunny/crossref_metadata_2025 huggingface dataset:
An Educational Reconstruction of Special Relativity Theory for Secondary Education
Authors: Kamphorst Floor , Vollebregt M. J. , Savelsbergh E. R. , van Joolingen W. R.
Published: October 2021

Einstein’s derivation of special relativity theory (SRT), based on hypothetical reasoning and thought experiments, is regarded as a prime example of physics theory development. In secondary education, the introduction of SRT could provide a great opportunity for students to engage in physics theorizing, but this opportunity is largely being missed in current teaching practice. One reason could be that secondary students lack some knowledge of electromagnetism that was central to Einstein’s argument. Therefore, we conducted an educational reconstruction to develop a teaching approach that would not rely on advanced understanding of electromagnetism, yet retain the modes of reasoning that were characteristic of Einstein’s approach. In our reconstruction, we identified the light postulate, which is notoriously difficult for students to grasp, as a central concept. We developed a teaching and learning sequence in which students perform relativistic thought experiments and try different interpretations of the light postulate. Through these activities, students experienced how the new concepts meet the requirements for a good theory. Experimental evaluation of the teaching and learning sequence indicates that this can be a fruitful approach to introduce SRT to secondary students.
Introduction of advanced laparoscopy for peritoneal dialysis catheter placement and the outcome in a University Hospital
Authors: van Laanen J. H. H. , Litjens E. J. , Snoeijs M. , van Loon M. M. , Peppelenbosch A. G.
Published: October 2021

Background

Peritoneal dialysis (PD) catheters can be obstructed by omental wrapping or migration, leading to catheter malfunction. Multiple catheter placement techniques have been described. Advanced laparoscopy with fixation of the catheter and omentum has been reported to improve functional outcome compared to basic laparoscopy without fixation. This feasibility study describes surgical technique, complications, and comparison of the functional outcome of advanced versus basic laparoscopic catheter placement.

Methods

Between July 2016 and April 2019, the advanced laparoscopy technique was applied in all eligible patients. Two experienced surgeons placed the catheters in a standardized procedure. Peri-operative complications and functional outcome of the catheter were scored. Results were compared to a historical cohort retrieved from our RCT performed earlier using basic laparoscopy.

Findings

The basic laparoscopic group (BLG) consisted of 46 patients and the advanced laparoscopic group (ALG) of 32. Complication rate in both groups was similar and low with 7% in the BLG and 6% in the ALG (p = 1.0). There was a trend toward better functional catheter outcome in the ALG (88%) compared to the BLG (70%) (p = 0.1). Part of the catheter failures in the ALG could be related to the learning curve. After revision surgery, 94% of patients in the ALG had a functional catheter. These findings lead to the set-up of a multi-center randomized-controlled trial, currently running, comparing basic to advanced laparoscopic techniques.
People’s Attitudes Towards the Use of Robots in the Social Services: A Multilevel Analysis Using Eurobarometer Data
Authors: Carradore Marco
Published: October 2021

Robots have been employed in the industrial sectors for over half a century; however, their appearance in the domestic sphere is a modern phenomenon, occurring in just the last decade. These so-called social robots are carrying out a variety of tasks traditionally carried out by humans, and in contexts in which they must interact with human beings. These kinds of social robots are now being used in the welfare services, providing assistive services and companionship for the infirm or elderly, and even children. Thus, the use of social robots in everyday life has triggered an animated debate about the acceptance of these devices by their end users. In this paper, multilevel analysis is applied using data from the Eurobarometer survey (sample size 27,901, covering 28 countries) to investigate how socio-demographic characteristics and country-level indicators of technological and economic development (the rate of high-technology manufactured exports, the cellular phone subscriptions rate and GDP) influence how robots are accepted in the realm of the social services. The results show that only individual (socio-demographic) and technology acceptance model (TAM) factors influence attitudes towards social robots. The effects of the contextual variables considered were not statistically strong enough to explain the attitudes towards social robots for social services.
Understanding the Increasing Hot Extremes over the Northern Extratropics Using Community Atmosphere Model
Authors: Zhao Siyu , Zhang Jiaying , Deng Yi , Wang Na
Published: October 2021

The past four decades have seen an increase of terrestrial hot extremes during summer in the northern extratropics, accompanied by the Northern Hemisphere (NH) sea surface temperature (SST) warming (mainly over 10°–70°N, 0°–360°) and CO2 concentration rising. This study aims to understand possible causes for the increasing hot extremes, which are defined on a daily basis. We conduct a series of numerical experiments using the Community Atmosphere Model version 5 model for two periods, 1979–1995 and 2002–2018. The experiment by changing the CO2 concentration only with the climatological SST shows less increase of hot extremes days than that observed, whereas that by changing the NH SST (over 10°–70°N, 0°–360°) with constant CO2 concentration strengthens the hot extremes change over mid-latitudes. The experiment with both SST and CO2 concentration changes shows hot extremes change closer to the observation compared to the single-change experiments, as well as more similar simulations of atmospheric circulations and feedbacks from cloud and radiative processes. Also discussed are roles of natural variability (e.g., Pacific Decadal Oscillation and Atlantic Multidecadal Oscillation) and other factors (e.g., Arctic sea ice and tropical SST).
Water-stained leaves: formation and application as a field indicator of wetland hydrology
Authors: Berkowitz Jacob F. , Pietroski Jason P.
Published: October 2021

