bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Total Pressure and Furnace Tube Material on the Oxidation of T22 in Humidified Air
Authors: Schlereth Clara , Galetz Mathias C.
Published: June 2021

Oxidation of the Fe-base alloy T22 in humid air at 500 °C was investigated. The samples were exposed for up to 1000 h at 1 bar and 20 bar. The influence of three furnace tube materials, alumina, ET45 and quartz glass, on the oxide scale morphology was investigated. Samples and their cross sections were examined using optical microscopy, scanning electron microscopy, electron probe micro analysis and Raman spectroscopy. Multilayered oxide scales consisting of hematite, magnetite and Fe–Cr spinel were found on all samples. However, the composition and morphology of the oxide scales depend on the furnace tube material and on the system pressure. The system pressure is assumed to change the reaction equilibria and adsorption rates. The tube material changed the initial gas composition by formation of volatile Cr species. This volatilization rate increased at higher system pressures.
Sleep quality and COVID-19 outcomes: the evidence-based lessons in the framework of predictive, preventive and personalised (3P) medicine
Authors: Richter Kneginja , Kellner Stefanie , Hillemacher Thomas , Golubnitschaja Olga
Published: June 2021

Sleep quality and duration play a pivotal role in maintaining physical and mental health. In turn, sleep shortage, deprivation and disorders are per evidence the risk factors and facilitators of a broad spectrum of disorders, amongst others including depression, stroke, chronic inflammation, cancers, immune defence insufficiency and individual predisposition to infection diseases with poor outcomes, for example, related to the COVID-19 pandemic. Keeping in mind that COVID-19-related global infection distribution is neither the first nor the last pandemic severely affecting societies around the globe to the costs of human lives accompanied with enormous economic burden, lessons by predictive, preventive and personalised (3P) medical approach are essential to learn and to follow being better prepared to defend against global pandemics. To this end, under extreme conditions such as the current COVID-19 pandemic, the reciprocal interrelationship between the sleep quality and individual outcomes becomes evident, namely, at the levels of disease predisposition, severe versus mild disease progression, development of disease complications, poor outcomes and related mortality for both - population and healthcare givers. The latter is the prominent example clearly demonstrating the causality of severe outcomes, when the long-lasting work overload and shift work rhythm evidently lead to the sleep shortage and/or deprivation that in turn causes immune response insufficiency and strong predisposition to the acute infection with complications. This article highlights and provides an in-depth analysis of the concerted risk factors related to the sleep disturbances under the COVID-19 pandemic followed by the evidence-based recommendations in the framework of predictive, preventive and personalised medical approach.
The freedom we mean: A causal independence account of creativity and academic freedom
Authors: Kronfeldner Maria
Published: June 2021

Academic freedom has often been defended in a progressivist manner: without academic freedom, creativity would be in peril, and with it the advancement of knowledge, i.e. the epistemic progress in science. In this paper, I want to critically discuss the limits of such a progressivist defense of academic freedom, also known under the label ‘argument from truth.’ The critique is offered, however, with a constructive goal in mind, namely to offer an alternative account that connects creativity and academic freedom in a way that goes beyond mere reference to epistemic progress and involves reference to the freedom to think independently as the freedom we mean when we point to creativityandwhen we point to academic freedom. The resulting causal independence account is not only epistemologically stronger than a progressivist account, it also allows to counter the curbing of academic freedom in the name of progress. The latter becomes key, for instance, when authoritarian political regimes limit or negate academic freedom with reference to an epistemic progress suitably defined for that regime.
Intergenerational Upward (Im)mobility and Political Support of Public Education Spending
Authors: Di Gioacchino Debora , Sabani Laura , Usai Stefano
Published: June 2021

This paper provides a simple model of hierarchical education to study the political determination of public education spending and its allocation between different tiers of education. The model integrates private education decisions by allowing parents, who are differentiated according to income and human capital, to top up public expenditures with private transfers. We identify four groups of households with conflicting preferences over the the size of the public education budget and its allocation. In equilibrium, public education budget, private expenditures and expenditure allocation among different tiers of education, depend on which group of households is in power and on country-specific features such as income inequality and intergenerational persistence in education. By running a cluster analysis on 32 OECD countries, we seek to establish if distinctive ‘education regimes’, akin to those identified in the theoretical analysis, could be discerned. Our main finding is that a high intergenerational persistence in education might foster the establishment of education regimes in which the size and the allocation of the public budget among different tiers of education prevent a stable and significant increase of the population graduation rate, thus plunging the country in a ‘low education’ trap.
MLatom 2: An Integrative Platform for Atomistic Machine Learning
Authors: Dral Pavlo O. , Ge Fuchun , Xue Bao-Xin , Hou Yi-Fan , Pinheiro Max , Huang Jianxing , Barbatti Mario
Published: June 2021

