bluuebunny/crossref_metadata_2025 huggingface dataset:
On characterizations for subclasses of directed co-graphs
Authors: Gurski Frank , Komander Dominique , Rehs Carolin
Published: November 2020

Undirected co-graphs are those graphs which can be generated from the single vertex graph by disjoint union and join operations. Co-graphs are exactly the $$P_4$$

P
4

-free graphs (where $$P_4$$

P
4

denotes the path on 4 vertices). The class of co-graphs itself and several subclasses haven been intensively studied. Among these are trivially perfect graphs, threshold graphs, weakly quasi threshold graphs, and simple co-graphs. Directed co-graphs are digraphs which can be defined by, starting with the single vertex graph, applying the disjoint union, order composition, and series composition. By omitting the series composition we obtain the subclass of oriented co-graphs which has been analyzed by Lawler in the 1970s. The restriction to linear expressions was recently studied by Boeckner. Until now, there are only a few versions of subclasses of directed co-graphs. By transmitting the restrictions of undirected subclasses to the directed classes, we define the corresponding subclasses for directed co-graphs. We consider directed and oriented versions of threshold graphs, simple co-graphs, co-simple co-graphs, trivially perfect graphs, co-trivially perfect graphs, weakly quasi threshold graphs and co-weakly quasi threshold graphs. For all these classes we give characterizations by finite sets of minimal forbidden induced subdigraphs. Additionally, we analyze the relations between these graph classes.
Thermal behavior of PLA plasticized by commercial and cardanol-derived plasticizers and the effect on the mechanical properties
Authors: Greco Antonio , Ferrari Francesca
Published: November 2020

This paper is aimed at studying the thermal properties of poly(lactic acid), PLA with different plasticizers. Plasticized PLA was obtained by mixing and extruding PLA with 20 mass% of neat cardanol, epoxidized cardanol acetate (ECA) and poly(ethylene glycol) (PEG) 400. The glass transition of completely amorphous samples, melting and crystallization behavior of plasticized PLA were analyzed by differential scanning calorimetry. Results obtained show that, below Tg, a higher enthalpy relaxation occurs for PLA plasticized by cardanol derivatives. This is indicative of a faster mobility of PLA chains below Tg, when cardanol derivatives are used as plasticizers. On the other hand, an opposite behavior was observed for the crystallization studies. In facts, a much faster crystallization was found for PLA plasticized by PEG, which in turn indicates a much higher mobility of PLA chains above Tg compared to PLA plasticized by cardanol derivatives. Mechanical properties obtained on completely amorphous samples show that PLA plasticized by ECA is characterized by lower modulus, which is indicative of a more efficient plasticization. On the other hand, the thicker crystals formed during crystallization of PLA plasticized by ECA involve a more relevant increase in the modulus in semicrystalline samples.
Application of divided convective-dispersive transport model to simulate variability of conservative transport processes inside a planted horizontal subsurface flow constructed wetland
Authors: Dittrich Ernő , Klincsik Mihály , Somfai Dávid , Dolgos-Kovács Anita , Kiss Tibor , Szekeres Anett
Published: November 2020

This paper offers a novel application of our model worked out in Maple environment to help understand the very complex transport processes in horizontal subsurface flow constructed wetland with coarse gravel (HSFCW-C). We made tracer measurements: Inside a constructed wetland, we had 9 sample points, and samples were taken from each point at two depths. Our model is a divided convective-dispersive transport (D-CDT) model which makes a fitted response curve from the sum of two separate CDT curves showing the contributions of the main and side streams. Analytical solutions of CDT curves are inverse Gaussian distribution functions. This model was fitted onto inner points of the measurements to demonstrate that the model gives better fitting to the inner points than the commonly used convective-dispersive transport model. The importance of this new application of the model is that it can resemble transport processes in these constructed wetlands more precisely than the regularly used convective-dispersive transport (CDT) model. The model allows for calculations of velocity and dispersion coefficients. The results showed that this model gave differences of 4–99% (of velocity) and 2–474% (of dispersion coefficient) compared with the CDT model and values were closer to actual hydraulic behavior. The results also demonstrated the main flow path in the system.
Properties of feedback mechanisms on digital platforms: an exploratory study
Authors: Steur Andreas J. , Seiter Mischa
Published: November 2020

Many digital platforms implement feedback mechanisms as a means to control the behavior of their users. However, there is a lack of theoretical explanation regarding the interrelation between design characteristics of feedback mechanisms and their effects. In this study, we interpret feedback mechanisms as a specific type of management control to propose properties as a new theoretical perspective on this problem. Our exploratory study has two objectives. First, we analyze how digital platforms design their feedback mechanisms. Second, we examine to what extent feedback mechanisms comply with standards given in the management control literature for our newly introduced properties. Analyzing the 102 most widely used platforms in Germany, we find dominant patterns in nearly all design characteristics (e.g., query method, submission category and scale level). Furthermore, we find mixed compliance of feedback mechanisms with our introduced properties (e.g., low precision but high sensitivity and verifiability). For a deeper understanding of these results, especially the reasons for the design choices, we conduct 14 semi-structured expert interviews. We find simplicity and inspiration from other platforms to be dominant drivers for design choices.
An integrated framework for visualizing and forecasting realized covariance matrices
Authors: Shigemoto Hideto , Morimoto Takayuki
Published: November 2020

