bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineering the Coordination Sphere of Isolated Active Sites to Explore the Intrinsic Activity in Single-Atom Catalysts
Authors: Wu Xin , Zhang Huabin , Zuo Shouwei , Dong Juncai , Li Yang , Zhang Jian , Han Yu
Published: June 2021

Reducing the dimensions of metallic nanoparticles to isolated, single atom has attracted considerable attention in heterogeneous catalysis, because it significantly improves atomic utilization and often leads to distinct catalytic performance. Through extensive research, it has been recognized that the local coordination environment of single atoms has an important influence on their electronic structures and catalytic behaviors. In this review, we summarize a series of representative systems of single-atom catalysts, discussing their preparation, characterization, and structure–property relationship, with an emphasis on the correlation between the coordination spheres of isolated reactive centers and their intrinsic catalytic activities. We also share our perspectives on the current challenges and future research promises in the development of single-atom catalysis. With this article, we aim to highlight the possibility of finely tuning the catalytic performances by engineering the coordination spheres of single-atom sites and provide new insights into the further development for this emerging research field.
Finite Strain Constitutive Modelling of Shape Memory Alloys Considering Partial Phase Transformation with Transformation-Induced Plasticity
Authors: Scalet Giulia , Karakalas Anargyros , Xu Lei , Lagoudas Dimitris
Published: June 2021

This paper presents a unified modelling effort to describe partial phase transformation during cyclic thermo-mechanical loading in Shape Memory Alloys (SMA). To this purpose, a three-dimensional (3D) finite strain constitutive model considering TRansformation-Induced Plasticity (TRIP) is combined with a modified hardening function to enable the accurate and efficient prediction of partial transformations during cyclic thermo-mechanical loading. The capabilities of the proposed model are demonstrated by predicting the behavior of the material under pseudoelastic and actuation operation using finite element analysis. Numerical results of the modified model are presented and compared with the original model without considering the partial transformation feature as well as with uniaxial actuation experimental data. Various aspects of cyclic material behavior under partial transformation are analyzed and discussed for different SMA systems.
Connecting Activity Implementation Characteristics to Student Buy-In Toward and Utilization of Formative Assessments Within Undergraduate Biology Courses
Authors: Brazeal Kathleen R. , Brown Tanya L. , Couch Brian A.
Published: June 2021

While formative assessments (FAs) can facilitate learning within undergraduate STEM courses, their impact likely depends on many factors, including how instructors implement them, whether students buy-in to them, and how students utilize them. FAs have many different implementation characteristics, including what kinds of questions are asked, whether questions are asked before or after covering the material in class, how feedback is provided, how students are graded, and other logistical considerations. We conducted 38 semi-structured interviews with students from eight undergraduate biology courses to explore how various implementation characteristics of in-class and out-of-class FAs can influence student perceptions and behaviors. We also interviewed course instructors to provide context for understanding student experiences. Using thematic analysis, we outlined various FA implementation characteristics, characterized the range of FA utilization behaviors reported by students, and identified emergent themes regarding the impact of certain implementation characteristics on student buy-in and utilization. Furthermore, we found that implementation characteristics have combined effects on student engagement and that students will tolerate a degree of “acceptable discomfort” with implementation features that contradict their learning preferences. These results can aid instructor reflection and guide future research on the complex connections between activity implementation and student engagement within STEM disciplines.
Wing component allocation for a morphing variable span of tapered wing using finite element method and topology optimisation – application to the UAS-S4
Authors: Elelwi M. , Calvet T. , Botez R.M. , Dao T.-M.
Published: June 2021

This work presents the Topology Optimisation of the Morphing Variable Span of Tapered Wing (MVSTW) using a finite element method. This topology optimisation aims to assess the feasibility of internal wing components such as ribs, spars and other structural components. This innovative approach is proposed for the telescopic mechanism of the MVSTW, which includes the sliding of the telescopically extended wing into the fixed wing segment. The optimisation is performed using the tools within ANSYS Mechanical, which allows the solving of topology optimisation problems. This study aims to minimise overall structural compliance and maximise stiffness to enhance structural performance, and thus to meet the structural integrity requirements of the MVSTW. The study evaluates the maximum displacements, stress and strain parameters of the optimised variable span morphing wing in comparison with those of the original wing. The optimised wing analyses are conducted on four wingspan extensions, that is, 0%, 25%, 50% and 75%, of the original wingspan, and for different flight speeds to include all flight phases (17, 34, 51 and 68m/s, respectively). Topology optimisation is carried out on the solid wing built with aluminium alloy 2024-T3 to distribute the wing components within the fixed and moving segments. The results show that the fixed and moving wing segments must be designed with two spar configurations, and seven ribs with their support elements in the high-strain area. The fixed and moving wing segments’ structural weight values were reduced to 16.3 and 10.3kg from 112 to 45kg, respectively. The optimised MVSTW was tested using different mechanical parameters such as strains, displacements and von Misses stresses. The results obtained from the optimised variable span morphing wing show the optimal mechanical behaviour and the structural wing integrity needed to achieve the multi-flight missions.
The Silencing of the World: Early Medieval Soundscapes and a New Aural Culture
Authors: Pancer Nira
Published: June 2021

