bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioarchaeology of Arsenic, an Invisible Natural Pollutant, and Its Effect on the Mitimaes of Camarones Cove, Arica, during Inca Times
Authors: Arriaza Bernardo , Standen Vivien G. , Figueroa Leonardo
Published: October 2022

During the expansion of Tawantinsuyo, the Inca Empire sustained its hegemony by using multiple strategies, including moving specialized groups called mitimaes to their conquered territories. This study examines bioarchaeological evidence from the Camarones 9 (CAM-9) Inca period cemetery at the mouth of the Camarones Valley in northern Chile. The waters in this valley contain concentrations of arsenic that are 100 times above the norm (10 μg/L) for human ingestion, causing serious health consequences. We study the environmental health effects on this population, using atomic absorption spectrometry and hydride generation to investigate arsenic concentration in the bone tissues of 16 individuals sampled from this burial site. Three of four individuals presented arsenic levels in their bones that were beyond the standard 1 μg/g, with a median of 3.6 μg/g; in some, the levels were nine times higher than those currently recommended by the World Health Organization. Considering previous and current bioarchaeological evidence, especially the high arsenic levels found in these individuals, we postulate that the CAM-9 site population corresponds to mitimaes who settled on the Camarones coast. This study is relevant to all regions of the world that present ecotoxic loads.
Well-Defined Interventions and Causal Variable Choice
Authors: Dong Zili
Published: October 2022

There has been much debate among scientists and philosophers about what it means for (hypothetical) interventions invoked in causal inference to be “well-defined” and how considerations of this sort should constrain the choice of causal variables. In this article, I propose that an intervention is well-defined just in case the effect of interest is well-defined, and that the intervention can serve as a suitable means to identify that effect. Based on this proposal, I identify several types of ambiguous intervention. Implications for variable choice are discussed using case studies drawn from the sciences.
40Ar–39Ar geochronology and palaeostress analysis using lamprophyre dikes and quartz veins in the Sizhuang gold deposit: new implications for Early Cretaceous stress regime in the Jiaodong Peninsula, North China Craton
Authors: Wang Zhongliang , Tranos Markos D , Wang Xuan , Zhao Rongxin , Zhang Rifeng
Published: October 2022

Lamprophyre dikes and quartz veins in the Sizhuang gold deposit are used to date and unravel the Early Cretaceous stress regime in the Jiaodong Peninsula, North China Craton. The lamprophyre dikes are grouped into two major sets, trending NNW–SSE and NNE–SSW, respectively, and a subsidiary one, trending WNW–ESE, whereas the quartz veins trend mainly NNE–SSW. The age of lamprophyre dikes’ intrusion was robustly calculated at c. 119 Ma by phlogopite 40Ar–39Ar dating. The fuzzy clustering technique defined four stress states, which were grouped into three stress regimes in Sizhuang. Furthermore, these stress regimes were interrelated with two regional far-field stress regimes, ST1 and ST2, defined by the available published fault-slip data near Sizhuang by applying the separation and stress inversion TR method (TRM). The palaeostress reconstruction indicates that extension and strike-slip tectonics (i.e. transtension) affect the emplacement of the lamprophyre dikes and quartz veins. More precisely, the dike emplacement occurred under unstable stress conditions related to the shift from E–W pure extension–transtension to WNW–ESE transtension, whereas the quartz veins formed under relatively stable WNW–ESE transtension with the variant and increasing fluid pressure (
${P_{\rm{f}}})$
giving rise to the strike-slip against dip-slip kinematics along the faults. The change from the ST1 to ST2 stress regimes reflects the significant clockwise rotation in the palaeo-Pacific plate subduction direction and defines the switching time at c. 119 Ma as precisely obtained by the lamprophyre dating.
Board Governance and Investment Sensitivity to Stock Price: International Evidence
Authors: Driss Hamdi
Published: October 2022

This article examines the effect of board governance on investment efficiency. I use the staggered enactment of board reforms in 41 countries as a shock to board structure that exogenously improves the quality of board oversight of managers. I find that investment-Q sensitivity improves by roughly half post-reform. This effect is more pronounced for firms that are more exposed to the reforms or when external governance mechanisms are less likely to discipline managers. These findings suggest that increased board oversight strengthens managers’ incentives to make investment decisions that are more in line with their firms’ growth opportunities.
Strengthening associations between psychotic like experiences and suicidal ideation and behavior across middle childhood and early adolescence
Authors: Karcher Nicole R. , O'Hare Kirstie , Jay Samantha Y. , Grattan Rebecca
Published: October 2022

Background

Understanding risk factors related to suicidal ideation (SI) and suicidal behaviors (SB) in youth is important for informing prevention and intervention efforts. While it appears that psychotic-like experiences (PLEs) are strongly associated with both SI and SB at different points across the lifespan, the longitudinal nature of this relationship in middle childhood and early adolescence is understudied.

Methods

The study used the unique longitudinal Adolescent Brain Cognitive Development Study data. Mixed effects linear models examined associations between PLEs and SI and SB over time using three time points of data from ages 9–13.

Results

First, analyses indicated that endorsement of SI and SB increased as youth grew older for those with increased distressing PLEs. Analyses found evidence of bidirectional relationships between PLEs with SI and SB, with evidence that PLEs at baseline were associated with worsening SI and SB over time, including a transition from SI to SB (β = 0.032, FDRp = 0.002). Exploratory analyses showed consistent evidence for strengthened associations over time for higher delusional ideation with both SI and SB (βs > 0.04, FDRps < 0.001), and for perceptual distortions with SB (βs = 0.046, FDRp < 0.001). When accounting for general psychopathology, for SB, the strengthened associations over time was significantly stronger for PLEs (β = 0.053, FDRp < 0.001) compared to general psychopathology (β = 0.022, FDRp = 0.01).

