bluuebunny/crossref_metadata_2025 huggingface dataset:
How Could We Know When a Robot was a Moral Patient?
Authors: Shevlin Henry
Published: June 2021

There is growing interest in machine ethics in the question of whether and under what circumstances an artificial intelligence would deserve moral consideration. This paper explores a particular type of moral status that the author terms psychological moral patiency, focusing on the epistemological question of what sort of evidence might lead us to reasonably conclude that a given artificial system qualified as having this status. The paper surveys five possible criteria that might be applied: intuitive judgments, assessments of intelligence, the presence of desires and autonomous behavior, evidence of sentience, and behavioral equivalence. The author suggests that despite its limitations, the latter approach offers the best way forward, and defends a variant of that, termed the cognitive equivalence strategy. In short, this holds that an artificial system should be considered a psychological moral patient to the extent that it possesses cognitive mechanisms shared with other beings such as nonhuman animals whom we also consider to be psychological moral patients.
The Desirability of Legal Rights for Novel Beings
Authors: Jowitt Joshua
Published: June 2021

The debate around whether novel beings should be legally recognized as legitimate rights holders is one that has produced a vast amount of commentary. This paper contributes to this discourse by shifting the normative focus of moral rights away from criteria possessed by the novel beings in question, and back toward the criterion upon which we ourselves are able to make legitimate rights claims. It draws heavily on the moral writing of Alan Gewirth’s identification of noumenal agency as the source of all legitimate rights claims. Taking Gewirthian ethical rationalism as providing a universally applicable hypothetical imperative which binds all agents to comply with its requirements, the paper argues that it is at least morally desirable that any legal system should recognize the moral rights claims of all agents as equally legitimate. By extension, it is at least morally desirable that the status of legal personhood should be granted by a legal system to all novel beings who are noumenal agents, insofar as this status is necessary for rights’ legal recognition. Having established the desirability of this extension, the paper closes with an examination of recent cases involving both biological and nonbiological novel beings in order to assess their conformity with the desirable approach outlined above. The paper demonstrates that such recognition is conceptually possible, thus requiring us to move beyond the current anthropocentricity of legal systems and recognize the legitimate moral claim for legal personhood for all novel beings who possess noumenal agency.
Stratified therapy for Kawasaki disease using a new scoring system to predict the response to a lower dose of intravenous immunoglobulin therapy
Authors: Matsuura Misa , Sugawara Daisuke , Makita Eishi , Hirakubo Yuka , Nonaka Kazuhito , Yamashita Shinichiro , Ichihashi Ko
Published: June 2021

Background:

Several studies have reported treatment options for patients with Kawasaki disease refractory to standard immunoglobulin therapy; however, no studies have reported low-dose immunoglobulin therapy for patients with a low risk of Kawasaki disease.

Methods:

A total of 277 patients with Kawasaki disease were included in this study. We used Kobayashi score and our Less high-risk score to divide the patients into three groups. Patients in the high-risk group (Kobayashi score ≥ 5 points) received 2 g/kg intravenous immunoglobulin and prednisolone. Patients in the moderate-risk group (Kobayashi score < 5 points and Less high-risk score ≥ 2 points) received 2 g/kg intravenous immunoglobulin treatment. Patients in the low-risk group (Kobayashi score < 5 points and Less high-risk score < 2 points) received 1 g/kg intravenous immunoglobulin treatment. The response rate and the incidence of coronary artery lesions at 4 weeks after treatment were evaluated in each group.

Results:

The treatment response rates in the high-risk (n = 110), moderate-risk (n = 80), and low-risk (n = 87) groups were 74.5, 72.5, and 77.0%, respectively. Coronary artery lesions occurred in 7.3, 3.8, and 2.3% of patients in the high-, moderate-, and low-risk groups, respectively. There were no significant differences between the groups regarding treatment response or coronary artery lesion rate.

Conclusion:

The therapeutic response rate and the therapeutic effect of low-dose intravenous immunoglobulin in the low-risk group identified with our new scoring were satisfactory. Stratified therapies for patients with Kawasaki disease based on the scoring system may be useful.
Diet quality among Indigenous and non-Indigenous children and youth in Canada in 2004 and 2015: a repeated cross-sectional design
Authors: Riediger Natalie D , LaPlante Jeff , Mudryj Adriana , Clair Luc
Published: June 2021

Objective:

The objectives were to describe changes in diet quality between off-reserve Indigenous and non-Indigenous children and youth from 2004 to 2015 and examine the association between food security and diet quality.

Design:

We utilised a repeated cross-sectional design using both the 2004 and 2015 nutrition-focused Canadian Community Health Surveys, including 24-h dietary recall. Diet quality was estimated according to the Healthy Eating Index (HEI).

Setting:

The surveys were conducted off-reserve in Canada’s ten provinces.

