bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping anorexia nervosa genes to clinical phenotypes
Authors: Johnson Jessica S. , Cote Alanna C. , Dobbyn Amanda , Sloofman Laura G. , Xu Jiayi , Cotter Liam , Charney Alexander W. ,   Eating Disorders Working Group of the Psychiatric Genomics Consortium, Birgegård Andreas , Jordan Jennifer , Kennedy Martin , Landén Mikaél , Maguire Sarah L. , Martin Nicholas G. , Mortensen Preben Bo , Thornton Laura M. , Bulik Cynthia M. , Huckins Laura M.
Published: April 2022

Background

Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.

Methods

Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.

Results

Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.

Conclusions

Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.
Dynamical electromagnetic actuation system for microscale manipulation
Authors: Çetin Levent , Alasli Abdulkareem , Akçura Nail , Kahveci Aytaç , Can Fatih Cemal , Tamer Özgür
Published: April 2022

Electromagnetic actuation systems (EMA) have excelled themselves in microscale manipulation. Yet, the fastened structure of the current systems tethers the controlled workspace. In this paper, a new electromagnetic actuation principle is investigated. The actuator structure consists of a pair of coaxially movable electromagnets integrated to a robotic manipulator. The pair induces a coaxial homogeneous magnetic field or gradient to control the magnitude of the magnetic torque or force by changing the distance between the electromagnets asymmetrically. The robotic manipulator, on the other hand, transports the pair at five degrees of freedom to manipulate a microrobot in 3D space by closed-loop control with integrated vision feedback system. Numerical analyses are performed to investigate the induced electromagnetic field at the symmetrical/asymmetrical configuration of the coaxial pair. Accordingly, a correlation between the magnitude of the magnetic force and the asymmetric distance is obtained for flexible force control. A proof of concept prototype is constructed to validate the proposed actuation principle and evaluate its performance experimentally. The experimental results verify the numerical analysis and show the system applicability of inducing controlled forces on a micro-object in 2D and 3D workspaces at a velocity range of 65 to 157
$\mu$
m/s. Moreover, micromanipulation on a helical route is also demonstrated with an absolute error mean from the reference path of 191
$\mu$
m.
The Surveillance State and the Surveillance Private Sector: Pathways to Undercover Policing in France and the United States
Authors: Ross Jacqueline E.
Published: April 2022

As a form of social control, undercover tactics played an important state-building role during the Nineteenth Century, in both the United States and France. Yet undercover policing played this role very differently in France than in the US, which made do with a less developed surveillance capacity at all levels of government. The instability of successive French regimes encouraged French political authorities to expand their use of infiltration and to privilege high policing purposes of undercover tactics over the crime-fighting purposes favored by local elites. And while nineteenth-century France, like the United States, often governed through delegations of authority to local elites, French authorities jealously guarded undercover tactics as their exclusive prerogative. As a result, undercover tactics became a marginal crime-fighting tactic in nineteenth century France, becoming identified primarily with the state's surveillance of its political opponents. In the United States, by contrast, the private sector was able to deploy undercover tactics against suspected criminals, organized labor, political radicals, and purveyors of vice. Though the private sector readily accepted delegations from the public sector, the direction of influence also ran in the opposite direction, from the private sector to the state, as American private sector used undercover tactics to replace, bypass, and harness state institutions in ways that their French counterparts could not. In the United States, the private sector's use of undercover tactics came to shape public policing, as prominent detectives entered government and brought their tactics with them, and as Progressive era reformers took up the undercover tactics pioneered by private detectives, modeled them for the state through public-private partnership, and used them to set the anti-corruption, anti-radical, and anti-vice enforcement agenda of government. If French undercover tactics helped to build the French state from the inside out, by consolidating the state's hold over territory and attempting to control disorder and dissent, American undercover tactics became a vector of private sector influence that helped build the state from the outside in by shaping both investigative means and ends at all levels of government.
The Larger Gifts of Taxation: Foundations and Tax Reform in the Jim Crow South
Authors: MALCZEWSKI JOAN
Published: April 2022

In “Disquisition on Government,” John C. Calhoun divided citizens into “tax-payers” and “tax-consumers,” foreshadowing the connection that would be made between taxation and citizenship rights in twentieth-century education policy and law. Recent scholarship has explored that relationship, analyzing the language of legal cases to demonstrate that court cases reflect citizens’ perceptions of economic stakes and related education rights. Northern foundations that focused on southern education reform during Jim Crow understood the importance of taxpayer perception to education reform and recognized that it was not a byproduct of tax policy but something that might be shaped by it. Foundations influenced education and taxation policies in North Carolina. Although they failed to address inequality and problems of the racial state, their work provides a useful framework for considering the role of both early twentieth-century foundations in education reform and, more generally, the role of foundations in civil society.
Business Support for Nature Protection in the Nineteenth Century
Authors: VOGEL DAVID
Published: April 2022