Conclusions

The present study indicates both SI and SB show strengthened associations with PLEs over time, and that baseline PLEs may predict worsening of suicidality over time. The findings are important clarifications about the nature of the associations between youth-reported PLEs and suicidality over time.
A call for renewed attention to construct validity and measurement in psychopathology research
Authors: Hayden Elizabeth P.
Published: October 2022

Psychopathologists have failed to make significant progress toward understanding the causes of psychopathology. Despite the foundational importance of construct validity and measurement to our field, insufficient attention is paid to these concerns in the assessment of psychopathology vulnerabilities prior to their implementation in causal models. I review the current state of construct validity and measurement in psychopathology research, highlighting the lack of consensus regarding how we should define and measure vulnerability constructs. The limited capacity of open science practices to address these definitional and measurement challenges is discussed. Recommendations for progress are made, including the need for consensus agreement on (1) working definitions and (2) measures of vulnerability constructs. Other recommendations include (3) the need to incentivize ‘pre-clinical’ descriptive work focused on measurement development, (4) the formation of open-access databases designed to facilitate measurement evaluation and development, and (5) increased exploration of the use of novel technologies to facilitate the collection of high-quality measures of vulnerability.
‘Nationalists of All Countries, Unite!’: Hans Keller and Nazi Internationalism in the 1930s
Authors: Hamre Martin Kristoffer
Published: October 2022

This paper presents a case study of German ‘Nazi internationalism’ as part of a broader, transnational counter-reaction to liberal and communist internationalism in the 1930s. It offers an analysis of the activities and main ideas of the Nationalist International (Internationale Arbeitsgemeinschaft der Nationalisten; IAdN), headed by the German jurist Hans Keller and active from 1934 to 1941. The IAdN promoted concepts such as Volk nationalism and a Third Europe as a solution to the European crisis, and attempted to establish an alternative law of nations to replace the post-1919 liberal order. The IAdN illustrates an early attempt to reconcile völkisch ideas with international cooperation, thus foreshadowing ‘ethno-pluralist’ concepts of the New Right in the post-war period.
“Are there Racists in Yugoslavia?” Debating Racism and Anti-blackness in Socialist Yugoslavia
Authors: Wright Peter
Published: October 2022

This article examines debates, scholarly studies, and literary representations of the phenomenon of racism in socialist Yugoslavia and Yugoslavs’ relationship to whiteness in the 1960s and 70s. I argue that the persistent activism of black African students helped provoke official, scholarly, and public discussions about the thorny question of racism in Yugoslav society during this time. The salience of black students’ accusations eventually made something that was taboo in the 1950s and early 1960s—namely, entertaining the prospect that anti-black racial prejudice existed in non-aligned, socialist, and anti-racist Yugoslavia—into an active subject of debate by the end of the decade. Importantly, the relative candidness with which academic studies and popular literature addressed racism indicates a reflexivity about “racial” questions on the part of socialist Yugoslav society, something that scholarship has largely neglected in favor of focusing on the suppression or elision of race and the inadequacy of state socialist responses to the problem of domestic expressions of prejudice.
Is Ukraine a Multiethnic Country?
Authors: Kulyk Volodymyr
Published: October 2022

This paper critically examines the widespread perception of Ukraine as a multiethnic country with clear boundaries between ethnic groups. It demonstrates that despite the Soviet legacy of rather strong institutionalization and discursive presentation of nationality, the post-Soviet state discontinued or downplayed most of the institutional mechanisms for the reproduction of ethnic distinctiveness and virtually abandoned the use of ethnic categories in official discourse. While several smaller minorities retained some institutional backing and discursive presence, the once very large group of ethnic Russians ceased to be publicly presented and popularly perceived as clearly distinct from the bulk of Ukrainians. At the same time, Ukrainian citizens differ greatly in their ethnocultural practices and ethnolinguistic identifications, hence Ukraine certainly remains ethnoculturally diverse, and this seems to be a more appropriate designation than “multiethnic.”
Concept Maps und Concept Mapping in der Pflege
Authors: Zanon-Di Nardo Dave , Leonie-Scheiber Claudia
Published: October 2022

Komplexe Pflegesituationen analysieren und visualisieren

Concept Maps sind grafische Darstellungen von Zusammenhängen in komplexen Pflegesituationen. Sie zeigen Muster auf aus den Merkmalen und Kennzeichen einer Situation und visualisieren damit das spezifische Bild der Patientin?/?des Patienten. Im Prozess des Concept Mappings kann somit die fallbezogene Pflegesituation im Rahmen des Pflegeprozesses differenziert analysiert und beurteilt werden. Concept Maps visualisieren gebündelt fallbezogene Assessmentdaten sowie Pflegediagnosen und deren Beziehungen zueinander. Das erlaubt es, Pflegeinterventionen zur Lösung oder Linderung aktueller und potenzieller Gesundheitsprobleme abzuleiten und Pflegeziele und erwünschte Pflegeergebnisse zu benennen. So wird das Buch zu einer wertvollen Toolbox für Lehrende, Ausbildung und Studium der Pflege und des Pflegeprozesses.
Die Autor_innen klären in Teil I die Grundlagen von Concept Maps und Concept Mapping und präsentieren in Teil II konkrete Beispiele der Umsetzung. 