Wetland delineations conducted in the United States utilize field indicators as proxy measures of the presence or absence of wetland hydrology. Water-stained leaves provide a practical, qualitative field indicator of wetland hydrology; however, the formation of water-stained leaves has not been elucidated. In response, leaves from six tree species were examined under five treatments to investigate the water-staining process and concomitant timeframes. Results indicate that leaf staining occurred within 14-21 days of continuous exposure to wetland waters and sediment under both laboratory and field conditions. Leaf staining was characterized by readily observable shifts in leaf color (i.e., decreasing Munsell hue, value, and chroma) causing the leaves to appear very dark or black. No color shifts associated with leaf staining occurred in treatments exposed to upland conditions. The timeframe associated with leaf staining corresponds with established wetland hydrology criteria requiring a minimum hydroperiod of 14 consecutive days of soil saturation, flooding, or ponding. Leaves exposed to wetland waters and sediment underwent color shifts significantly faster and to a greater extent than leaves inundated with deionized water, likely as a result of increased microbial abundance and the presence of anaerobic conditions in the simulated wetland treatments. Results suggest that water-stained leaves 1) are a useful and reliable wetland hydrology field indicator for wetland delineation purposes, 2) may provide a proxy measure of wetland hydroperiod, and 3) Munsell color measurements can help differentiate between leaves exposed to wetland and upland conditions.
Barriers and Drivers for Mainstreaming Nature-Based Solutions for Flood Risks: The Case of South Korea
Authors: Han Sungju , Kuhlicke Christian
Published: October 2021

Nature-based solutions (NBS) are seen as a promising adaptation measure that sustainably deals with diverse societal challenges, while simultaneously delivering multiple benefits. Nature-based solutions have been highlighted as a resilient and sustainable means of mitigating floods and other hazards globally. This study examined diverging conceptualizations of NBS, as well as the attitudinal (for example, emotions and beliefs) and contextual (for example, legal and political aspects) barriers and drivers of NBS for flood risks in South Korea. Semistructured interviews were conducted with 11 experts and focused on the topic of flood risk measures and NBS case studies. The analysis found 11 barriers and five drivers in the attitudinal domain, and 13 barriers and two drivers in the contextual domain. Most experts see direct monetary benefits as an important attitudinal factor for the public. Meanwhile, the cost-effectiveness of NBS and their capacity to cope with flood risks were deemed influential factors that could lead decision makers to opt for NBS. Among the contextual factors, insufficient systems to integrate NBS in practice and the ideologicalization of NBS policy were found to be peculiar barriers, which hinder consistent realization of initiatives and a long-term national plan for NBS. Understanding the barriers and drivers related to the mainstreaming of NBS is critical if we are to make the most of such solutions for society and nature. It is also essential that we have a shared definition, expectation, and vision of NBS.
Das kollektive Ritual als Performance? Die Herstellung von religiöser „Authentizität“ in der differenzierten Gesellschaft
Authors: Pruisken Insa , Loebell Josefa
Published: October 2021

Der Beitrag greift Jeffrey Alexanders (2004) These auf, dass die einzelnen Komponenten kollektiver Rituale in der modernen Gesellschaft zwar zunehmend differenziert und somit religiös „entleert“ werden, in der Inszenierung aber „re-fusioniert“ werden können. Das Religiöse wird somit subjektiviert, mediatisiert und eventisiert. Rationalisierungsprozesse wie Organisations- und Marktbildung sowie Digitalisierung treiben diese Entwicklung voran. Im empirischen Teil vergleichen wir drei kollektive Rituale aus dem amerikanischen Evangelikalismus, die unterschiedliche Grade der Differenzierung aufweisen: Im Fall der (1) traditionellen Gemeinde wird religiöse Authentizität aus den engen sozialen Beziehungen innerhalb der Gemeinde und zur Denomination erzeugt. (2) Im Megakirchengottesdienst derLakewood Churchwird Authentizität in der professionellen Event-Inszenierung hergestellt. (3) Die evangelikale Vloggerin hingegen erzeugt Authentizität – und damit eine Bindung an ihr Publikum –, indem Skript und Darstellerin in der Inszenierung vollständig verschmelzen.
Analysis of Inter-particle Contact Parameters of Garlic Cloves Using Discrete Element Method
Authors: Park Donghyeok , Lee Chun Gu , Yang Doee , Kim Daehyun , Kim Joon Yong , Rhee Joong Yong
Published: October 2021

Purpose

The discrete element method (DEM) can be used in agricultural fields such as crop sowing, harvesting, and crop transportation. Nevertheless, modeling complex crops as appropriately shaped particles remains challenging. The modeling of particles and the calibration of input parameters are important for simulating the realistic behaviors of particles using the DEM.

