bluuebunny/crossref_metadata_2025 huggingface dataset:
ISL1 promoted tumorigenesis and EMT via Aurora kinase A-induced activation of PI3K/AKT signaling pathway in neuroblastoma
Authors: Li Mengzhen , Sun Chengtao , Bu Xiaoyun , Que Yi , Zhang Lian , Zhang Yu , Zhang Li , Lu Suying , Huang Junting , Zhu Jia , Wang Juan , Sun Feifei , Zhang Yizhuo
Published: June 2021

Neuroblastoma (NB) is the most common extracranial solid malignancy in children and its mortality rate is relatively high. However, driver genes of NB are not clearly identified. Using bioinformatics analysis, we determined the top 8 differentially expressed genes (DEGs) in NB, including GFAP, PAX6, FOXG1, GAD1, PTPRC, ISL1, GRM5, and GATA3. Insulin gene enhancer binding protein 1 (ISL1) is a LIM homeodomain transcription factor which has been found to be highly expressed in a variety of malignant tumors, but the function of ISL1 in NB has not been fully elucidated. We identified ISL1 as an oncogene in NB. ISL1 is preferentially upregulated in NB tissues compared with normal tissues. High ISL1 expression is significantly associated with poor outcome of NB patients. Knockdown of ISL1 markedly represses proliferation and induces cell apoptosis in vitro, and suppresses tumorigenicity in vivo, while overexpression of ISL1 has the opposite effects. Mechanistically, we demonstrate that ISL1 promotes cell proliferation and EMT transformation through PI3K/AKT signaling pathway by upregulating Aurora kinase A (AURKA), a serine-threonine kinase that is essential for the survival of NB cells. The blockade of AURKA attenuates the function of ISL1 overexpression in the regulation of cell proliferation and migration, Conclusively, this study showed that ISL1 targeted AURKA to facilitate the development of NB, which provided new insights into the tumorigenesis of NB. Thus, ISL1 may be a promising therapeutic target in the future.
RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer’s disease
Authors: Pérez-Sisqués Leticia , Sancho-Balsells Anna , Solana-Balaguer Júlia , Campoy-Campos Genís , Vives-Isern Marcel , Soler-Palazón Ferran , Anglada-Huguet Marta , López-Toledano Miguel-Ángel , Mandelkow Eva-Maria , Alberch Jordi , Giralt Albert , Malagelada Cristina
Published: June 2021

RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death. Its downregulation in Parkinson’s and Huntington’s disease models ameliorates the pathological phenotypes. In the context of Alzheimer’s disease (AD), the coding gene for RTP801, DDIT4, is responsive to Aβ and modulates its cytotoxicity in vitro. Also, RTP801 mRNA levels are increased in AD patients’ lymphocytes. However, the involvement of RTP801 in the pathophysiology of AD has not been yet tested. Here, we demonstrate that RTP801 levels are increased in postmortem hippocampal samples from AD patients. Interestingly, RTP801 protein levels correlated with both Braak and Thal stages of the disease and with GFAP expression. RTP801 levels are also upregulated in hippocampal synaptosomal fractions obtained from murine 5xFAD and rTg4510 mice models of the disease. A local RTP801 knockdown in the 5xFAD hippocampal neurons with shRNA-containing AAV particles ameliorates cognitive deficits in 7-month-old animals. Upon RTP801 silencing in the 5xFAD mice, no major changes were detected in hippocampal synaptic markers or spine density. Importantly, we found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD.
Influence of maternal and paternal pre-conception overweight/obesity on offspring outcomes and strategies for prevention
Authors: Hieronimus Bettina , Ensenauer Regina
Published: June 2021