Participants:

Our analysis included children and youth 2–17 years old (n 18 189). Indigenous and non-Indigenous participants were matched, and using a general linear model, we tested time period and (non-)Indigenous identifiers, including their interaction effect, as predictors of HEI.

Results:

Both Indigenous and non-Indigenous children and youth had significantly higher HEI scores in 2015 as compared to 2004. There was not a significant (non-)Indigenous and time period interaction effect, indicating the improvements in diet quality in 2015 were similar between both Indigenous and non-Indigenous populations. Improvements in diet quality are largely attributed to reductions in percentage energy from ‘other’ foods, though a disparity between Indigenous and non-Indigenous children and youth persisted in 2015. Overall, food security was lower among the Indigenous population and positively, and independently, associated with diet quality overall, though this relationship differed between boys and girls.

Conclusions:

School policies may have contributed to similar improvements in diet quality among Indigenous and non-Indigenous populations. However, an in-depth sex and gender-based analysis of the relationship between food security and diet quality is required.
Beyond “imagined” nostalgia: Gunsan's heritagization of Japanese colonial architecture in South Korea
Authors: Lee Hyun Kyung
Published: June 2021

In South Korea, romanticization of the era of Japanese colonial rule (1910–1945) has long been taboo: the period is widely regarded as one of the most painful and shameful parts of South Korean history. However, during the past decade unexpected cracks have appeared in established national narratives on the colonial period. This paper explores the dissonance between long-standing national narratives and the commodification of local heritage sites for tourism, by examining the heritagization of Japanese colonial architecture in the city of Gunsan. Despite the Gunsan Municipal Government positions the city's colonial stories in ways that largely align with national official narratives on Japanese colonial history, such efforts have unexpectedly generated feelings of imagined nostalgia in three ways: (1) through clashes between official colonial history and the means by which colonial daily life is depicted in Gunsan's Modern Cultural Belt; (2) through the interwoven colonial and post-colonial stories presented in the city's Modern Historic Landscape District and (3) through the commercialized colonial and post-colonial stories articulated by private businesses in Gunsan. This paper suggests that productive nostalgia can help to overcome the limit of the current form of Gunsan's heritagization, and to construct Gunsan's diverse local memories
Commodity frontiers and the transformation of the global countryside: a research agenda
Authors: Beckert Sven , Bosma Ulbe , Schneider Mindi , Vanhaute Eric
Published: June 2021

Over the past 600 years, commodity frontiers – processes and sites of the incorporation of resources into the expanding capitalist world economy – have absorbed ever more land, ever more labour and ever more natural assets. In this paper, we claim that studying the global history of capitalism through the lens of commodity frontiers and using commodity regimes as an analytical framework is crucial to understanding the origins and nature of capitalism, and thus the modern world. We argue that commodity frontiers identify capitalism as a process rooted in a profound restructuring of the countryside and nature. They connect processes of extraction and exchange with degradation, adaptation and resistance in rural peripheries. To account for the enormous variety of actors and places involved in this history is a critical challenge in the social sciences, and one to which global history can contribute crucial insights.
Epidemiological surveillance and performance assessment: the two roles of health indicators during the COVID-19 pandemic
Authors: Genicot Nathan
Published: June 2021

The COVID-19 pandemic has given rise to the massive development and use of health indicators. Drawing on the history of international public health and of the management of infectious disease, this paper attempts to show that the normative power acquired by metrics during the pandemic can be understood in light of two rationales: epidemiological surveillance and performance assessment. On the one hand, indicators are established to evaluate and rank countries’ responses to the outbreak; on the other, the evolution of indicators has a direct influence on the content of public health policies. Although quantitative data are an absolute necessity for coping with such disasters, it is critical to bear in mind the inherent partiality and precarity of the information provided by health indicators. Given the growing importance of normative quantitative devices during the pandemic, and assuming that their influence is unlikely to decrease in the future, they call for close scrutiny.
Photoablative atherectomy followed by a paclitaxel-coated balloon to	inhibit restenosis in instent femoro-popliteal obstructions	(PHOTOPAC)
Authors: Böhme Tanja , Noory Elias , Beschorner Ulrich , Lerke Frederik , Schmidt Andrej , Scheinert Dierk , Ito Wulf , Zeller Thomas , Rastan Aljoscha
Published: June 2021