Aus dem Inhalt 
•Concept Maps als Muster in Pflegesituationen 
•Concept Mapping im Pflegeprozess 
•Didaktische Methoden des Concept Mappings 
•Evaluation der Concept Maps 
Die Arbeitsmaterialien zu diesem Buch können nach erfolgter Registrierung von der Hogrefe Website heruntergeladen werden.
My Name Is Forrest Mozer
Authors: Mozer Forrest
Published: October 2022

Plain Language Summary

A brief description of my career and some advice for young scientists.
Hourly and Daily PM2.5 Estimations Using MERRA‐2: A Machine Learning Approach
Authors: Sayeed Alqamah , Lin Paul , Gupta Pawan , Tran Nhu Nguyen Minh , Buchard Virginie , Christopher Sundar
Published: October 2022

Health and environmental hazards related to high pollution concentrations have become a serious issue from public policy perspectives and human health. Using Machine Learning (ML) approach, this research aims to improve the estimation of grid‐wise PM2.5, a criteria pollutant, by reducing systematic bias from speciation provided by MERRA‐from the Modern‐Era Retrospective analysis for Research and Applications version 2 (MERRA‐2). The ML model was trained using various meteorological parameters and aerosol species simulated by MERRA‐2 and ground measurements from Environmental Protection Agency (EPA) air quality system stations. The ML approach significantly improved performance and reduced mean bias in the 0–10 μg m−3 range. We also used the Random Forest ML model for each EPA region using 1 year of collocated data sets. The resulting ML models for each EPA region were validated, and the aggregate data set has a Spearman Rank correlation (SR) of 0.73 (RMSE = 4.8 μg m−3) and 0.69 (RMSE = 5.8 μg m−3) for training and testing, respectively. The SR (and RMSE in μg m−3) increased to 0.81 (3.9), 0.89 (1.6), and 0.90 (1.1) for daily, monthly, and yearly averages, respectively. The results from the initial implementation of the ML model for the global region are encouraging. Still, they require more research and development to overcome challenges associated with data gaps in many parts of the world.
Urban‐Rural Gradient in Urban Heat Island Variations Responsive to Large‐Scale Human Activity Changes During Chinese New Year Holiday
Authors: Zhan Wenfeng , Liu Zihan , Bechtel Benjamin , Li Jiufeng , Lai Jiameng , Fu Huyan , Li Long , Huang Fan , Wang Chunli , Chen Yangyi
Published: October 2022

Large‐scale human activity changes in megacities during Chinese New Year (CNY) are believed to significantly affect urban heat islands (UHIs). However, the urban‐rural gradient in UHI variations responsive to human activity changes in cities remains largely unclear. Using in‐situ surface air temperature obtained from a meteorological network that includes 3000‐plus stations, we show that the mean UHI intensity (UHII) in 31 Chinese capitals is 0.52 ± 0.23 K during the CNY holiday and 0.77 ± 0.29 K in the reference period, indicating a UHII reduction of 0.25 ± 0.20 K during the holiday. The reduced UHII decreased more from city core (0.54 K) to city periphery (0.071 K). We find that these UHII reductions were larger at night than during the day and were larger in northern subtropical and warm temperate climates than in other climates. These UHII reductions were mainly attributable to the decline in anthropogenic heat release.
Statistical Characteristics of the Local Proton Cyclotron Band Emissions Observed by the CSES
Authors: Wang Yalu , Zhima Zeren , Wang Xiao , Wu Yingyan , Ouyang Xin‐Yan , Hu Yunpeng , Lu Hengxin , Shen Xuhui , Dong Lei
Published: October 2022

We present observations on the local proton cyclotron band emissions (PCBEs), which is one type of hiss wave in the upper ionosphere, recorded by the China Seismo‐Electromagnetic Satellite (CSES). The PCBEs are characterized by narrow‐band electromagnetic emissions along the local proton cyclotron frequency (), exhibiting a sharp cutoff effect. The lower cutoff frequency () is closely along the local , decreasing with magnetic latitude, while the upper cutoff frequency () is diffuse and deviates from the local . We developed an algorithm to automatically extract PCBEs from CSES's massive electromagnetic data and statistically examined their occurrence and bandwidth's dependence on location and season. The global morphology of PCBEs in 2019 shows that they primarily occur in the mid‐high magnetic latitude (approximately 20°–55°) dayside ionosphere, with the maximum occurrence happening around the South Atlantic Anomaly region. Their bandwidth shows a decreasing tendency with magnetic latitude and strong seasonal dependence, with a wider bandwidth in local winter and a narrower one in local summer. The ratio of and also shows a seasonal dependence, with greater values in local summer and smaller values in local winter. This characteristic of is similar to that of the H+‐He+ cutoff frequency (). This study provides statistical characteristics of occurrence and the cutoff features of PCBEs based on the CSES operating in the upper ionosphere.
Off‐Fault Deformation in Regions of Complex Fault Geometries: The 2013, Mw7.7, Baluchistan Rupture (Pakistan)
Authors: Antoine S. L. , Klinger Y. , Delorme A. , Gold R. D.
Published: October 2022