This paper proposes an integrated framework for visualizing and forecasting realized covariance matrices to enable the efficient construction and prediction of an optimal portfolio. Multivariate realized kernels are typically derived from intra-day high-frequency data, and are then used to estimate the realized covariance matrix via the graphical lasso algorithm. To forecast the realized covariances, we employ the conditional autoregressive Wishart model and its variants. Finally, we compute the Stein loss function and execute the model-confidence-set procedure to obtain the best model for optimal portfolio selection.
Distribution and cementation characteristics of beachrocks along southern, southwestern and western coast of Sri Lanka
Authors: Nayanthara Pahala Ge Nishadi , Dassanayake Anjula Buddhika Nayomi , Nakashima Kazunori , Kawasaki Satoru
Published: November 2020

Beachrocks are sedimentary structures where gravelly or sandy beaches have been transformed into rock outcrops formed through precipitation of connective cements amid their interstices. They are well-noted coastal features along the coastal belt of Sri Lanka due to the prevalent tropical climate. This study was aimed at gathering data on surface nature and cementation characteristics of beachrock occurrences along a part of Sri Lankan shoreline through field observations and a series of analyses including X-ray diffraction, X-ray fluorescence, scanning electron microscopy (SEM) techniques and petrographic thin-section analysis. The combined research findings from different techniques are also employed as a preliminary step to determine the formation mechanism of the studied beachrocks. The seaward-inclined low-angle beds running parallel to present shoreline are composed mostly of sandstone with occasional conglomerate. Almost all the beachrocks are made of quartz grains amalgamated by cement. One remarkable feature of Sri Lankan beachrocks is the presence of heavy minerals generally in thin lamina form. The cementing agents are predominantly composed of metastable carbonate phases, high magnesium calcite (HMC) and aragonite (Ar) with varying microfabrics and textures. From SEM examinations and thin-section images, main morphologies identified are acicular Ar, scalenohedral magnesium calcites along with bridge cements and micritic coatings which are typical of a marine-phreatic precipitation with the exception of occasional meniscus cements. Further, the presence of evidences of living organisms may be an indication of influence from the biological aspects which can be confirmed by more detailed analyses.
Development of a Single-Cell Technique to Increase Yield and Use of Gastrointestinal Cancer Organoids for Personalized Medicine Application
Authors: Gao Mei , Harper Megan M. , Lin Miranda , Qasem Shadi A. , Patel Reema A. , Mardini Samuel H. , Gabr Moamen M. , Cavnar Michael J. , Pandalai Prakash K. , Kim Joseph
Published: November 2020

BACKGROUND:

Organoids are excellent 3-dimensional in vitro models of gastrointestinal cancers. However, patient-derived organoids (PDOs) remain inconsistent and unreliable for rapid actionable drug sensitivity testing due to size variation and limited material.

STUDY DESIGN:

On day10/passage 2 after standard creation of organoids, half of PDOs were dissociated into single-cells with TrypLE Express Enzyme/DNase I and mechanical dissociation; and half of PDOs were expanded by the standard technique. Hematoxylin and eosin and immunohistochemistry with CK7 and CK20 were performed for characterization. Drug sensitivity testing was completed for single-cells and paired standard PDOs to assess reproducibility.

RESULTS:

After 2 to 3 days, >50% of single-cells reformed uniform miniature PDOs (˜50 μm). We developed 10 PDO single-cell lines (n = 4, gastric cancer, [GC]; and n = 6, pancreatic ductal adenocarcinoma, [PDAC]), which formed epithelialized cystic structures and by IHC, exhibited CK7(high)/CK20(low) expression patterns mirroring parent tissues. Compared with paired standard PDOs, single-cells (n = 2, PDAC; = 2, GC) showed similar architecture, albeit smaller and more uniform. Importantly, single cells demonstrated similar sensitivity to cytotoxic drugs to matched PDOs.

CONCLUSIONS:

PDO single-cells are accurate for rapid clinical drug testing in gastrointestinal cancers. Using early passage PDO single-cells facilitates high-volume drug testing, decreasing time from tumor sampling to actionable clinical decisions, and provides a personalized medicine platform to optimally select drugs for gastrointestinal cancer patients.
Care leavers, ambiguous loss and early parenting: explaining high rates of pregnancy and parenting amongst young people transitioning from out-of-home care
Authors: Purtell Jade , Mendes Philip , Saunders Bernadette J.
Published: November 2020

This paper is a narrative review examining the high prevalence of care leaver early parenting in the context of (i) key transitions from care studies taken from the last few decades, (ii) a structured review using Scopus of studies from 2015–2020 focussed specifically on young people transitioning from care and early parenting and (iii) Boss’s (2010) Ambiguous Loss theory. Young care leavers’ challenges, in general, put them at higher risk of protective interventions with their children and may contribute to the growing numbers of children being placed in increasingly over-stretched out-of-home care systems. Questions of surveillance bias for service-connected young people are examined in light of recent large-scale studies using administrative data sets. Serious oversights in responding to young people’s experiences of trauma and exploitation are identified. The relevance of sexual health programs for young people actively seeking pregnancies is discussed with emerging evidence that disengagement from schooling may have more of a role in explaining early pregnancy and parenting than previously thought. The authors test the relevance of Ambiguous Loss theory in understanding how removal from families of origin and placement experiences may affect young people and lead to ‘wanted’ pregnancies.
Artificial intelligence for political decision-making in the European Union: Effects on citizens’ perceptions of input, throughput, and output legitimacy
Authors: Starke Christopher , Lünich Marco
Published: November 2020