Atomistic machine learning (AML) simulations are used in chemistry at an ever-increasing pace. A large number of AML models has been developed, but their implementations are scattered among different packages, each with its own conventions for input and output. Thus, here we give an overview of our MLatom 2 software package, which provides an integrative platform for a wide variety of AML simulations by implementing from scratch and interfacing existing software for a range of state-of-the-art models. These include kernel method-based model types such as KREG (native implementation), sGDML, and GAP-SOAP as well as neural-network-based model types such as ANI, DeepPot-SE, and PhysNet. The theoretical foundations behind these methods are overviewed too. The modular structure of MLatom allows for easy extension to more AML model types. MLatom 2 also has many other capabilities useful for AML simulations, such as the support of custom descriptors, farthest-point and structure-based sampling, hyperparameter optimization, model evaluation, and automatic learning curve generation. It can also be used for such multi-step tasks as Δ-learning, self-correction approaches, and absorption spectrum simulation within the machine-learning nuclear-ensemble approach. Several of these MLatom 2 capabilities are showcased in application examples.
Zur (Fach‑)Spezifität von Unterrichtsqualität im Fach Sport
Authors: Richartz Alfred , Kohake Kathrin
Published: June 2021

In der empirischen Unterrichtsforschung wird Unterrichtqualität anhand von Merkmalen beurteilt, die sich auf die Wirksamkeit von Unterricht beziehen. Auch der Sportunterricht wird zunehmend unter der Perspektive der Unterrichtsqualität analysiert. Dabei spielen generische Qualitätsdimensionen wie Klassen- und Zeitmanagement und sozio-emotionale Unterstützung der Schüler*innen eine wesentliche Rolle. Fachtypische Lerngelegenheiten des Sportunterrichts weisen Überschneidungsbereiche jedoch auch maßgebliche Unterschiede zu anderen Fächern auf: Schüler*innen sollen einerseits fachspezifisches Wissen und Können erwerben, um ihre Teilnahme an der Sport- und Bewegungskultur zu fördern. Andererseits sollen Schüler*innen aber wie in anderen Fächern Zusammenhänge verstehen und kritische Bewertungen vornehmen, um ihr Sporttreiben selbstbestimmt und verantwortlich zu gestalten. Die Qualität der Lernunterstützung im Sport muss sich daher auf drei Bereiche beziehen: auf motorisches Lernen, auf spieltaktisches Lernen und auf verständnis- und bewertungsbezogenes Lernen. Der Beitrag zeigt, dass generische Qualitätsmerkmale ergänzt werden sollten um Merkmale effektiver Unterstützung in den beiden sportspezifischen Lernfeldern. Hierzu zählen eine für das Bewegungslernen geeignete Aufmerksamkeitslenkung, spezifische Feedbacktechniken, sinnvolle didaktische Reduktion sowie ausreichende Lernzeit für die beim motorischen und taktischen Lernen erforderlichen Prozeduralisierungsprozesse.
From the past to the future: what we learn from China’s 2020 Census
Authors: Zheng Zhenzhen
Published: June 2021

The population of China has entered an era of low fertility and aging, with a slower growth rate in the last decade. This commentary briefly reviews demographic changes in China in the last seven decades with some important years of change in mortality, fertility and urbanization, and discusses future trends according to the information provided by the 2020 Census. China has experienced “compressed” population change, and population aging will continue to advance, meanwhile the size of the population is expected to reach its peak in the near future. To prepare proper response to the challenges proactively, institutional change which adapts to population changes is necessary.
Politics and ‘Politiques' in Sixteenth-Century France
Authors: Claussen Emma
Published: June 2021

During the French Wars of Religion, the nature and identity of politics was the subject of passionate debate and controversy. The word 'politique', in both sixteenth-century and contemporary French, refers to the theory and practice of politics - 'la politique' - and the statesman or politician - 'le politique' - who theorised and practised this art. The term became invested with significance and danger in early modern France. Its mobilisation in dialogues, treatises, debates, and polemics of the French Wars of Religion was a crucial feature of sixteenth-century experiences of the political. Emma Claussen investigates questions of language and power over the course of a tumultuous century, when politics, emerging as a discipline in its own right, seemed to offer a solution to civil discord but could be fatally dangerous in the wrong hands. By placing this important term in the context of early modern political, doctrinal and intellectual debates, Emma Claussen demonstrates how politics can be understood in relation to the wider linguistic and conceptual struggles of the age, and in turn influenced them.
Municipio de Mariana v BHP Group: Implications of the UK High Court’s Decision
Authors: FARRINGTON Francesca
Published: June 2021

The High Court of England and Wales in its November 2020 judgment in Municipio de Mariana v BHP Group1 (BHP) declined jurisdiction to hear the case initiated by victims of the Fundão Dam collapse in Brazil on the grounds of abuse of process. The decision raises serious questions about the Court’s willingness to vindicate the fair trial rights of victims of human rights abuses linked to multinational enterprises (MNEs). In this judgment, Turner J also made obiter comments on the possibility of staying the case on application of Article 34 of the Recast Brussels Regulation (Recast Regulation),2 the doctrine of forum non conveniens (FNC), and/or the Court’s case management discretion.
A COMPARISON OF VARIOUS ANALYTIC CHOICE PRINCIPLES
Authors: D’AURIAC PAUL-ELLIOT ANGLÈS , KIHARA TAKAYUKI
Published: June 2021