While ancient texts contain many descriptions of soundscapes, early medieval literature remains largely silent. How can we explain the dwindling references to sound following the passage from antiquity to the early Middle Ages? Does this “silencing of the world” point to an alteration of the “objective” soundscape induced by changes in the material and physical environment, or does it indicate a deeper shift in the aural culture of the period? If there is reason to suppose that the decline in noise can be partly explained by an overall change in infrastructures, this transformation cannot account for the growing scarcity of sound references in the literature of the time. In order to understand this phenomenon, one must focus on the didactic character of hagiographic literature and on the theological motivations of its authors, whose goal was to sensitize their flock to a “sacred sonography.”
COVID-19 Pandemic: Knowledge, Attitude, and Perception of Medical Students Toward the Novel Coronavirus Disease
Authors: Elsayed Emara Hesham , Alhindi Abdallah Ahmoud , Orebi Hisham Ahmed , Kabbash Ibrahim Ali , Elghazally Noha M.
Published: June 2021

Background:

Medical students are vulnerable to infection by the coronavirus. Their awareness of the disease is crucial for their safety and for the management of the epidemic by spreading supportive information in their communities. The aim of this study was to assess coronavirus disease 2019 (COVID-19)-related knowledge, attitude, and preventive practices among Egyptian medical students.

Methods:

We conducted a cross-sectional study from the beginning of April to June 2020; a total of 439 undergraduate medical students (1st to 6th academic years) were assessed using an online questionnaire. The questionnaire consisted of 33 questions, including 5 items regarding socio-demographic features, 23 items concerning COVID-19 related knowledge, 2 items regarding attitude, and 3 items related to preventive measures.

Results:

We observed an acceptable level of knowledge (74.3%) among the sample studied. Preclinical and female students were significantly more optimistic as 69.1% expected successful control of COVID-19, and 48.9% predicted that Egypt will win the fight against COVID-19. The majority of participants reported wearing a facemask in public places as a preventive measure (56.7%).

Conclusions:

Egyptian medical students had an acceptable level of knowledge, positive attitude, and good practices of preventive measures regarding the COVID-19 virus. There is no significant difference in almost all items of knowledge, attitude, and practices in relation to gender or academic grade.
Centre–Province Relations in Personalist Autocracies: Explaining the Emergence and Survival of Powerful Provincial Leaders
Authors: Tolstrup Jakob , Souleimanov Emil
Published: June 2021

We have limited knowledge of how the insecure environment characteristic of personalist dictatorships affects the behaviour of provincial leaders. In this article, we argue that such provincial leaders face a trade-off: either they can keep a low profile but remain vulnerable to the capriciousness of the ruler (the acquiescent strategy), or they can gamble and try to build a power base of their own as a defence against the whims of the dictator (the power-accruing strategy). Next, we specify three contextual conditions, each of which makes provincial leaders more likely to choose and succeed with a power-accruing strategy, which in turn allows them to rule their province with an iron fist. Finally, empirically, we illustrate our arguments through a number of example cases and an in-depth study of a contemporary, very powerful provincial leader in a personalist authoritarian regime: Ramzan Kadyrov, leader of the Chechen Republic within Vladimir Putin's Russia.
Populism and Polarization in Comparative Perspective: Constitutive, Spatial and Institutional Dimensions
Authors: Roberts Kenneth M.
Published: June 2021

Polarization may be the most consistent effect of populism, as it is integral to the logic of constructing populist subjects. This article distinguishes between constitutive, spatial and institutional dimensions of polarization, adopting a cross-regional comparative perspective on different subtypes of populism in Europe, Latin America and the US. It explains why populism typically arises in contexts of low political polarization (the US being a major, if partial, outlier), but has the effect of sharply increasing polarization by constructing an anti-establishment political frontier, politicizing new policy or issue dimensions, and contesting democracy's institutional and procedural norms. Populism places new issues on the political agenda and realigns partisan and electoral competition along new programmatic divides or political cleavages. Its polarizing effects, however, raise the stakes of political competition and intensify conflict over the control of key institutional sites.
Pachamanka: Inka Earthen Ovens from Tambo Viejo, Peru
Authors: Valdez Lidio M. , Bettcher Katrina J.
Published: June 2021

Early Spaniards reported that the Inka state organized public celebrations involving extravagant banquets and drinking, in addition to singing and dancing. Cieza de León and Cobo noted that large number of llamas were slaughtered for such special celebrations. Although it is understood that food was an integral part of the festivities and that the Inka state used food as a political tool, until recently the meal preparation details for such large gatherings remained unknown. Recent archaeological excavation at Tambo Viejo revealed the presence of earthen ovens, similar in fashion to contemporarypachamanka, that were used for cooking at Inka state public celebrations.
Studies of distance one surgeries on the lens space L(p, 1)
Authors: WU ZHONGTAO , YANG JINGLING
Published: June 2021

