bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Characterization of Phosphate-Based Glass Coatings via Suspension High-Velocity Oxy-Fuel (SHVOF) Thermal Spray Process
Authors: Bano S. , Rincon Romero A. , Islam Md Towhidul , Grant D. M. , Ahmed I. , Hussain T.
Published: July 2021

Phosphate-based glasses (PBGs) are promising materials for biomedical applications due to their biocompatible and fully resorbable characteristics in aqueous environments. These glasses can be coated onto metal substrate via the technique of suspension high-velocity oxy-fuel (SHVOF) thermal spraying to produce nanostructured coatings with improved physical and mechanical properties. PBGs coatings were produced using SHVOF thermal spray process at 50 and 75 kW flame power. The 75 kW coating was rougher (Ra = 3.6 ± 0.1 µm) than the 50 kW coating (Ra = 2.7 ± 0.1 µm), whereas the 50 kW coating was much thicker (24.6 ± 2.3 µm) than the 75 kW coating (16.0 ± 3.4 µm). Due to the rougher surface, the 75 kW coating showed high degradation and ion release rates. Moreover, structural changes were observed by Raman analysis, and the initial glass formulation contained Q1 (phosphate tetrahedra with one-bridging oxygen) and Q2 (phosphate tetrahedra with two-bridging oxygen) species. However, the coatings showed a reduction of Q2 species and higher concentrations of Q1 and Q0 (phosphate tetrahedra with no-bridging oxygen) species, which led to lower degradation rates and reduced ion release profiles in the glass coating compared to the initial glass.
Sexuality of People with Intellectual Disabilities: A Proposal to use the Positive Sexuality Model
Authors: Parchomiuk Monika
Published: July 2021

The aim of this research was to determine the trends in the field of analyzing positive aspects of sexuality of people with intellectual disabilities (ID). In relation to these findings, the possibilities of applying the model of positive sexuality were presented. A literature search covering studies published between 1980 and 2020 was conducted. 19 studies were included. Researchers focus on partnerships, mainly heterosexual ones, associated experiences, plans and ideas. The results show that people with ID are able to report on experiences accompanying relationships and their depiction is relatively rich. People who do not have such experiences expect them in the future, treating them as a very important aspect of life. Referring to the model of positive sexuality, the areas of research in the population of people with intellectual disability were specified, and the theoretical justification of the model, general methodological aspects and practical usefulness were provided.
Innovation and the theory of fields
Authors: Fligstein Neil
Published: July 2021

Innovation does not just involve the creation of new products, but also includes the need for new kinds of processes and organizations. Field theory can help us understand why some innovations are more piecemeal and others more revolutionary. It explicitly links innovation to the process of the emergence, adjustment, and transformation of markets (conceived of as fields). To illustrate this perspective, the case of the transition in the U.S. from a mortgage market dominated by savings and loan banks to the emergence of mortgage securitization dominated by the government sponsored enterprises and the largest private banks, is explicated. Field theory helps us understand the logic of this transition and the myriad players and innovations that helped produce a large part of what we consider to be modern finance. The case also shows the limits of economic theories of financial innovation and the sociology of finance. I end with a discussion of how field theory can inform subsequent research on innovation.
Derivation of water flooding characteristic curve for offshore low-amplitude structural reservoir with strong bottom water
Authors: Liu Ying-xian , Tan Jie , Cai Hui , Li Yan-lai , Liu Chun-yan
Published: July 2021

The water flooding characteristic curve method is one of the essential techniques to predict recoverable reserves. However, the recoverable reserves indicated by the existing water flooding characteristic curves of low-amplitude reservoirs with strong bottom water increase gradually, and the current local recovery degree of some areas has exceeded the predicted recovery rate. The applicability of the existing water flooding characteristic curves in low-amplitude reservoirs with strong bottom water is lacking, which affects the accurate prediction of development performance. By analyzing the derivation process of the conventional water flooding characteristic curve method, this manuscript finds out the reasons for the poor applicability of the existing water flooding characteristic curve in low-amplitude reservoir with strong bottom water and corrects the existing water flooding characteristic curve according to the actual situation of the oilfield and obtains the improvement method of water flooding characteristic curve in low-amplitude reservoir with strong bottom water. After correction, the correlation coefficient between $$\frac{{k_{ro} }}{{k_{rw} }}$$

k

ro

k

rw

and $$S_{w}$$

S
w

is 95.92%. According to the comparison between the actual data and the calculated data, in 2021/3, the actual water cut is 97.29%, the water cut predicted by the formula is 97.27%, the actual cumulative oil production is 31.19 × 104t, and the predicted cumulative oil production is 31.31 × 104t. The predicted value is consistent with the actual value. It provides a more reliable method for predicting low-amplitude reservoirs' recoverable ability with strong bottom water and guides the oilfield's subsequent decision-making.
On the supercritical defocusing NLW outside a ball
Authors: D’Ancona Piero
Published: July 2021