This article explores the role of business in supporting and benefiting from nature protection during the second half of the nineteenth century. It begins with the support of business for protecting scenic wilderness in California and the creation of Yellowstone, as well as the role of the railroads in encouraging easterners to visit to the nation’s western national parks—all designed to create economic value by promoting tourism. It then examines the efforts of a wide range of business interests to protect the White Mountains of New Hampshire and the Adirondack forest in New York State. The later effort was led by business interests from New York City who worried that deforestation would impair freight traffic on the Erie Canal and Hudson River as well as endanger the city’s water supplies. This article compliments Hay’s research on business and conservation during the Progressive Era by demonstrating that business also played a critical role in supporting wilderness and forest protection.
Geospatial analysis of a COVID-19 outbreak at the University of Wisconsin–Madison: potential role of a cluster of local bars
Authors: Harris Jeffrey E.
Published: April 2022

We combined smartphone mobility data with census track-based reports of positive case counts to study a coronavirus disease 2019 (COVID-19) outbreak at the University of Wisconsin–Madison campus, where nearly 3000 students had become infected by the end of September 2020. We identified a cluster of twenty bars located at the epicentre of the outbreak, in close proximity to campus residence halls. Smartphones originating from the two hardest-hit residence halls (Sellery-Witte), where about one in five students were infected, were 2.95 times more likely to visit the 20-bar cluster than smartphones originating in two more distant, less affected residence halls (Ogg-Smith). By contrast, smartphones from Sellery-Witte were only 1.55 times more likely than those from Ogg-Smith to visit a group of 68 restaurants in the same area [rate ratio 1.91, 95% confidence interval (CI) 1.29–2.85, P < 0.001]. We also determined the per-capita rates of visitation to the 20-bar cluster and to the 68-restaurant comparison group by smartphones originating in each of 21 census tracts in the university area. In a multivariate instrumental variables regression, the visitation rate to the bar cluster was a significant determinant of the per-capita incidence of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests in each census tract (elasticity 0.88, 95% CI 0.08–1.68, P = 0.032), while the restaurant visitation rate showed no such relationship. The potential super-spreader effects of clusters or networks of places, rather than individual sites, require further attention.
Advancing research on early autism through an integrated risk and resilience perspective
Authors: Stallworthy Isabella C. , Masten Ann S.
Published: April 2022

To date, a deficit-oriented approach dominates autism spectrum disorder (ASD) research, including studies of infant siblings of children with ASD at high risk (HR) for the disabilities associated with this disorder. Despite scientific advances regarding early ASD-related risk, there remains little systematic investigation of positive development, limiting the scope of research and quite possibly a deeper understanding of pathways toward and away from ASD-related impairments. In this paper, we argue that integrating a resilience framework into early ASD research has the potential to enhance knowledge on prodromal course, phenotypic heterogeneity, and developmental processes of risk and adaptation. We delineate a developmental systems resilience framework with particular reference to HR infants. To illustrate the utility of a resilience perspective, we consider the “female protective effect” and other evidence of adaptation in the face of ASD-related risk. We suggest that a resilience framework invites focal questions about the nature, timing, levels, interactions, and mechanisms by which positive adaptation occurs in relation to risk and developmental pathways toward and away from ASD-related difficulties. We conclude with recommendations for future research, including more focus on adaptive development and multisystem processes, pathways away from disorder, and reconsideration of extant evidence within an integrated risk-and-resilience framework.
HOPF BIFURCATION ANALYSIS OF A FRACTIONAL-ORDER HOLLING–TANNER PREDATOR-PREY MODEL WITH TIME DELAY
Authors: CELIK C. , DEGERLİ K.
Published: April 2022

We study a fractional-order delayed predator-prey model with Holling–Tanner-type functional response. Mainly, by choosing the delay time
$\tau $
as the bifurcation parameter, we show that Hopf bifurcation can occur as the delay time
$\tau $
passes some critical values. The local stability of a positive equilibrium and the existence of the Hopf bifurcations are established, and numerical simulations for justifying the theoretical analysis are also presented.
Meta-analyses as a privileged information source for informing teachers' practice?
Authors: Renkl Alexander
Published: April 2022