Observations of recent earthquake surface ruptures show that ground deformations include a localized component occurring on faults, and an off‐fault component affecting the surrounding medium. This second component is also referred to as off‐fault deformation (OFD). The localized component generally occurs on complex networks of faults that connect at depth onto a unique fault plane, whereas OFD consists of distributed fracturing and diffuse deformation of the bulk volume, and occurs over scales of hundreds of meters to kilometers around the faults. High‐resolution optical image correlation presents a unique potential to characterize the complexity of the surface displacements, including on‐fault displacements and OFDs. In this study, we used sub‐pixel correlation of 0.5‐m resolution optical images to measure the surface displacement field with a <20 cm accuracy for a 30‐km long section of the 2013 Mw7.7 Baluchistan, Pakistan, rupture. Our results document significant variability in the fault displacements, associated with large proportions of OFD in regions of fault geometrical complexity. Conversely, in regions where the fault geometry is simple, surface deformation is entirely accommodated by the primary faults with 0% OFD. When combining the localized deformation on faults with the OFD, we show that the total surface displacement budget is constant along the strike of the rupture, despite strong variations observed in the rupture geometry. Based on this analysis, we propose an idealized scenario of earthquake surface deformation as a function of the rupture geometrical variations.
Subinertial Variability in Four Southeast Greenland Fjords in Realistic Numerical Simulations
Authors: Gelderloos Renske , Haine Thomas W. N. , Almansi Mattia
Published: October 2022

We identified the nature and driving mechanisms of subinertial variability (variability at a time scale of several days) in four fjords in Southeast Greenland, in three high‐resolution numerical simulations. We find two dominant frequency ranges in along‐fjord velocity, volume transport of Atlantic Water, and along‐fjord heat transport: one around 2–4 days and one around 10 days. The higher frequency is most prominent in the two smaller fjords (Sermilik Fjord and Kangerdlugssuaq Fjord), while the lower frequency peak dominates in the larger fjords (Scoresby Sund and King Oscar Fjord). The cross‐fjord structure of variability patterns is determined by the fjord's dynamic width, while the vertical structure is determined by the stratification in the fjord. The dominant frequency range is a function of stratification and fjord length, through the travel time of resonant internal Kelvin waves. We find that the subinertial variability is the imprint of Coastal Trapped Waves, which manifest as Rossby‐type waves on the continental shelf and as internal Kelvin‐type waves inside the fjords. Between 50% and 80% of the variability in the fjord is directly forced by Coastal Trapped Waves propagating in from the shelf, with an additional role played by alongshore wind forcing on the shelf.
Impacts of Historical Atmospheric and Oceanic Warming on Heavy Snowfall in December 2020 in Japan
Authors: Kawase H. , Imada Y. , Watanabe S.
Published: October 2022

Strong cold air outbreaks caused heavy snowfall over the inland areas of the Sea of Japan coast of Japan in mid‐December 2020. The 48‐hr accumulated snowfall during the term broke a snowfall record at some observational stations of the Japan Meteorological Agency (JMA). We investigated the impacts of atmospheric and oceanic temperature changes due to historical global warming since the pre‐industrial period on this heavy snowfall event. Hindcast and pseudo non‐warming experiments were conducted using the nonhydrostatic model developed by the JMA. The historical climatic differences were obtained from the database for policy decision‐making for future climate change (d4PDF). Our experiments indicated that historical global warming enhanced precipitation over the whole region and enhanced heavy snowfall over the inland areas on the Sea of Japan side. In this event, the contribution of conversion from snowfall to rainfall due to warming was limited over coastal areas. The enhancement of precipitation was mainly caused by oceanic warming, which increased latent heat flux over the Sea of Japan and made the low‐level atmosphere less stable. Historical atmospheric warming suppressed precipitation due to atmospheric stabilization. Our results indicated that the heavy snowfall was caused by the cold air outbreaks under the warm sea surface temperatures in December and enhanced by historical global warming.
Partitioning of Sensible and Latent Heat Fluxes in Different Vegetation Types and Their Spatiotemporal Variations Based on 203 FLUXNET Sites
Authors: Lin Huiqing , Li Yan , Zhao Lei
Published: October 2022

Bowen ratio reflects the partitioning between sensible and latent heat fluxes and plays a crucial role in land–atmosphere interaction. In this study, the spatiotemporal variations of Bowen ratio among 12 vegetation types were analyzed using observations from 203 FLUXNET sites and compared against Community Land Model (CLM) simulations. Results showed that the annual mean Bowen ratio across all sites was 1.48 ± 1.20 (mean ± SD). Sites with Bowen ratios less than 1 were found across all continents, and the ones with a higher Bowen ratio appeared in dry and warm areas. Open shrublands showed the highest Bowen ratio (3.04 ± 0.58), whereas wetlands showed the lowest (0.74 ± 0.09). In terms of seasonality, Bowen ratio generally showed lower values in local summer and higher in spring and autumn in the northern hemisphere; the opposite occurred in the southern hemisphere. The spatiotemporal variations in Bowen ratio can be explained by climatic, geographical, and biological factors, with climate factors having the greatest impact. The spatial correlation analyses suggested Bowen ratio increased under higher VPD (R = 0.45, p < 0.001) and hotter (R = 0.14, p < 0.05) conditions and decreased with higher precipitation (R = −0.34, p < 0.001), albedo (R = −0.16, p > 0.05), and leaf area index (R = −0.25, p < 0.001). Compared to FLUXNET observations, CLM well reproduced the global annual mean Bowen ratio (1.48 for CLM vs. 1.56 for FLUXNET) but showed larger differences for certain vegetation types. Our results could enhance our understanding of biotic and environmental controls on land surface energy fluxes and help improve the land surface and climate models.
The emerging importance of METTL5-mediated ribosomal RNA methylation
Authors: Turkalj Elena M. , Vissers Caroline
Published: October 2022