Summary: Background: To evaluate the safety and effectiveness of preparing instent femoropopliteal lesion with photoablative laser atherectomy or plain balloon angioplasty (POBA) prior to drug-coated balloon (DCB) angioplasty. Patients and methods: The prospective, multicenter, randomized study enrolled patients with Rutherford-Becker-class (RBC) 1 to 5 and instent lesions located in superficial femoral artery and/or popliteal artery above the knee joint. Primary endpoint was target lesion percent stenosis at 1 year as determined by the angiographic core-laboratory. Secondary endpoints included procedural success, major adverse event rate, clinical improvement and improvement in ankle-brachial index (ABI), clinically-driven target lesion revascularization (CD-TLR), and primary patency rate at until 2-year follow-up. Results: The study was terminated prior to the enrollment goal due to slow enrollment. Thirty patients were included in the laser plus DCB cohort and 31 patients in the control cohort. Primary endpoint was not significantly different (p=0.331). Procedural success was 83.3% and 87.1% for the laser plus DCB and the control cohort, respectively. Serious adverse events at 30 days and 1-year were not statistically different between the two cohorts. For the ABI, significant improvements were present at discharge as well as at the follow-up visits. This was also evident for the RBC at the follow-up visits. One- and two-year freedom from CD-TLR was 86.7% vs. 87.1%, and 63.6% vs. 72%, respectively. Duplex derived primary patency was 90% at 6-months, 65.5% at one year and 56.5% at two year for the laser cohort and 90.3%, 75.9% and 53.8% for the control cohort. Conclusions: Safety of instent photoablative laser atherectomy followed by DCB angioplasty is confirmed by this study. Due to the small sample size, no benefit over POBA as vessel preparation could be shown.
CME-Sonografie 98: Thoraxsonografie
Authors: Bürge Tobias , Tuma Jan
Published: June 2021

Zusammenfassung. Die Thoraxsonografie zähl seit Langem zu einem wichtigen Bestandteil der Ultraschalldiagnostik. Historisch war zuerst der Nachweis von Pleuraergüssen da. Später kamen auch periphere Konsolidationen (Pneumonie, Tumore, Lungenembolie) und Pneumothorax dazu. Die COVID-19-Pandemie mit oft massivem Lungenbefall hat das Interesse an der Thoraxsonografie deutlich verstärkt. Die zum Teil spezifischen Veränderungen durch COVID-19 werden nachfolgend vorgestellt.
COVID-19 ed ecografia polmonare: un approccio innovativo alla malattia nello studio medico di medicina generale
Authors: Griffa Andrea , Rezzonico Sara , Giongo Alessandro
Published: June 2021

Sommario. La malattia da SARS-CoV-2 ha richiesto ai medici curanti uno sforzo notevole nell’adattare il proprio metodo di lavoro. In breve tempo abbiamo dovuto conoscere la malattia e attuare una strategia per la presa in carico dei pazienti. Lo scopo è quello di riuscire a fornire nella Praxis una consulenza sicura (senza contaminazioni dei pazienti), con diagnosi precoce e follow-up riproducibile. L’ecografia polmonare è risultata essere una metodica sicura e affidabile per la diagnosi di questa malattia durante la pandemia. In questo articolo viene descritta l’esperienza conseguita su 116 pazienti nel periodo compreso tra febbraio 2020 a marzo 2021.
Satellite‐Based Estimate of Intrinsic Predictability Limits at Convective Scales Over Northeast India
Authors: Ramanathan Arun , Satyanarayana A. N. V.
Published: June 2021

Spheroscale estimates are essential not only for incorporating the seemingly incompatible phenomenon of atmospheric convection within the framework of wide‐range horizontal and vertical scaling in the atmosphere, but also to make semi‐empirical estimates of the storm‐scale atmospheric predictability limits. Since spheroscales are extremely variable, this study computes yearly spheroscales during convective weather events over a selected part of northeast India for 5 different years using the ensemble‐averaged fluctuations of radar reflectivity from the CloudSat geometric profile data set. All these spheroscale estimates are consistently less than 100 m and are directly proportional to the maximum reflectivity observed during the corresponding year. This is in agreement with the fact that spheroscales for unstable atmospheric fields are larger than that of stable atmospheric fields. The semi‐empirical angle‐averaged predictability limits estimated using these spheroscale estimates illustrate that atmospheric fields with larger spheroscales are weakly stable and have smaller intrinsic predictability limits thereby making them less predictable.
Anthropogenic Effects on the Contemporary Sediment Budget of the Lower Rhine‐Meuse Delta Channel Network
Authors: Cox J. R. , Huismans Y. , Knaake S. M. , Leuven J. R. F. W. , Vellinga N. E. , van der Vegt M. , Hoitink A. J. F. , Kleinhans M. G.
Published: June 2021