In this paper, we study distance one surgeries between lens spaces L(p, 1) with p ≥ 5 prime and lens spaces L(n, 1) for $$n \in \mathbb{Z}$$ and band surgeries from T (2, p) to T (2, n). In particular, we prove that L(n, 1) is obtained by a distance one surgery from L(5, 1) only if n=±1, 4, ±5, 6 or ±9, and L(n, 1) is obtained by a distance one surgery from L(7, 1) if and only if n=±1, 3, 6, 7, 8 or 11.
Posttraumatic stress disorder and growth: Examination of joint trajectories in children and adolescents
Authors: Zhou Xiao , Wu Xinchun
Published: June 2021

Positive health endpoints are not the opposite of negative endpoints. Previous studies examining posttraumatic stress disorders (PTSD) and posttraumatic growth (PTG) trajectories have overlooked the co-existence of PTSD and PTG, making it difficult to accurately distinguish individuals with various posttraumatic presentations, causing the effects of targeted interventions to be discounted. To fill this gap, the current study sought to examine joint PTSD and PTG trajectories in children and adolescents. Eight hundred and seventy-six Chinese children and adolescents were recruited to complete self-report questionnaires 6, 12, and 18 months after the Ya'an earthquake. Multiple-process growth mixture modeling analysis was used to test the study proposal. Five distinct joint PTSD and PTG trajectory types were found: recovery, growth, struggling, resistant, and delayed symptoms. Female students and students who felt trapped or fearful were more likely to be in the struggling group, and students who experienced injury to themselves or family members were more likely to belong to the delayed symptom group. These findings suggest that postdisaster psychological services should be provided to relieve delayed symptoms in individuals who experience injury to themselves or their family members, and individuals in the struggling group should be supported to achieve growth.
COVID-19: A Crisis of Borders
Authors: Boucher Anna , Hooijer Gerda , King Desmond , Napier Isabelle , Stears Marc
Published: June 2021

The public health crisis of COVID-19 has compounded preexisting crises of democratic stability and effective governance, spurring debate about the ability of developed democracies to respond effectively to emergencies confronting their citizens. These crises, much discussed in recent political science, are joined by a further crisis which complicates and reinforces them: A migration crisis. Widespread travel and immigration restrictions instigated the largest and fastest decline in global human mobility in modern history, and COVID-19 may fundamentally change immigration over the longer term.

The migration crisis heightens three crucial and preexisting concerns within immigration policy: the role of visa design; the status of undocumented migrants and other migrants without recourse to public funds; and the interaction of immigration and the labor market policy. It could reinforce a rising tide of nationalism and anti-immigrant sentiment, protectionist sentiment within labor-market policy debates, and a K-shaped recovery in migration patterns.
Slip Model of the 2020 Yutian (Northwestern Tibetan Plateau) Earthquake Derived From Joint Inversion of InSAR and Teleseismic Data
Authors: Li Qi , Li Chengtao , Tan Kai , Lu Xiaofei , Zuo Xiao
Published: June 2021

Interferometric synthetic aperture radar and teleseismic P‐wave data were combined to investigate the source rupture characteristics of the 2020 Mw 6.3 Yutian, China, earthquake. We first utilized the near‐field displacements together with 29 broadband teleseismic P waveforms to investigate the uniform slip model by using a Bayesian bootstrap optimization nonlinear inversion method to resolve the nucleation point location, origin time and fault geometrical parameters. Based on these results, the kinematic rupture process of the earthquake was inverted. We conclude that the 2020 Yutian earthquake occurred on a west‐dipping blind normal fault with a dip of ∼60° at the junction of Bayan Har block (BHB) and western Kunlun block (WKB). The rupture nucleation point was located at longitude = 82.435°E, latitude = 35.619°N, and a depth of 6.377 km, making it shallower than estimated from other point source inversions. The earthquake started at 21:05:20 UTC on June 25, 2020 and was delayed by ∼2.07 s compared with GeoForschungsZentrum. The rupture lasted for ∼12 s, with a total seismic moment of ∼3.28 × 1018 Nm, corresponding to a moment magnitude of 6.3. The slip was mainly confined between ∼3.0 and 9.0 km in depth and the peak slip was ∼1.40 m, which occurred at a depth of ∼6.377 km. The slip was predominantly normal slip with slight right‐lateral strike‐slip components, which agrees with the southeastward movement of the BHB relative to the WKB.
Analysis of the Daytime Urban Heat Island Mechanism in East China
Authors: Li Congyuan , Zhang Ning
Published: June 2021