Methods

In this study, particle models representing the morphological characteristics and size deviations of garlic cloves were proposed. Additionally, the coefficients of friction were analyzed as the contact parameters of the particles based on the heap formation experiments and simultations of the swing-arm method using 150 garlic cloves.

Results

The simulation results were analyzed that the residual number of particles, a bulk property that can be measured simply in the experiment, is related to the coefficients of friction. In the heap formation experiments with low particle counts, the bulk properties were more clearly differentiated by the residual number of particles than the angle of repose. Moreover, the bulk properties similar to the actual garlic could not be expressed as a spherical particle model. Thus, an equation for predicting the residual number of particles was derived for the non-spherical garlic clove particle model. Five sets of coefficients of friction were presented using the prediction equation, and all the simulation results were close to the actual residual number of particles and angle of repose of the garlic.

Conclusions

Although the sizes of garlic cloves have a wide distribution, appropriate inter-particle contact parameters could be predicted. Therefore, the calibration process of the DEM can be shortened using the proposed prediction equation for the residual number of particles with non-spherical particles.
Multi-objective optimization for autonomous driving strategy based on Deep Q Network
Authors: Hu Tianmeng , Luo Biao , Yang Chunhua
Published: October 2021

Autonomous driving is an important development direction of automobile technology, and driving strategy is the core of the autonomous driving system. Most works in this area focus on single-objective tasks, such as maximizing vehicle speed or lane-keeping, and rare attention has been paid to the quality of driving skills. Therefore, a multi-objective learning method is proposed for autonomous driving strategy based on deep Q-network, where two optimization objectives are involved, i.e., vehicle speed and passenger comfort. An end-to-end autonomous driving model is designed by using vehicle front camera images as inputs to the Q-network and makes decisions based on the output Q values. Considering the vehicle speed and passenger comfort, the reward function is designed for multi-objective optimization. To evaluate the effectiveness of the method, training and testing are performed in a simulator, and a single-objective strategy with the goal of maximizing speed is designed for comparison. The results show that the proposed multi-objective autonomous driving strategy can strike a balance between vehicle speed and passenger comfort. Compared with the single-objective strategy, the multi-objective strategy has a significant improvement in comfort, while the average speed is only slightly reduced.
Interventions to address loneliness and social isolation in young people: A systematic review of the evidence on acceptability and effectiveness
Authors: Osborn Tom , Weatherburn Peter , French Rebecca S.
Published: October 2021

Introduction

Loneliness is prevalent and associated with negative health outcomes in young people. Our understanding of how it can be best addressed is limited. This systematic review aims to assess the acceptability and effectiveness of interventions to reduce and prevent loneliness and social isolation in young people.

Methods

Six bibliographic databases were searched; references of included studies were screened for relevant literature. A pre‐defined framework was used for data extraction. Quality appraisal was performed using the Mixed Method Appraisal Tool. Data were synthesised narratively.

Results

9,358 unique references were identified; 28 publications from 16 interventions met the inclusion criteria. The majority of interventions were high intensity, individual or small group interventions, often targeted at specific ‘at risk’ populations. While 14 interventions were associated with a statistically significant reduction in loneliness or social isolation, the heterogeneous measures of loneliness, small sample sizes, short periods of follow‐up and high attrition rates limit evidence on effectiveness. Interventions implemented in more general populations of young people appeared more acceptable than those in specific ‘at risk’ populations.

Conclusion

High intensity interventions are unlikely to be feasible at a population level. Further work is required to develop and evaluate theoretically‐informed loneliness interventions for young people that reach wider audiences.
A requirements elicitation process for a purposeful general aviation (GA) aircraft design based on emerging economies
Authors: Khandoker A. , Hamid M.A. , Shahriar A.S. , Rahman A.T.S. , Gessl G.
Published: October 2021

Design success mostly depends on understanding and realising product requirements, which are nested with different levels of stakeholders and specific market demands. Emerging markets are volatile and non-linear for understanding user-specific needs, particularly related to aircraft design. We attempt herein to elicit specific requirements through a proposed requirements elicitation process based on functional, physical and behavioural viewpoints. An evaluation of those critical requirements is also performed through Quality Function Deployment (QFD) to reveal the fitness of the customer requirements (raw requirements) in relation to the technical measures. After selecting all projected potential users, a Systems Modelling Language (SysML) use-case diagram is also summarised to illustrate the user’s relation to the system functions. Some raw requirements are verified through constraint analysis and cost examination as an exemplary approach to present the transformation from raw to final requirements. The data are collected and analysed to construct the aircraft’s key specifications. Most importantly, how to identify good requirements that define the needs, attainability, clarity and verifiability is demonstrated.