The study of the epitranscriptome has thus far focused largely on mRNA methylation. Recent human genetics studies suggest that methylation of ribosomal RNA also contributes to brain development and cognition. In particular, the m6A modification at the A-1832 position of the 18S rRNA is installed by METTL5. Mutations or deletions of Mettl5 in humans and mice, respectively, cause abnormal translation and gene expression that in turn mediates stem cell behaviors such as differentiation. In this review, we provide an overview of the current knowledge of the methyltransferase METTL5, as well as the molecular biology surrounding m6A on rRNA and how it regulates cell behavior.
Financial implications of protocol-based hypertension treatment: an insight into medication costs in public and private health sectors in India
Authors: Sahoo Swagata Kumar , Pathni Anupam Khungar , Krishna Ashish , Sharma Bhawna , Cazabon Danielle , Moran Andrew E. , Hering Dagmara
Published: October 2022

Hypertension is a major public health challenge in low- and middle-income countries (LMICs) and calls for large-scale effective hypertension control programs. Adoption of drug and dose-specific treatment protocols recommended by the World Health Organization-HEARTS Initiative is key for hypertension control programs in LMICs. We estimated the annual medication cost per patient using three such protocols (protocol-1 and protocol-2 with Amlodipine, Telmisartan, using add-on doses and different drug orders, adding Chlorthalidone; protocol-3 with a single-pill combination (SPC) of Amlodipine/Telmisartan with dose up-titration, and addition of Chlorthalidone, if required) in India. The medication cost was simulated with different hypertension control assumptions for each protocol and calculated based on prices in the public and private sectors in India. The estimated annual medication cost per patient for protocol-1 and protocol-2 was $33.88–58.44 and $51.57–68.83 for protocol-3 in the private sector. The medication cost was lower in the generic stores ($5.78–9.57 for protocol-1 and protocol-2, and $7.35–9.89 for protocol-3). The medication cost for patients was the lowest ($2.05–3.89 for protocol-1 and protocol-2, and $2.94–3.98 for protocol-3) in the public sector. At less than $4 per patient per annum, scaling up a hypertension control program with specific treatment protocols is a potentially cost-effective public health intervention. Expanding low-cost generic retail networks would extend affordability in the private sector. The cost of treatment with SPC is comparable with non-SPC protocols and can be adopted in a public health program considering the advantage of simplified logistics, reduced pill burden, improved treatment adherence, and blood pressure control.
E3 ubiquitin ligase RNF5 attenuates pathological cardiac hypertrophy through STING
Authors: Yang Lu-Lu , Xiao Wen-Chang , Li Huan , Hao Zheng-Yang , Liu Gui-Zhi , Zhang Dian-Hong , Wu Lei-Ming , Wang Zheng , Zhang Yan-Qing , Huang Zhen , Zhang Yan-Zhou
Published: October 2022

Ring-finger protein 5 (RNF5) is an E3 ubiquitin ligase which is expressed in a variety of human tissues. RNF5 is involved in the regulation of endoplasmic reticulum stress, inflammation, and innate immunity and plays an important role in the occurrence and development of various tumors. However, the role of RNF5 in cardiac hypertrophy has not been reported. In this study, we found the expression of RNF5 was increased in the hearts of mice with pathological cardiac hypertrophy. The loss-of-function research demonstrated that RNF5 deficiency exacerbated cardiac hypertrophy, whereas gain-of-function studies revealed that overexpression of RNF5 had opposite effects. The stimulator of interferon genes (STING) is a signaling molecule that can activate type I interferon immunity, which can meditate inflammation and immune response in many diseases. The protein–protein interaction experiments confirmed that STING interacted with RNF5. Further studies showed that RNF5 inhibited cardiac hypertrophy by promoting STING degradation through K48-linked polyubiquitination. Therefore, we defined RNF5 as importantly regulated signaling for cardiac hypertrophy.
A TNFR1–UBCH10 axis drives lung squamous cell carcinoma dedifferentiation and metastasis through a cell-autonomous signaling loop
Authors: Xiao Zuoxiang , Shi Gongping , Xi Sichuan , Singh Amit Kumar , Willette-Brown Jami , Li Xin , Zhu Feng , Su Ling , Wu Xiaolin , Schrump David S. , Hu Yinling
Published: October 2022

Tumor necrosis factor receptor 1 (TNFR1), encoded byTNFRSF1A, is a critical transducer of inflammatory pathways, but its physiological role in human cancer is not completely understood. Here, we observed high expression of TNFR1 in many human lung squamous cell carcinoma (SCCs) samples and in spontaneous lung SCCs derived from kinase-deadIkkαknock-in (KA/KA) mice. Knocking outTnfrf1ainKA/KAmice blocked lung SCC formation. When injected via tail vein, KALLU+lung SCC cells that highly expressed TNFR1/TNF, Sox2, c-Myc, Twist1, Bcl2, and UBCH10, generated dedifferentiated spindle cell carcinomas with epithelial–mesenchymal transition markers in mouse lungs. In contrast, KALLU+cells with silenced TNFR1 and KALLU-cells that expressed low levels of TNFR1 generated well-differentiated lung SCCs and were less tumorigenic and metastatic. We identified a downstream effector of TNFR1: oncogenic UBCH10, an E2 ubiquitin-conjugating enzyme with targets including Twist1, c-Myc, and Sox2, which enhanced SCC cell dedifferentiation. Furthermore, Tg-K5.TNFR1;KA/KAmice, which expressed transgenic TNFR1 in keratin 5-positve epithelial cells, developed more poorly differentiated and metastatic lung SCCs than those found inKA/KAmice. These findings demonstrate that an overexpressed TNFR1–UBCH10 axis advances lung carcinogenesis and metastasis through a dedifferentiation mechanism. Constituents in this pathway may contribute to the development of differentiation-related therapies for lung SCC.
The accumulation of miR-125b-5p is indispensable for efficient erythroblast enucleation
Authors: Fang Fang , Xu Lei , Liang Liqing , Qu Mingyi , Yao Hailei , Yue Wen , Chen Lin , Chen Dongli , Fan Zeng , He Lijuan , Nan Xue , Zhang Huanhuan , Xie Xiaoyan , Pei Xuetao
Published: October 2022