Deltas and estuaries worldwide face the challenge of capturing sufficient sediment to keep up with relative sea‐level rise. Knowledge about sediment pathways and fluxes is crucial to combat adverse effects on channel morphology, for example, erosion which enhances bank collapse and increasing tidal penetration. Here, we construct sediment budgets which quantify annual changes for the urbanized Rhine‐Meuse Delta of the Netherlands, a typical urban delta experiences changing fluvial and coastal fluxes of sediment, engineering works and dredging and dumping activities. The delta shows a negative sediment budget (more outgoing than incoming sediment) since the 1980s, due to anthropogenic intervention. Following a large offshore port expansion, dredging in ports and harbors in the region has doubled in the past 5 years, likely due to the induced change in net sediment fluxes. In addition, the deeper navigation channels, ports, and harbors are now trapping siltier sediment, changing the sediment composition in the mouth. The removal of sediment by dredging is adverse to the necessity for sediment in heavily eroding branches. To allow for sustainable sediment management in the future and to cope with sea‐level rise, further measurements are required to properly quantify the amount of incoming sediment at the boundaries of the system and the internal mechanisms of transport. The varied response of the branches has important consequences for navigation, ecology and flood safety and management of the sediment in the system. These effects will be of pivotal importance in coming decades with similar implications for many urbanized deltas worldwide.
Gulf Stream Intrusions Feed Diatom Hot Spots
Authors: Wheeling Kate
Published: June 2021

Previous research suggested that the intrusion of low-nutrient Gulf Stream water into the Mid-Atlantic Bight would reduce productivity, but a new study finds that it can also lead to chlorophyll hot spots.
Simulation‐Derived Radar Cross Sections of a New Meteor Head Plasma Distribution Model
Authors: Sugar G. , Marshall R. , Oppenheim M. M. , Dimant Y. S. , Close S.
Published: June 2021

We present results and analysis of finite‐difference time‐domain (FDTD) simulations of electromagnetic waves scattering off meteor head plasma using an analytical model and a simulation‐derived model of the head plasma distribution. The analytical model was developed by (Dimant & Oppenheim, 2017b, https://doi.org/10.1002/2017JA023963) and the simulation‐derived model is based on particle‐in‐cell (PIC) simulations presented in (Sugar et al., 2019, https://doi.org/10.1029/2018JA026434). Both of these head plasma distribution models show the meteor head plasma is significantly different than the spherically symmetric distributions used in previous studies of meteor head plasma. We use the FDTD simulation results to fit a power law model that relates the meteoroid ablation rate to the head echo radar cross section (RCS), and show that the RCS of plasma distributions derived from the Dimant‐Oppenheim analytical model and the PIC simulations agree to within 4 dBsm. The power law model yields more accurate meteoroid mass estimates than previous methods based on spherically symmetric plasma distributions.
The Biophysical Role of Water and Ice Within Permafrost Nearing Collapse: Insights From Novel Geophysical Observations
Authors: James S. R. , Minsley B. J. , McFarland J. W. , Euskirchen E. S. , Edgar C. W. , Waldrop M. P.
Published: June 2021

The impact of permafrost thaw on hydrologic, thermal, and biotic processes remains uncertain, in part due to limitations in subsurface measurement capabilities. To better understand subsurface processes in thermokarst environments, we collocated geophysical and biogeochemical instruments along a thaw gradient between forested permafrost and collapse‐scar bogs at the Alaska Peatland Experiment site near Fairbanks, Alaska. Ambient seismic noise monitoring provided continuous high‐temporal resolution measurements of water and ice saturation changes. Maps of seismic velocity change identified areas of large summertime velocity reductions nearest the youngest bog, indicating potential thaw and expansion at the bog margin. These results corresponded well with complementary borehole nuclear magnetic resonance measurements of unfrozen water content with depth, which showed permafrost soils nearest the bog edges contained the largest amount of unfrozen water along the study transect, up to 25% by volume. In situ measurements of methane within permafrost soils revealed high concentrations at these bog‐edge locations, up to 30% soil gas. Supra‐permafrost talik zones were observed at the bog margins, indicating talik formation and perennial liquid water may drive lateral bog expansion and enhanced permafrost carbon losses preceding thaw. Comparison of seismic monitoring with wintertime surface carbon dioxide fluxes revealed differential responses depending on time and proximity to the bogs, capturing the controlling influence of subsurface water and ice on microbial activity and surficial emissions. This study demonstrates a multidisciplinary approach for gaining new understanding of how subsurface physical properties influence greenhouse gas production, emissions, and thermokarst development.
Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome
Authors: Chapman Gareth , Alsaqati Mouhamed , Lunn Sharna , Singh Tanya , Linden Stefanie C. , Linden David E. J. , van den Bree Marianne B. M. , Ziller Mike , Owen Michael J. , Hall Jeremy , Harwood Adrian J. , Syed Yasir Ahmed
Published: June 2021

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.
FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to promote lung adenocarcinoma progression via IKK/NF-κB signaling
Authors: Zong Shuai , Jiao Yulian , Liu Xin , Mu Wenli , Yuan Xiaotian , Qu Yunyun , Xia Yu , Liu Shuang , Sun Huanxin , Wang Laicheng , Cui Bin , Liu Xiaowen , Li Ping , Zhao Yueran
Published: June 2021