A lack of political legitimacy undermines the ability of the European Union (EU) to resolve major crises and threatens the stability of the system as a whole. By integrating digital data into political processes, the EU seeks to base decision-making increasingly on sound empirical evidence. In particular, artificial intelligence (AI) systems have the potential to increase political legitimacy by identifying pressing societal issues, forecasting potential policy outcomes, and evaluating policy effectiveness. This paper investigates how citizens’ perceptions of EU input, throughput, and output legitimacy are influenced by three distinct decision-making arrangements: (a) independent human decision-making by EU politicians; (b) independent algorithmic decision-making (ADM) by AI-based systems; and (c) hybrid decision-making (HyDM) by EU politicians and AI-based systems together. The results of a preregistered online experiment (n = 572) suggest that existing EU decision-making arrangements are still perceived as the most participatory and accessible for citizens (input legitimacy). However, regarding the decision-making process itself (throughput legitimacy) and its policy outcomes (output legitimacy), no difference was observed between the status quo and HyDM. Respondents tend to perceive ADM systems as the sole decision-maker to be illegitimate. The paper discusses the implications of these findings for (a) EU legitimacy and (b) data-driven policy-making and outlines (c) avenues for future research.
Yes, DI did it: the impact of Direct Instruction on literacy outcomes for Very Remote Indigenous schools
Authors: Pearson Noel
Published: November 2020

Abstract
In the journal article Did DI do it? The impact of a programme designed to improve literacy for Aboriginal and Torres Strait Islander students in remote schools, Guenther and Osborne (2020) compare schoolwide NAPLAN reading scale scores for 25 Very Remote Indigenous schools implementing Direct Instruction through the Flexible Literacy for Remote Primary Schools Program (‘Flexible Literacy’ or ‘the program’) with those for 118 Very Remote Indigenous schools not involved with the program, to assert the program has not improved literacy outcomes. Good to Great Schools Australia (GGSA) undertook an analysis of the same school data for Reading, Writing, Spelling and Grammar and Punctuation scores. Our findings contradict theirs. In all areas, schools participating in the program show significant growth compared with all Australian and all Very Remote Indigenous schools. In Reading, schools involved in the program from 2015 to 2017 averaged 124% growth, while the average growth for comparable ages was 19 and 34% for Australian and Very Remote Indigenous schools, respectively. In Grammar and Punctuation schools involved in the program in the same period grew 180%, whilst growth for Australian schools was 15%, and for Very Remote Indigenous schools, 28%. These contrasting results illustrate the importance of evaluating growth to assess the impact of educational programs, rather than achievement alone, particularly in the case of Very Remote Indigenous schools where achievement levels are far below Australian grade levels. Guenther and Osborne's comparison of achievement across schools rather than measuring growth within schools obscures real gains and is misleading.
The effects of reducing chronic inflammation in overweight women on serum hepcidin and iron absorption with and without supplemental ascorbic acid
Authors: Stoffel Nicole U. , Cepeda-Lopez Ana Carla , Cervantes-Gracia Karla , Llanas-Cornejo Daniel , Delgado González Erika A. , Herter-Aeberli Isabelle , Zimmermann Michael B.
Published: November 2020

Although hepcidin synthesis is stimulated by inflammation and inhibited by Fe deficiency, the strength of their opposing effects on serum hepcidin (SHep) in humans remains unclear. It was recently shown that an inflammatory stimulus in anaemic women did not increase SHep or decrease Fe absorption. The enhancing effect of ascorbic acid on Fe absorption may not be effective during inflammation because of increased SHep. Our study aim was to test whether reducing inflammation in Fe-depleted overweight (OW) women with low-grade inflammation would lower SHep and improve Fe absorption with and without ascorbic acid, compared with normal-weight (NW) women without inflammation. Before and after 14 d of anti-inflammatory treatment (3 × 600 mg ibuprofen daily) in OW and NW women (n36; 19–46 years of age), we measured SHep and fractional Fe absorption (FIA) (erythrocyte Fe incorporation) from57Fe- and58Fe-labelled test meals with and without ascorbic acid. There were significant group effects on IL-6, C-reactive protein, serum ferritin and SHep (for all,P< 0·05). There was a significant treatment effect on SHep (P< 0·05): in OW women, treatment decreased IL-6 by approximately 30 % and SHep by approximately 45 %. However, there were no significant treatment or group effects on FIA. Body Fe stores (BIS) were a significant positive predictor of SHep before and after treatment (P< 0·001), but IL-6 was not. Reducing chronic inflammation in OW women halved SHep but did not affect Fe absorption with or without ascorbic acid, and the main predictor of Fe absorption was BIS.
Systemic Banking Crises, Institutional Environment, and Corporate Leverage
Authors: Öztekin Özde
Published: November 2020