Erythroblast enucleation is a precisely regulated but not clearly understood process. Polycythemia shows pathological erythroblast enucleation, and we discovered a low miR-125b-5p level in terminal erythroblasts of patients with polycythemia vera (PV) compared to those of healthy controls. Exogenous upregulation of miR-125b-5p levels restored the enucleation rate to normal levels. Direct downregulation of miR-125b-5p in mouse erythroblasts simulated the enucleation issue found in patients with PV, and miR-125b-5p accumulation was found in enucleating erythroblasts, collectively suggesting the importance of miR-125b-5p accumulation for erythroblast enucleation. To elucidate the role of miR-125b-5p in enucleation, gain- and loss-of-function studies were performed. Overexpression of miR-125b-5p improved the enucleation of erythroleukemia cells and primary erythroblasts. Infused erythroblasts with higher levels of miR-125b-5p also exhibited accelerated enucleation. In contrast, miR-125b-5p inhibitors significantly suppressed erythrocyte enucleation. Intracellular imaging revealed that in addition to cytoskeletal assembly and nuclear condensation, miR-125b-5p overexpression resulted in mitochondrial reduction and depolarization. Real-time PCR, western blot analysis, luciferase reporter assays, small molecule inhibitor supplementation and gene rescue assays revealed that Bcl-2, as a direct target of miR-125b-5p, was one of the key mediators of miR-125b-5p during enucleation. Following suppression of Bcl-2, the activation of caspase-3 and subsequent activation of ROCK-1 resulted in cytoskeletal rearrangement and enucleation. In conclusion, this study is the first to reveal the pivotal role of miR-125b-5p in erythroblast enucleation.
HDAC6-dependent deacetylation of TAK1 enhances sIL-6R release to promote macrophage M2 polarization in colon cancer
Authors: Xu Guangying , Niu Liling , Wang Youhui , Yang Guang , Zhu Xingwu , Yao Yuan , Zhao Gang , Wang Shaowei , Li Hui
Published: October 2022

Histone deacetylase 6 (HDAC6), a member of the HDAC family, has been identified as a potential therapeutic target for tumor therapy, but the function and underlying mechanisms of HDAC6 in colon cancer are incompletely characterized. Our study showed that the infiltration ratio of M2 macrophages was increased in colon cancer tissues with high HDAC6 expression. Similarly, the knockdown of HDAC6 in colon cancer cells inhibited cocultured macrophage M2 polarization in vitro. Analysis of the antibody chip revealed that HDAC6 promoted sIL-6R release to enhance macrophage M2 polarization. Mass spectrometry and immunoprecipitation demonstrated that, mechanistically, HDAC6 interacted with transforming growth factor β–activated kinase 1 (TAK1), deacetylated TAK1 at T178 and promoted TAK1 phosphorylation. TAK1-p38 MAPK signaling could further increase the phosphorylation and activity of ADAM17, which is responsible for shedding of IL-6R. Notably, the expression of phosphorylated TAK1 was positively correlated with HDAC6 expression and macrophage M2 polarization in human colon cancer tissues. Our study revealed a new HDAC6-TAK1-ADAM17 regulatory axis that mediates sIL-6R release and macrophage polarization in colon cancer.
Diverse maturity-dependent and complementary anti-apoptotic brakes safeguard human iPSC-derived neurons from cell death
Authors: Wilkens Ruven , Hoffrichter Anne , Kleinsimlinghaus Karolina , Bohl Bettina , Haag Carolin , Lehmann Nadja , Schmidt Malin , Muñoz Perez-Vico Elena , Wangemann Julia , Rehder Klara Franziska , Horschitz Sandra , Köhr Georg , Ladewig Julia , Koch Philipp
Published: October 2022

In humans, most neurons are born during embryonic development and have to persist throughout the entire lifespan of an individual. Thus, human neurons have to develop elaborate survival strategies to protect against accidental cell death. We set out to decipher the developmental adaptations resulting in neuronal resilience. We demonstrate that, during the time course of maturation, human neurons install a complex and complementary anti-apoptotic signaling network. This includes i.) a downregulation of central proteins of the intrinsic apoptosis pathway including several caspases, ii.) a shift in the ratio of pro- and anti-apoptotic BCL-2 family proteins, and iii.) an elaborate regulatory network resulting in upregulation of the inhibitor of apoptosis protein (IAP) XIAP. Together, these adaptations strongly increase the threshold for apoptosis initiation when confronted with a wide range of cellular stressors. Our results highlight how human neurons are endowed with complex and redundant preemptive strategies to protect against stress and cell death.
Thermodynamic approach for enhancing superconducting critical current performance
Authors: Miura Masashi , Tsuchiya Go , Harada Takumu , Sakuma Keita , Kurokawa Hodaka , Sekiya Naoto , Kato Yasuyuki , Yoshida Ryuji , Kato Takeharu , Nakaoka Koichi , Izumi Teruo , Nabeshima Fuyuki , Maeda Atsutaka , Okada Tatsumori , Awaji Satoshi , Civale Leonardo , Maiorov Boris
Published: October 2022