In addition, it is demonstrated through this study that there is a need of a specific type of general aviation aircraft that may fulfil the unique demands of emerging economies by satisfying their socio-economic conditions.
Observation and modelling of stimulated Raman scattering driven by an optically smoothed laser beam in experimental conditions relevant for shock ignition
Authors: Cristoforetti G. , Hüller S. , Koester P. , Antonelli L. , Atzeni S. , Baffigi F. , Batani D. , Baird C. , Booth N. , Galimberti M. , Glize K. , Héron A. , Khan M. , Loiseau P. , Mancelli D. , Notley M. , Oliveira P. , Renner O. , Smid M. , Schiavi A. , Tran G. , Woolsey N. C. , Gizzi L. A.
Published: October 2021

We report results and modelling of an experiment performed at the Target Area West Vulcan laser facility, aimed at investigating laser–plasma interaction in conditions that are of interest for the shock ignition scheme in inertial confinement fusion (ICF), that is, laser intensity higher than

${10}^{16}$

 

$\mathrm{W}/{\mathrm{cm}}^2$

impinging on a hot (

$T>1$

keV), inhomogeneous and long scalelength pre-formed plasma. Measurements show a significant stimulated Raman scattering (SRS) backscattering (

$\sim 4\%{-}20\%$

of laser energy) driven at low plasma densities and no signatures of two-plasmon decay (TPD)/SRS driven at the quarter critical density region. Results are satisfactorily reproduced by an analytical model accounting for the convective SRS growth in independent laser speckles, in conditions where the reflectivity is dominated by the contribution from the most intense speckles, where SRS becomes saturated. Analytical and kinetic simulations well reproduce the onset of SRS at low plasma densities in a regime strongly affected by non-linear Landau damping and by filamentation of the most intense laser speckles. The absence of TPD/SRS at higher densities is explained by pump depletion and plasma smoothing driven by filamentation. The prevalence of laser coupling in the low-density profile justifies the low temperature measured for hot electrons (

$7\!{-}\!12$

keV), which is well reproduced by numerical simulations.
Impact of number of lumens in central-venous catheters on central-line bloodstream infection (CLABSI) and venous thromboembolism (VTE) risk in patients with acute leukemia
Authors: Varabyeva Alina , Lo Christabel Pui-See , Brancaccio Adamo , Perissinotti Anthony J. , Patel Twisha , Sandison Katie , Benitez Lydia L. , Pettit Kristen , Burke Patrick W. , Bixby Dale L. , Marini Bernard L.
Published: October 2021

This retrospective study was conducted to determine whether the number of peripherally inserted central-catheter lumens affected the rate of central-line associated bloodstream infections (CLABSIs) in adult patients with acute leukemia. The results show that CLABSI rates were not significantly different between patients with triple-lumen or double-lumen PICCs (22.1% vs 23.4%; P = .827).
Influence of fluid pressure changes on the reactivation potential of pre-existing fractures: a case study in the Archaean metavolcanics of the Chitradurga region, India
Authors: Bhowmick Sreyashi , Mondal Tridib Kumar
Published: October 2021

The metavolcanics of Chitradurga region host numerous shallow crustal veins and fractures and faults of multiple orientations. Several high and lowPfcycles have been recorded in the region, leading to the reactivation of most of the pre-existing fractures for highPfand selective reactivation of some well-oriented fractures under lowPfconditions. The pre-existing anisotropy (magnetic fabric) in the metavolcanics acted as the most prominent planar fabric for fracture propagation and vein emplacement under both conditions, thereby attaining maximum vein thickness. In this study, we emphasize the reactivation propensity of these pre-existing fracture planes under conditions of fluid pressure variation, related to the high and lowPfcycles. Multiple cycles of fluid-induced fracture reactivation make it difficult to quantify the maximum/minimum fluid pressure magnitudes. However, in this study we use the most appropriate fluid pressure magnitudes mathematically feasible for a shallow crustal depth of ∼2.4 km. We determine the changes in the reactivation potential with states of stress for the respective fracture orientations under both high and lowPfconditions. Dependence of fluid pressure variation on the opening angle of the fractures is also monitored. Finally, we comment on the failure mode and deformation behaviour of the fractures within the prevailing stress field inducing volumetric changes at the time of deformation. We find that deformation behaviour is directly related to the dip of the fracture planes.
The self-focusing condition of a charged particle beam in a resistive plasma
Authors: Ning Xiao-Chuan , Liang Tian-Yi , Wu D. , Sheng Zheng-Mao
Published: October 2021