Urban heat islands (UHIs) are one of the most typical changes to surface climate induced by human activities, which manifest as higher temperatures in urban areas than in their surroundings. In this study, we synthetically analyzed spatiotemporal features of daytime surface UHI intensity in east China over the period from 2009 to 2018 carried out with several offline simulations coupled with four land‐use data sets, and identified the causes of UHIs with two attribution methods. The results indicate that spatial variations of summer daytime UHI intensity in east China are dominated by variations in the efficiency of evaporating water (∼3°C) between urban and rural areas. Geographic variations of winter UHI intensity mainly depend on the urban‐rural contrast of heat storage capacity (∼1°C). Additionally, we found that forest‐covered rural areas have an extremely higher convection efficiency than urban areas and nonforest rural landscapes, resulting in a remarkable contribution to summer daytime UHI intensity (∼6°C). However, rural areas largely comprising croplands and grasslands evaporate water more efficiently, expanding summer daytime UHI intensity by approximately 3°C. The prominent capacity of heat storage in nonforest vegetation rural areas accounts for 1°C warming of winter daytime UHI intensity. The major discrepancy between the two attribution methods lies in the evapotranspiration performances of forest‐covered rural lands. Furthermore, the inter‐comparison of several modeling experiments for land‐use data sets suggests that the disparity in UHI intensity could increase by up to 0.4°C, which may exceed 1°C at the local scale.
Does Bad Air Cause Lung Cancer?
Authors: Filippelli Gabriel
Published: June 2021

Papers are welcomed for a new cross-journal special collection exploring the links between air quality and lung cancer.
Comparison of Bubble Shape Model Results With Textural Analysis: Implications for the Velocity Profile Across a Volcanic Conduit
Authors: Ohashi Masatoshi , Ichihara Mie , Kennedy Ben , Gravley Darren
Published: June 2021

Tube pumice, which is characterized by aligned elongated bubbles, is valuable for our understanding of the shear field in a volcanic conduit. Most previous studies interpreted that tube pumice forms through simple shear, assuming a parabolic velocity profile across a volcanic conduit. However, simple shear cannot account for the observation that tube pumice is rare in plinian fall deposits but frequent in ignimbrites at the Taupō volcano, if the pyroclastic flows that formed them erupted through a wider vent and had a lower average shear rate. Here, we analyze the dynamics of bubble deformation that occurred during the 232 CE Taupō eruption by combining a bubble deformation model with a conduit flow model. The results indicate that bubble deformation is largely controlled by the velocity profile across a conduit. If the conduit flow has a parabolic velocity profile, the amount of bubble elongation is unrealistic compared to the Taupō fall deposits. It is more likely that the conduit flow has a plug‐like velocity profile due to viscous heating. We numerically confirmed that bubbles in the plug‐like flow are subject mainly to pure shear and accumulate less strain for elongation. We also calculated a viscous heating flow of the ignimbrite phase. We modeled a wider conduit, which suppresses viscous heating around the conduit walls and causes a higher proportion of the conduit to experience parabolic flow, compared to the plinian phase. The increased proportion of a parabolic profile may explain the high frequency of elongated bubbles in the ignimbrite phase pumice.
Salinity Effect on Trace Element Incorporation in Cultured Shells of the Large Benthic Foraminifer Operculinaammonoides
Authors: Hauzer Hagar , Evans David , Müller Wolfgang , Rosenthal Yair , Erez Jonathan
Published: June 2021

The ratio of sodium to calcium in the shells of foraminifera (Na/Cashell) has been experimentally calibrated as a proxy for past ocean Ca concentrations (Hauzer et al., 2018, https://doi.org/10.1016/j.epsl.2018.06.004). In parallel, it has been suggested that Na/Cashell could be used as a proxy for paleo‐salinity. In this study, we determined the extent to which foraminiferal Na/Ca (and other elements) change with salinity for the shallow‐dwelling large benthic foraminifer Operculina ammonoides, an extant relative of the abundant Eocene Nummulites. The culture experiment was conducted under four salinities between 33 and 43 psu. Shell chemistry was measured by LA‐ICPMS with the newly precipitated CaCO3 identified by a 135Ba‐spike added to the experimental seawater. Na/Cashell, Mg/Cashell and Li/Cashell in O. ammonoides increased slightly with salinity, while Sr/Cashell showed no resolvable change. The change in Na/Cashell due to salinity was small (∼1.4%/psu) compared to the changes in this ratio caused by varying seawater calcium concentrations (Casw) with a sensitivity of ∼5%/(mmol kg−1) Casw. Moreover, the change in salinity in most regions of the past open oceans is minor compared to the large secular variations in Casw during the Phanerozoic (10–40 mmol kg−1). Thus, if at all, paleo‐salinity may be reconstructed based on Na/Cashell only for samples younger than Casw residence time (∼1 Myr). Furthermore, both regional and global changes in ocean salinity over geological time do not pose a significant complication for the use of Na/Cashell as a proxy for past changes in seawater calcium concentrations.
Planar liquid crystal polarization optics for near-eye displays
Authors: Lu Yan-qing , Li Yan
Published: June 2021