Overweight, obesity, and their comorbidities remain global health challenges. When established early in life, overweight is often sustained into adulthood and contributes to the early onset of non-communicable diseases. Parental pre-conception overweight and obesity is a risk factor for overweight and obesity in childhood and beyond. This increased risk likely is based on an interplay of genetic alterations and environmental exposures already at the beginning of life, although mechanisms are still poorly defined. In this narrative review, potential routes of transmission of pre-conceptional overweight/obesity from mothers and fathers to their offspring as well as prevention strategies are discussed. Observational evidence suggests that metabolic changes due to parental overweight/obesity affect epigenetic markers in oocytes and sperms alike and may influence epigenetic programming and reprogramming processes during embryogenesis. While weight reduction in overweight/obese men and women, who plan to become pregnant, seems advisable to improve undesirable outcomes in offspring, caution might be warranted. Limited evidence suggests that weight loss in men and women in close proximity to conception might increase undesirable offspring outcomes at birth due to nutritional deficits and/or metabolic disturbances in the parent also affecting gamete quality. A change in the dietary pattern might be more advisable. The data reviewed here suggest that pre-conception intervention strategies should shift from women to couples, and future studies should address possible interactions between maternal and paternal contribution to longitudinal childhood outcomes. Randomized controlled trials focusing on effects of pre-conceptional diet quality on long-term offspring health are warranted.
Cross-border climate vulnerabilities of the European Union to drought
Authors: Ercin Ertug , Veldkamp Ted I. E. , Hunink Johannes
Published: June 2021

European Union’s vulnerability to climate change stretches far beyond its borders because many of its economic sectors, such as meat and dairy, use raw materials sourced from far afield. Cross-border climate vulnerability is a relatively new subject in scientific literature, while of high societal and economic relevance. We quantify these climate vulnerabilities with a focus on drought risk and assessed them for 2030, 2050, 2085 and for RCP 2.6 and 6.0 climate scenarios. Here we find that more than 44% of the EU agricultural imports will become highly vulnerable to drought in future because of climate change. The drought severity in production locations of the agricultural imports in 2050 will increase by 35% compared to current levels of drought severity. This is particularly valid for imports that originate from Brazil, Indonesia, Vietnam, Thailand, India and Turkey. At the same time, imports from Russia, Nigeria, Peru, Ecuador, Uganda and Kenya will be less vulnerable in future. We also report that the climate vulnerabilities of meat and dairy, chocolate (cocoa), coffee, palm oil-based food and cosmetic sectors mainly lie outside the EU borders rather than inside.
Integrated analysis of Xist upregulation and X-chromosome inactivation with single-cell and single-allele resolution
Authors: Pacini Guido , Dunkel Ilona , Mages Norbert , Mutzel Verena , Timmermann Bernd , Marsico Annalisa , Schulz Edda G.
Published: June 2021

To ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist upregulation and gene silencing are thought to be coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cell RNA-sequencing. Specifically, we assess the onset of random XCI in differentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploiting the inter-cellular heterogeneity of XCI onset, we identify putative Xist regulators. Moreover, we show that transient Xist upregulation from both X chromosomes results in biallelic gene silencing right before transitioning to the monoallelic state, confirming a prediction of the stochastic model of XCI. Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known X-controlling element (Xce) effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo.
Tailoring Dzyaloshinskii–Moriya interaction in a transition metal dichalcogenide by dual-intercalation
Authors: Zheng Guolin , Wang Maoyuan , Zhu Xiangde , Tan Cheng , Wang Jie , Albarakati Sultan , Aloufi Nuriyah , Algarni Meri , Farrar Lawrence , Wu Min , Yao Yugui , Tian Mingliang , Zhou Jianhui , Wang Lan
Published: June 2021

Dzyaloshinskii–Moriya interaction (DMI) is vital to form various chiral spin textures, novel behaviors of magnons and permits their potential applications in energy-efficient spintronic devices. Here, we realize a sizable bulk DMI in a transition metal dichalcogenide (TMD) 2H-TaS2 by intercalating Fe atoms, which form the chiral supercells with broken spatial inversion symmetry and also act as the source of magnetic orderings. Using a newly developed protonic gate technology, gate-controlled protons intercalation could further change the carrier density and intensely tune DMI via the Ruderman–Kittel–Kasuya–Yosida mechanism. The resultant giant topological Hall resistivity $${\rho }_{{xy}}^{T}$$

ρ

x
y

T

of $$1.41{\mathrm{\mu}} \Omega \cdot {{\mathrm{cm}}}$$
1.41
μ
Ω
⋅
cm
at $${V}_{g}=-5.2{\mathrm{V}}$$