The self-focusing condition of a charged particle beam in a resistive plasma has been studied. When plasma heating is weak, the beam focusing is intensified by increasing the beam density or velocity. However, when plasma heating is strong, the beam focusing is only determined by the beam velocity. Especially, in weak heating conditions, the beam trends to be focused into the centre as a whole, and in strong heating conditions, a double-peak structure with a hollow centre is predicted to appear. Furthermore, it is found that the beam radius has a significant effect on focusing distance: a larger the beam radius will result in a longer focusing distance. Simulation results also show that when the beam radius is large enough, filamentation of the beam appears. Our results will serve as a reference for relevant beam–plasma experiments and theoretical analyses, such as heavy ion fusion and ion-beam-driven high energy density physics.
Exploration of factors associated with spatial−temporal veterinary surveillance diagnoses of rumen fluke (Calicophoron daubneyi) infections in ruminants using zero-inflated mixed modelling
Authors: Jones Rhys Aled , Williams Hefin Wyn , Mitchell Sian , Robertson Sara , Macrelli Michele
Published: October 2021

Rumen fluke (Calicophoron daubneyi) has emerged as a prominent parasite of ruminants in Europe over the past decades. Epidemiological questions remain regarding this observed increase in prevalence as well as the prospect for future paramphistomosis risk. This study aimed to identify factors associated with the temporal−spatial prevalence of rumen fluke as measured by veterinary surveillance in a temperate region using zero-inflated negative binomial mixed modelling. Modelling revealed that summer rainfall, raindays and sunshine hours and mean winter temperature as significant positively associated climate variables for rumen fluke prevalence over space and time (P< 0.05). Rumen fluke prevalence was also higher in counties with higher cattle/sheep densities and was positively associated with rumen fluke case rates in the previous years (P< 0.05). Equivalent models for fasciolosis prevalence revealed no significant association with winter temperature and sunshine hours, (P> 0.05). These results confirm a strong association between rainfall and the prevalence of both fluke species in a temperate environment, likely due to the role ofGalba truncatulaas their intermediate snail host. It also highlights the potential added importance of winter temperature and sunshine hours in rumen fluke epidemiology when compared to liver fluke.
Sources of vitamin D for humans
Authors: Benedik Evgen
Published: October 2021

Abstract. Both vitamin D insufficiency and deficiency are now well-documented worldwide in relation to human health, and this has raised interest in vitamin D research. The aim of this article is therefore to review the literature on sources of vitamin D. It can be endogenously synthesised under ultraviolet B radiation in the skin, or ingested through dietary supplements and dietary sources, which include food of animal and plant origin, as well as fortified foods. Vitamin D is mainly found in two forms, D3 (cholecalciferol) and D2 (ergocalciferol). In addition to the D3 and D2 forms of vitamin D, 25-hydroxy vitamin D also contributes significantly to dietary vitamin D intake. It is found in many animal-derived products. Fortified food can contain D3 or D2 forms or vitamin D metabolite 25-hydroxy vitamin D. Not many foods are a rich source (> 4 μg/100 g) of vitamin D (D represents D3 and/or D2), e.g., many but not all fish (5–25 μg/100 g), mushrooms (21.1–58.7 μg/100 g), Reindeer lichen (87 μg/100 g) and fish liver oils (250 μg/100 g). Other dietary sources are cheese, beef liver and eggs (1.3–2.9 μg/100 g), dark chocolate (4 μg/100 g), as well as fortified foods (milk, yoghurt, fat spreads, orange juice, breakfast grains, plant-based beverages). Since an adequate intake of vitamin D (15 μg/day set by the European Food Safety Authority) is hard to achieve through diet alone, dietary supplements of vitamin D are usually recommended. This review summarizes current knowledge about different sources of vitamin D for humans.
Voices of Undergraduate Students With Disabilities During the COVID-19 Pandemic
Authors: Kourea Lefki , Christodoulidou Panayiota , Fella Argyro
Published: October 2021

Abstract. Social distancing, lockdown, and other restrictive measures imposed because of the COVID-19 pandemic led universities to transfer to remote online instruction. Several studies examined the impact of online instruction on students’ academic and socioemotional performance, whereas only limited research evidence exists concerning the performance of university students with disabilities (SWD) during online learning. This exploratory qualitative study aims to understand the experiences of nine undergraduate SWD during the COVID-19 pandemic. A thematic analysis revealed that SWD experienced multiple adversities related to academic (e.g., accommodations, communication with university instructors, academic advisor) and socioemotional (stress, routine disruption, lockdown effects) areas. We compared and contrasted our study findings with existing literature on creating equitable academic environments and reducing access barriers for all students.
Organoids as host models for infection biology – a review of methods
Authors: Aguilar Carmen , Alves da Silva Marta , Saraiva Margarida , Neyazi Mastura , Olsson I. Anna S. , Bartfeld Sina
Published: October 2021

Infectious diseases are a major threat worldwide. With the alarming rise of antimicrobial resistance and emergence of new potential pathogens, a better understanding of the infection process is urgently needed. Over the last century, the development of in vitro and in vivo models has led to remarkable contributions to the current knowledge in the field of infection biology. However, applying recent advances in organoid culture technology to research infectious diseases is now taking the field to a higher level of complexity. Here, we describe the current methods available for the study of infectious diseases using organoid cultures.
Organoids in image-based phenotypic chemical screens
Authors: Lukonin Ilya , Zinner Marietta , Liberali Prisca
Published: October 2021