As a promising candidate for next-generation mobile platforms, virtual reality and augmented reality have the potential to revolutionize the way we perceive and interact with various types of digital information. In the meantime, ultrathin planar liquid crystal polarization optics are enabling a new evolutionary trend in near-eye displays. A recent invited review paper published in eLight provides an insightful review on liquid crystal optical elements and their applications toward AR and VR.
Improving clinical paediatric research and learning from COVID-19: recommendations by the Conect4Children expert advice group
Authors: Ramanan Athimalaipet V. , Modi Neena , de Wildt Saskia N. ,   c4c Learning from COVID-19 Group, Aurich Beate , Bakhtadze Sophia , Sirvent Francisco J. Bautista , Cabañas Fernando , Campbell Lisa , Casanova Michaela , Charlton Philippa , Crandall Wallace , Eichler Irmgard , Fregonese Laura , Hawcutt Daniel B. , Iveli Pablo , Jaki Thomas , Jocic-Jakubi Bosanka , Johnson Mats , Kaguelidou Florentina , Karadag Bülent , Kelly Lauren E. , Lim Ming , Moreno Carmen , Neumann Eva , Ollivier Cécile , Oualha Mehdi , Raffaeli Genny , Ribeiro Maria A. , Roilides Emmanuel , de Rojas Teresa , Simón Alba Rubio San , Ruperto Nicolino , Scarpa Maurizio , Schwab Matthias , Siapkara Angeliki , Singh Yogen , Smits Anne , Striano Pasquale , Urru Silvana A. M. , Vivarelli Marina , de Wildt Saskia , Zivkoviz Zorica
Published: June 2021

Background

The COVID-19 pandemic has had a devastating impact on multiple aspects of healthcare, but has also triggered new ways of working, stimulated novel approaches in clinical research and reinforced the value of previous innovations. Conect4children (c4c, www.conect4children.org) is a large collaborative European network to facilitate the development of new medicines for paediatric populations, and is made up of 35 academic and 10 industry partners from 20 European countries, more than 50 third parties, and around 500 affiliated partners.

Methods

We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equity.

Findings

We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equityWe provide examples of research innovation, and follow this with recommendations to improve the efficiency of future trials, drawing on industry perspectives, regulatory considerations, infrastructure requirements and parent–patient–public involvement. We end with a comment on progress made towards greater international harmonisation of paediatric research and how lessons learned from COVID-19 studies might assist in further improvements in this important area.
Psychosocial and behavioral problems of children and adolescents in the early stage of reopening schools after the COVID-19 pandemic: a national cross-sectional study in China
Authors: Wang Lin , Zhang Yiwen , Chen Li , Wang Jianhong , Jia Feiyong , Li Fei , Froehlich Tanya E. , Hou Yan , Hao Yan , Shi Yuan , Deng Hongzhu , Zhang Jie , Huang Linjuan , Xie Xianghui , Fang Shuanfeng , Xu Liang , Xu Qi , Guan Hongyan , Wang Weijie , Shen Jianna , Qian Ying , Wang Xi , Shan Ling , Tan Chuanxue , Yu Yabin , Wang Xiaoyan , Chen Fangfang , Zhang Lili , Li Xiaomeng , Shi Xinmiao , Ke Xiaoyan , Li Tingyu
Published: June 2021

This study aims to explore the psychosocial and behavioral problems of children and adolescents in the early stage of reopening schools. In this national cross-sectional study, a total of 11072 students from China were naturally divided into two groups based on their schooling status: reopened schools (RS) and home schooling (HS) group. The psychosocial and behavioral functioning were measured by Achenbach Child Behaviour Checklist (CBCL) and compared in these two groups. Multivariable logistic regression analyses were conducted to explore the independent predictors associated with the psychosocial and behavioral problems. Our results showed that the students in the RS group had more adverse behaviors than that of HS group. The RS group had the higher rates of parent-offspring conflict, prolonged homework time, increased sedentary time and sleep problems (all p < 0.001). When separate analyses were conducted in boys and girls, the RS group had the higher scores for (1) overall behavioral problems (p = 0.02 and p = 0.01), internalizing (p = 0.02 and p = 0.02) and externalizing (p = 0.02 and p = 0.004) behaviors in the 6–11 age group; (2) externalizing (p = 0.049 and p = 0.006) behaviors in the 12–16 age group. Multivariable regression showed parent-offspring conflict and increased sedentary time were the most common risk factors, while physical activity and number of close friends were protective factors for behavior problems in RS students (p < 0.01 or 0.05). The present study revealed that students’ psychosocial and behavioral problems increased in the early stage of schools reopened unexpectedly. These findings suggest that close attention must be paid and holistic strategies employed in the school reopening process of post-COVID-19 period.
Oxytocin receptor induces mammary tumorigenesis through prolactin/p-STAT5 pathway
Authors: Li Dan , San Mingjun , Zhang Jing , Yang Anlan , Xie Wanhua , Chen Yang , Lu Xiaodan , Zhang Yuntao , Zhao Mingyue , Feng Xuechao , Zheng Yaowu
Published: June 2021