V

g

=
−
5.2
V
(about $$424 \%$$
424
%
larger than the zero-bias value) is larger than most known chiral magnets. Theoretical analysis indicates that such a large topological Hall effect originates from the two-dimensional Bloch-type chiral spin textures stabilized by DMI, while the large anomalous Hall effect comes from the gapped Dirac nodal lines by spin–orbit interaction. Dual-intercalation in 2H-TaS2 provides a model system to reveal the nature of DMI in the large family of TMDs and a promising way of gate tuning of DMI, which further enables an electrical control of the chiral spin textures and related electromagnetic phenomena.
Insights into household transmission of SARS-CoV-2 from a population-based serological survey
Authors: Bi Qifang , Lessler Justin , Eckerle Isabella , Lauer Stephen A. , Kaiser Laurent , Vuilleumier Nicolas , Cummings Derek A. T. , Flahault Antoine , Petrovic Dusan , Guessous Idris , Stringhini Silvia , Azman Andrew S. ,   SEROCoV-POP Study Group, Stringhini Silvia , Guessous Idris , Baysson Hélène , Collombet Prune , De Ridder David , d’Ippolito Paola , Rinella Matilde D’asaro-Aglieri , Dibner Yaron , Merjani Nacira El , Francioli Natalie , Frangville Marion , Marcus Kailing , Martinez Chantal , Noel Natacha , Pennacchio Francesco , Perez-Saez Javier , Petrovic Dusan , Picazio Attilio , Pishkenari Alborz , Piumatti Giovanni , Portier Jane , Pugin Caroline , Rakotomiaramanana Barinjaka , Richard Aude , Salzmann-Bellard Lilas , Schrempft Stephanie , Zaballa Maria-Eugenia , Waldmann Zoé , Wisniak Ania , Davidovic Alioucha , Duc Joséphine , Guérin Julie , Lombard Fanny , Will Manon , Flahault Antoine , Vernez Isabelle Arm , Keiser Olivia , Mattera Loan , Schellongova Magdalena , Kaiser Laurent , Eckerle Isabella , Lescuyer Pierre , Meyer Benjamin , Poulain Géraldine , Vuilleumier Nicolas , Yerly Sabine , Chappuis François , Welker Sylvie , Courvoisier Delphine , Gétaz Laurent , Nehme Mayssam , Pardo Febronio , Violot Guillemette , Hurst Samia , Matute Philippe , Maugey Jean-Michel , Pittet Didier , L’Huillier Arnaud G. , Posfay-Barbe Klara M. , Pradeau Jean-François , Tacchino Michel , Trono Didier
Published: June 2021

Understanding the risk of infection from household- and community-exposures and the transmissibility of asymptomatic infections is critical to SARS-CoV-2 control. Limited previous evidence is based primarily on virologic testing, which disproportionately misses mild and asymptomatic infections. Serologic measures are more likely to capture all previously infected individuals. We apply household transmission models to data from a cross-sectional, household-based population serosurvey of 4,534 people ≥5 years from 2,267 households enrolled April-June 2020 in Geneva, Switzerland. We found that the risk of infection from exposure to a single infected household member aged ≥5 years (17.3%,13.7-21.7) was more than three-times that of extra-household exposures over the first pandemic wave (5.1%,4.5-5.8). Young children had a lower risk of infection from household members. Working-age adults had the highest extra-household infection risk. Seropositive asymptomatic household members had 69.4% lower odds (95%CrI,31.8-88.8%) of infecting another household member compared to those reporting symptoms, accounting for 14.5% (95%CrI, 7.2-22.7%) of all household infections.
Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease
Authors: Su Haixia , Yao Sheng , Zhao Wenfeng , Zhang Yumin , Liu Jia , Shao Qiang , Wang Qingxing , Li Minjun , Xie Hang , Shang Weijuan , Ke Changqiang , Feng Lu , Jiang Xiangrui , Shen Jingshan , Xiao Gengfu , Jiang Hualiang , Zhang Leike , Ye Yang , Xu Yechun
Published: June 2021

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.
Intrinsic ecological dynamics drive biodiversity turnover in model metacommunities
Authors: O’Sullivan Jacob D. , Terry J. Christopher D. , Rossberg Axel G.
Published: June 2021