Abstract. Inspired by evidence-based medicine, many researchers in the field of learning and instruction assume that meta-analyses are the best scientific information source to inform teachers' practice. This position is evaluated critically. For this purpose, I first clarify my fundamental assumptions about employing evidence for educational practice, as they form the basis for later argumentations (e.g., scientific evidence is just one of several important information sources for teachers). Then, the numerous disadvantages of meta-analyses as an information source for teachers are outlined (e.g., piecemeal information, partly inconsistent information) and, on this basis, I argue that they should not be considered a privileged source. Theories (including instructional models) provide some key advantages (e.g., coherent information) so that they should be seen as a prime information source. Nevertheless, theories also have some disadvantages so that teachers might be best advised to rely on multiple sources, and integrate them when trying to improve their practice. Finally, potential objections to theories as privileged information source are discussed.
Intra-Individual Variability in Creativity
Authors: Barbot Baptiste
Published: April 2022

Abstract. Individual differences perspectives have dominated the scientific study of creativity since the 1950’s. These perspectives, however, mainly emphasize group-level variations or inter-individual differences, with limited interest in individual-level variations. Yet, (1) group-level findings are often used to make inferences at the person-level, which might not apply consistently across individuals, and (2) a focus on intra-individual variations could supplement knowledge based on inter-individual differences and accurately inform creativity as a dynamic and multifaceted psychological construct. Indeed, when observed at the individual level, creativity can vary from moment to moment, task to task, and even item to item, which is not well reflected in the current understanding of creativity. After introducing the historical context for the study of individual differences in creativity, this article presents and illustrates three fundamental and distinct aspects of intra-individual variability as they apply to creativity, namely (in)consistency (or processing fluctuation), dispersion, and intraindividual change. While doing so, recent developments in apparatus and methods to assess creativity as a more dynamic phenomenon are presented. The article concludes by discussing the promise of accounting for intra-individual variability in creative performance and potential and the new knowledge it may elicit for both creativity research and practice.
Cyberbullying and Cyber Victimization as Online Risks for Children and Adolescents
Authors: Strohmeier Dagmar , Gradinger Petra
Published: April 2022

Abstract. Cyberbullying is one example of a psychosocial developmental phenomenon caused by mediatization, a meta-process that increasingly shapes everyday practices and social relationships via mediating technologies and media organizations. Research on cyberbullying started less than two decades ago and has grown exponentially during the last few years. Despite the large body of evidence, the research field still is in its “forming” phase, and there are still major topics of debate. The main goal of this paper is to discuss some of the major challenges, identify major research gaps, and give some directions for future research. Summarizing the main findings from meta-analyses and systematic reviews, topics like definition and measurement, theoretical perspectives, risk and protective factors, developmental patterns, as well as prevention and intervention of cyberbullying and cyber victimization are discussed, and promising avenues for future research are outlined.
Large Divergence in Tropical Hydrological Projections Caused by Model Spread in Vegetation Responses to Elevated CO2
Authors: Zhou Sha , Keenan Trevor F. , Williams A. Park , Lintner Benjamin R. , Zhang Yao , Gentine Pierre
Published: April 2022

Increasing atmospheric CO2 and associated global warming are expected to alter the global hydrological cycle, thereby posing widespread threats to freshwater availability. However, future hydrological projections differ greatly between models, particularly over the tropical regions. The large difference between model projections directly limits policy planning efforts, and the responsible modeling processes remain unclear. Here, we identify the primary processes accounting for model differences in tropical hydrological changes using multiple CO2 sensitivity experiments in the Coupled Model Intercomparison Project. We show that differences in projected changes to tropical evapotranspiration, precipitation, and surface water availability mainly arise from model representations of vegetation cover and stomatal conductance responses to elevated CO2 and associated changes in atmospheric moisture and circulation. Atmospheric responses to sea surface warming contribute additionally to the divergence in hydrological projections. Given the importance of vegetation responses to elevated CO2 and associated atmosphere feedbacks, our results underscore the need to improve representations of the vegetation physiological response to rising CO2 and its coupling to the atmosphere, to provide reliable tropical hydrological projections.
Global Daily Actual and Snow‐Free Blue‐Sky Land Surface Albedo Climatology From 20‐Year MODIS Products
Authors: Jia Aolin , Wang Dongdong , Liang Shunlin , Peng Jingjing , Yu Yunyue
Published: April 2022