Oxytocin receptor (OXTR) is involved in social behaviors, thermoregulation, and milk ejection, yet little is known about its role in breast cancer. To investigate the role of OXTR in mammary gland development and tumorigenesis, a transgenic mouse model of OXTR overexpression (++Oxtr) was used. Overexpression of OXTR-induced progressive mammary hyperplasia, unexpected milk production, and tumorigenesis in females. OXTR-induced mammary tumors showed ERBB2 upregulation and mixed histological subtypes with predomination of papillary and medullary carcinomas. OXTR overexpression led to an activation of prolactin (PRL)/p-STAT5 pathway and created a microenvironment that promotes mammary-specific tumorigenesis. PRL inhibitor bromocriptine (Br) could mitigate OXTR-driven mammary tumor growth. The study demonstrates Oxtr is an oncogene and a potential drug target for HER2-type breast cancer.
Reduced hyaluronan cross-linking induces breast cancer malignancy in a CAF-dependent manner
Authors: Zhang Guoliang , He Yiqing , Liu Yiwen , Du Yan , Yang Cuixia , Gao Feng
Published: June 2021

Hyaluronan (HA) cross-linking is a conformational state of HA, a covalent complex between HA and heavy chains (HCs) from inter-α-trypsin inhibitor (I-α-I) mediated by tumor necrosis factor-induced protein 6 (TSG6). Cross-linked HA has been identified as a protective factor in physiological and inflammatory conditions. However, the state of HA cross-linking in tumor microenvironment has not been fully elucidated. As a major constituent of the extracellular matrix (ECM), HA is mainly synthesized by cancer-associated fibroblasts (CAFs). Our study aimed to clarify the role of HA cross-linking in breast cancer malignancy. Compared to normal mammary gland tissues, cross-linked HA levels were significantly decreased in breast cancer and associated with tumor malignancy. When NFbs were activated into CAFs, the levels of cross-linked HA and TSG6 were both suppressed. Through upregulating TSG6, CAFs restored the high level of cross-linked HA and significantly inhibited breast cancer malignancy, whereas NFbs promoted the malignancy when the cross-linked HA level was reduced. Furthermore, the inhibitory role of HA cross-linking in tumor malignancy was directly verified using the synthesized HA-HC complex. Collectively, our study found that the deficiency of cross-linked HA induced breast cancer malignancy in a CAF-dependent manner, suggesting that recovering HA cross-linking may be a potential therapeutic strategy.
Leveraging supervised learning for functionally informed fine-mapping of cis-eQTLs identifies an additional 20,913 putative causal eQTLs
Authors: Wang Qingbo S. , Kelley David R. , Ulirsch Jacob , Kanai Masahiro , Sadhuka Shuvom , Cui Ran , Albors Carlos , Cheng Nathan , Okada Yukinori ,   The Biobank Japan Project, Matsuda Koichi , Yamanashi Yuji , Furukawa Yoichi , Morisaki Takayuki , Murakami Yoshinori , Kamatani Yoichiro , Muto Kaori , Nagai Akiko , Obara Wataru , Yamaji Ken , Takahashi Kazuhisa , Asai Satoshi , Takahashi Yasuo , Suzuki Takao , Sinozaki Nobuaki , Yamaguchi Hiroki , Minami Shiro , Murayama Shigeo , Yoshimori Kozo , Nagayama Satoshi , Obata Daisuke , Higashiyama Masahiko , Masumoto Akihide , Koretsune Yukihiro , Aguet Francois , Ardlie Kristin G. , MacArthur Daniel G. , Finucane Hilary K.
Published: June 2021

The large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants’ effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes.
Crowdsourced mapping of unexplored target space of kinase inhibitors
Authors: Cichońska Anna , Ravikumar Balaguru , Allaway Robert J. , Wan Fangping , Park Sungjoon , Isayev Olexandr , Li Shuya , Mason Michael , Lamb Andrew , Tanoli Ziaurrehman , Jeon Minji , Kim Sunkyu , Popova Mariya , Capuzzi Stephen , Zeng Jianyang , Dang Kristen , Koytiger Gregory , Kang Jaewoo , Wells Carrow I. , Willson Timothy M. ,   The IDG-DREAM Drug-Kinase Binding Prediction Challenge Consortium,   User oselot, Tan Mehmet ,   Team N121, Huang Chih-Han , Shih Edward S. C. , Chen Tsai-Min , Wu Chih-Hsun , Fang Wei-Quan , Chen Jhih-Yu , Hwang Ming-Jing ,   Team Let_Data_Talk, Wang Xiaokang , Ben Guebila Marouen , Shamsaei Behrouz , Singh Sourav ,   User thinng, Nguyen Thin ,   Team KKT, Karimi Mostafa , Wu Di , Wang Zhangyang , Shen Yang ,   Team Boun, Öztürk Hakime , Ozkirimli Elif , Özgür Arzucan ,   Team KinaseHunter, Lim Hansaim , Xie Lei ,   Team AmsterdamUMC-KU-team, Kanev Georgi K. , Kooistra Albert J. , Westerman Bart A. ,   Team DruginaseLearning, Terzopoulos Panagiotis , Ntagiantas Konstantinos , Fotis Christos , Alexopoulos Leonidas ,   Team KERMIT-LAB - Ghent University, Boeckaerts Dimitri , Stock Michiel , De Baets Bernard , Briers Yves ,   Team QED, Luo Yunan , Hu Hailin , Peng Jian ,   Team METU_EMBLEBI_CROssBAR, Dogan Tunca , Rifaioglu Ahmet S. , Atas Heval , Atalay Rengul Cetin , Atalay Volkan , Martin Maria J. ,   Team DMIS_DK, Jeon Minji , Lee Junhyun , Yun Seongjun , Kim Bumsoo , Chang Buru ,   Team AI Winter is Coming,   Team hulab, Turu Gábor , Misák Ádám , Szalai Bence , Hunyady László ,   Team ML-Med, Lienhard Matthias , Prasse Paul , Bachmann Ivo , Ganzlin Julia , Barel Gal , Herwig Ralf ,   Team Prospectors, Oršolić Davor , Lučić Bono , Stepanić Višnja , Šmuc Tomislav ,   Challenge organizers, Oprea Tudor I. , Schlessinger Avner , Drewry David H. , Stolovitzky Gustavo , Wennerberg Krister , Guinney Justin , Aittokallio Tero
Published: June 2021