This study examines corporate leverage during systemic banking crises in an international setting, including 85 countries from 1987 to 2017. Using the historically determined component of institutions and exogenous variations in institution building, the analyses show that leverage cyclicality varies substantially across institutional settings. Leverage is strongly countercyclical under more binding constraints on the capital supply, suggesting important supply effects of such crises on leverage. Weak institutions are more conducive to crises and uncertainty. Leverage countercyclicality is more pronounced during crises that coincide with higher uncertainty, whereas leverage is procyclical with stronger legal systems and information sharing in capital markets.
Changes in telepsychiatry regulations during the COVID-19 pandemic: 17 countries and regions' approaches to an evolving healthcare landscape
Authors: Kinoshita Shotaro , Cortright Kelley , Crawford Allison , Mizuno Yuya , Yoshida Kazunari , Hilty Donald , Guinart Daniel , Torous John , Correll Christoph U. , Castle David J. , Rocha Deyvis , Yang Yuan , Xiang Yu-tao , Kølbæk Pernille , Dines David , ElShami Mohammad , Jain Prakhar , Kallivayalil Roy , Solmi Marco , Favaro Angela , Veronese Nicola , Seedat Soraya , Shin Sangho , Salazar de Pablo Gonzalo , Chang Chun-Hung , Su Kuan-Pin , Karas Hakan , Kane John M. , Yellowlees Peter , Kishimoto Taishiro
Published: November 2020

Background

During the COVID-19 pandemic, the use of telemedicine as a way to reduce COVID-19 infections was noted and consequently deregulated. However, the degree of telemedicine regulation varies from country to country, which may alter the widespread use of telemedicine. This study aimed to clarify the telepsychiatry regulations for each collaborating country/region before and during the COVID-19 pandemic.

Methods

We used snowball sampling within a global network of international telepsychiatry experts. Thirty collaborators from 17 different countries/regions responded to a questionnaire on barriers to the use and implementation of telepsychiatric care, including policy factors such as regulations and reimbursement at the end of 2019 and as of May 2020.

Results

Thirteen of 17 regions reported a relaxation of regulations due to the pandemic; consequently, all regions surveyed stated that telepsychiatry was now possible within their public healthcare systems. In some regions, restrictions on prescription medications allowed via telepsychiatry were eased, but in 11 of the 17 regions, there were still restrictions on prescribing medications via telepsychiatry. Lower insurance reimbursement amounts for telepsychiatry consultations v. in-person consultations were reevaluated in four regions, and consequently, in 15 regions telepsychiatry services were reimbursed at the same rate (or higher) than in-person consultations during the COVID-19 pandemic.

Conclusions

Our results confirm that, due to COVID-19, the majority of countries surveyed are altering telemedicine regulations that had previously restricted the spread of telemedicine. These findings provide information that could guide future policy and regulatory decisions, which facilitate greater scale and spread of telepsychiatry globally.
Is p-value 0.05 enough? A study on the statistical evaluation of classifiers
Authors: Neumann Nadine M. , Plastino Alexandre , Pinto Junior Jony A. , Freitas Alex A.
Published: November 2020

Statistical significance analysis, based on hypothesis tests, is a common approach for comparing classifiers. However, many studies oversimplify this analysis by simply checking the condition p-value < 0.05, ignoring important concepts such as the effect size and the statistical power of the test. This problem is so worrying that the American Statistical Association has taken a strong stand on the subject, noting that although the p-value is a useful statistical measure, it has been abusively used and misinterpreted. This work highlights problems caused by the misuse of hypothesis tests and shows how the effect size and the power of the test can provide important information for better decision-making. To investigate these issues, we perform empirical studies with different classifiers and 50 datasets, using the Student’s t-test and the Wilcoxon test to compare classifiers. The results show that an isolated p-value analysis can lead to wrong conclusions and that the evaluation of the effect size and the power of the test contributes to a more principled decision-making.
Projections of Landscape Evolution on a 10,000 Year Timescale With Assessment and Partitioning of Uncertainty Sources
Authors: Barnhart Katherine R. , Tucker Gregory E. , Doty Sandra G. , Glade Rachel C. , Shobe Charles M. , Rossi Matthew W. , Hill Mary C.
Published: November 2020

Long‐term erosion can threaten infrastructure and buried waste, with consequences for management of natural systems. We develop erosion projections over 10 ky for a 5 km2 watershed in New York, USA. Because there is no single landscape evolution model appropriate for the study site, we assess uncertainty in projections associated with model structure by considering a set of alternative models, each with a slightly different governing equation. In addition to model structure uncertainty, we consider the following uncertainty sources: selection of a final model set; each model's parameter values estimated through calibration; simulation boundary conditions such as the future incision of downstream rivers and future climate; and initial conditions (e.g., site topography which may undergo near‐term anthropogenic modification). We use an analysis‐of‐variance approach to assess and partition uncertainty in projected erosion into the variance attributable to each source. Our results suggest one sixth of the watershed will experience erosion exceeding 5 m in the next 10 ky. Uncertainty in projected erosion increases with time, and the projection uncertainty attributable to each source manifests in a distinct spatial pattern. Model structure uncertainty is relatively low, which reflects our ability to constrain parameter values and reduce the model set through calibration to the recent geologic past. Beyond site‐specific findings, our work demonstrates what information prediction‐under‐uncertainty studies can provide about geomorphic systems. Our results represent the first application of a comprehensive multi‐model uncertainty analysis for long‐term erosion forecasting.
RBD-Fc-based COVID-19 vaccine candidate induces highly potent SARS-CoV-2 neutralizing antibody response
Authors: Liu Zezhong , Xu Wei , Xia Shuai , Gu Chenjian , Wang Xinling , Wang Qian , Zhou Jie , Wu Yanling , Cai Xia , Qu Di , Ying Tianlei , Xie Youhua , Lu Lu , Yuan Zhenghong , Jiang Shibo
Published: November 2020