Turnover of species composition through time is frequently observed in ecosystems. It is often interpreted as indicating the impact of changes in the environment. Continuous turnover due solely to ecological dynamics—species interactions and dispersal—is also known to be theoretically possible; however the prevalence of such autonomous turnover in natural communities remains unclear. Here we demonstrate that observed patterns of compositional turnover and other important macroecological phenomena can be reproduced in large spatially explicit model ecosystems, without external forcing such as environmental change or the invasion of new species into the model. We find that autonomous turnover is triggered by the onset of ecological structural instability—the mechanism that also limits local biodiversity. These results imply that the potential role of autonomous turnover as a widespread and important natural process is underappreciated, challenging assumptions implicit in many observation and management tools. Quantifying the baseline level of compositional change would greatly improve ecological status assessments.
A Late Cretaceous true polar wander oscillation
Authors: Mitchell Ross N. , Thissen Christopher J. , Evans David A. D. , Slotznick Sarah P. , Coccioni Rodolfo , Yamazaki Toshitsugu , Kirschvink Joseph L.
Published: June 2021

True polar wander (TPW), or planetary reorientation, is well documented for other planets and moons and for Earth at present day with satellites, but testing its prevalence in Earth’s past is complicated by simultaneous motions due to plate tectonics. Debate has surrounded the existence of Late Cretaceous TPW ca. 84 million years ago (Ma). Classic palaeomagnetic data from the Scaglia Rossa limestone of Italy are the primary argument against the existence of ca. 84 Ma TPW. Here we present a new high-resolution palaeomagnetic record from two overlapping stratigraphic sections in Italy that provides evidence for a ~12° TPW oscillation from 86 to 78 Ma. This observation represents the most recent large-scale TPW documented and challenges the notion that the spin axis has been largely stable over the past 100 million years.
Nanoscale bubble domains with polar topologies in bulk ferroelectrics
Authors: Yin Jie , Zong Hongxiang , Tao Hong , Tao Xuefei , Wu Haijun , Zhang Yang , Zhao Li-Dong , Ding Xiangdong , Sun Jun , Zhu Jianguo , Wu Jiagang , Pennycook Stephen J.
Published: June 2021

Multitudinous topological configurations spawn oases of many physical properties and phenomena in condensed-matter physics. Nano-sized ferroelectric bubble domains with various polar topologies (e.g., vortices, skyrmions) achieved in ferroelectric films present great potential for valuable physical properties. However, experimentally manipulating bubble domains has remained elusive especially in the bulk form. Here, in any bulk material, we achieve self-confined bubble domains with multiple polar topologies in bulk Bi0.5Na0.5TiO3 ferroelectrics, especially skyrmions, as validated by direct Z-contrast imaging. This phenomenon is driven by the interplay of bulk, elastic and electrostatic energies of coexisting modulated phases with strong and weak spontaneous polarizations. We demonstrate reversable and tip-voltage magnitude/time-dependent donut-like domain morphology evolution towards continuously and reversibly modulated high-density nonvolatile ferroelectric memories.
Molecular benchmarks of a SARS-CoV-2 epidemic
Authors: Jonsson Hakon , Magnusson Olafur T. , Melsted Pall , Berglund Jonas , Agustsdottir Arna B. , Eiríksdottir Berglind , Fridriksdottir Run , Garðarsdottir Elisabet Eir , Georgsson Gudmundur , Gretarsdottir Olafia S. , Guðmundsson Kjartan R. , Gunnarsdottir Thora Rosa , Eggertsson Hannes , Gylfason Arnaldur , Holm Hilma , Jensson Brynjar O. , Jonasdottir Aslaug , Jonsson Frosti , Josefsdottir Kamilla S. , Thordardottir Marianna , Kristinsson Karl G. , Kristjánsson Þórður , Magnusdottir Droplaug N. , Roux Louise le , Saemundsdottir Jona , Sigurdsson Asgeir , Sigmundsdottir Gudrun , Sveinbjornsson Gardar , Rognvaldsson Solvi , Eiriksson Ogmundur , Magnusson Magnus Karl , Sveinsdottir Kristin Eva , Sveinsdottir Maney , Thorarensen Emil Aron , Thorbjornsson Bjarni , Löve Arthur , Norddahl Gudmundur L. , Jonsdottir Ingileif , Sulem Patrick , Masson Gisli , Moller Alma , Gudnason Thorolfur , Kristjansson Mar , Helgason Agnar , Gudbjartsson Daniel F. , Thorsteinsdottir Unnur , Stefansson Kari
Published: June 2021