We investigate computability theoretic and descriptive set theoretic contents of various kinds of analytic choice principles by performing a detailed analysis of the Medvedev lattice of
$\Sigma ^1_1$
-closed sets. Among others, we solve an open problem on the Weihrauch degree of the parallelization of the
$\Sigma ^1_1$
-choice principle on the integers. Harrington’s unpublished result on a jump hierarchy along a pseudo-well-ordering plays a key role in solving this problem.
Are Policy Analogies Persuasive? The Household Budget Analogy and Public Support for Austerity
Authors: Barnes Lucy , Hicks Timothy
Published: June 2021

Public opinion on complex policy questions is shaped by the ways in which elites simplify the issues. Given the prevalence of metaphor and analogy as tools for cognitive problem solving, the deployment of analogies is often proposed as a tool for this kind of influence. For instance, a prominent explanation for the acceptance of austerity is that voters understand government deficits through an analogy to household borrowing. Indeed, there are theoretical reasons to think the household finance analogy represents a most likely case for the causal influence of analogical reasoning on policy preferences. This article examines this best-case scenario using original survey data from the United Kingdom. It reports observational and experimental analyses that find no evidence of causation running from the household analogy to preferences over the government budget. Rather, endorsement of the analogy is invoked ex post to justify support for fiscal consolidation.
Cultivating Self-Control in FinTech: Evidence from a Field Experiment on Online Consumer Borrowing
Authors: Bu Di , Hanspal Tobin , Liao Yin , Liu Yong
Published: June 2021

We report the results of a longitudinal intervention with students across 5 universities in China designed to reduce online consumer debt. We allocate participants to either a financial literacy treatment group, a self-control treatment group, or a zero-touch control group. Our self-control training intervention features detailed tracking of spending and borrowing, budgeting, and introspection about consumption choices. This intervention reduces online borrowing and delinquency charges, mainly driven by a reduction in entertainment-related spending and borrowing. In contrast, financial literacy interventions improve test scores but only marginally affect borrowing. Our results suggest that cultivating self-regulation and budgeting skills can improve borrowing behavior on e-commerce platforms.
Experiencing Southeast Asian Studies in China: A reverse culture shock
Authors: Xie Kankan
Published: June 2021

Southeast Asian Studies (SEAS) in China has experienced significant changes in the past twenty years. China's rising political and economic power has stimulated growing demands for better understanding of the wider world, resulting in the rapid development of area studies in recent years. Although SEAS in China predated the relatively recent notion of ‘area studies’ by at least half a century, the boom in area studies has profoundly transformed the field, most notably by attracting a large number of scholars to conduct policy-relevant research. Not only does the ‘policy turn’ reflect shifts of research paradigms in the field of SEAS, but it is also consistent with some larger trends prevailing in China's higher education sector and rapidly changing society in general. This article shows that SEAS in China has grown even more imbalanced, as indicated by the rapid growth of language programmes, absolute domination of short-term policy research, and further marginalisation of humanistic subjects. To respond, Chinese universities have adopted new approaches to SEAS depending on their distinct disciplinary foundations, language coverage, faculty interests, and local governments’ policy preferences.
Mechanism of leaf rust resistance in wheat wild relatives, Triticum monococcum L. and T. boeoticum L.
Authors: Riar Amandeep K. , Chhuneja Parveen , Keller Beat , Singh Kuldeep
Published: June 2021

Triticum monococcum L. and T. boeoticum L., diploid wild relatives of bread wheat (T. aestivum L.), possess resistance to leaf rust (also known as brown rust) caused by Puccinia triticina Eriks. Haustorium formation-based resistance mechanisms (i.e. pre-haustorial and post-haustorial resistance) to leaf rust have been studied and reported in various T. monococcum accessions. In the present study, the mechanism of leaf rust resistance in T. monococcum and T. boeoticum accessions was studied using confocal laser scanning microscopy. Components of resistance studied at a histological level against leaf rust pathotypes, a Mexican pathotype (TCB/TD) and a Swiss pathotype (97512-19), indicated different types of resistance mechanism operative in the two accessions. The resistance in T. monococcum ranged from pre-haustorial resistance against 97512-19 to post-haustorial resistance against TCB/TD. The response in T. boeoticum was post-haustorial with necrosis against the two pathotypes. Pre-haustorial resistance observed in T. monococcum could serve as a potential source of durable rust resistance in wheat breeding.
THE DEVELOPMENT AND EVALUATION OF THE STIGMA OF ILLEGALITY AND MARGINALIZATION OF LATINXS (SIML) SCALE
Authors: Santos Carlos E. , Cadenas Germán A. , Menjívar Cecilia , Cisneros Jesús
Published: June 2021