Land surface albedo plays a critical role in climate, hydrological and biogeochemical modeling, and weather forecasting. It is often assigned in models and satellite retrievals by albedo climatology look‐up tables using land cover type and other variables; however, there are considerable differences in albedo simulations among models, which partially result from uncertainty in obsolete albedo climatology. Therefore, this study introduces a new global 500 m daily blue‐sky land surface albedo climatology data set under both actual and snow‐free surface conditions utilizing 20‐year Moderate Resolution Imaging Spectroradiometer products from Google Earth Engine. In situ measurements from 38 long‐term‐maintained sites were utilized to validate the accuracies of different albedo climatology datasets. The root‐mean‐square error, bias, and correlation coefficient of the new climatology are 0.031, −0.003, and 0.96, respectively, which are more accurate than the Global Land Surface Satellite, GlobAlbedo, and 16 model datasets. Data intercomparison suggests that ERA5 exhibits better performance than Modern‐Era Retrospective Analysis for Research and Applications Version 2 (MERRA2) and 14 Coupled Model Intercomparison Projects Phase 6 models. However, it contains positive biases in the snow‐free season, while MERRA2 underestimates the snow albedo. Global albedo variation associated with basic surface plant functional types was also characterized, and snow impact was considered separately. Temporal variability analysis indicates that traditional climatology datasets with coarser temporal resolutions (≥8 days) cannot capture albedo variation over areas with distinct snow seasons, especially in central Eurasia and boreal regions. These results confirm the high reliability and robustness of the new albedo climatology in model assessment, data assimilation, and satellite product retrievals.
Surface Divergent Eddy Heat Fluxes and Their Impacts on Mixed Layer Eddy‐Mean Flow Interactions
Authors: Guo Yiming , Bishop Stuart P.
Published: April 2022

In this study, the global surface divergent eddy heat flux (EHF) is estimated using remote sensing observations of sea surface height (SSH) and sea surface temperature (SST) over two decades (1993–2017). These results are used as a metric to assess model fidelity in a mesoscale eddy‐resolving version of the Community Earth System Model. The estimated EHFs show that the midlatitudes significantly contribute to the poleward transport of heat because of strong regional variability in SSH and SST. A Helmholtz decomposition is performed on the global EHFs to remove prominent nondynamic rotational wave‐like structures that appear in these fluxes. The dynamic divergent EHFs are responsible for driving cross‐frontal exchange and positive Baroclinic Conversion (BC) rates, suggesting a conversion of mean potential energy to eddy potential energy within the mixed layer. The results show that the model captures the same spatial patterns of EHFs and BC rates, but with relatively higher values in the midlatitudes than observations. The mixed layer geostrophic meridional eddy heat transport reaches maximums of 0.07 PW and 0.1 PW in the midlatitudes in the observations and climate model, respectively. The global integrated BC rate is 0.11 TW in the observations, which is ∼30% weaker than the climate model (0.16 TW). A cross‐spectral analysis further shows that the model has higher energy in low‐frequency bands for periods greater than 10 months in the northern hemisphere western boundary currents, but can capture the major spectral peaks in EHFs that are seen in observations.
Nogo-B promotes angiogenesis and improves cardiac repair after myocardial infarction via activating Notch1 signaling
Authors: Zheng Yanjun , Lin Jingrong , Liu Dingsheng , Wan Guoqing , Gu Xuefeng , Ma Jian
Published: April 2022

Nogo-B (Reticulon 4B) is reportedly a regulator of angiogenesis during the development and progression of cancer. However, whether Nogo-B regulates angiogenesis and post-myocardial infarction (MI) cardiac repair remains elusive. In the present study, we aimed to explore the role and underlying mechanisms of Nogo-B in cardiac repair during MI. We observed an increased expression level of Nogo-B in the heart of mouse MI models, as well as in isolated cardiac microvascular endothelial cells (CMECs). Moreover, Nogo-B was significantly upregulated in CMECs exposed to oxygen-glucose deprivation (OGD). Nogo-B overexpression in the endothelium via cardiotropic adeno-associated virus serotype 9 (AAV9) with the mouse endothelial-specific promoterTie2improved heart function, reduced scar size, and increased angiogenesis. RNA-seq data indicated that Notch signaling is a deregulated pathway in isolated CMECs along the border zone of the infarct with Nogo-B overexpression. Mechanistically, Nogo-B activated Notch1 signaling and upregulated Hes1 in the MI hearts. Inhibition of Notch signaling using a specific siRNA and γ-secretase inhibitor abolished the promotive effects of Nogo-B overexpression on network formation and migration of isolated cardiac microvascular endothelial cells (CMECs). Furthermore, endothelial Notch1 heterozygous deletion inhibited Nogo-B-induced cardioprotection and angiogenesis in the MI model. Collectively, this study demonstrates that Nogo-B is a positive regulator of angiogenesis by activating the Notch signaling pathway, suggesting that Nogo-B is a novel molecular target for ischemic disease.
Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial–mesenchymal transition via integrin β1-ILK-SNAIL1 pathway in ovarian cancer
Authors: Lu Ziwen , Yuan Sirui , Ruan Lingling , Tu Zhigang , Liu Hanqing
Published: April 2022