FKBP4 belongs to the family of immunophilins, which serve as a regulator for steroid receptor activity. Thus, FKBP4 has been recognized to play a critical role in several hormone-dependent cancers, including breast and prostate cancer. However, there is still no research to address the role of FKBP4 on lung adenocarcinoma (LUAD) progression. We found that FKBP4 expression was elevated in LUAD samples and predicted significantly shorter overall survival based on TCGA and our cohort of LUAD patients. Furthermore, FKBP4 robustly increased the proliferation, metastasis, and invasion of LUAD in vitro and vivo. Mechanistic studies revealed the interaction between FKBP4 and IKK kinase complex. We found that FKBP4 potentiated IKK kinase activity by interacting with Hsp90 and IKK subunits and promoting Hsp90/IKK association. Also, FKBP4 promotes the binding of IKKγ to IKKβ, which supported the facilitation role in IKK complex assembly. We further identified that FKBP4 TPR domains are essential for FKBP4/IKK interaction since its association with Hsp90 is required. In addition, FKBP4 PPIase domains are involved in FKBP4/IKKγ interaction. Interestingly, the association between FKBP4 and Hsp70/RelA favors the transport of RelA toward the nucleus. Collectively, FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to potentiate the transcriptional activity and nuclear translocation of NF-κB, thereby promoting LUAD progression. Our findings suggest that FKBP4 may function as a prognostic biomarker of LUAD and provide a newly mechanistic insight into modulating IKK/NF-κB signaling.
LncRNA CTD-2528L19.6 prevents the progression of IPF by alleviating fibroblast activation
Authors: Chen Tingting , Guo Yingying , Wang Jiayi , Ai Liqiang , Ma Lu , He Wenxin , Li Zhixin , Yu Xiaojiang , Li Jinrui , Fan Xingxing , Gu Yunyan , Liang Haihai
Published: June 2021

Long non-coding RNAs (lncRNAs) have emerged as critical factors for regulating multiple biological processes during organ fibrosis. However, the mechanism of lncRNAs in idiopathic pulmonary fibrosis (IPF) remains incompletely understood. In the present study, two sets of lncRNAs were defined: IPF pathogenic lncRNAs and IPF progression lncRNAs. IPF pathogenic and progression lncRNAs-mRNAs co-expression networks were constructed to identify essential lncRNAs. Network analysis revealed a key lncRNA CTD-2528L19.6, which was up-regulated in early-stage IPF compared to normal lung tissue, and subsequently down-regulated during advanced-stage IPF. CTD-2528L19.6 was indicated to regulate fibroblast activation in IPF progression by mediating the expression of fibrosis related genes LRRC8C, DDIT4, THBS1, S100A8 and TLR7 et al. Further studies showed that silencing of CTD-2528L19.6 increases the expression of Fn1 and Collagen I both at mRNA and protein levels, promoted the transition of fibroblasts into myofibroblasts and accelerated the migration and proliferation of MRC-5 cells. In contrast, CTD-2528L19.6 overexpression alleviated fibroblast activation in MRC-5 cells induced by TGF-β1. LncRNA CTD-2528L19.6 inhibited fibroblast activation through regulating the expression of LRRC8C in vitro assays. Our results suggest that CTD-2528L19.6 may prevent the progression of IPF from early-stage and alleviate fibroblast activation during the advanced-stage of IPF. Thus, exploring the regulatory effect of lncRNA CTD-2528L19.6 may provide new sights for the prevention and treatment of IPF.
A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex
Authors: Smith Rebecca G. , Pishva Ehsan , Shireby Gemma , Smith Adam R. , Roubroeks Janou A. Y. , Hannon Eilis , Wheildon Gregory , Mastroeni Diego , Gasparoni Gilles , Riemenschneider Matthias , Giese Armin , Sharp Andrew J. , Schalkwyk Leonard , Haroutunian Vahram , Viechtbauer Wolfgang , van den Hove Daniel L. A. , Weedon Michael , Brokaw Danielle , Francis Paul T. , Thomas Alan J. , Love Seth , Morgan Kevin , Walter Jörn , Coleman Paul D. , Bennett David A. , De Jager Philip L. , Mill Jonathan , Lunnon Katie
Published: June 2021

Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).
Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis
Authors: Jungwirth Ute , van Weverwijk Antoinette , Evans Rachel J. , Jenkins Liam , Vicente David , Alexander John , Gao Qiong , Haider Syed , Iravani Marjan , Isacke Clare M.
Published: June 2021

Profiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability, which coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into, how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.
TLR4 signalling via Piezo1 engages and enhances the macrophage mediated host response during bacterial infection
Authors: Geng Jing , Shi Yiran , Zhang Jinjia , Yang Bingying , Wang Ping , Yuan Weihong , Zhao Hao , Li Junhong , Qin Funiu , Hong Lixin , Xie Changchuan , Deng Xianming , Sun Yujie , Wu Congying , Chen Lanfen , Zhou Dawang
Published: June 2021