Drawing on two online studies among predominantly U.S.-born and lawful permanent resident Latinxs, we developed a self-report scale intended to capture how discrimination related to perceived legal status, as well as perceptions of racial/ethnic marginalization of Latinxs in U.S. society, are experienced among a wide swath of the Latinx population. We also explore how these processes may be associated with psychological distress in this population. In line with the immigration scholarship that has identified a spillover effect of immigration enforcement and the racialization of legal status beyond the undocumented population, our exploratory factor analysis results from Study I (N= 355 Latinxs) collected in fall of 2013 revealed four factors among our study population:Fear of Deportation, Marginalization of Latinxs in U.S. Society, Marginalization Due to Perceived Illegality,andFear Due to Perceived Illegality.Results from a confirmatory factor analysis from a separate study conducted in spring of 2016 (Study II;N= 295 Latinxs) provided evidence in support of the structure identified in Study I. Results also revealed evidence of the association between theStigma of Illegality and Marginalization of Latinxs(SIML) subscales and psychological distress, measured as anxiety and depression. Implications of these findings are discussed.
Potato injury risk and weed control from reduced rates of PPO-inhibiting herbicides
Authors: Colquhoun Jed B. , Heider Daniel J. , Rittmeyer Richard A.
Published: June 2021

The ability to use the protoporphyrinogen oxidase (PPO)-inhibiting herbicides fomesafen, flumioxazin, and sulfentrazone in potato is limited regionally or by soil texture, largely because of crop injury noted in research in the 1990s. With that in mind, we evaluated whether reducing the herbicide rates could maintain weed control while providing more consistent crop safety. Studies were conducted on a silt loam and a coarse-textured loamy sand soil. Soil texture played a greater than anticipated role in PPO-inhibitor herbicide injury risk as it relates to high-precipitation events. For example, in 2020 at the silt loam location, there were five precipitation events across the season that exceeded 2.5 cm, including one 6 d after treatment (DAT), and a seasonal total precipitation that was over 10 cm greater than the previous year. Despite excessive moisture and initial potato injury as high as 27% where flumioxazin was applied at the high rate with S-metolachlor, by 29 DAT injury was less than 10% in all treatments, and marketable tuber yield was similar among treatments. In contrast, in 2020 at the loamy sand location, there were four precipitation events across the season that exceeded 2.5 cm, and potato injury was as much as 60%. In 2020 the high amount of injury from flumioxazin was hypothesized to be caused by precipitation before herbicide application and not after, suggesting a need for more research in this area. This work documents the fine line between yield reduction presumably caused by reduced weed control and yield reduction assumed to be related to herbicide injury. This delineation between adequate weed control and consistent crop safety may differ by soil texture and environmental conditions, supporting the notion that custom-tailored weed management may become more necessary as high-precipitation events become more common in upper midwestern U.S. agricultural systems.
POST control of Italian ryegrass in hazelnut orchards
Authors: Moretti Marcelo L.
Published: June 2021

Italian ryegrass has become a problematic weed in hazelnut orchards of Oregon because of the presence of herbicide-resistant populations. Resistant and multiple-resistant Italian ryegrass populations are now the predominant biotypes in Oregon; there is no information on which herbicides effectively control Italian ryegrass in hazelnut orchards. Six field studies were conducted in commercial orchards to evaluate Italian ryegrass control with POST herbicides. Treatments included flazasulfuron, glufosinate, glyphosate, paraquat, rimsulfuron, and sethoxydim applied alone or in selected mixtures during early spring when plants were in the vegetative stage. Treatment efficacy was dependent on the experimental site. The observed range of weed control 28 d after treatment was 13% to 76% for glyphosate, 1% to 72% for paraquat, 58% to 88% for glufosinate, 16% to 97% for flazasulfuron, 8% to 94% for rimsulfuron, and 25% to 91% for sethoxydim. Herbicides in mixtures improved control of Italian ryegrass compared to single active ingredients based on contrast analysis. Herbicides in mixture increased control by 27% compared to glyphosate, 18% to rimsulfuron, 15% to flazasulfuron, 19% to sethoxydim, and 12% compared to glufosinate when averaged across all sites, but mixture did not always improve reduction of ground coverage or of biomass. This complex site-specific response highlights the importance of record-keeping for efficient herbicide use. Glufosinate is an effective option to manage Italian ryegrass. However, the glufosinate-resistant biotypes documented in Oregon may jeopardize this practice. Nonchemical weed control options are needed for sustainable weed management in hazelnuts.
Tagebuchstudie zu Activity-Based Flexible Offices
Authors: Becker Cathrin , Soucek Roman , Gunkel Jennifer , Lanfer Sarah Lütke , Göritz und Anja S.
Published: June 2021

Zusammenfassung. Die Digitalisierung und Globalisierung fordern von Unternehmen vermehrte Flexibilität, was sich in der Gestaltung von Bürokonzepten niederschlägt. Es entstehen häufig Activity-Based Flexible Offices, die sich durch ein offenes und flexibles Raumkonzept auszeichnen. Dabei befindet sich ein Großteil der Arbeitsplätze in offenen Bereichen ohne Zwischenwände und ohne fest zugewiesene Arbeitsplätze. Dieses Konzept ist für den Austausch ausgelegt, bietet aber auch Rückzugsmöglichkeiten wie etwa Konzentrationszellen. In drei international agierenden Unternehmen wurde eine webbasierte Tagebuchstudie durchgeführt, die den Einfluss der aufgabenbezogenen Konzentrationserfordernisse und des Arbeitsortes auf die wahrgenommene Passung zwischen Arbeitsaufgabe und Arbeitsort sowie das psychische Wohlbefinden untersuchte. Die Ergebnisse zeigen, dass offene Arbeitsbereiche bei Aufgaben mit hohen Konzentrationserfordernissen als nicht passend wahrgenommen werden, jedoch nicht im Homeoffice. Generell geht die Passung zwischen Arbeitsaufgabe und Arbeitsort mit dem psychischen Wohlbefinden der Beschäftigten einher. Zusammenfassend sollte das Activity-Based Flexible Office als ganzheitliches Konzept mit Rückzugsmöglichkeiten innerhalb als auch außerhalb des Unternehmens verstanden werden.
Associations of Multiple Measures of Openness to Experience with a	Brief Questionnaire of Positive, Negative, and Disorganized	Schizotypy
Authors: Kemp Kathryn C. , Raulin Michael L. , Burgin Chris J. , Barrantes-Vidal Neus , Kwapil Thomas R.
Published: June 2021