The addition of artificial pinning centers has led to an impressive increase in the critical current density (Jc) of superconductors, enabling record-breaking all-superconducting magnets and other applications. The Jc of superconductors has reached ~0.2–0.3 Jd, where Jd is the depairing current density, and the numerical factor depends on the pinning optimization. By modifying λ and/or ξ, the penetration depth and coherence length, respectively, we can increase Jd. For (Y0.77Gd0.23)Ba2Cu3Oy ((Y,Gd)123), we can achieve this by controlling the carrier density, which is related to λ and ξ. We can also tune λ and ξ by controlling the chemical pressure in Fe-based superconductors, i.e., BaFe2(As1−xPx)2 films. The variation in λ and ξ leads to an intrinsic improvement in Jc via Jd, allowing extremely high values of Jc of 130 MA/cm2 and 8.0 MA/cm2 at 4.2 K, consistent with an enhancement in Jd of a factor of 2 for both incoherent nanoparticle-doped (Y,Gd)123 coated conductors (CCs) and BaFe2(As1−xPx)2 films, showing that this new material design is useful for achieving high critical current densities in a wide array of superconductors. The remarkably high vortex-pinning force in combination with this thermodynamic and pinning optimization route for the (Y,Gd)123 CCs reached ~3.17 TN/m3 at 4.2 K and 18 T (H||c), the highest values ever reported for any superconductor.
CRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro
Authors: Meijboom Katharina E. , Abdallah Abbas , Fordham Nicholas P. , Nagase Hiroko , Rodriguez Tomás , Kraus Carolyn , Gendron Tania F. , Krishnan Gopinath , Esanov Rustam , Andrade Nadja S. , Rybin Matthew J. , Ramic Melina , Stephens Zachary D. , Edraki Alireza , Blackwood Meghan T. , Kahriman Aydan , Henninger Nils , Kocher Jean-Pierre A. , Benatar Michael , Brodsky Michael H. , Petrucelli Leonard , Gao Fen-Biao , Sontheimer Erik J. , Brown Robert H. , Zeier Zane , Mueller Christian
Published: October 2022

A GGGGCC24+ hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), fatal neurodegenerative diseases with no cure or approved treatments that substantially slow disease progression or extend survival. Mechanistic underpinnings of neuronal death include C9ORF72 haploinsufficiency, sequestration of RNA-binding proteins in the nucleus, and production of dipeptide repeat proteins. Here, we used an adeno-associated viral vector system to deliver CRISPR/Cas9 gene-editing machineries to effectuate the removal of the HRE from the C9ORF72 genomic locus. We demonstrate successful excision of the HRE in primary cortical neurons and brains of three mouse models containing the expansion (500–600 repeats) as well as in patient-derived iPSC motor neurons and brain organoids (450 repeats). This resulted in a reduction of RNA foci, poly-dipeptides and haploinsufficiency, major hallmarks of C9-ALS/FTD, making this a promising therapeutic approach to these diseases.
Experimentally validated memristive memory augmented neural network with efficient hashing and similarity search
Authors: Mao Ruibin , Wen Bo , Kazemi Arman , Zhao Yahui , Laguna Ann Franchesca , Lin Rui , Wong Ngai , Niemier Michael , Hu X. Sharon , Sheng Xia , Graves Catherine E. , Strachan John Paul , Li Can
Published: October 2022

Lifelong on-device learning is a key challenge for machine intelligence, and this requires learning from few, often single, samples. Memory-augmented neural networks have been proposed to achieve the goal, but the memory module must be stored in off-chip memory, heavily limiting the practical use. In this work, we experimentally validated that all different structures in the memory-augmented neural network can be implemented in a fully integrated memristive crossbar platform with an accuracy that closely matches digital hardware. The successful demonstration is supported by implementing new functions in crossbars, including the crossbar-based content-addressable memory and locality sensitive hashing exploiting the intrinsic stochasticity of memristor devices. Simulations show that such an implementation can be efficiently scaled up for one-shot learning on more complex tasks. The successful demonstration paves the way for practical on-device lifelong learning and opens possibilities for novel attention-based algorithms that were not possible in conventional hardware.
Baby skyrmions in Chern ferromagnets and topological mechanism for spin-polaron formation in twisted bilayer graphene
Authors: Khalaf Eslam , Vishwanath Ashvin
Published: October 2022

The advent of moiré materials has galvanized interest in the nature of charge carriers in topological bands. In contrast to conventional materials with electron-like charge carriers, topological bands allow for more exotic possibilities where charge is carried by nontrivial topological textures, such as skyrmions. However, the real-space description of skyrmions is ill-suited to address the limit of small skyrmions and to account for momentum-space band features. Here, we develop a momentum-space approach to study the formation of the smallest skyrmions – spin polarons, formed as bound states of an electron and a spin flip – in topological ferromagnets. We show that, quite generally, there is an attraction between an electron and a spin flip that is purely topological in origin, promoting the formation of spin polarons. Applying our results to twisted bilayer graphene, we identify a range of parameters where spin polarons are formed and discuss their possible experimental signatures.
Global mapping of GalNAc-T isoform-specificities and O-glycosylation site-occupancy in a tissue-forming human cell line
Authors: Nielsen Mathias I. , de Haan Noortje , Kightlinger Weston , Ye Zilu , Dabelsteen Sally , Li Minyan , Jewett Michael C. , Bagdonaite Ieva , Vakhrushev Sergey Y. , Wandall Hans H.
Published: October 2022