TLR4 signaling plays key roles in the innate immune response to microbial infection. Innate immune cells encounter different mechanical cues in both health and disease to adapt their behaviors. However, the impact of mechanical sensing signals on TLR4 signal-mediated innate immune response remains unclear. Here we show that TLR4 signalling augments macrophage bactericidal activity through the mechanical sensor Piezo1. Bacterial infection or LPS stimulation triggers assembly of the complex of Piezo1 and TLR4 to remodel F-actin organization and augment phagocytosis, mitochondrion-phagosomal ROS production and bacterial clearance and genetic deficiency of Piezo1 results in abrogation of these responses. Mechanistically, LPS stimulates TLR4 to induce Piezo1-mediated calcium influx and consequently activates CaMKII-Mst1/2-Rac axis for pathogen ingestion and killing. Inhibition of CaMKII or knockout of either Mst1/2 or Rac1 results in reduced macrophage bactericidal activity, phenocopying the Piezo1 deficiency. Thus, we conclude that TLR4 drives the innate immune response via Piezo1 providing critical insight for understanding macrophage mechanophysiology and the host response.
Cell segmentation-free inference of cell types from in situ transcriptomics data
Authors: Park Jeongbin , Choi Wonyl , Tiesmeyer Sebastian , Long Brian , Borm Lars E. , Garren Emma , Nguyen Thuc Nghi , Tasic Bosiljka , Codeluppi Simone , Graf Tobias , Schlesner Matthias , Stegle Oliver , Eils Roland , Ishaque Naveed
Published: June 2021

Multiplexed fluorescence in situ hybridization techniques have enabled cell-type identification, linking transcriptional heterogeneity with spatial heterogeneity of cells. However, inaccurate cell segmentation reduces the efficacy of cell-type identification and tissue characterization. Here, we present a method called Spot-based Spatial cell-type Analysis by Multidimensional mRNA density estimation (SSAM), a robust cell segmentation-free computational framework for identifying cell-types and tissue domains in 2D and 3D. SSAM is applicable to a variety of in situ transcriptomics techniques and capable of integrating prior knowledge of cell types. We apply SSAM to three mouse brain tissue images: the somatosensory cortex imaged by osmFISH, the hypothalamic preoptic region by MERFISH, and the visual cortex by multiplexed smFISH. Here, we show that SSAM detects regions occupied by known cell types that were previously missed and discovers new cell types.
Deciphering an AgRP-serotoninergic neural circuit in distinct control of energy metabolism from feeding
Authors: Han Yong , Xia Guobin , Srisai Dollada , Meng Fantao , He Yanlin , Ran Yali , He Yang , Farias Monica , Hoang Giang , Tóth István , Dietrich Marcelo O. , Chen Miao-Hsueh , Xu Yong , Wu Qi
Published: June 2021

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4RdlDRN neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4RdlDRN signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders.
Projected losses of ecosystem services in the US disproportionately affect non-white and lower-income populations
Authors: Gourevitch Jesse D. , Alonso-Rodríguez Aura M. , Aristizábal Natalia , de Wit Luz A. , Kinnebrew Eva , Littlefield Caitlin E. , Moore Maya , Nicholson Charles C. , Schwartz Aaron J. , Ricketts Taylor H.
Published: June 2021

Addressing how ecosystem services (ES) are distributed among groups of people is critical for making conservation and environmental policy-making more equitable. Here, we evaluate the distribution and equity of changes in ES benefits across demographic and socioeconomic groups in the United States (US) between 2020 and 2100. Specifically, we use land cover and population projections to model potential shifts in the supply, demand, and benefits of the following ES: provision of clean air, protection against a vector-borne disease (West Nile virus), and crop pollination. Across the US, changes in ES benefits are unevenly distributed among socioeconomic and demographic groups and among rural and urban communities, but are relatively uniform across geographic regions. In general, non-white, lower-income, and urban populations disproportionately bear the burden of declines in ES benefits. This is largely driven by the conversion of forests and wetlands to cropland and urban land cover in counties where these populations are expected to grow. In these locations, targeted land use policy interventions are required to avoid exacerbating inequalities already present in the US.
Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice
Authors: Lowes Daniel C. , Chamberlin Linda A. , Kretsge Lisa N. , Holt Emma S. , Abbas Atheir I. , Park Alan J. , Yusufova Lyubov , Bretton Zachary H. , Firdous Ayesha , Enikolopov Armen G. , Gordon Joshua A. , Harris Alexander Z.
Published: June 2021

Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.
IrW nanochannel support enabling ultrastable electrocatalytic oxygen evolution at 2 A cm−2 in acidic media
Authors: Li Rui , Wang Haiyun , Hu Fei , Chan K. C. , Liu Xiongjun , Lu Zhaoping , Wang Jing , Li Zhibin , Zeng Longjiao , Li Yuanyuan , Wu Xiaojun , Xiong Yujie
Published: June 2021

A grand challenge for proton exchange membrane electrolyzers is the rational design of oxygen evolution reaction electrocatalysts to balance activity and stability. Here, we report a support-stabilized catalyst, the activated ~200 nm-depth IrW nanochannel that achieves the current density of 2 A cm−2 at an overpotential of only ~497 mV and maintains ultrastable gas evolution at 100 mA cm−2 at least 800 h with a negligible degradation rate of ~4 μV h−1. Structure analyses combined with theoretical calculations indicate that the IrW support alters the charge distribution of surface (IrO2)n clusters and effectively confines the cluster size within 4 (n≤4). Such support-stabilizing effect prevents the surface Ir from agglomeration and retains a thin layer of electrocatalytically active IrO2 clusters on surface, realizing a win-win strategy for ultrahigh OER activity and stability. This work would open up an opportunity for engineering suitable catalysts for robust proton exchange membrane-based electrolyzers.
Automated scoring of pre-REM sleep in mice with deep learning
Authors: Grieger Niklas , Schwabedal Justus T. C. , Wendel Stefanie , Ritze Yvonne , Bialonski Stephan
Published: June 2021

Reliable automation of the labor-intensive manual task of scoring animal sleep can facilitate the analysis of long-term sleep studies. In recent years, deep-learning-based systems, which learn optimal features from the data, increased scoring accuracies for the classical sleep stages of Wake, REM, and Non-REM. Meanwhile, it has been recognized that the statistics of transitional stages such as pre-REM, found between Non-REM and REM, may hold additional insight into the physiology of sleep and are now under vivid investigation. We propose a classification system based on a simple neural network architecture that scores the classical stages as well as pre-REM sleep in mice. When restricted to the classical stages, the optimized network showed state-of-the-art classification performance with an out-of-sample F1 score of 0.95 in male C57BL/6J mice. When unrestricted, the network showed lower F1 scores on pre-REM (0.5) compared to the classical stages. The result is comparable to previous attempts to score transitional stages in other species such as transition sleep in rats or N1 sleep in humans. Nevertheless, we observed that the sequence of predictions including pre-REM typically transitioned from Non-REM to REM reflecting sleep dynamics observed by human scorers. Our findings provide further evidence for the difficulty of scoring transitional sleep stages, likely because such stages of sleep are under-represented in typical data sets or show large inter-scorer variability. We further provide our source code and an online platform to run predictions with our trained network.
Extraversion level predicts perceived benefits from social resources and tool use
Authors: Murday Vincent , Campos-Moinier Kévin , Osiurak François , Brunel Lionel
Published: June 2021

Social baseline theory states that there are differences in how humans integrate social resources into their economy of action when they face environmental demands. However, although several authors suggested that extraversion may be an indicator of the social baseline, no study has demonstrated it. The present study aims to test this hypothesis and, in particular, examines whether extraversion is a specific indicator of the social baseline. In two experiments, participants were asked to move rolls either alone (with their hands), or with the help of a social resource (Experiment 1), or a tool (Experiment 2). Results showed that extraversion predicted the choice to use both types of resource. Specifically, the more participants were extraverted, the more they tended to consider the use of the social resource or the tool as beneficial. We argue that these results indicate that extraversion is not specifically an indicator of the social baseline, but rather an indicator of how individuals integrate technical and social resources into their economy of action. In addition, this study encourages future research endeavors to define what constitutes a resource and how it could fit into the Social Baseline Theory.
In-situ remediation of nitrogen and phosphorus of beverage industry by potential strains Bacillus sp. (BK1) and Aspergillus sp. (BK2)
Authors: Bhambri Anne , Karn Santosh Kumar , Singh R. K.
Published: June 2021