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed serious threats to global health and economy, thus calling for the development of safe and effective vaccines. The receptor-binding domain (RBD) in the spike protein of SARS-CoV-2 is responsible for its binding to angiotensin-converting enzyme 2 (ACE2) receptor. It contains multiple dominant neutralizing epitopes and serves as an important antigen for the development of COVID-19 vaccines. Here, we showed that immunization of mice with a candidate subunit vaccine consisting of SARS-CoV-2 RBD and Fc fragment of human IgG, as an immunopotentiator, elicited high titer of RBD-specific antibodies with robust neutralizing activity against both pseudotyped and live SARS-CoV-2 infections. The mouse antisera could also effectively neutralize infection by pseudotyped SARS-CoV-2 with several natural mutations in RBD and the IgG extracted from the mouse antisera could also show neutralization against pseudotyped SARS-CoV and SARS-related coronavirus (SARSr-CoV). Vaccination of human ACE2 transgenic mice with RBD-Fc could effectively protect mice from the SARS-CoV-2 challenge. These results suggest that SARS-CoV-2 RBD-Fc has good potential to be further developed as an effective and broad-spectrum vaccine to prevent infection of the current SARS-CoV-2 and its mutants, as well as future emerging SARSr-CoVs and re-emerging SARS-CoV.
Fruquintinib inhibits VEGF/VEGFR2 axis of choroidal endothelial cells and M1-type macrophages to protect against mouse laser-induced choroidal neovascularization
Authors: Liu Xiaojuan , Guo Aisong , Tu Yuanyuan , Li Wendie , Li Lele , Liu Wangrui , Ju Yuanyuan , Zhou Yamei , Sang Aimin , Zhu Manhui
Published: November 2020

Wet age-related macular degeneration, which is characterized by choroidal neovascularization (CNV) and induces obvious vision loss. Vascular endothelial growth factor (VEGF) family member VEGF-A (also named as VEGF) and its receptor VEGFR2 contribute to the pathogenesis of CNV. Choroidal endothelial cells (CECs) secret C–C motif chemokine ligand 2 (CCL2), which attracts macrophages to CNV lesion and promotes macrophage M1 polarization. Accordingly, infiltrating macrophages secret inflammatory cytokines to promote CNV. In vivo, intravitreal injection of fruquintinib (HMPL-013), an antitumor neovascularization drug, alleviated mouse CNV formation without obvious ocular toxicity. Meanwhile, HMPL-013 inhibited VEGF/VEGFR2 binding in CECs and macrophages, as well as macrophage M1 polarization. In vitro, noncontact coculture of human choroidal vascular endothelial cells (HCVECs) and macrophages under hypoxia conditions was established. HMPL-013 downregulated VEGF/VEGFR2/phosphoinositide-3-kinase/protein kinase B (AKT)/nuclear factor kappa B pathway and CCL2 secretion in HCVECs, as well as VEGF/VEGFR2-induced macrophage M1 polarization under hypoxia condition. In addition, HMPL-013 inhibited HCEVC derived CCL2-induced macrophage migration and M1 polarization, along with macrophage M1 polarization-induced HCVECs proliferation, migration, and tube formation. Altogether, HMPL-013 alleviated CNV formation might via breaking detrimental cross talk between CECs and macrophages.
A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer
Authors: Gormley Mark , Dudding Tom , Sanderson Eleanor , Martin Richard M. , Thomas Steven , Tyrrell Jessica , Ness Andrew R. , Brennan Paul , Munafò Marcus , Pring Miranda , Boccia Stefania , Olshan Andrew F. , Diergaarde Brenda , Hung Rayjean J. , Liu Geoffrey , Davey Smith George , Richmond Rebecca C.
Published: November 2020

The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.
Feedforward prediction error signals during episodic memory retrieval
Authors: Haque Rafi U. , Inati Sara K. , Levey Allan I. , Zaghloul Kareem A.
Published: November 2020

Our memories enable us to form expectations for our future experiences, yet the precise neural mechanisms underlying how we compare any experience to our memory remain unknown. Here, using intracranial EEG recordings, we show that episodic memories formed after a single visual experience establish expectations for future experience within neocortical-medial temporal lobe circuits. When subsequent experiences violate these expectations, we find a 80–120 Hz prediction error signal that emerges in both visual association areas and the medial temporal lobe. Critically, this error signal emerges in visual association areas first and then propagates to the medial temporal lobe. This error signal is accompanied by alpha coherence between the two regions. Our data therefore suggest that internal models formed from episodic memories are generated throughout the visual hierarchy after just a single exposure, and that these internal models are then used for comparison with future experiences.
Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates
Authors: Savastano Adriana , Ibáñez de Opakua Alain , Rankovic Marija , Zweckstetter Markus
Published: November 2020