We study a defocusing semilinear wave equation, with a power nonlinearity $$|u|^{p-1}u$$

|
u
|

p
-
1

u

, defined outside the unit ball of $$\mathbb {R}^{n}$$

R

n

, $$n\ge 3$$

n
≥
3

, with Dirichlet boundary conditions. We prove that if $$p>n+3$$

p
>
n
+
3

and the initial data are nonradial perturbations of large radial data, there exists a global smooth solution. The solution is unique among energy class solutions satisfying an energy inequality. The main tools used are the Penrose transform and a Strichartz estimate for the exterior linear wave equation perturbed with a large, time dependent potential.
Modeling of Asphalt Aging Based on Short-Term Aging Temperature and Time of Normal Asphalt Mixture for Quantifying Binder Aging
Authors: An Soonyong , Jo Youngjin , Park Taesoon , Kim Kwang W. , Kim Sungun
Published: July 2021

The binder in hot-mix asphalt (HMA) is aged (oxidized) in a short-time period during haul-and-queue in the field. Since the oxidative aging of asphalt is a complex chemical process, it is difficult to define the asphalt aging as a function of limited variables. When comparing the same types of asphalt mixes, however, the mix temperature (T) and time (t) kept at the T will be the primary source of variation affecting aging levels of the binder in the mix. Since the binder aging level is not easy to estimate without measuring a physical property, this study concentrated on developing an aging quantity (AQ) model for estimating aging levels of the binder in the mix based on T and t. The loose asphalt mixes were artificially short-term aged at various Ts for different t; 130, 160, and 180 °C for 1, 2, 4, and 8 h. The absolute viscosity (AV) values, which represent aging levels of the recovered binder after each short-term aging (SA) of normal dense-graded mix, were used for regression with AQ values computed by the AQ model. The best-fit AQ model was selected by trial-and-error regression iterations between measured AV and computed AQ. The AQ was then used to estimate AV (EAV) of the aged asphalts in various normal asphalt mixes. It was found that the AQ was useful for estimating AV of the binder in the SA-treated mix, and the EAV by AQ showed an excellent correlation with the measured AV with R2 > 0.99. Therefore, it was possible to conclude that the AQ could be used to predict aging level of various short-term-aged normal asphalt mixes if the materials sources were limited.
Optimal preliminary design of variable section beams criterion
Authors: Cucuzza Raffaele , Rosso Marco Martino , Marano Giuseppe Carlo
Published: July 2021

The present paper discusses about optimal shape solution for a non-prismatic planar beam. The proposed model is based on the standard Timoshenko kinematics hypothesis (i.e., planar cross-section remains planar in consequence of a deformation, but it is able to rotate with respect to the beam center-line). The analytical solution for this type of beam is thus used to obtain deformations and stresses of the beam, under different constraints, when load is assumed as the sum of a generic external variable vertical one and the self-weight. The solution is obtained by numerical integration of the beam equation and constraints are posed both on deflection and maximum stress under the hypothesis of an ideal material. The section variability is, thus, described assuming a rectangular cross section with constant base and variable height which can be described in general with a trigonometric series. Other types of empty functions could also be analyzed in order to find the best strategy to get the optimal solution. Optimization is thus performed by minimizing the beam volume considering the effects of non-prismatic geometry on the beam behavior. Finally, several analytical and numerical solutions are compared with results existing in literature, evaluating the solutions’ sensibility to some key parameters like beam span, material density, maximum allowable stress and load distribution. In conclusion, the study finds a critical threshold in terms of emptying function beyond which it is not possible to neglect the arch effect and the curvature of the actual axis for every different case study described in this work. In order to achieve this goal, the relevance of beam span, emptying function level and maximum allowable stress are investigated.
Labour Market Demands, Employability and Authenticity
Authors: Nikunen Minna
Published: July 2021

Finding employment has been a challenge for young adults in recent years. This is not only due to high unemployment rates, but also because entering working life is more complicated than before. It is no longer just a question of credentials and skills. ‘Employability’ depends on investments in personal capacities: labour market demands in recruitment exceed the capacity of employees’ bodies and minds. This article asks what demands for increasing one’s employability young adults (aged 18–30) experience in relation to their education and working life and how they respond to these ideas, especially to the idea of modifying their minds and bodies—habitus—in order to increase their employability. What demands are they complying with or resisting? How and why are they doing so? The article draws on interviews with 40 young Finnish women and men. The data analysis reveals that employability ideals emphasising affective and bodily capacities or dispositions are not shared by everyone. However, modifying one’s attitude or demeanour seems to be less threatening for young adults than does changing one’s appearance or body. Changes to one’s body are associated with rules and codes dictated from above, whereas changing one’s mindset is usually conceived of as self-development; thus, it is not seen as contrary to authenticity. Identification with a line of work is an important factor in accepting demands on one’s body or demeanour. It should be asked if the importance of authenticity for young adults entering working life should be taken into consideration in governmental youth and employment policies.
Team effectiveness model for science (TEMS): Using a mutual learning shared mindset to design, develop, and sustain science teams
Authors: Schwarz Roger M. , Bennett L. Michelle
Published: July 2021