The bioremediation of beverage (treated and untreated) effluent was investigated in the current study by using the potential strains of Bacillus sp. (BK1) and Aspergillus sp. (BK2). Effluent was collected from the beverage industry (initial concentration of nitrogen were 3200 ± 0.5 mg/L and 4400 ± 0.6 mg/L whereas phosphorus were 4400 ± 2 mg/L and 2600 ± 1 mg/L in treated and untreated effluent correspondingly). Further, the BK1 and BK2 exhibited high removal competence after 1 week of incubation; BK1 removed phosphorus 99.95 ± 0.7% and BK2 95.69 ± 1% in treated effluent while nitrogen removed about 99.90 ± 0.4% by BK1 and 81.25 ± 0.8% by BK2 (initial concentration of phosphorus 4400 ± 2 mg/L and nitrogen 3200 ± 0.5 mg/L). Next, in the untreated effluent BK1 removed 99.81 ± 1% and BK2 99.85 ± 0.8% of phosphorus while removed nitrogen 99.93 ± 0.5% by BK1 and 99.95 ± 1.2% by BK2 correspondingly, (initial concentration of phosphorus 2600 ± 1 mg/L and nitrogen 4400 ± 0.6 mg/L). The physiochemical composition of sample such as pH, total carbohydrates, total proteins, total solids of treated and untreated effluent were also analysed before and after treatment of both the samples. BK1 and BK2 increased the pH by 8.94 ± 0.3 and 9.5 ± 0.4 correspondingly in treated effluent whereas 6.34 ± 0.5 and 7.5 ± 0.2 correspondingly in untreated effluent (initial pH of treated and untreated effluent 7.07 ± 0.8 and 4.85 ± 0.3 correspondingly). Total Carbohydrates removed about 17,440 ± 4.6 mg/L and 10,680 ± 3.2 mg/L by BK1 and BK2 correspondingly in treated effluent whereas 18,050 ± 3.5 mg/L and 18,340 ± 2.3 mg/L correspondingly in untreated effluent (initial concentration of treated and untreated effluent 25,780 ± 1.6 mg/L and 35,000 ± 1.5 mg/L correspondingly) while BK1 and BK2 removed total proteins by 30.336 ± 4.6 mg/L and 40.417 ± 2.3 mg/L correspondingly in treated effluent whereas 18.929 ± 1.2 mg/L and 17.526 ± 0.8 mg/L correspondingly in untreated effluent (initial concentration of treated and untreated effluent 49.225 ± 1.5 mg/L and 20.565 ± 1 mg/L correspondingly). Next, total solids removed by BK1 and BK2 2.5 ± 0.3 mg/L and 1.6 ± 0.6 mg/L correspondingly in treated effluent whereas 5.5 ± 0.8 mg/L and 4.6 ± 0.6 mg/L in untreated effluent (initial concentration of treated and untreated effluent 5.6 ± 1.5 mg/L and 9.48 ± 1.2 mg/L correspondingly). Both the strains BK1 and BK2 are highly efficient in the nitrogen and phosphorus removal therefore this strain may be applied for the potential remediation.
Oral pH value predicts the incidence of radiotherapy related caries in nasopharyngeal carcinoma patients
Authors: Li Zheng , Wu Qiuji , Meng Xiangyu , Yu Haijun , Jiang Dazhen , Chen Gaili , Hu Xiaoyan , Hua Xinying , Wang Xiaoyong , Wang Dajiang , Zhao Hongli , Zhong Yahua
Published: June 2021

Radiotherapy-related caries is a complication of radiotherapy for nasopharyngeal carcinoma; however, factors influencing the occurrence, accurate prediction of onset, and protective factors of radiotherapy-related caries remain unclear. This study analyzed risk factors, disease predictors, and protective factors for radiotherapy-related caries in nasopharyngeal carcinoma. This prospective study included 138 nasopharyngeal carcinoma patients receiving radical radiotherapy at our hospital during June 2012–December 2016 and were followed up for dental caries. Patients’ clinical data on radiotherapy were collected, dynamic monitoring was performed to assess changes in oral pH values, and a questionnaire survey was administered to collect patients’ lifestyle habits. Time-dependent cox regression trees, event-free Kaplan–Meier curve, Mann–Whitely U test were used to analysis the results. The median follow-up time was 30 (12–60) months. Radiotherapy-related caries occurred in 28 cases (20.3%). Univariate analyses showed that radiotherapy-related caries was associated with patient’s age, oral saliva pH value, green tea consumption, and radiation dose to sublingual glands, but not with the radiation dose to the parotid and submandibular glands. Multivariate analysis showed that oral saliva pH value [hazard ratio (HR) = 0.390, 95% confidence interval = 0.204–0.746] was an independent prognostic factor for radiotherapy-related caries. Patients with oral saliva pH values ≤ 5.3 in the 9th month after radiotherapy represented a significantly higher risks for radiotherapy-related caries (p < 0.001). Green tea consumption was associated with the occurrence of radiotherapy-related caries, and oral saliva pH values could predict the occurrence of radiotherapy-related caries. Limiting radiation doses to sublingual glands can reduce the occurrence of radiotherapy-related caries.
Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19
Authors: Le Brian L. , Andreoletti Gaia , Oskotsky Tomiko , Vallejo-Gracia Albert , Rosales Romel , Yu Katharine , Kosti Idit , Leon Kristoffer E. , Bunis Daniel G. , Li Christine , Kumar G. Renuka , White Kris M. , García-Sastre Adolfo , Ott Melanie , Sirota Marina
Published: June 2021

The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov–Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated 16 of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.