Abstract. The vulnerability for schizophrenia-spectrum disorders is expressed across a continuum of clinical and subclinical symptoms and impairment known as schizotypy. Schizotypy is a multidimensional construct with positive, negative, and disorganized dimensions. Openness to experience offers a useful personality domain for exploring multidimensional schizotypy. This study examined the factor structure of openness and its relation to schizotypy using the Multidimensional Schizotypy Scale-Brief (MSS-B) in a sample of 2,236 adults. Positive schizotypy was broadly associated with elevated openness and negative schizotypy was generally associated with diminished openness. Principal components analysis of 15 openness facets replicated the four-factor structure of openness including Fantasy/Feelings, Eccentricity, Nontraditionalism, and Ideas factors. All three schizotypy dimensions were associated with Eccentricity. Positive schizotypy was associated with Fantasy/Feelings, whereas negative schizotypy was inversely associated with Fantasy/Feelings. Results support the construct validity of the MSS-B, use of alternative openness measures in examining schizotypy, and the multidimensional structures of schizotypy and openness.
Planning and Planting Future Forests with Climate Change in Mind
Authors: Besl J.
Published: June 2021

The climate is warming too fast for some trees to catch up. Planting seeds from warmer regions can bolster future forests, but that requires a significant shift in forestry practice.
Potential Mechanisms Responsible for Spatial Variability in Intensity and Thickness of Oxygen Minimum Zone in the Bay of Bengal
Authors: Udaya Bhaskar T. V. S. , Sarma V. V. S. S. , Pavan Kumar J.
Published: June 2021

Spatial variability in boundaries and thickness of oxygen minimum zone (OMZ) is derived based on measured dissolved oxygen data obtained from sensors on board biogeochemical (BGC) Argo floats between 2013 and 2019 in the Bay of Bengal (BoB). Upper and lower boundaries of the OMZ varied from 60 to 200 m and 100 to 800 m respectively with the thickness of 80–650 m in the BoB. Relatively thicker OMZ is noticed in the northern than southern BoB associated with stratification. The oxygen concentrations in the OMZ in the NW was low (<1.5 μM) than NE BoB (2.5 μM) indicating that thick and intense OMZ occurs in the NW region associating with stratification and high primary production. Significant decrease in particle‐back‐scatter signal was observed toward offshore from shelf indicating organic matter from the shelf sediments may be supporting bacterial carbon demand in the OMZ. The particle backscatter signal peaked in the OMZ region with a higher signal in the north than southern BoB and it is consistent with the low oxygen concentration in the former indicating that organic matter from shelf sediments may be supporting carbon needs in the OMZ. In addition to this, the occurrence of eddies significantly controls the intensity of the OMZ in the BoB through mixing at the upper boundary of OMZ. Therefore, this study suggests that spatial variations in intensity of OMZ in the BoB are governed by stratification, primary and export productions, organic matter decomposition, and eddy‐driven mixing.
Personalized machine learning of depressed mood using wearables
Authors: Shah Rutvik V. , Grennan Gillian , Zafar-Khan Mariam , Alim Fahad , Dey Sujit , Ramanathan Dhakshin , Mishra Jyoti
Published: June 2021

Depression is a multifaceted illness with large interindividual variability in clinical response to treatment. In the era of digital medicine and precision therapeutics, new personalized treatment approaches are warranted for depression. Here, we use a combination of longitudinal ecological momentary assessments of depression, neurocognitive sampling synchronized with electroencephalography, and lifestyle data from wearables to generate individualized predictions of depressed mood over a 1-month time period. This study, thus, develops a systematic pipeline for N-of-1 personalized modeling of depression using multiple modalities of data. In the models, we integrate seven types of supervised machine learning (ML) approaches for each individual, including ensemble learning and regression-based methods. All models were verified using fourfold nested cross-validation. The best-fit as benchmarked by the lowest mean absolute percentage error, was obtained by a different type of ML model for each individual, demonstrating that there is no one-size-fits-all strategy. The voting regressor, which is a composite strategy across ML models, was best performing on-average across subjects. However, the individually selected best-fit models still showed significantly less error than the voting regressor performance across subjects. For each individual’s best-fit personalized model, we further extracted top-feature predictors using Shapley statistics. Shapley values revealed distinct feature determinants of depression over time for each person ranging from co-morbid anxiety, to physical exercise, diet, momentary stress and breathing performance, sleep times, and neurocognition. In future, these personalized features can serve as targets for a personalized ML-guided, multimodal treatment strategy for depression.
Gene expression studies in Depression development and treatment: an overview of the underlying molecular mechanisms and biological processes to identify biomarkers
Authors: Mariani Nicole , Cattane Nadia , Pariante Carmine , Cattaneo Annamaria
Published: June 2021