A pressing concern in the SARS-CoV-2 epidemic and other viral outbreaks, is the extent to which the containment measures are halting the viral spread. A straightforward way to assess this is to tally the active cases and the recovered ones throughout the epidemic. Here, we show how epidemic control can be assessed with molecular information during a well characterized epidemic in Iceland. We demonstrate how the viral concentration decreased in those newly diagnosed as the epidemic transitioned from exponential growth phase to containment phase. The viral concentration in the cases identified in population screening decreased faster than in those symptomatic and considered at high risk and that were targeted by the healthcare system. The viral concentration persists in recovering individuals as we found that half of the cases are still positive after two weeks. We demonstrate that accumulation of mutations in SARS-CoV-2 genome can be exploited to track the rate of new viral generations throughout the different phases of the epidemic, where the accumulation of mutations decreases as the transmission rate decreases in the containment phase. Overall, the molecular signatures of SARS-CoV-2 infections contain valuable epidemiological information that can be used to assess the effectiveness of containment measures.
Significant underestimation of radiative forcing by aerosol–cloud interactions derived from satellite-based methods
Authors: Jia Hailing , Ma Xiaoyan , Yu Fangqun , Quaas Johannes
Published: June 2021

Satellite-based estimates of radiative forcing by aerosol–cloud interactions (RFaci) are consistently smaller than those from global models, hampering accurate projections of future climate change. Here we show that the discrepancy can be substantially reduced by correcting sampling biases induced by inherent limitations of satellite measurements, which tend to artificially discard the clouds with high cloud fraction. Those missed clouds exert a stronger cooling effect, and are more sensitive to aerosol perturbations. By accounting for the sampling biases, the magnitude of RFaci (from −0.38 to −0.59 W m−2) increases by 55 % globally (133 % over land and 33 % over ocean). Notably, the RFacifurther increases to −1.09 W m−2when switching total aerosol optical depth (AOD) to fine-mode AOD that is a better proxy for CCN than AOD. In contrast to previous weak satellite-based RFaci, the improved one substantially increases (especially over land), resolving a major difference with models.
In silico voltage-sensitive dye imaging reveals the emergent dynamics of cortical populations
Authors: Newton Taylor H. , Reimann Michael W. , Abdellah Marwan , Chevtchenko Grigori , Muller Eilif B. , Markram Henry
Published: June 2021

Voltage-sensitive dye imaging (VSDI) is a powerful technique for interrogating membrane potential dynamics in assemblies of cortical neurons, but with effective resolution limits that confound interpretation. To address this limitation, we developed an in silico model of VSDI in a biologically faithful digital reconstruction of rodent neocortical microcircuitry. Using this model, we extend previous experimental observations regarding the cellular origins of VSDI, finding that the signal is driven primarily by neurons in layers 2/3 and 5, and that VSDI measurements do not capture individual spikes. Furthermore, we test the capacity of VSD image sequences to discriminate between afferent thalamic inputs at various spatial locations to estimate a lower bound on the functional resolution of VSDI. Our approach underscores the power of a bottom-up computational approach for relating scales of cortical processing.
IL-6 regulates autophagy and chemotherapy resistance by promoting BECN1 phosphorylation
Authors: Hu Fuqing , Song Da , Yan Yumeng , Huang Changsheng , Shen Chentao , Lan Jingqin , Chen Yaqi , Liu Anyi , Wu Qi , Sun Li , Xu Feng , Hu Fayong , Chen Lisheng , Luo Xuelai , Feng Yongdong , Huang Shengyou , Hu Junbo , Wang Guihua
Published: June 2021

Extracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy.
Seasonality of agricultural exposure as an important predictor of seasonal yellow fever spillover in Brazil
Authors: Hamlet Arran , Ramos Daniel Garkauskas , Gaythorpe Katy A. M. , Romano Alessandro Pecego Martins , Garske Tini , Ferguson Neil M.
Published: June 2021