Despite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound–kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome.
miR-802 regulates Paneth cell function and enterocyte differentiation in the mouse small intestine
Authors: Goga Algera , Yagabasan Büsra , Herrmanns Karolin , Godbersen Svenja , Silva Pamuditha N. , Denzler Remy , Zünd Mirjam , Furter Markus , Schwank Gerald , Sunagawa Shinichi , Hardt Wolf-Dietrich , Stoffel Markus
Published: June 2021

The intestinal epithelium is a complex structure that integrates digestive, immunological, neuroendocrine, and regenerative functions. Epithelial homeostasis is maintained by a coordinated cross-talk of different epithelial cell types. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here we show that the intestine-enriched miR-802 is a central regulator of intestinal epithelial cell proliferation, Paneth cell function, and enterocyte differentiation. Genetic ablation of mir-802 in the small intestine of mice leads to decreased glucose uptake, impaired enterocyte differentiation, increased Paneth cell function and intestinal epithelial proliferation. These effects are mediated in part through derepression of the miR-802 target Tmed9, a modulator of Wnt and lysozyme/defensin secretion in Paneth cells, and the downstream Wnt signaling components Fzd5 and Tcf4. Mutant Tmed9 mice harboring mutations in miR-802 binding sites partially recapitulate the augmented Paneth cell function of mice lacking miR-802. Our study demonstrates a broad miR-802 network that is important for the integration of signaling pathways of different cell types controlling epithelial homeostasis in the small intestine.
Laboratory measurements of the physics of auroral electron acceleration by Alfvén waves
Authors: Schroeder J. W. R. , Howes G. G. , Kletzing C. A. , Skiff F. , Carter T. A. , Vincena S. , Dorfman S.
Published: June 2021

While the aurora has attracted attention for millennia, important questions remain unanswered. Foremost is how auroral electrons are accelerated before colliding with the ionosphere and producing auroral light. Powerful Alfvén waves are often found traveling Earthward above auroras with sufficient energy to generate auroras, but there has been no direct measurement of the processes by which Alfvén waves transfer their energy to auroral electrons. Here, we show laboratory measurements of the resonant transfer of energy from Alfvén waves to electrons under conditions relevant to the auroral zone. Experiments are performed by launching Alfvén waves and simultaneously recording the electron velocity distribution. Numerical simulations and analytical theory support that the measured energy transfer process produces accelerated electrons capable of reaching auroral energies. The experiments, theory, and simulations demonstrate a clear causal relationship between Alfvén waves and accelerated electrons that directly cause auroras.
Chemodivergent manganese-catalyzed C–H activation: modular synthesis of fluorogenic probes
Authors: Kaplaneris Nikolaos , Son Jongwoo , Mendive-Tapia Lorena , Kopp Adelina , Barth Nicole D. , Maksso Isaac , Vendrell Marc , Ackermann Lutz
Published: June 2021

Bioorthogonal late-stage diversification of amino acids and peptides bears enormous potential for drug discovery and molecular imaging. Despite major accomplishments, these strategies largely rely on traditional, lengthy prefunctionalization methods, heavily involving precious transition-metal catalysis. Herein, we report on a resource-economical manganese(I)-catalyzed C–H fluorescent labeling of structurally complex peptides ensured by direct alkynylation and alkenylation manifolds. This modular strategy sets the stage for unraveling structure-activity relationships between structurally discrete fluorophores towards the rational design of BODIPY fluorogenic probes for real-time analysis of immune cell function.
Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance
Authors: Garcia Laura Ramos , Tenev Tencho , Newman Richard , Haich Rachel O. , Liccardi Gianmaria , John Sidonie Wicky , Annibaldi Alessandro , Yu Lu , Pardo Mercedes , Young Samuel N. , Fitzgibbon Cheree , Fernando Winnie , Guppy Naomi , Kim Hyojin , Liang Lung-Yu , Lucet Isabelle S. , Kueh Andrew , Roxanis Ioannis , Gazinska Patrycja , Sims Martin , Smyth Tomoko , Ward George , Bertin John , Beal Allison M. , Geddes Brad , Choudhary Jyoti S. , Murphy James M. , Aurelia Ball K. , Upton Jason W. , Meier Pascal
Published: June 2021

Necroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.
SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care
Authors: Gutmann Clemens , Takov Kaloyan , Burnap Sean A. , Singh Bhawana , Ali Hashim , Theofilatos Konstantinos , Reed Ella , Hasman Maria , Nabeebaccus Adam , Fish Matthew , McPhail Mark JW. , O’Gallagher Kevin , Schmidt Lukas E. , Cassel Christian , Rienks Marieke , Yin Xiaoke , Auzinger Georg , Napoli Salvatore , Mujib Salma F. , Trovato Francesca , Sanderson Barnaby , Merrick Blair , Niazi Umar , Saqi Mansoor , Dimitrakopoulou Konstantina , Fernández-Leiro Rafael , Braun Silke , Kronstein-Wiedemann Romy , Doores Katie J. , Edgeworth Jonathan D. , Shah Ajay M. , Bornstein Stefan R. , Tonn Torsten , Hayday Adrian C. , Giacca Mauro , Shankar-Hari Manu , Mayr Manuel
Published: June 2021

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22–2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified ‘Age, RNAemia’ and ‘Age, PTX3’ as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.
Chemical combinations potentiate human pluripotent stem cell-derived 3D pancreatic progenitor clusters toward functional β cells
Authors: Liu Haisong , Li Ronghui , Liao Hsin-Kai , Min Zheying , Wang Chao , Yu Yang , Shi Lei , Dan Jiameng , Hayek Alberto , Martinez Martinez Llanos , Nuñez Delicado Estrella , Izpisua Belmonte Juan Carlos
Published: June 2021

Human pluripotent stem cell (hPSC)-derived pancreatic β cells are an attractive cell source for treating diabetes. However, current derivation methods remain inefficient, heterogeneous, and cell line dependent. To address these issues, we first devised a strategy to efficiently cluster hPSC-derived pancreatic progenitors into 3D structures. Through a systematic study, we discovered 10 chemicals that not only retain the pancreatic progenitors in 3D clusters but also enhance their potentiality towards NKX6.1+/INS+ β cells. We further systematically screened signaling pathway modulators in the three steps from pancreatic progenitors toward β cells. The implementation of all these strategies and chemical combinations resulted in generating β cells from different sources of hPSCs with high efficiency. The derived β cells are functional and can reverse hyperglycemia in mice within two weeks. Our protocol provides a robust platform for studying human β cells and developing hPSC-derived β cells for cell replacement therapy.
Cis-regulatory evolution spotlights species differences in the adaptive potential of gene expression plasticity
Authors: He F. , Steige K. A. , Kovacova V. , Göbel U. , Bouzid M. , Keightley P. D. , Beyer A. , de Meaux J.
Published: June 2021

Phenotypic plasticity is the variation in phenotype that a single genotype can produce in different environments and, as such, is an important component of individual fitness. However, whether the effect of new mutations, and hence evolution, depends on the direction of plasticity remains controversial. Here, we identify the cis-acting modifications that have reshaped gene expression in response to dehydration stress in three Arabidopsis species. Our study shows that the direction of effects of most cis-regulatory variants differentiating the response betweenA. thalianaand the sister speciesA. lyrataandA. halleridepends on the direction of pre-existing plasticity in gene expression. A comparison of the rate of cis-acting variant accumulation in each lineage indicates that the selective forces driving adaptive evolution in gene expression favors regulatory changes that magnify the stress response inA. lyrata. The evolutionary constraints measured on the amino-acid sequence of these genes support this interpretation. In contrast, regulatory changes that mitigate the plastic response to stress evolved more frequently inA. halleri. Our results demonstrate that pre-existing plasticity may be a stepping stone for adaptation, but its selective remodeling differs between lineages.
Smart-watch-programmed green-light-operated percutaneous control of therapeutic transgenes
Authors: Mansouri Maysam , Hussherr Marie-Didiée , Strittmatter Tobias , Buchmann Peter , Xue Shuai , Camenisch Gieri , Fussenegger Martin
Published: June 2021

Wearable smart electronic devices, such as smart watches, are generally equipped with green-light-emitting diodes, which are used for photoplethysmography to monitor a panoply of physical health parameters. Here, we present a traceless, green-light-operated, smart-watch-controlled mammalian gene switch (Glow Control), composed of an engineered membrane-tethered green-light-sensitive cobalamin-binding domain of Thermus thermophilus (TtCBD) CarH protein in combination with a synthetic cytosolic TtCBD-transactivator fusion protein, which manage translocation of TtCBD-transactivator into the nucleus to trigger expression of transgenes upon illumination. We show that Apple-Watch-programmed percutaneous remote control of implanted Glow-controlled engineered human cells can effectively treat experimental type-2 diabetes by producing and releasing human glucagon-like peptide-1 on demand. Directly interfacing wearable smart electronic devices with therapeutic gene expression will advance next-generation personalized therapies by linking biopharmaceutical interventions to the internet of things.