The etiologic agent of the Covid-19 pandemic is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral membrane of SARS-CoV-2 surrounds a helical nucleocapsid in which the viral genome is encapsulated by the nucleocapsid protein. The nucleocapsid protein of SARS-CoV-2 is produced at high levels within infected cells, enhances the efficiency of viral RNA transcription, and is essential for viral replication. Here, we show that RNA induces cooperative liquid–liquid phase separation of the SARS-CoV-2 nucleocapsid protein. In agreement with its ability to phase separate in vitro, we show that the protein associates in cells with stress granules, cytoplasmic RNA/protein granules that form through liquid-liquid phase separation and are modulated by viruses to maximize replication efficiency. Liquid–liquid phase separation generates high-density protein/RNA condensates that recruit the RNA-dependent RNA polymerase complex of SARS-CoV-2 providing a mechanism for efficient transcription of viral RNA. Inhibition of RNA-induced phase separation of the nucleocapsid protein by small molecules or biologics thus can interfere with a key step in the SARS-CoV-2 replication cycle.
Exploring the trade-offs between electric heating policy and carbon mitigation in China
Authors: Wang Jianxiao , Zhong Haiwang , Yang Zhifang , Wang Mu , Kammen Daniel M. , Liu Zhu , Ma Ziming , Xia Qing , Kang Chongqing
Published: November 2020

China has enacted a series of policies since 2015 to substitute electricity for in-home combustion for rural residential heating. The Electric Heating Policy (EHP) has contributed to significant improvements in air quality, benefiting hundreds of millions of people. This shift, however, has resulted in a sharp increase in electric loads and associated carbon emissions. Here, we show that China’s EHP will greatly increase carbon emissions. We develop a theoretical model to quantify the carbon emissions from power generation and rural residential heating sectors. We found that in 2015, an additional 101.69–162.89 megatons of CO2could potentially be emitted if EHP was implemented in 45–55% of rural residents in Northern China. In 2020, the incremental carbon emission is expected to reach 130.03–197.87 megatons. Fortunately, the growth of carbon emission will slow down due to China’s urbanization progress. In 2030, the carbon emission increase induced by EHP will drop to 119.19–177.47 megatons. Finally, we conclude two kinds of practical pathways toward low-carbon electric heating, and provide techno-economic analyses.
Tumor evolutionary trajectories during the acquisition of invasiveness in early stage lung adenocarcinoma
Authors: Wang Siwei , Du Mulong , Zhang Jingyuan , Xu Weizhang , Yuan Qianyu , Li Ming , Wang Jie , Zhu Hongyu , Wang Yuzhuo , Wang Cheng , Gong Yuhua , Wang Xiaonan , Hu Zhibin , Christiani David C. , Xu Lin , Shen Hongbing , Yin Rong
Published: November 2020

The evolutionary trajectories of early lung adenocarcinoma (LUAD) have not been fully elucidated. We hypothesize that genomic analysis between pre-invasive and invasive components will facilitate the description of LUAD evolutionary patterns. We micro-dissect malignant pulmonary nodules (MPNs) into paired pre-invasive and invasive components for panel-genomic sequencing and recognize three evolutionary trajectories. Evolutionary mode 1 (EM1) demonstrates none of the common driver events between paired components, but another two modes, EM2A and EM2B, exhibit critical private alterations restricted to pre-invasive and invasive components, respectively. When ancestral clones harbor EGFR mutations, truncal mutation abundance significantly decrease after the acquisition of invasiveness, which may be associated with the intratumoral accumulation of infiltrated B cells. Harboring EGFR mutations is critical to the selective pressure and further impacts the prognosis. Our findings extend the understanding of evolutionary trajectories during invasiveness acquisition in early LUAD.
Nutrients cause grassland biomass to outpace herbivory
Authors: Borer E. T. , Harpole W. S. , Adler P. B. , Arnillas C. A. , Bugalho M. N. , Cadotte M. W. , Caldeira M. C. , Campana S. , Dickman C. R. , Dickson T. L. , Donohue I. , Eskelinen A. , Firn J. L. , Graff P. , Gruner D. S. , Heckman R. W. , Koltz A. M. , Komatsu K. J. , Lannes L. S. , MacDougall A. S. , Martina J. P. , Moore J. L. , Mortensen B. , Ochoa-Hueso R. , Olde Venterink H. , Power S. A. , Price J. N. , Risch A. C. , Sankaran M. , Schütz M. , Sitters J. , Stevens C. J. , Virtanen R. , Wilfahrt P. A. , Seabloom E. W.
Published: November 2020