Image-based phenotypic screening relies on the extraction of multivariate information from cells cultured under a large variety of conditions. Technical advances in high-throughput microscopy enable screening in increasingly complex and biologically relevant model systems. To this end, organoids hold great potential for high-content screening because they recapitulate many aspects of parent tissues and can be derived from patient material. However, screening is substantially more difficult in organoids than in classical cell lines from both technical and analytical standpoints. In this review, we present an overview of studies employing organoids for screening applications. We discuss the promises and challenges of small-molecule treatments in organoids and give practical advice on designing, running, and analyzing high-content organoid-based phenotypic screens.
Gastrointestinal cancer organoids—applications in basic and translational cancer research
Authors: Seidlitz Therese , Stange Daniel E.
Published: October 2021

Cancer is a major health problem and a leading cause of death worldwide. Early cancer detection and continuous changes in treatment strategies have improved overall patient survival. The recent development of targeted drugs offers new opportunities for personalized cancer treatment. Nevertheless, individualized treatment is accompanied by the need for biomarkers predicting the response of a patient to a certain drug. One of the most promising breakthroughs in recent years that might help to overcome this problem is the organoid technology. Organoid cultures exhibit self-renewal capacity, self-organization, and long-term proliferation, while recapitulating many aspects of their primary tissue. Generated patient-derived organoid (PDO) libraries constitute “living” biobanks, allowing the in-depth analysis of tissue function, development, tumor initiation, and cancer pathobiology. Organoids can be derived from all gastrointestinal tissues, including esophageal, gastric, liver, pancreatic, small intestinal and colorectal tissues, and cancers of these tissues. PDOs are amenable to various techniques, including sequencing analyses, drug screening, targeted therapy testing, tumor microenvironment studies, and genetic engineering capabilities. In this review, we discuss the different applications of gastrointestinal organoids in basic cancer biology and clinical translation.
The culture of research communication in neonatal intensive care units: key stakeholder perspectives
Authors: Degl Jennifer , Ariagno Ronald , Aschner Judy , Beauman Sandra , Eklund Wakako , Faro Elissa , Iwami Hiroko , Jackson Yamile , Kenner Carole , Kim Ivone , Klein Agnes , Short Mary , Sorrells Keira , Turner Mark A. , Ward Robert , Winiecki Scott , Bucci-Rechtweg Christina ,   International Neonatal Consortium
Published: October 2021

Objective

To assess the perspectives of neonatologists, neonatal nurses, and parents on research-related education and communication practices in the neonatal intensive care unit (NICU).

Study design

Questionnaire circulated through interest groups and administered using the internet.

Results

323 respondents responded to the survey. 52 were neonatologists, 188 were neonatal nurses, and 83 were parents of NICU graduates. Analysis was descriptive. Differences were noted between stakeholder groups with respect to whether current medications meet the needs of sick neonates, research as central to the mission of the NICU, availability of appropriate education/training for all members of the research team, and adequacy of information provided to parents before, during, and after a research study is completed.

Conclusion

Engagement of nurses and parents at all stages of NICU research is currently suboptimal; relevant good practices, including education, should be shared among neonatal units.
Appropriate exercise level attenuates gut dysbiosis and valeric acid increase to improve neuroplasticity and cognitive function after surgery in mice
Authors: Lai Zhongmeng , Shan Weiran , Li Jun , Min Jia , Zeng Xianzhang , Zuo Zhiyi
Published: October 2021

Postoperative cognitive dysfunction (POCD) affects the outcome of millions of patients each year. Aging is a risk factor for POCD. Here, we showed that surgery induced learning and memory dysfunction in adult mice. Transplantation of feces from surgery mice but not from control mice led to learning and memory impairment in non-surgery mice. Low intensity exercise improved learning and memory in surgery mice. Exercise attenuated surgery-induced neuroinflammation and decrease of gut microbiota diversity. These exercise effects were present in non-exercise mice receiving feces from exercise mice. Exercise reduced valeric acid, a gut microbiota product, in the blood. Valeric acid worsened neuroinflammation, learning and memory in exercise mice with surgery. The downstream effects of exercise included attenuating growth factor decrease, maintaining astrocytes in the A2 phenotypical form possibly via decreasing C3 signaling and improving neuroplasticity. Similar to these results from adult mice, exercise attenuated learning and memory impairment in old mice with surgery. Old mice receiving feces from old exercise mice had better learning and memory than those receiving control old mouse feces. Surgery increased blood valeric acid. Valeric acid blocked exercise effects on learning and memory in old surgery mice. Exercise stabilized gut microbiota, reduced neuroinflammation, attenuated growth factor decrease and preserved neuroplasticity in old mice with surgery. These results provide direct evidence that gut microbiota alteration contributes to POCD development. Valeric acid is a mediator for this effect and a potential target for brain health. Low intensity exercise stabilizes gut microbiota in the presence of insult, such as surgery.
Inhibiting microcephaly genes as alternative to microtubule targeting agents to treat brain tumors
Authors: Iegiani Giorgia , Di Cunto Ferdinando , Pallavicini Gianmarco
Published: October 2021