A combination of different risk factors, such as genetic, environmental and psychological factors, together with immune system, stress response, brain neuroplasticity and the regulation of neurotransmitters, is thought to lead to the development of major depressive disorder (MDD). A growing number of studies have tried to investigate the underlying mechanisms of MDD by analysing the expression levels of genes involved in such biological processes. These studies have shown that MDD is not just a brain disorder, but also a body disorder, and this is mainly due to the interplay between the periphery and the Central Nervous System (CNS). To this purpose, most of the studies conducted so far have mainly dedicated to the analysis of the gene expression levels using postmortem brain tissue as well as peripheral blood samples of MDD patients. In this paper, we reviewed the current literature on candidate gene expression alterations and the few existing transcriptomics studies in MDD focusing on inflammation, neuroplasticity, neurotransmitters and stress-related genes. Moreover, we focused our attention on studies, which have investigated mRNA levels as biomarkers to predict therapy outcomes. This is important as many patients do not respond to antidepressant medication or could experience adverse side effects, leading to the interruption of treatment. Unfortunately, the right choice of antidepressant for each individual still remains largely a matter of taking an educated guess.
A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells
Authors: Wen Jie , Chen Wenqian , Zhao Baoxiang , Xu Qiuping , Liu Chang , Zhang Qun , Xie Zhiwei , Yan Yonggan , Guo Jing , Huang Jun , Miao Junying , Wu Xunwei
Published: June 2021

p53, the major tumor suppressor, is frequently mutated in many cancers, and up to 84% of human melanomas harbor wild-type p53, which is considered to be an ideal target for melanoma therapy. Here, we evaluated the antitumor activity of a carbazole derivative, 9-ethyl-9H-carbazole-3-carbaldehyde (ECCA), on melanoma cells. ECCA had a selectively strong inhibitory activity against the growth of BRAF-mutated and BRAF-wild-type melanoma cells but had little effect on normal human primary melanocytes. ECCA inhibited melanoma cell growth by increasing cell apoptosis, which was associated with the upregulation of caspase activities and was significantly abrogated by the addition of a caspase inhibitor. In vivo assays confirmed that ECCA suppressed melanoma growth by enhancing cell apoptosis and reducing cell proliferation, and importantly ECCA did not have any evident toxic effects on normal tissues. RNA-Seq analysis identified several pathways related to cell apoptosis that were affected by ECCA, notably, activation of the p53 signaling pathway. Biochemical assays demonstrated that ECCA enhanced the phosphorylation of p53 at Ser15 in melanoma cells harboring wild-type p53, and importantly, the knockdown or deletion of p53 in those cells counteracted the ECCA-induced apoptosis, as well as senescence. Further investigations revealed that ECCA enhanced the phosphorylation of p38-MAPK and c-Jun N-terminal kinase (JNK), and treatment with either a p38-MAPK or a JNK inhibitor rescued the cell growth inhibition elicited by ECCA, which depended on the expression of the p53 gene. Finally, the combination of ECCA with a BRAF inhibitor significantly enhanced the growth inhibition of melanoma cells. In summary, our study demonstrates that the carbazole derivative, ECCA, induces melanoma cell apoptosis and senescence through the activation of p53 to significantly and selectively suppress the growth of melanoma cells without affecting normal human melanocytes, suggesting its potential to develop a new drug for melanoma therapy.
Stress granules, RNA-binding proteins and polyglutamine diseases: too much aggregation?
Authors: Marcelo Adriana , Koppenol Rebekah , de Almeida Luís Pereira , Matos Carlos A. , Nóbrega Clévio
Published: June 2021

Stress granules (SGs) are membraneless cell compartments formed in response to different stress stimuli, wherein translation factors, mRNAs, RNA-binding proteins (RBPs) and other proteins coalesce together. SGs assembly is crucial for cell survival, since SGs are implicated in the regulation of translation, mRNA storage and stabilization and cell signalling, during stress. One defining feature of SGs is their dynamism, as they are quickly assembled upon stress and then rapidly dispersed after the stress source is no longer present. Recently, SGs dynamics, their components and their functions have begun to be studied in the context of human diseases. Interestingly, the regulated protein self-assembly that mediates SG formation contrasts with the pathological protein aggregation that is a feature of several neurodegenerative diseases. In particular, aberrant protein coalescence is a key feature of polyglutamine (PolyQ) diseases, a group of nine disorders that are caused by an abnormal expansion of PolyQ tract-bearing proteins, which increases the propensity of those proteins to aggregate. Available data concerning the abnormal properties of the mutant PolyQ disease-causing proteins and their involvement in stress response dysregulation strongly suggests an important role for SGs in the pathogenesis of PolyQ disorders. This review aims at discussing the evidence supporting the existence of a link between SGs functionality and PolyQ disorders, by focusing on the biology of SGs and on the way it can be altered in a PolyQ disease context.
Pump-probe X-ray holographic imaging of laser-induced cavitation bubbles with femtosecond FEL pulses
Authors: Vassholz M. , Hoeppe H. P. , Hagemann J. , Rosselló J. M. , Osterhoff M. , Mettin R. , Kurz T. , Schropp A. , Seiboth F. , Schroer C. G. , Scholz M. , Möller J. , Hallmann J. , Boesenberg U. , Kim C. , Zozulya A. , Lu W. , Shayduk R. , Schaffer R. , Madsen A. , Salditt T.
Published: June 2021