Partitioning-defective protein 6 (Par6) family proteins have been demonstrated to be closely associated with the occurrence and development of cancers. It is well accepted that dysregulation of epithelial–mesenchymal transition (EMT) greatly contributes to carcinogenesis and metastases of ovarian cancer. So far, the roles of Par6 in EMT of ovarian cancer are not clear. Functional experiments were carried out to study the roles of PARD6A in EMT of ovarian cancer in vitro and in vivo, and EMT pathways potentially affected by PARD6A expression were screened. We found that PARD6A was significantly highly expressed in tissues of ovarian cancer patients in III-IV stages, poorly differentiated or with lymphatic metastases versus I-II stages, moderately or well differentiated, or without lymphatic metastases, respectively. PARD6A knockdown suppressed EMT of SKOV3 and A2780 cells in vitro and ovarian cancer metastasis in vivo, while overexpression of PARD6A promoted EMT in HO8910 and OVCAR8 cells. It was indicated that PARD6A affected EMT of ovarian cancer cells through SNAIL1 signaling pathway and subsequently modulated the expression of VIMENTIN and E-cadherin, which was further confirmed by knockdown and overexpression of SNAIL1 experiments. PARD6A was also demonstrated to regulate expression of SNAIL1 by modulating integrin β1 and ILK proteins, specifically it was shown that the transcription of SNAIL1 was regulated by ILK in this study. In addition, expression of ILK in ovarian cancer tissues was demonstrated to be correlated with tumor stages and lymphatic metastases clinically. In this study, we identified a novel role of PARD6A as an inducer of cell migration and invasion, which is likely to play an important role in metastasis of ovarian cancer. The molecular pathways of EMT mediated by PARD6A-Integrin β1-ILK-SNAIL1 and finally implemented by E-cadherin and VIMENTIN may provide a novel strategy for drug development for ovarian cancer therapy in the near future.
The nociceptin receptor promotes autophagy through NF-kB signaling and is transcriptionally regulated by E2F1 in HCC
Authors: Zhou Xiaoshuang , Chen Dongtai , Yan Yan , Li Qiang , Xing Wei , Liu Yanling , Chen Yonghua , Wang Dongyin , Yuan Yunfei , Xie Jingdun , Zeng Weian , Pan Jiahao
Published: April 2022

Opioids and their receptors are involved in cancer progression. However, the roles of the nociceptin receptor (NOP) and its antagonist (JTC801) in hepatocellular carcinoma (HCC) are poorly understood. The prognostic value of NOP expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human HCC cohort. The biological role and mechanism of NOP in HCC tumor growth were determined in vitro and in vivo. We found that NOP was associated with the clinicopathological features and survival outcomes of HCC patients. NOP overexpression promoted HCC growth in vitro and in vivo. Mechanistically, NOP activated NF-kB signaling to promote autophagy, which inhibited apoptosis, in HCC cells. An inhibitor of autophagy, 3-MA, and an inhibitor of NF-kB, JSH-23, attenuated the function of NOP in HCC. E2F1 was identified as a transcription factor of NOP. The oncogenic role of NOP was positively regulated by E2F1. Furthermore, JTC801, a selective antagonist of NOP, abolished the function of NOP by inhibiting NF-kB signaling and autophagy. Our study demonstrates that NOP is an oncogene in HCC. We provide a potential therapeutic candidate and prognostic predictor for HCC. JTC801 could become a potential drug for HCC therapy.
Revealing global risks of labor abuse and illegal, unreported, and unregulated fishing
Authors: Selig Elizabeth R. , Nakayama Shinnosuke , Wabnitz Colette C. C. , Österblom Henrik , Spijkers Jessica , Miller Nathan A. , Bebbington Jan , Decker Sparks Jessica L.
Published: April 2022

Labor abuse on fishing vessels and illegal, unreported and unregulated (IUU) fishing violate human rights, jeopardize food security, and deprive governments of revenues. We applied a multi-method approach, combining new empirical data with satellite information on fishing activities and vessel characteristics to map risks of labor abuse and IUU fishing, understand their relationships, and identify major drivers. Port risks were globally pervasive and often coupled, with 57% of assessed ports associated with labor abuse or IUU fishing. For trips ending in assessed ports, 82% were linked to labor abuse or IUU fishing risks. At-sea risk areas were primarily driven by fishing vessel flags linked to poor control of corruption by the flag state, high ownership by countries other than the flag state, and Chinese-flagged vessels. Transshipment risk areas were related to the gear type of fishing vessels engaged in potential transshipment and carrier vessel flags. Measures at port offer promise for mitigating risks, through the Port State Measures Agreement for IUU fishing, and ensuring sufficient vessel time at port to detect and respond to labor abuse. Our results highlight the need for coordinated action across actors to avoid risk displacement and make progress towards eliminating these socially, environmentally and economically unsustainable practices.
Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells
Authors: Shah Kathleen , Maradana Muralidhara Rao , Joaquina Delàs M. , Metidji Amina , Graelmann Frederike , Llorian Miriam , Chakravarty Probir , Li Ying , Tolaini Mauro , Shapiro Michael , Kelly Gavin , Cheshire Chris , Bhurta Deendyal , Bharate Sandip B. , Stockinger Brigitta
Published: April 2022