Mucin-type-O-glycosylation on proteins is integrally involved in human health and disease and is coordinated by an enzyme family of 20N-acetylgalactosaminyltransferases (GalNAc-Ts). Detailed knowledge on the biological effects of site-specific O-glycosylation is limited due to lack of information on specific glycosylation enzyme activities and O-glycosylation site-occupancies. Here we present a systematic analysis of the isoform-specific targets of all GalNAc-Ts expressed within a tissue-forming human skin cell line, and demonstrate biologically significant effects of O-glycan initiation on epithelial formation. We find over 300 unique glycosylation sites across a diverse set of proteins specifically regulated by one of the GalNAc-T isoforms, consistent with their impact on the tissue phenotypes. Notably, we discover a high variability in the O-glycosylation site-occupancy of 70 glycosylated regions of secreted proteins. These findings revisit the relevance of individual O-glycosylation sites in the proteome, and provide an approach to establish which sites drive biological functions.
Temporally programmed polymer – solvent interactions using a chemical reaction network
Authors: Klemm Benjamin , Lewis Reece W. , Piergentili Irene , Eelkema Rienk
Published: October 2022

Out of equilibrium operation of chemical reaction networks (CRNs) enables artificial materials to autonomously respond to their environment by activation and deactivation of intermolecular interactions. Generally, their activation can be driven by various chemical conversions, yet their deactivation to non-interacting building blocks remains largely limited to hydrolysis and internal pH change. To achieve control over deactivation, we present a new, modular CRN that enables reversible formation of positive charges on a tertiary amine substrate, which are removed using nucleophilic signals that control the deactivation kinetics. The modular nature of the CRN enables incorporation in diverse polymer materials, leading to a temporally programmed transition from collapsed and hydrophobic to solvated, hydrophilic polymer chains by controlling polymer-solvent interactions. Depending on the layout of the CRN, we can create stimuli-responsive or autonomously responding materials. This concept will not only offer new opportunities in molecular cargo delivery but also pave the way for next-generation interactive materials.
Antibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane
Authors: Manioglu Selen , Modaresi Seyed Majed , Ritzmann Noah , Thoma Johannes , Overall Sarah A. , Harms Alexander , Upert Gregory , Luther Anatol , Barnes Alexander B. , Obrecht Daniel , Müller Daniel J. , Hiller Sebastian
Published: October 2022

Polymyxins are last-resort antibiotics with potent activity against multi-drug resistant pathogens. They interact with lipopolysaccharide (LPS) in bacterial membranes, but mechanistic details at the molecular level remain unclear. Here, we characterize the interaction of polymyxins with native, LPS-containing outer membrane patches of Escherichia coli by high-resolution atomic force microscopy imaging, along with structural and biochemical assays. We find that polymyxins arrange LPS into hexagonal assemblies to form crystalline structures. Formation of the crystalline structures is correlated with the antibiotic activity, and absent in polymyxin-resistant strains. Crystal lattice parameters alter with variations of the LPS and polymyxin molecules. Quantitative measurements show that the crystalline structures decrease membrane thickness and increase membrane area as well as stiffness. Together, these findings suggest the formation of rigid LPS–polymyxin crystals and subsequent membrane disruption as the mechanism of polymyxin action and provide a benchmark for optimization and de novo design of LPS-targeting antimicrobials.
DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
Authors: Fazio Antonella , Bordoni Dora , Kuiper Jan W. P. , Weber-Stiehl Saskia , Stengel Stephanie T. , Arnold Philipp , Ellinghaus David , Ito Go , Tran Florian , Messner Berith , Henning Anna , Bernardes Joana P. , Häsler Robert , Luzius Anne , Imm Simon , Hinrichsen Finn , Franke Andre , Huber Samuel , Nikolaus Susanna , Aden Konrad , Schreiber Stefan , Sommer Felix , Natoli Gioacchino , Mishra Neha , Rosenstiel Philip
Published: October 2022

Genetic variants in the DNA methyltransferase 3 A (DNMT3A) locus have been associated with inflammatory bowel disease (IBD). DNMT3A is part of the epigenetic machinery physiologically involved in DNA methylation. We show that DNMT3A plays a critical role in maintaining intestinal homeostasis and gut barrier function. DNMT3A expression is downregulated in intestinal epithelial cells from IBD patients and upon tumor necrosis factor treatment in murine intestinal organoids. Ablation of DNMT3A in Caco-2 cells results in global DNA hypomethylation, which is linked to impaired regenerative capacity, transepithelial resistance and intercellular junction formation. Genetic deletion of Dnmt3a in intestinal epithelial cells (Dnmt3aΔIEC) in mice confirms the phenotype of an altered epithelial ultrastructure with shortened apical-junctional complexes, reduced Goblet cell numbers and increased intestinal permeability in the colon in vivo. Dnmt3aΔIEC mice suffer from increased susceptibility to experimental colitis, characterized by reduced epithelial regeneration. These data demonstrate a critical role for DNMT3A in orchestrating intestinal epithelial homeostasis and response to tissue damage and suggest an involvement of impaired epithelial DNMT3A function in the etiology of IBD.