Cavitation bubbles can be seeded from a plasma following optical breakdown, by focusing an intense laser in water. The fast dynamics are associated with extreme states of gas and liquid, especially in the nascent state. This offers a unique setting to probe water and water vapor far-from equilibrium. However, current optical techniques cannot quantify these early states due to contrast and resolution limitations. X-ray holography with single X-ray free-electron laser pulses has now enabled a quasi-instantaneous high resolution structural probe with contrast proportional to the electron density of the object. In this work, we demonstrate cone-beam holographic flash imaging of laser-induced cavitation bubbles in water with nanofocused X-ray free-electron laser pulses. We quantify the spatial and temporal pressure distribution of the shockwave surrounding the expanding cavitation bubble at time delays shortly after seeding and compare the results to numerical simulations.
Unique and universal dew-repellency of nanocones
Authors: Lecointre Pierre , Laney Sophia , Michalska Martyna , Li Tao , Tanguy Alexandre , Papakonstantinou Ioannis , Quéré David
Published: June 2021

Surface structuring provides a broad range of water-repellent materials known for their ability to reflect millimetre-sized raindrops. Dispelling water at the considerably reduced scale of fog or dew, however, constitutes a significant challenge, owing to the comparable size of droplets and structures. Nonetheless, a surface comprising nanocones was recently reported to exhibit strong anti-fogging behaviour, unlike pillars of the same size. To elucidate the origin of these differences, we systematically compare families of nanotexture that transition from pillars to sharp cones. Through environmental electron microscopy and modelling, we show that microdroplets condensing on sharp cones adopt a highly non-adhesive state, even at radii as low as 1.5 µm, contrasting with the behaviour on pillars where pinning results in impedance of droplet ejection. We establish the antifogging abilities to be universal over the range of our cone geometries, which speaks to the unique character of the nanocone geometry to repel dew. Truncated cones are finally shown to provide both pinning and a high degree of hydrophobicity, opposing characteristics that lead to a different, yet efficient, mechanism of dew ejection that relies on multiple coalescences.
A DNA packaging motor inchworms along one strand allowing it to adapt to alternative double-helical structures
Authors: Castillo Juan P. , B. Tong Alexander , Tafoya Sara , Jardine Paul J. , Bustamante Carlos
Published: June 2021

Ring ATPases that translocate disordered polymers possess lock-washer architectures that they impose on their substrates during transport via a hand-over-hand mechanism. Here, we investigate the operation of ring motors that transport ordered, helical substrates, such as the bacteriophage ϕ29 dsDNA packaging motor. This pentameric motor alternates between an ATP loading dwell and a hydrolysis burst wherein it packages one turn of DNA in four steps. When challenged with DNA-RNA hybrids and dsRNA, the motor matches its burst to the shorter helical pitches, keeping three power strokes invariant while shortening the fourth. Intermittently, the motor loses grip on the RNA-containing substrates, indicating that it makes optimal load-bearing contacts with dsDNA. To rationalize these observations, we propose a helical inchworm translocation mechanism in which, during each cycle, the motor increasingly adopts a lock-washer structure during the ATP loading dwell and successively regains its planar form with each power stroke during the burst.
Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
Authors: Brisuda Antonín , Ho James C. S. , Kandiyal Pancham S. , Ng Justin T-Y. , Ambite Ines , Butler Daniel S. C. , Háček Jaromir , Wan Murphy Lam Yim , Tran Thi Hien , Nadeem Aftab , Tran Tuan Hiep , Hastings Anna , Storm Petter , Fortunati Daniel L. , Esmaeili Parisa , Novotna Hana , Horňák Jakub , Mu Y. G. , Mok K. H. , Babjuk Marek , Svanborg Catharina
Published: June 2021

Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.
Curvature in the reproductive tract alters sperm–surface interactions
Authors: Raveshi Mohammad Reza , Abdul Halim Melati S. , Agnihotri Sagar N. , O’Bryan Moira K. , Neild Adrian , Nosrati Reza
Published: June 2021