The aryl hydrocarbon receptor (AHR) is an environmental sensor that integrates microbial and dietary cues to influence physiological processes within the intestinal microenvironment, protecting against colitis and colitis-associated colorectal cancer development. Rapid tissue regeneration upon injury is important for the reinstatement of barrier integrity and its dysregulation promotes malignant transformation. Here we show that AHR is important for the termination of the regenerative response and the reacquisition of mature epithelial cell identity post injury in vivo and in organoid cultures in vitro. Using an integrative multi-omics approach in colon organoids, we show that AHR is required for timely termination of the regenerative response through direct regulation of transcription factors involved in epithelial cell differentiation as well as restriction of chromatin accessibility to regeneration-associatedYap/Teadtranscriptional targets. Safeguarding a regulated regenerative response places AHR at a pivotal position in the delicate balance between controlled regeneration and malignant transformation.
Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies
Authors: Absalom Nathan L. , Liao Vivian W. Y. , Johannesen Katrine M. H. , Gardella Elena , Jacobs Julia , Lesca Gaetan , Gokce-Samar Zeynep , Arzimanoglou Alexis , Zeidler Shimriet , Striano Pasquale , Meyer Pierre , Benkel-Herrenbrueck Ira , Mero Inger-Lise , Rummel Jutta , Chebib Mary , Møller Rikke S. , Ahring Philip K.
Published: April 2022

Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABAA receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABAA receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.
Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition
Authors: Liang Wenguang G. , Wijaya Juwina , Wei Hui , Noble Alex J. , Mancl Jordan M. , Mo Swansea , Lee David , Lin King John V. , Pan Man , Liu Chang , Koehler Carla M. , Zhao Minglei , Potter Clinton S. , Carragher Bridget , Li Sheng , Tang Wei-Jen
Published: April 2022

Presequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid β (Aβ). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by air-water interface adsorption. Thereby, we elucidate cryoEM structures of three apo-PreP open states along with Aβ- and citrate synthase presequence-bound PreP at 3.3–4.6 Å resolution. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives a rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations.
ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury
Authors: Rohlfing Anne-Katrin , Kolb Kyra , Sigle Manuel , Ziegler Melanie , Bild Alexander , Münzer Patrick , Sudmann Jessica , Dicenta Valerie , Harm Tobias , Manke Mailin-Christin , Geue Sascha , Kremser Marcel , Chatterjee Madhumita , Liang Chunguang , von Eysmondt Hendrik , Dandekar Thomas , Heinzmann David , Günter Manina , von Ungern-Sternberg Saskia , Büttcher Manuela , Castor Tatsiana , Mencl Stine , Langhauser Friederike , Sies Katharina , Ashour Diyaa , Beker Mustafa Caglar , Lämmerhofer Michael , Autenrieth Stella E. , Schäffer Tilman E. , Laufer Stefan , Szklanna Paulina , Maguire Patricia , Heikenwalder Matthias , Müller Karin Anne Lydia , Hermann Dirk M. , Kilic Ertugrul , Stumm Ralf , Ramos Gustavo , Kleinschnitz Christoph , Borst Oliver , Langer Harald F. , Rath Dominik , Gawaz Meinrad
Published: April 2022

Platelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion.
Chiral structures of electric polarization vectors quantified by X-ray resonant scattering
Authors: Kim Kook Tae , McCarter Margaret R. , Stoica Vladimir A. , Das Sujit , Klewe Christoph , Donoway Elizabeth P. , Burn David M. , Shafer Padraic , Rodolakis Fanny , Gonçalves Mauro A. P. , Gómez-Ortiz Fernando , Íñiguez Jorge , García-Fernández Pablo , Junquera Javier , Susarla Sandhya , Lovesey Stephen W. , van der Laan Gerrit , Park Se Young , Martin Lane W. , Freeland John W. , Ramesh Ramamoorthy , Lee Dong Ryeol
Published: April 2022

Resonant elastic X-ray scattering (REXS) offers a unique tool to investigate solid-state systems providing spatial knowledge from diffraction combined with electronic information through the enhanced absorption process, allowing the probing of magnetic, charge, spin, and orbital degrees of spatial order together with electronic structure. A new promising application of REXS is to elucidate the chiral structure of electrical polarization emergent in a ferroelectric oxide superlattice in which the polarization vectors in the REXS amplitude are implicitly described through an anisotropic tensor corresponding to the quadrupole moment. Here, we present a detailed theoretical framework and analysis to quantitatively analyze the experimental results of Ti L-edge REXS of a polar vortex array formed in a PbTiO3/SrTiO3 superlattice. Based on this theoretical framework, REXS for polar chiral structures can become a useful tool similar to x-ray resonant magnetic scattering (XRMS), enabling a comprehensive study of both electric and magnetic REXS on the chiral structures.
Group testing via hypergraph factorization applied to COVID-19
Authors: Hong David , Dey Rounak , Lin Xihong , Cleary Brian , Dobriban Edgar
Published: April 2022