Medulloblastoma (MB) and gliomas are the most frequent high-grade brain tumors (HGBT) in children and adulthood, respectively. The general treatment for these tumors consists in surgery, followed by radiotherapy and chemotherapy. Despite the improvement in patient survival, these therapies are only partially effective, and many patients still die. In the last decades, microtubules have emerged as interesting molecular targets for HGBT, as various microtubule targeting agents (MTAs) have been developed and tested pre-clinically and clinically with encouraging results. Nevertheless, these treatments produce relevant side effects since they target microtubules in normal as well as in cancerous cells. A possible strategy to overcome this toxicity could be to target proteins that control microtubule dynamics but are required by HGBT cells much more than in normal cell types. The genes mutated in primary hereditary microcephaly (MCPH) are ubiquitously expressed in proliferating cells, but under normal conditions are selectively required during brain development, in neural progenitors. There is evidence that MB and glioma cells share molecular profiles with progenitors of cerebellar granules and of cortical radial glia cells, in which MCPH gene functions are fundamental. Moreover, several studies indicate that MCPH genes are required for HGBT expansion. Among the 25 known MCPH genes, we focus this review on KNL1, ASPM, CENPE, CITK and KIF14, which have been found to control microtubule stability during cell division. We summarize the current knowledge about the molecular basis of their interaction with microtubules. Moreover, we will discuss data that suggest these genes are promising candidates as HGBT-specific targets.
PDZD-8 and TEX-2 regulate endosomal PI(4,5)P2 homeostasis via lipid transport to promote embryogenesis in C. elegans
Authors: Jeyasimman Darshini , Ercan Bilge , Dharmawan Dennis , Naito Tomoki , Sun Jingbo , Saheki Yasunori
Published: October 2021

Different types of cellular membranes have unique lipid compositions that are important for their functional identity. PI(4,5)P2 is enriched in the plasma membrane where it contributes to local activation of key cellular events, including actomyosin contraction and cytokinesis. However, how cells prevent PI(4,5)P2 from accumulating in intracellular membrane compartments, despite constant intermixing and exchange of lipid membranes, is poorly understood. Using the C. elegans early embryo as our model system, we show that the evolutionarily conserved lipid transfer proteins, PDZD-8 and TEX-2, act together with the PI(4,5)P2 phosphatases, OCRL-1 and UNC-26/synaptojanin, to prevent the build-up of PI(4,5)P2 on endosomal membranes. In the absence of these four proteins, large amounts of PI(4,5)P2 accumulate on endosomes, leading to embryonic lethality due to ectopic recruitment of proteins involved in actomyosin contractility. PDZD-8 localizes to the endoplasmic reticulum and regulates endosomal PI(4,5)P2 levels via its lipid harboring SMP domain. Accumulation of PI(4,5)P2 on endosomes is accompanied by impairment of their degradative capacity. Thus, cells use multiple redundant systems to maintain endosomal PI(4,5)P2 homeostasis.
Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19
Authors: Boras Britton , Jones Rhys M. , Anson Brandon J. , Arenson Dan , Aschenbrenner Lisa , Bakowski Malina A. , Beutler Nathan , Binder Joseph , Chen Emily , Eng Heather , Hammond Holly , Hammond Jennifer , Haupt Robert E. , Hoffman Robert , Kadar Eugene P. , Kania Rob , Kimoto Emi , Kirkpatrick Melanie G. , Lanyon Lorraine , Lendy Emma K. , Lillis Jonathan R. , Logue James , Luthra Suman A. , Ma Chunlong , Mason Stephen W. , McGrath Marisa E. , Noell Stephen , Obach R. Scott , O’ Brien Matthew N. , O’Connor Rebecca , Ogilvie Kevin , Owen Dafydd , Pettersson Martin , Reese Matthew R. , Rogers Thomas F. , Rosales Romel , Rossulek Michelle I. , Sathish Jean G. , Shirai Norimitsu , Steppan Claire , Ticehurst Martyn , Updyke Lawrence W. , Weston Stuart , Zhu Yuao , White Kris M. , García-Sastre Adolfo , Wang Jun , Chatterjee Arnab K. , Mesecar Andrew D. , Frieman Matthew B. , Anderson Annaliesa S. , Allerton Charlotte
Published: October 2021

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.
GproDIA enables data-independent acquisition glycoproteomics with comprehensive statistical control
Authors: Yang Yi , Yan Guoquan , Kong Siyuan , Wu Mengxi , Yang Pengyuan , Cao Weiqian , Qiao Liang
Published: October 2021