The fallopian tube is lined with a highly complex folded epithelium surrounding a lumen that progressively narrows. To study the influence of this labyrinthine complexity on sperm behavior, we use droplet microfluidics to create soft curved interfaces over a range of curvatures corresponding to the in vivo environment. We reveal a dynamic response mechanism in sperm, switching from a progressive surface-aligned motility mode at low curvatures (larger droplets), to an aggressive surface-attacking mode at high curvatures (smaller droplets of <50 µm-radius). We show that sperm in the attacking mode swim ~33% slower, spend 1.66-fold longer at the interface and have a 66% lower beating amplitude than in the progressive mode. These findings demonstrate that surface curvature within the fallopian tube alters sperm motion from a faster surface aligned locomotion in distal regions to a prolonged physical contact with the epithelium near the site of fertilization, the latter being known to promote capacitation and fertilization competence.
HIRA stabilizes skeletal muscle lineage identity
Authors: Esteves de Lima Joana , Bou Akar Reem , Machado Léo , Li Yuefeng , Drayton-Libotte Bernadette , Dilworth F. Jeffrey , Relaix Frédéric
Published: June 2021

The epigenetic mechanisms coordinating the maintenance of adult cellular lineages and the inhibition of alternative cell fates remain poorly understood. Here we show that targeted ablation of the histone chaperone HIRA in myogenic cells leads to extensive transcriptional modifications, consistent with a role in maintaining skeletal muscle cellular identity. We demonstrate that conditional ablation of HIRA in muscle stem cells of adult mice compromises their capacity to regenerate and self-renew, leading to tissue repair failure. Chromatin analysis of Hira-deficient cells show a significant reduction of histone variant H3.3 deposition and H3K27ac modification at regulatory regions of muscle genes. Additionally, we find that genes from alternative lineages are ectopically expressed in Hira-mutant cells via MLL1/MLL2-mediated increase of H3K4me3 mark at silent promoter regions. Therefore, we conclude that HIRA sustains the chromatin landscape governing muscle cell lineage identity via incorporation of H3.3 at muscle gene regulatory regions, while preventing the expression of alternative lineage genes.
Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40
Authors: Yang Fan , He Zhenqiang , Duan Hao , Zhang Duo , Li Juehui , Yang Huijuan , Dorsey Jay F. , Zou Wei , Nabavizadeh S. Ali , Bagley Stephen J. , Abdullah Kalil , Brem Steven , Zhang Lin , Xu Xiaowei , Byrne Katelyn T. , Vonderheide Robert H. , Gong Yanqing , Fan Yi
Published: June 2021

Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.
PRMT5-mediated arginine methylation activates AKT kinase to govern tumorigenesis
Authors: Yin Shasha , Liu Liu , Brobbey Charles , Palanisamy Viswanathan , Ball Lauren E. , Olsen Shaun K. , Ostrowski Michael C. , Gan Wenjian
Published: June 2021

AKT is involved in a number of key cellular processes including cell proliferation, apoptosis and metabolism. Hyperactivation of AKT is associated with many pathological conditions, particularly cancers. Emerging evidence indicates that arginine methylation is involved in modulating AKT signaling pathway. However, whether and how arginine methylation directly regulates AKT kinase activity remain unknown. Here we report that protein arginine methyltransferase 5 (PRMT5), but not other PRMTs, promotes AKT activation by catalyzing symmetric dimethylation of AKT1 at arginine 391 (R391). Mechanistically, AKT1-R391 methylation cooperates with phosphatidylinositol 3,4,5 trisphosphate (PIP3) to relieve the pleckstrin homology (PH)-in conformation, leading to AKT1 membrane translocation and subsequent activation by phosphoinositide-dependent kinase-1 (PDK1) and the mechanistic target of rapamycin complex 2 (mTORC2). As a result, deficiency in AKT1-R391 methylation significantly suppresses AKT1 kinase activity and tumorigenesis. Lastly, we show that PRMT5 inhibitor synergizes with AKT inhibitor or chemotherapeutic drugs to enhance cell death. Altogether, our study suggests that R391 methylation is an important step for AKT activation and its oncogenic function.
Dynamics of replication origin over-activation
Authors: Fu Haiqing , Redon Christophe E. , Thakur Bhushan L. , Utani Koichi , Sebastian Robin , Jang Sang-Min , Gross Jacob M. , Mosavarpour Sara , Marks Anna B. , Zhuang Sophie Z. , Lazar Sarah B. , Rao Mishal , Mencer Shira T. , Baris Adrian M. , Pongor Lorinc S. , Aladjem Mirit I.
Published: June 2021

Safeguards against excess DNA replication are often dysregulated in cancer, and driving cancer cells towards over-replication is a promising therapeutic strategy. We determined DNA synthesis patterns in cancer cells undergoing partial genome re-replication due to perturbed regulatory interactions (re-replicating cells). These cells exhibited slow replication, increased frequency of replication initiation events, and a skewed initiation pattern that preferentially reactivated early-replicating origins. Unlike in cells exposed to replication stress, which activated a novel group of hitherto unutilized (dormant) replication origins, the preferred re-replicating origins arose from the same pool of potential origins as those activated during normal growth. Mechanistically, the skewed initiation pattern reflected a disproportionate distribution of pre-replication complexes on distinct regions of licensed chromatin prior to replication. This distinct pattern suggests that circumventing the strong inhibitory interactions that normally prevent excess DNA synthesis can occur via at least two pathways, each activating a distinct set of replication origins.