In this paper, we introduce the Team Effectiveness Model for Science (TEMS) and describe a multiphase set of interventions for forming a new team or developing an existing team. TEMS uses a shared mutual learning mindset as the model’s central and guiding element. It shows how team mindset leads to behavior and to results and how this affects the characteristics of effective team functioning. TEMS addresses two related questions: What are the variables that contribute to effective teams? and How do the variables need to be designed to make their relevant contributions? Team models often answer the first question without fully answering the second. By addressing three gaps, TEMS contributes to enhancing science team effectiveness. Gap 1 is the absence of explicit core values, assumptions, and norms that serve as the foundation for developing and maintaining science team effectiveness. Gap 2 is the absence of a process for integrating the science and relationship aspects of a science team. Gap 3 is the absence of team processes and structures that are derived from the team’s values, assumptions, and norms. Using TEMS to design new or intervene with existing teams focuses on shifting mindset, developing behavioral skills, and designing processes and structures congruent with the new mindset.
Disaster Risk Reduction in Iranian Primary and Secondary School Textbooks: A Content Analysis
Authors: Seddighi Hamed , Yousefzadeh Sepideh , López López Mónica , Sajjadi Homeira , Vameghi Meroe , Rafiey Hassan , Khankeh Hamidreza
Published: July 2021

Objective:

School textbooks have a significant role in transferring knowledge to the students and changing their behavior. This work aims to analyze school textbooks to find the representation of natural hazards in Iran, which is vital for supporting children in disaster situations.

Methods:

In this study, a qualitative content analysis was used. Data were analyzed qualitatively by using MAXQDA 2018 software. For the 2019–2020 school year, 300 Iranian school textbooks in Persian language were collected.

Results:

Findings of this work show that students receive information about disaster risk reduction (DRR) education through the primary and secondary grade levels in all 12 grades. The educational content covers various types of natural hazards, including geophysical, hydrological, climatological, meteorological, and biological disasters. In addition, the textbooks contain discussions about local hazards, causes and effects of disasters, and the disaster management cycle.

Conclusions:

The coverage of DRR and the relevant contents in school textbooks reveals that the discourse of natural hazards is important for Iranian authorities, especially in the education system. This study helps decision-makers and practitioners design more effective interventions to prepare children for disasters.
Markovian random iterations of homeomorphisms of the circle
Authors: MATIAS EDGAR
Published: July 2021

In this paper we prove a local exponential synchronization for Markovian random iterations of homeomorphisms of the circle
$S^{1}$
, providing a new result on stochastic circle dynamics even for
$C^1$
-diffeomorphisms. This result is obtained by combining an invariance principle for stationary random iterations of homeomorphisms of the circle with a Krylov–Bogolyubov-type result for homogeneous Markov chains.
Forced Migration, Oceanic Humanitarianism, and the Paradox of Danger and Saviour of a Vietnamese Refugee Boat Journey
Authors: Damousi Joy , Nelli Filippo , Nguyen Austen Anh , Toffoli Alessandro , Tomsic Mary
Published: July 2021

The ocean is a central site of escape, danger, and rescue for refugees. It is also a place where oceanic humanitarianism is enacted. In histories of refugee migration, the combination of the ocean, weather, and climate in determining the fate of refugees has not been adequately examined. This article provides a critical analysis of a Vietnamese refugee boat journey in 1982, to demonstrate the paradoxical nature of the ocean as both a site of danger and saviour. Conventional historical methodologies alone cannot capture the complex role of the ocean and the weather in determining boat refugee journeys and rescues. Interdisciplinary research between historians and ocean engineers provides new evidence and understanding of how the ocean and weather influences the outcomes of refugees seeking asylum by boat. Numerical model predictions of sea state and ship motion – which enables the vessel's journey in past environmental conditions to be understood – integrated within historical analysis contributes to a fuller and more complex understanding of the nexus between environmental conditions and forced migration journeys. Ocean engineering produces a scientific narrative that historians can use, alongside oral histories and other sources, to theorize the ocean as an active agent.
Exploring teachers’ professional development through participation in virtual exchange
Authors: O’Dowd Robert , Dooly Melinda
Published: July 2021