Yellow fever virus (YFV) is a zoonotic arbovirus affecting both humans and non-human primates (NHP’s) in Africa and South America. Previous descriptions of YF’s seasonality have relied purely on climatic explanations, despite the high proportion of cases occurring in people involved in agriculture. We use a series of random forest classification models to predict the monthly occurrence of YF in humans and NHP’s across Brazil, by fitting four classes of covariates related to the seasonality of climate and agriculture (planting and harvesting), crop output and host demography. We find that models captured seasonal YF reporting in humans and NHPs when they considered seasonality of agriculture rather than climate, particularly for monthly aggregated reports. These findings illustrate the seasonality of exposure, through agriculture, as a component of zoonotic spillover. Additionally, by highlighting crop types and anthropogenic seasonality, these results could directly identify areas at highest risk of zoonotic spillover.
Ladder-like energy-relaying exciplex enables 100% internal quantum efficiency of white TADF-based diodes in a single emissive layer
Authors: Han Chunmiao , Du Ruiming , Xu Hui , Han Sanyang , Ma Peng , Bian Jinkun , Duan Chunbo , Wei Ying , Sun Mingzhi , Liu Xiaogang , Huang Wei
Published: June 2021

Development of white organic light-emitting diodes based on purely thermally activated delayed fluorescence with a single-emissive-layer configuration has been a formidable challenge. Here, we report the rational design of a donor-acceptor energy-relaying exciplex and its utility in fabricating single-emissive-layer, thermally activated delayed fluorescence-based white organic light-emitting diodes that exhibit 100% internal quantum efficiency, 108.2 lm W−1 power efficiency, and 32.7% external quantum efficiency. This strategy enables thin-film fabrication of an 8 cm × 8 cm thermally activated delayed fluorescence white organic light-emitting diodes (10 inch2) prototype with 82.7 lm W−1 power efficiency and 25.0% external quantum efficiency. Introduction of a phosphine oxide-based acceptor with a steric group to the exciplex limits donor-acceptor triplet coupling, providing dual levels of high-lying and low-lying triplet energy. Transient spectroscopic characterizations confirm that a ladder-like energy relaying occurs from the high-lying triplet level of the exciplex to a blue emitter, then to the low-lying triplet level of the phosphine oxide acceptor, and ultimately to the yellow emitter. Our results demonstrate the broad applicability of energy relaying in multicomponent systems for exciton harvesting, providing opportunities for the development of third-generation white organic light-emitting diode light sources.
Influence of static disorder of charge transfer state on voltage loss in organic photovoltaics
Authors: Yan Jun , Rezasoltani Elham , Azzouzi Mohammed , Eisner Flurin , Nelson Jenny
Published: June 2021

Spectroscopic measurements of charge transfer (CT) states provide valuable insight into the voltage losses in organic photovoltaics (OPVs). Correct interpretation of CT-state spectra depends on knowledge of the underlying broadening mechanisms, and the relative importance of molecular vibrational broadening and variations in the CT-state energy (static disorder). Here, we present a physical model, that obeys the principle of detailed balance between photon absorption and emission, of the impact of CT-state static disorder on voltage losses in OPVs. We demonstrate that neglect of CT-state disorder in the analysis of spectra may lead to incorrect estimation of voltage losses in OPV devices. We show, using measurements of polymer:non-fullerene blends of different composition, how our model can be used to infer variations in CT-state energy distribution that result from variations in film microstructure. This work highlights the potential impact of static disorder on the characteristics of disordered organic blend devices.
Skin strata delineation in reflectance confocal microscopy images using recurrent convolutional networks with attention
Authors: Bozkurt Alican , Kose Kivanc , Coll-Font Jaume , Alessi-Fox Christi , Brooks Dana H. , Dy Jennifer G. , Rajadhyaksha Milind
Published: June 2021