Large scale screening is a critical tool in the life sciences, but is often limited by reagents, samples, or cost. An important recent example is the challenge of achieving widespread COVID-19 testing in the face of substantial resource constraints. To tackle this challenge, screening methods must efficiently use testing resources. However, given the global nature of the pandemic, they must also be simple (to aid implementation) and flexible (to be tailored for each setting). Here we propose HYPER, a group testing method based on hypergraph factorization. We provide theoretical characterizations under a general statistical model, and carefully evaluate HYPER with alternatives proposed for COVID-19 under realistic simulations of epidemic spread and viral kinetics. We find that HYPER matches or outperforms the alternatives across a broad range of testing-constrained environments, while also being simpler and more flexible. We provide an online tool to aid lab implementation: http://hyper.covid19-analysis.org.
Structure-based design of stabilized recombinant influenza neuraminidase tetramers
Authors: Ellis Daniel , Lederhofer Julia , Acton Oliver J. , Tsybovsky Yaroslav , Kephart Sally , Yap Christina , Gillespie Rebecca A. , Creanga Adrian , Olshefsky Audrey , Stephens Tyler , Pettie Deleah , Murphy Michael , Sydeman Claire , Ahlrichs Maggie , Chan Sidney , Borst Andrew J. , Park Young-Jun , Lee Kelly K. , Graham Barney S. , Veesler David , King Neil P. , Kanekiyo Masaru
Published: April 2022

Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an “open” state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We use homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the “closed” state, yielding two near-atomic resolution structures of NA by cryo-EM. In addition to enhancing thermal stability, conformational stabilization improves affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. Stabilized NAs can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, and establish design strategies for reinforcing the conformational integrity of recombinant NA proteins.
Non-invasive digital etching of van der Waals semiconductors
Authors: Zhou Jian , Zhang Chunchen , Shi Li , Chen Xiaoqing , Kim Tae Soo , Gyeon Minseung , Chen Jian , Wang Jinlan , Yu Linwei , Wang Xinran , Kang Kibum , Orgiu Emanuele , Samorì Paolo , Watanabe Kenji , Taniguchi Takashi , Tsukagoshi Kazuhito , Wang Peng , Shi Yi , Li Songlin
Published: April 2022

The capability to finely tailor material thickness with simultaneous atomic precision and non-invasivity would be useful for constructing quantum platforms and post-Moore microelectronics. However, it remains challenging to attain synchronized controls over tailoring selectivity and precision. Here we report a protocol that allows for non-invasive and atomically digital etching of van der Waals transition-metal dichalcogenides through selective alloying via low-temperature thermal diffusion and subsequent wet etching. The mechanism of selective alloying between sacrifice metal atoms and defective or pristine dichalcogenides is analyzed with high-resolution scanning transmission electron microscopy. Also, the non-invasive nature and atomic level precision of our etching technique are corroborated by consistent spectral, crystallographic, and electrical characterization measurements. The low-temperature charge mobility of as-etched MoS2reaches up to 1200 cm2 V−1s−1, comparable to that of exfoliated pristine counterparts. The entire protocol represents a highly precise and non-invasive tailoring route for material manipulation.
Local large temperature difference and ultra-wideband photothermoelectric response of the silver nanostructure film/carbon nanotube film heterostructure
Authors: Lv Bocheng , Liu Yu , Wu Weidong , Xie Yan , Zhu Jia-Lin , Cao Yang , Ma Wanyun , Yang Ning , Chu Weidong , Jia Yi , Wei Jinquan , Sun Jia-Lin
Published: April 2022

Photothermoelectric materials have important applications in many fields. Here, we joined a silver nanostructure film and a carbon nanotube film by van der Waals force to form a heterojunction, which shows excellent photothermal and photoelectric conversion properties. The local temperature difference and the output photovoltage increase rapidly when the heterojunction is irradiated by lasers with wavelengths ranging from ultraviolet to terahertz. The maximum temperature difference reaches 215.9 K, which is significantly higher than that of other photothermoelectric materials reported in the literature. The photothermal and photoelectric responsivity depend on the wavelength of lasers, which are 175~601 K W-1 and 9.35~40.4 mV W-1, respectively. We demonstrate that light absorption of the carbon nanotube is enhanced by local surface plasmons, and the output photovoltage is dominated by Seebeck effect. The proposed heterostructure can be used as high-efficiency sensitive photothermal materials or as ultra-wideband fast-response photoelectric materials.
Black carbon-climate interactions regulate dust burdens over India revealed during COVID-19
Authors: Wei Linyi , Lu Zheng , Wang Yong , Liu Xiaohong , Wang Weiyi , Wu Chenglai , Zhao Xi , Rahimi Stefan , Xia Wenwen , Jiang Yiquan
Published: April 2022