Virtual exchange (VE) is an umbrella term used to refer to the engagement of groups of students in sustained online intercultural interaction and collaboration with international partners under the guidance of their teachers. In the computer-assisted language learning literature, telecollaboration and eTandem approaches to VE have been researched extensively. However, this research has principally focused to date on learner gains and the impact on teachers has been much less explored. This paper identifies the impact of VE on foreign language teachers’ practices and their professional development by examining the results of a qualitative study of 31 teacher trainers who engaged their classes in VE projects as part of a large-scale European project. The findings of the study suggest that participation in VE projects provides teachers with valuable experience in continued professional development and methodological innovation. In particular, VE was seen to open up opportunities for teachers to develop new professional partnerships, collaborative academic initiatives, to develop their own online collaboration skills, and also to introduce more innovative approaches in their current teaching practice.
Paralonchothrixgen. nov., the first record of Echimyini (Rodentia, Octodontoidea) in the late Miocene of Southern South America
Authors: PIÑERO Pedro , OLIVARES A. Itatí , VERZI Diego H. , CONTRERAS Victor H.
Published: July 2021

Echimyidae is the most widely diversified family among hystricognath rodents, both in the number of species and variety of lifestyles. In the Patagonian Subregion of southern South America, extinct echimyids related to living arboreal species (Echimyini) are recorded up to the middle Miocene, whereas all the known southern fossils since the late Miocene are linked to terrestrial and fossorial lineages currently inhabiting the Chacoan open biome in eastern South America. In this work, we describe a new genus of echimyid rodent,Paralonchothrixgen. nov., from the late Miocene of northwestern Argentina and western Brazil. Its single recognised species,Paralonchothrix ponderosuscomb. nov., is represented by two hemimandibles. One of them comes from a level of Loma de Las Tapias Formation, underlying a tuff dated at 7.0 ± 0.9 Ma (Huayquerian age, late Miocene); the other specimen comes from the ‘Araucanense’ of Valle de Santa María (type locality, Huayquerian age, late Miocene). A phylogenetic analysis linkedParalonchothrixtoLonchothrix, both being the sister group toMesomys. Thereby, for the first time, an echimyid linked to living Amazonian arboreal clades is recognised for the late Miocene of southern South America.Paralonchothrixgen. nov. thus represents an exceptional record that raises the need to review the postulated evolutionary pattern for echimyids recorded at high latitudes since the late Miocene. The new genus provides a minimum age (ca.7 Ma) in the fossil record for the divergence betweenMesomysandLonchothrix. The palaeoenvironmental conditions inferred for the late Miocene in western and northwestern Argentina suggest savanna-type environments, with areas with more closed woodlands in peri-Andean valleys. The record ofParalonchothrixgen. nov. supports the hypothesis that this area would have maintained connections with tropical biomes of northern South America during the late Miocene.
Verfügbare Ressourcen und Bullyingerfahrungen von Schülern und Schülerinnen mit und ohne sonderpädagogischen Förderbedarf
Authors: Wiemann Ann-Katrin , Lohaus Arnold
Published: July 2021

Zusammenfassung. Internationale Studien fanden, dass Schüler und Schülerinnen mit sonderpädagogischem Förderbedarf (SPF) ein höheres Risiko haben, Bullying zu erleben, als Schüler und Schülerinnen ohne SPF. In Deutschland wurde Bullying bisher jedoch kaum vor dem Hintergrund der inklusiven Beschulung untersucht. Bei Betrachtung unterschiedlicher personaler und umgebungsbezogener Ressourcen wurden in vorangegangen Studien sowohl bei Schülern und Schülerinnen, die von Bullyingerfahrungen betroffen waren, als auch bei Schülern und Schülerinnen mit SPF häufig weniger zur Verfügung stehende Ressourcen gefunden als bei ihren Mitschülern und Mitschülerinnen. Im Rahmen einer Pilotstudie sollte daher untersucht werden, ob sich die Bullyingerfahrungen und die verfügbaren personalen und umgebungsbezogenen Ressourcen von Schülern und Schülerinnen mit und ohne SPF unterscheiden. Dazu wurden Fragebogendaten von N = 420 Schülern und Schülerinnen der 3. bis 10. Klasse ausgewertet, die angegeben haben, entweder Bullying erlebt zu haben oder nicht in Bullying involviert zu sein. Um zu prüfen, ob sich die verfügbaren Ressourcen in Abhängigkeit von den Bullyingerfahrungen und dem SPF unterscheiden, wurden aus der Gesamtstichprobe mittels Propensity Score Matching n = 45 Schüler und Schülerinnen ohne SPF ausgewählt und mit den Schülern und Schülerinnen mit SPF ( n = 45) verglichen. Die Ergebnisse zeigten, dass Schüler und Schülerinnen, die von Bullying betroffen waren, insbesondere über weniger umgebungsbezogene Ressourcen verfügten als ihre Mitschüler und Mitschülerinnen. Beim Vorliegen von Bullyingerfahrungen unterschieden sich Schüler und Schülerinnen mit SPF in der Verfügbarkeit von Ressourcen jedoch nicht von Schülern und Schülerinnen ohne SPF.
Drift Velocity Estimation of Ionospheric Bubbles Using GNSS Observations
Authors: Souza Ana L. C. , Camargo Paulo O. , Muella Marcio T. A. H. , Tardelli‐Coelho Flavia
Published: July 2021