Human activities are transforming grassland biomass via changing climate, elemental nutrients, and herbivory. Theory predicts that food-limited herbivores will consume any additional biomass stimulated by nutrient inputs (‘consumer-controlled’). Alternatively, nutrient supply is predicted to increase biomass where herbivores alter community composition or are limited by factors other than food (‘resource-controlled’). Using an experiment replicated in 58 grasslands spanning six continents, we show that nutrient addition and vertebrate herbivore exclusion each caused sustained increases in aboveground live biomass over a decade, but consumer control was weak. However, at sites with high vertebrate grazing intensity or domestic livestock, herbivores consumed the additional fertilization-induced biomass, supporting the consumer-controlled prediction. Herbivores most effectively reduced the additional live biomass at sites with low precipitation or high ambient soil nitrogen. Overall, these experimental results suggest that grassland biomass will outstrip wild herbivore control as human activities increase elemental nutrient supply, with widespread consequences for grazing and fire risk.
Viral Bcl2s’ transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis
Authors: García-Murria Maria Jesús , Duart Gerard , Grau Brayan , Diaz-Beneitez Elisabet , Rodríguez Dolores , Mingarro Ismael , Martínez-Gil Luis
Published: November 2020

Viral control of programmed cell death relies in part on the expression of viral analogs of the B-cell lymphoma 2 (Bcl2) protein known as viral Bcl2s (vBcl2s). vBcl2s control apoptosis by interacting with host pro- and anti-apoptotic members of the Bcl2 family. Here, we show that the carboxyl-terminal hydrophobic region of herpesviral and poxviral vBcl2s can operate as transmembrane domains (TMDs) and participate in their homo-oligomerization. Additionally, we show that the viral TMDs mediate interactions with cellular pro- and anti-apoptotic Bcl2 TMDs within the membrane. Furthermore, these intra-membrane interactions among viral and cellular proteins are necessary to control cell death upon an apoptotic stimulus. Therefore, their inhibition represents a new potential therapy against viral infections, which are characterized by short- and long-term deregulation of programmed cell death.
Three host peculiarities of a cycloalkane-based micelle toward large metal-complex guests
Authors: Hanafusa Mamiko , Tsuchida Yamato , Matsumoto Kyosuke , Kondo Kei , Yoshizawa Michito
Published: November 2020

Linear alkanes are essential building blocks for natural and artificial assemblies in water. As compared with typical, linear alkane-based micelles and recent aromatic micelles, we herein develop a cycloalkane-based micelle, consisting of bent amphiphiles with two cyclohexyl frameworks. This uncommon type of micelle, with a spherical core diameter of ~ 2 nm, forms in water in a spontaneous and quantitative manner. The cycloalkane-based, hydrophobic cavity displays peculiar host abilities as follows: (i) highly efficient uptake of sterically demanding Zn(II)-tetraphenylporphyrin and rubrene dyes, (ii) selective uptake of substituted Cu(II)-phthalocyanines and spherical nanocarbons, and (iii) uptake-induced solution-state emission of [Au(I)-dimethylpyrazolate]3 in water. These host functions toward the large metal-complex and other guests studied herein remain unaccomplished by previously reported micelles and supramolecular containers.
Tumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma
Authors: Federico Cinzia , Alhallak Kinan , Sun Jennifer , Duncan Kathleen , Azab Feda , Sudlow Gail P. , de la Puente Pilar , Muz Barbara , Kapoor Vaishali , Zhang Luna , Yuan Fangzheng , Markovic Matea , Kotsybar Joseph , Wasden Katherine , Guenthner Nicole , Gurley Shannon , King Justin , Kohnen Daniel , Salama Noha N. , Thotala Dinesh , Hallahan Dennis E. , Vij Ravi , DiPersio John F. , Achilefu Samuel , Azab Abdel Kareem
Published: November 2020

Drug resistance and dose-limiting toxicities are significant barriers for treatment of multiple myeloma (MM). Bone marrow microenvironment (BMME) plays a major role in drug resistance in MM. Drug delivery with targeted nanoparticles have been shown to improve specificity and efficacy and reduce toxicity. We aim to improve treatments for MM by (1) using nanoparticle delivery to enhance efficacy and reduce toxicity; (2) targeting the tumor-associated endothelium for specific delivery of the cargo to the tumor area, and (3) synchronizing the delivery of chemotherapy (bortezomib; BTZ) and BMME-disrupting agents (ROCK inhibitor) to overcome BMME-induced drug resistance. We find that targeting the BMME with P-selectin glycoprotein ligand-1 (PSGL-1)-targeted BTZ and ROCK inhibitor-loaded liposomes is more effective than free drugs, non-targeted liposomes, and single-agent controls and reduces severe BTZ-associated side effects. These results support the use of PSGL-1-targeted multi-drug and even non-targeted liposomal BTZ formulations for the enhancement of patient outcome in MM.
Dynamic changes in anti-SARS-CoV-2 antibodies during SARS-CoV-2 infection and recovery from COVID-19
Authors: Li Kening , Huang Bin , Wu Min , Zhong Aifang , Li Lu , Cai Yun , Wang Zhihua , Wu Lingxiang , Zhu Mengyan , Li Jie , Wang Ziyu , Wu Wei , Li Wanlin , Bosco Bakwatanisa , Gan Zhenhua , Qiao Qinghua , Wu Jian , Wang Qianghu , Wang Shukui , Xia Xinyi
Published: November 2020