Large-scale profiling of intact glycopeptides is critical but challenging in glycoproteomics. Data independent acquisition (DIA) is an emerging technology with deep proteome coverage and accurate quantitative capability in proteomics studies, but is still in the early stage of development in the field of glycoproteomics. We propose GproDIA, a framework for the proteome-wide characterization of intact glycopeptides from DIA data with comprehensive statistical control by a 2-dimentional false discovery rate approach and a glycoform inference algorithm, enabling accurate identification of intact glycopeptides using wide isolation windows. We further utilize a semi-empirical spectrum prediction strategy to expand the coverage of spectral libraries of glycopeptides. We benchmark our method for N-glycopeptide profiling on DIA data of yeast and human serum samples, demonstrating that DIA with GproDIA outperforms the data-dependent acquisition-based methods for glycoproteomics in terms of capacity and data completeness of identification, as well as accuracy and precision of quantification. We expect that this work can provide a powerful tool for glycoproteomic studies.
Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis
Authors: Diesch Jeannine , Le Pannérer Marguerite-Marie , Winkler René , Casquero Raquel , Muhar Matthias , van der Garde Mark , Maher Michael , Herráez Carolina Martínez , Bech-Serra Joan J. , Fellner Michaela , Rathert Philipp , Brooks Nigel , Zamora Lurdes , Gentilella Antonio , de la Torre Carolina , Zuber Johannes , Götze Katharina S. , Buschbeck Marcus
Published: October 2021

The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis.
Bright single photon emitters with enhanced quantum efficiency in a two-dimensional semiconductor coupled with dielectric nano-antennas
Authors: Sortino Luca , Zotev Panaiot G. , Phillips Catherine L. , Brash Alistair J. , Cambiasso Javier , Marensi Elena , Fox A. Mark , Maier Stefan A. , Sapienza Riccardo , Tartakovskii Alexander I.
Published: October 2021

Single photon emitters in atomically-thin semiconductors can be deterministically positioned using strain induced by underlying nano-structures. Here, we couple monolayer WSe2 to high-refractive-index gallium phosphide dielectric nano-antennas providing both optical enhancement and monolayer deformation. For single photon emitters formed on such nano-antennas, we find very low (femto-Joule) saturation pulse energies and up to 104 times brighter photoluminescence than in WSe2 placed on low-refractive-index SiO2 pillars. We show that the key to these observations is the increase on average by a factor of 5 of the quantum efficiency of the emitters coupled to the nano-antennas. This further allows us to gain new insights into their photoluminescence dynamics, revealing the roles of the dark exciton reservoir and Auger processes. We also find that the coherence time of such emitters is limited by intrinsic dephasing processes. Our work establishes dielectric nano-antennas as a platform for high-efficiency quantum light generation in monolayer semiconductors.
Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy
Authors: Abbas Hussein A. , Hao Dapeng , Tomczak Katarzyna , Barrodia Praveen , Im Jin Seon , Reville Patrick K. , Alaniz Zoe , Wang Wei , Wang Ruiping , Wang Feng , Al-Atrash Gheath , Takahashi Koichi , Ning Jing , Ding Maomao , Beird Hannah C. , Mathews Jairo T. , Little Latasha , Zhang Jianhua , Basu Sreyashi , Konopleva Marina , Marques-Piubelli Mario L. , Solis Luisa M. , Parra Edwin Roger , Lu Wei , Tamegnon Auriole , Garcia-Manero Guillermo , Green Michael R. , Sharma Padmanee , Allison James P. , Kornblau Steven M. , Rai Kunal , Wang Linghua , Daver Naval , Futreal Andrew
Published: October 2021

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8+ cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy-resistant patients. Trajectory analysis reveals a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8+ T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia.
Conformer-specific polar cycloaddition of dibromobutadiene with trapped propene ions
Authors: Kilaj Ardita , Wang Jia , Straňák Patrik , Schwilk Max , Rivero Uxía , Xu Lei , von Lilienfeld O. Anatole , Küpper Jochen , Willitsch Stefan
Published: October 2021

Diels–Alder cycloadditions are efficient routes for the synthesis of cyclic organic compounds. There has been a long-standing discussion whether these reactions proceed via stepwise or concerted mechanisms. Here, we adopt an experimental approach to explore the mechanism of the model polar cycloaddition of 2,3-dibromo-1,3-butadiene with propene ions by probing its conformational specificities in the entrance channel under single-collision conditions in the gas phase. Combining a conformationally controlled molecular beam with trapped ions, we find that both conformers of the diene, gauche and s-trans, are reactive with capture-limited reaction rates. Aided by quantum-chemical and quantum-capture calculations, this finding is rationalised by a simultaneous competition of concerted and stepwise reaction pathways, revealing an interesting mechanistic borderline case.