Equatorial plasma bubble (EPB) irregularities are large‐scale plasma depleted structures that exist in the equatorial and low‐latitude ionosphere. Thus, particularly in these regions, much attention must be given to the effects of the EPBs in the life critical applications based on global navigation satellite systems (GNSS). The study on the dynamics of plasma bubbles, particularly in the determination of their drift velocities, and their impact on ground‐based augmentation system is of fundamental importance for civilian aviation. In this regard, we proposed a methodology to estimate the zonal drift velocities of the plasma bubble irregularities using slant total electron content (TEC) measurements derived from two spaced ground‐based GNSS receivers. The experiments were performed with the purpose to evaluate if the drift velocities obtained using the methodology proposed in this study agree with the velocities deduced from all‐sky imaging systems. The results revealed that the TEC‐estimated mean eastward drift velocities were comparable with the values deduced from the airglow techniques, and with the results obtained from previous studies. Therefore, the methodology proposed in this work to infer the plasma bubble drift velocities seem to have the potential in future investigations to provide a new data source in this field.
Hear Ye! Hear Ye! A Declaration of the Rights of the Moon
Authors: Evans Kate
Published: July 2021

What are the ethics of mining the Moon? Could humans cause environmental damage to Earth’s only satellite? And could a new Declaration of the Rights of the Moon be one way of mitigating those impacts?
NASA CERES Spurious Calibration Drifts Corrected by Lunar Scans to Show the Sun Is not Increasing Global Warming and Allow Immediate CRF Detection
Authors: Matthews Grant
Published: July 2021

Orbital Earth Radiation Budget measurement comparisons to models, are critical for climate prediction confidence. Satellite systems must reduce calibration drifts for this purpose. NASA Clouds and the Earth's Radiant Energy System (CERES) measures Earth albedo reductions that if correct, would increase solar forcing and suggest greater sunlight absorption is driving much of recent temperature increases. Such results are presented, alongside those from the Moon and Earth Radiation Budget Experiment (MERBE). MERBE uses constant lunar reflectivity for tracking and compensation of instrument telescope degradation, undetectable by CERES. MERBE finds Earth albedo constant compared to that of the Moon, because Arctic solar warming effects are balanced by solar cooling elsewhere, likely due to negative feedbacks. Contrary to NASA, this shows the Sun is not increasing warming and that CERES results are not as stable as claimed and assumed. Furthermore, MERBE can actually resolve Cloud Radiative Forcing (CRF) signals from the existing record, rather than in decades with official observations.
Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC
Authors: Chang Hanyue , Xu Qiaoshi , Li Jiayi , Li Mingyu , Zhang Zhiyuan , Ma Hailong , Yang Xi
Published: July 2021

Pyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was detected using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of Galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. The mechanism of lactate regulating Galectin-9 expression through NF-κB signaling was explored in vitro. Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. The glycolysis and glycolytic capacity are significantly decreased after PKM2 silencing. Lactate secretion induced by PKM2 significantly promotes migration and invasion capacity. Furthermore, a positive correlation between PKM2 and Galectin-9 expression is observed in HNSCC tissues. The induction of Galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor. Mechanically, lactate impeded the suppressive transcriptional complex formation of NF-κB and histone deacetylase 3 (HDAC3), which released the transcription of Galectin-9 mediated by NF-κB signaling. Our findings demonstrate that lactate produced by PKM2 upregulation promotes tumor progression and Galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-Galectin-9 axis might be a potential therapeutic target in HNSCC.
Genome-wide CRISPR/Cas9 screening identifies CARHSP1 responsible for radiation resistance in glioblastoma
Authors: Zhu Guo-dong , Yu Jing , Sun Zheng-yu , Chen Yan , Zheng Hong-mei , Lin Mei-lan , Ou-yang Shi , Liu Guo-long , Zhang Jie-wen , Shao Feng-min
Published: July 2021

Glioblastomas (GBM) is the most common primary malignant brain tumor, and radiotherapy plays a critical role in its therapeutic management. Unfortunately, the development of radioresistance is universal. Here, we identified calcium-regulated heat-stable protein 1 (CARHSP1) as a critical driver for radioresistance utilizing genome-wide CRISPR activation screening. This is a protein with a cold-shock domain (CSD)-containing that is highly similar to cold-shock proteins. CARHSP1 mRNA level was upregulated in irradiation-resistant GBM cells and knockdown of CARHSP1 sensitized GBM cells to radiotherapy. The high expression of CARHSP1 upon radiation might mediate radioresistance by activating the inflammatory signaling pathway. More importantly, patients with high levels of CARHSP1 had poorer survival when treated with radiotherapy. Collectively, our findings suggested that targeting the CARHSP1/TNF-α inflammatory signaling activation induced by radiotherapy might directly affect radioresistance and present an attractive therapeutic target for GBM, particularly for patients with high levels of CARHSP1.
A single-amino-acid in-frame deletion in CYP17A1 results in combined 17-hydroxylase and 17,20-lyase deficiency in an Iranian family despite the protein mutation site
Authors: Habib Ashkan , Shojazadeh Alireza , Molayemat Mohadeseh , Jafari Khamirani Hossein , Zoghi Sina , Dastgheib Seyed Alireza , Habib Asadollah
Published: July 2021