Deciphering the dynamic changes in antibodies against SARS-CoV-2 is essential for understanding the immune response in COVID-19 patients. Here we analyze the laboratory findings of 1,850 patients to describe the dynamic changes of the total antibody, spike protein (S)-, receptor-binding domain (RBD)-, and nucleoprotein (N)-specific immunoglobulin M (IgM) and G (IgG) levels during SARS-CoV-2 infection and recovery. The generation of S-, RBD-, and N-specific IgG occurs one week later in patients with severe/critical COVID-19 compared to patients with mild/moderate disease, while S- and RBD-specific IgG levels are 1.5-fold higher in severe/critical patients during hospitalization. The RBD-specific IgG levels are 4-fold higher in older patients than in younger patients during hospitalization. In addition, the S- and RBD-specific IgG levels are 2-fold higher in the recovered patients who are SARS-CoV-2 RNA negative than those who are RNA positive. Lower S-, RBD-, and N-specific IgG levels are associated with a lower lymphocyte percentage, higher neutrophil percentage, and a longer duration of viral shedding. Patients with low antibody levels on discharge might thereby have a high chance of being tested positive for SARS-CoV-2 RNA after recovery. Our study provides important information for COVID-19 diagnosis, treatment, and vaccine development.
Survival of the weakest in non-transitive asymmetric interactions among strains of E. coli
Authors: Liao Michael J. , Miano Arianna , Nguyen Chloe B. , Chao Lin , Hasty Jeff
Published: November 2020

Hierarchical organization in ecology, whereby interactions are nested in a manner that leads to a dominant species, naturally result in the exclusion of all but the dominant competitor. Alternatively, non-hierarchical competitive dynamics, such as cyclical interactions, can sustain biodiversity. Here, we designed a simple microbial community with three strains of E. coli that cyclically interact through (i) the inhibition of protein production, (ii) the digestion of genomic DNA, and (iii) the disruption of the cell membrane. We find that intrinsic differences in these three major mechanisms of bacterial warfare lead to an unbalanced community that is dominated by the weakest strain. We also use a computational model to describe how the relative toxin strengths, initial fractional occupancies, and spatial patterns affect the maintenance of biodiversity. The engineering of active warfare between microbial species establishes a framework for exploration of the underlying principles that drive complex ecological interactions.
Comprehensive prediction of secondary metabolite structure and biological activity from microbial genome sequences
Authors: Skinnider Michael A. , Johnston Chad W. , Gunabalasingam Mathusan , Merwin Nishanth J. , Kieliszek Agata M. , MacLellan Robyn J. , Li Haoxin , Ranieri Michael R. M. , Webster Andrew L. H. , Cao My P. T. , Pfeifle Annabelle , Spencer Norman , To Q. Huy , Wallace Dan Peter , Dejong Chris A. , Magarvey Nathan A.
Published: November 2020

Novel antibiotics are urgently needed to address the looming global crisis of antibiotic resistance. Historically, the primary source of clinically used antibiotics has been microbial secondary metabolism. Microbial genome sequencing has revealed a plethora of uncharacterized natural antibiotics that remain to be discovered. However, the isolation of these molecules is hindered by the challenge of linking sequence information to the chemical structures of the encoded molecules. Here, we present PRISM 4, a comprehensive platform for prediction of the chemical structures of genomically encoded antibiotics, including all classes of bacterial antibiotics currently in clinical use. The accuracy of chemical structure prediction enables the development of machine-learning methods to predict the likely biological activity of encoded molecules. We apply PRISM 4 to chart secondary metabolite biosynthesis in a collection of over 10,000 bacterial genomes from both cultured isolates and metagenomic datasets, revealing thousands of encoded antibiotics. PRISM 4 is freely available as an interactive web application at http://prism.adapsyn.com.
Comparison of overexpansion capabilities and thrombogenicity at the side branch ostia after implantation of four different drug eluting stents
Authors: Gasior Pawel , Lu Shengjie , Ng Chen Koon Jaryl , Toong Wee Yee Daniel , Wong En Hou Philip , Foin Nicolas , Kedhi Elvin , Wojakowski Wojciech , Ang Hui Ying
Published: November 2020

Interventions in bifurcation lesions often requires aggressive overexpansion of stent diameter in the setting of long tapering vessel segment. Overhanging struts in front of the side branch (SB) ostium are thought to act as a focal point for thrombi formation and consequently possible stent thrombosis. This study aimed to evaluate the overexpansion capabilities and thrombogenicity at the SB ostia after implantation of four latest generation drug-eluting stents (DES) in an in-vitro bifurcation model. Four clinically available modern DES were utilized: one bifurcation dedicated DES (Bioss LIM C) and three conventional DES (Ultimaster, Xience Sierra, Biomime). All devices were implanted in bifurcation models with proximal optimization ensuring expansion before perfusing with porcine blood. Optical coherence tomography (OCT), immunofluorescence (IF) and scanning electron microscope analysis were done to determine thrombogenicity and polymer coating integrity at the over-expanded part of the stents. Computational fluid dynamics (CFD) was performed to study the flow disruption. OCT (p = 0.113) and IF analysis (p = 0.007) demonstrated lowest thrombus area at SB ostia in bifurcation dedicated DES with favorable biomechanical properties compared to conventional DES. The bifurcated DES also resulted in reduced area of high shear rate and maximum shear rate in the CFD analysis. This study demonstrated numerical differences in terms of mechanical properties and acute thrombogenicity at SB ostia between tested devices.