India as a hotspot for air pollution has heavy black carbon (BC) and dust (DU) loadings. BC has been identified to significantly impact the Indian climate. However, whether BC-climate interactions regulate Indian DU during the premonsoon season is unclear. Here, using long-term Reanalysis data, we show that Indian DU is positively correlated to northern Indian BC while negatively correlated to southern Indian BC. We further identify the mechanism of BC-dust-climate interactions revealed during COVID-19. BC reduction in northern India due to lockdown decreases solar heating in the atmosphere and increases surface albedo of the Tibetan Plateau (TP), inducing a descending atmospheric motion. Colder air from the TP together with warmer southern Indian air heated by biomass burning BC results in easterly wind anomalies, which reduces dust transport from the Middle East and Sahara and local dust emissions. The premonsoon aerosol-climate interactions delay the outbreak of the subsequent Indian summer monsoon.
Structural basis for the SUMO protease activity of the atypical ubiquitin-specific protease USPL1
Authors: Li Ying , Varejão Nathalia , Reverter David
Published: April 2022

Post-translational protein modifications by ubiquitin and ubiquitin-like modifiers regulate many major pathways in the cell. These modifications can be reversed by de-ubiquitinating enzymes such as ubiquitin-specific proteases (USPs). Proteolytic activity towards ubiquitin-modified substrates is common to all USP family members except for USPL1, which shows a unique preference for the ubiquitin-like modifier SUMO. Here, we present the crystal structure of USPL1 bound to SUMO2, defining the key structural elements for the unusual deSUMOylase activity of USPL1. We identify specific contacts between SUMO2 and the USPL1 subdomains, including a unique hydrogen bond network of the SUMO2 C-terminal tail. In addition, we find that USPL1 lacks major structural elements present in all canonical USPs members such as the so-called blocking loops, which facilitates SUMO binding. Our data give insight into how a structural protein scaffold designed to bind ubiquitin has evolved to bind SUMO, providing an example of divergent evolution in the USP family.
acorde unravels functionally interpretable networks of isoform co-usage from single cell data
Authors: Arzalluz-Luque Angeles , Salguero Pedro , Tarazona Sonia , Conesa Ana
Published: April 2022

Alternative splicing (AS) is a highly-regulated post-transcriptional mechanism known to modulate isoform expression within genes and contribute to cell-type identity. However, the extent to which alternative isoforms establish co-expression networks that may be relevant in cellular function has not been explored yet. Here, we present acorde, a pipeline that successfully leverages bulk long reads and single-cell data to confidently detect alternative isoform co-expression relationships. To achieve this, we develop and validate percentile correlations, an innovative approach that overcomes data sparsity and yields accurate co-expression estimates from single-cell data. Next, acorde uses correlations to cluster co-expressed isoforms into a network, unraveling cell type-specific alternative isoform usage patterns. By selecting same-gene isoforms between these clusters, we subsequently detect and characterize genes with co-differential isoform usage (coDIU) across cell types. Finally, we predict functional elements from long read-defined isoforms and provide insight into biological processes, motifs, and domains potentially controlled by the coordination of post-transcriptional regulation. The code for acorde is available at https://github.com/ConesaLab/acorde.
Ultraviolet optical horn antennas for label-free detection of single proteins
Authors: Barulin Aleksandr , Roy Prithu , Claude Jean-Benoît , Wenger Jérôme
Published: April 2022

Single-molecule fluorescence techniques have revolutionized our ability to study proteins. However, the presence of a fluorescent label can alter the protein structure and/or modify its reaction with other species. To avoid the need for a fluorescent label, the intrinsic autofluorescence of proteins in the ultraviolet offers the benefits of fluorescence techniques without introducing the labelling drawbacks. Unfortunately, the low autofluorescence brightness of proteins has greatly challenged single molecule detection so far. Here we introduce optical horn antennas, a dedicated nanophotonic platform enabling the label-free detection of single proteins in the UV. This design combines fluorescence plasmonic enhancement, efficient collection up to 85° angle and background screening. We detect the UV autofluorescence from immobilized and diffusing single proteins, and monitor protein unfolding and dissociation upon denaturation. Optical horn antennas open up a unique and promising form of fluorescence spectroscopy to investigate single proteins in their native states in real time.