In this study, we detected homozygous mutations in the CYP17A1 gene (NM_000102.4:c.1053_1055delCCT; p.Leu353del; SCV001479329) in a 28-year-old female patient (46,XX) and her phenotypically female 30-year-old sister (46,XY) who had phenotypes consistent with combined 17-hydroxylase and 17,20-lyase deficiency. The phenotypes were not expected based on the location of the mutation in the CYP17A1 redox partner-binding site and a previous description of the same mutation linked with isolated 17,20-lyase deficiency.
Distinct cortical systems reinstate the content and context of episodic memories
Authors: Kragel James E. , Ezzyat Youssef , Lega Bradley C. , Sperling Michael R. , Worrell Gregory A. , Gross Robert E. , Jobst Barbara C. , Sheth Sameer A. , Zaghloul Kareem A. , Stein Joel M. , Kahana Michael J.
Published: July 2021

Episodic recall depends upon the reinstatement of cortical activity present during the formation of a memory. Evidence from functional neuroimaging and invasive recordings in humans suggest that reinstatement organizes our memories by time or content, yet the neural systems involved in reinstating these unique types of information remain unclear. Here, combining computational modeling and intracranial recordings from 69 epilepsy patients, we show that two cortical systems uniquely reinstate the semantic content and temporal context of previously studied items during free recall. Examining either the posterior medial or anterior temporal networks, we find that forward encoding models trained on the brain’s response to the temporal and semantic attributes of items can predict the serial position and semantic category of unseen items. During memory recall, these models uniquely link reinstatement of temporal context and semantic content to these posterior and anterior networks, respectively. These findings demonstrate how specialized cortical systems enable the human brain to target specific memories.
Reactivation of a developmentally silenced embryonic globin gene
Authors: King Andrew J. , Songdej Duantida , Downes Damien J. , Beagrie Robert A. , Liu Siyu , Buckley Megan , Hua Peng , Suciu Maria C. , Marieke Oudelaar A. , Hanssen Lars L. P. , Jeziorska Danuta , Roberts Nigel , Carpenter Stephanie J. , Francis Helena , Telenius Jelena , Olijnik Aude-Anais , Sharpe Jacqueline A. , Sloane-Stanley Jacqueline , Eglinton Jennifer , Kassouf Mira T. , Orkin Stuart H. , Pennacchio Len A. , Davies James O. J. , Hughes Jim R. , Higgs Douglas R. , Babbs Christian
Published: July 2021

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.
Temporal stability of stimulus representation increases along rodent visual cortical hierarchies
Authors: Piasini Eugenio , Soltuzu Liviu , Muratore Paolo , Caramellino Riccardo , Vinken Kasper , Op de Beeck Hans , Balasubramanian Vijay , Zoccolan Davide
Published: July 2021

Cortical representations of brief, static stimuli become more invariant to identity-preserving transformations along the ventral stream. Likewise, increased invariance along the visual hierarchy should imply greater temporal persistence of temporally structured dynamic stimuli, possibly complemented by temporal broadening of neuronal receptive fields. However, such stimuli could engage adaptive and predictive processes, whose impact on neural coding dynamics is unknown. By probing the rat analog of the ventral stream with movies, we uncovered a hierarchy of temporal scales, with deeper areas encoding visual information more persistently. Furthermore, the impact of intrinsic dynamics on the stability of stimulus representations grew gradually along the hierarchy. A database of recordings from mouse showed similar trends, additionally revealing dependencies on the behavioral state. Overall, these findings show that visual representations become progressively more stable along rodent visual processing hierarchies, with an important contribution provided by intrinsic processing.
Ageing is associated with disrupted reinforcement learning whilst learning to help others is preserved
Authors: Cutler Jo , Wittmann Marco K. , Abdurahman Ayat , Hargitai Luca D. , Drew Daniel , Husain Masud , Lockwood Patricia L.
Published: July 2021

Reinforcement learning is a fundamental mechanism displayed by many species. However, adaptive behaviour depends not only on learning about actions and outcomes that affect ourselves, but also those that affect others. Using computational reinforcement learning models, we tested whether young (age 18–36) and older (age 60–80, total n = 152) adults learn to gain rewards for themselves, another person (prosocial), or neither individual (control). Detailed model comparison showed that a model with separate learning rates for each recipient best explained behaviour. Young adults learned faster when their actions benefitted themselves, compared to others. Compared to young adults, older adults showed reduced self-relevant learning rates but preserved prosocial learning. Moreover, levels of subclinical self-reported psychopathic traits (including lack of concern for others) were lower in older adults and the core affective-interpersonal component of this measure negatively correlated with prosocial learning. These findings suggest learning to benefit others is preserved across the lifespan with implications for reinforcement learning and theories of healthy ageing.
Superconductivity in an extreme strange metal
Authors: Nguyen D. H. , Sidorenko A. , Taupin M. , Knebel G. , Lapertot G. , Schuberth E. , Paschen S.
Published: July 2021

Some of the highest-transition-temperature superconductors across various materials classes exhibit linear-in-temperature ‘strange metal’ or ‘Planckian’ electrical resistivities in their normal state. It is thus believed by many that this behavior holds the key to unlock the secrets of high-temperature superconductivity. However, these materials typically display complex phase diagrams governed by various competing energy scales, making an unambiguous identification of the physics at play difficult. Here we use electrical resistivity measurements into the micro-Kelvin regime to discover superconductivity condensing out of an extreme strange metal state—with linear resistivity over 3.5 orders of magnitude in temperature. We propose that the Cooper pairing is mediated by the modes associated with a recently evidenced dynamical charge localization–delocalization transition, a mechanism that may well be pertinent also in other strange metal superconductors.
Above- and belowground biodiversity jointly tighten the P cycle in agricultural grasslands
Authors: Oelmann Yvonne , Lange Markus , Leimer Sophia , Roscher Christiane , Aburto Felipe , Alt Fabian , Bange Nina , Berner Doreen , Boch Steffen , Boeddinghaus Runa S. , Buscot François , Dassen Sigrid , De Deyn Gerlinde , Eisenhauer Nico , Gleixner Gerd , Goldmann Kezia , Hölzel Norbert , Jochum Malte , Kandeler Ellen , Klaus Valentin H. , Kleinebecker Till , Le Provost Gaëtane , Manning Peter , Marhan Sven , Prati Daniel , Schäfer Deborah , Schöning Ingo , Schrumpf Marion , Schurig Elisabeth , Wagg Cameron , Wubet Tesfaye , Wilcke Wolfgang
Published: July 2021

Experiments showed that biodiversity increases grassland productivity and nutrient exploitation, potentially reducing fertiliser needs. Enhancing biodiversity could improve P-use efficiency of grasslands, which is beneficial given that rock-derived P fertilisers are expected to become scarce in the future. Here, we show in a biodiversity experiment that more diverse plant communities were able to exploit P resources more completely than less diverse ones. In the agricultural grasslands that we studied, management effects either overruled or modified the driving role of plant diversity observed in the biodiversity experiment. Nevertheless, we show that greater above- (plants) and belowground (mycorrhizal fungi) biodiversity contributed to tightening the P cycle in agricultural grasslands, as reduced management intensity and the associated increased biodiversity fostered the exploitation of P resources. Our results demonstrate that promoting a high above- and belowground biodiversity has ecological (biodiversity protection) and economical (fertiliser savings) benefits. Such win-win situations for farmers and biodiversity are crucial to convince farmers of the benefits of biodiversity and thus counteract global biodiversity loss.
Neonatal thyroxine activation modifies epigenetic programming of the liver
Authors: Fonseca Tatiana L. , Garcia Tzintzuni , Fernandes Gustavo W. , Nair T. Murlidharan , Bianco Antonio C.
Published: July 2021

The type 2 deiodinase (D2) in the neonatal liver accelerates local thyroid hormone triiodothyronine (T3) production and expression of T3-responsive genes. Here we show that this surge in T3 permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increases H3K9me3 levels during post-natal days 1–5 (P1–P5), and results in methylation of 1,508 DNA sites (H-sites) in the adult mouse liver. These sites are associated with 1,551 areas of reduced chromatin accessibility (RCA) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,363 genes. There is strong spatial correlation between density of H-sites and RCA sites. Chromosome conformation capture (Hi-C) data reveals a set of 81 repressed genes with a promoter RCA in contact with an intergenic RCA ~300 Kbp apart, within the same topologically associating domain (χ2 = 777; p < 0.00001). These data explain how the systemic hormone T3 acts locally during development to define future expression of hepatic genes.
A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade
Authors: Geuijen Cecile , Tacken Paul , Wang Liang-Chuan , Klooster Rinse , van Loo Pieter Fokko , Zhou Jing , Mondal Arpita , Liu Yao-bin , Kramer Arjen , Condamine Thomas , Volgina Alla , Hendriks Linda J. A. , van der Maaden Hans , Rovers Eric , Engels Steef , Fransen Floris , den Blanken-Smit Renate , Zondag-van der Zande Vanessa , Basmeleh Abdul , Bartelink Willem , Kulkarni Ashwini , Marissen Wilfred , Huang Cheng-Yen , Hall Leslie , Harvey Shane , Kim Soyeon , Martinez Marina , O’Brien Shaun , Moon Edmund , Albelda Steven , Kanellopoulou Chrysi , Stewart Shaun , Nastri Horacio , Bakker Alexander B. H. , Scherle Peggy , Logtenberg Ton , Hollis Gregory , de Kruif John , Huber Reid , Mayes Patrick A. , Throsby Mark
Published: July 2021

Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.
Case-control study of hypertension and Parkinson’s disease
Authors: Ng Yuen-Fann , Ng Ebonne , Lim Ee-Wei , Prakash Kumar M. , Tan Louis C. S. , Tan Eng-King
Published: July 2021

We evaluate the association of hypertension with PD in an Asian population and performed a meta-analysis on similar studies to address the effect of hypertension on PD risk. A matched case-control study involving 1342 Chinese subjects (671 PD and 671 age and gender-matched controls (with a mean age of 63.9 ± 9.7 and 63.5 ± 9.8 years, and identical proportion of gender distribution) was conducted. Hypertension increases PD risk by 1.9 times [OR 1.86 (1.46–2.38)]. The literature search identified 618 studies initially; however, only three matched case-control studies (all in Caucasians) met the inclusion criteria for meta-analysis. Overall analysis showed that hypertension decreases PD risk by 0.2 times [OR 0.80 (0.66–0.96)]. Hypertension increases PD risk by 1.9 times in our Asian population. However, a meta-analysis comprising of Caucasian populations showed a protective effect of hypertension suggesting that ethnic differences or other genetic or environmental factors may contribute to the divergent observation. Early diagnosis and treatment of hypertension may potentially reduce the risk of PD, at least in our population.
Genetic overlap and causal associations between smoking behaviours and mental health
Authors: Barkhuizen Wikus , Dudbridge Frank , Ronald Angelica
Published: July 2021

Cigarette smoking is a modifiable behaviour associated with mental health. We investigated the degree of genetic overlap between smoking behaviours and psychiatric traits and disorders, and whether genetic associations exist beyond genetic influences shared with confounding variables (cannabis and alcohol use, risk-taking and insomnia). Second, we investigated the presence of causal associations between smoking initiation and psychiatric traits and disorders. We found significant genetic correlations between smoking and psychiatric disorders and adult psychotic experiences. When genetic influences on known covariates were controlled for, genetic associations between most smoking behaviours and schizophrenia and depression endured (but not with bipolar disorder or most psychotic experiences). Mendelian randomization results supported a causal role of smoking initiation on psychiatric disorders and adolescent cognitive and negative psychotic experiences, although not consistently across all sensitivity analyses. In conclusion, smoking and psychiatric disorders share genetic influences that cannot be attributed to covariates such as risk-taking, insomnia or other substance use. As such, there may be some common genetic pathways underlying smoking and psychiatric disorders. In addition, smoking may play a causal role in vulnerability for mental illness.
A precision medicine approach to sex-based differences in ideal cardiovascular health
Authors: Leopold Jane A. , Antman Elliott M.
Published: July 2021

Cardiovascular disease risk factor profiles and health behaviors are known to differ between women and men. Sex-based differences in ideal cardiovascular health were examined in the My Research Legacy study, which collected cardiovascular health and lifestyle data via Life’s Simple 7 survey and digital health devices. As the study overenrolled women (n = 1251) compared to men (n = 310), we hypothesized that heterogeneity among women would affect comparisons of ideal cardiovascular health. We identified 2 phenogroups of women in our study cohort by cluster analysis. The phenogroups differed significantly across all 7 cardiovascular health and behavior domains (all p < 0.01) with women in phenogroup 1 having a lower Life’s Simple 7 Health Score than those in phenogroup 2 (5.9 ± 1.3 vs. 7.6 ± 1.3, p < 0.01). Compared to men, women in phenogroup 1 had a higher burden of cardiovascular disease risk factors, exercised less, and had lower ideal cardiovascular health scores (p < 0.01). In contrast, women in phenogroup 2 had fewer cardiovascular risk factors but similar exercise habits and higher ideal cardiovascular health scores than men (p < 0.01). These findings suggest that heterogeneity among study participants should be examined when evaluating sex-based differences in ideal cardiovascular health.
SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells
Authors: Trnski Diana , Sabol Maja , Tomić Sanja , Štefanac Ivan , Mrčela Milanka , Musani Vesna , Rinčić Nikolina , Kurtović Matea , Petrić Tina , Levanat Sonja , Ozretić Petar
Published: July 2021

Prostate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.