Reflectance confocal microscopy (RCM) is an effective non-invasive tool for cancer diagnosis. However, acquiring and reading RCM images requires extensive training and experience, and novice clinicians exhibit high discordance in diagnostic accuracy. Quantitative tools to standardize image acquisition could reduce both required training and diagnostic variability. To perform diagnostic analysis, clinicians collect a set of RCM mosaics (RCM images concatenated in a raster fashion to extend the field view) at 4–5 specific layers in skin, all localized in the junction between the epidermal and dermal layers (dermal-epidermal junction, DEJ), necessitating locating that junction before mosaic acquisition. In this study, we automate DEJ localization using deep recurrent convolutional neural networks to delineate skin strata in stacks of RCM images collected at consecutive depths. Success will guide to automated and quantitative mosaic acquisition thus reducing inter operator variability and bring standardization in imaging. Testing our model against an expert labeled dataset of 504 RCM stacks, we achieved $$88.07\%$$

88.07
%

classification accuracy and nine-fold reduction in the number of anatomically impossible errors compared to the previous state-of-the-art.
Alcohol intoxication, but not hangover, differentially impairs learning and automatization of complex motor response sequences
Authors: Opitz Antje , Ghin Filippo , Hubert Jan , Verster Joris C. , Beste Christian , Stock Ann-Kathrin
Published: June 2021

Behavioral automatization usually makes us more efficient and less error-prone, but may also foster dysfunctional behavior like alcohol abuse. Yet, it has remained unclear whether alcohol itself causes the shift from controlled to habitual behavior commonly observed in alcohol use disorder (AUD). We thus investigated how the acute and post-acute effects of binge drinking affect the automatization of motor response sequences and the execution of automated vs. controlled motor response sequences.N = 70 healthy young men performed a newly developed automatization paradigm once sober and once after binge drinking (half of them intoxicated and half of them hungover). While we found no significant effects of alcohol hangover, acute intoxication (~ 1.2 ‰) had two dissociable effects: Firstly, it impaired the automatization of complex motor response sequence execution. Secondly, it eliminated learning effects in response selection and pre-motor planning processes. The results suggest that alcohol hangover did not affect controlled or automated processes, and disprove the assumption that alcohol intoxication generally spares or facilitates motor response sequence automatization. As these effects could be specific to the investigated explicit learning context, acute intoxication might potentially still improve the execution of pre-existing automatisms and/or the implicit acquisition of motor response sequence automatisms.
Physical activity attenuates the associations of systemic immune-inflammation index with total and cause-specific mortality among middle-aged and older populations
Authors: Li Hang , Wu Xiulong , Bai Yansen , Wei Wei , Li Guyanan , Fu Ming , Jie Jiali , Wang Chenming , Guan Xin , Feng Yue , Meng Hua , Li Mengying , He Meian , Zhang Xiaomin , Guo Huan
Published: June 2021

Systemic immune-inflammation index (SII) emerged as a biomarker of chronic inflammation and an independent prognostic factor for many cancers. We aimed to investigate the associations of SII level with total and cause-specific mortality risks in the general populations, and the potential modification effects of lifestyle-related factors on the above associations. In this study, we included 30,521 subjects from the Dongfeng-Tongji (DFTJ) cohort and 25,761 subjects from the National Health and Nutrition Examination Survey (NHANES) 1999–2014. Cox proportional hazards regression models were used to estimate the associations of SII with mortality from all-cause, cardiovascular diseases (CVD), cancer and other causes. In the DFTJ cohort, compared to subjects in the low SII subgroup, those within the middle and high SII subgroups had increased risks of total mortality [hazard ratio, HR (95% confidence interval, CI) = 1.12 (1.03–1.22) and 1.26 (1.16–1.36), respectively) and CVD mortality [HR (95%CI) = 1.36 (1.19–1.55) and 1.50 (1.32–1.71), respectively]; those within the high SII subgroup had a higher risk of other causes mortality [HR (95%CI) = 1.28 (1.09–1.49)]. In the NHANES 1999–2014, subjects in the high SII subgroup had higher risks of total, CVD, cancer and other causes mortality [HR (95%CI) = 1.38 (1.27–1.49), 1.33 (1.11–1.59), 1.22 (1.04–1.45) and 1.47 (1.32–1.63), respectively]. For subjects with a high level of SII, physical activity could attenuate a separate 30% and 32% risk of total and CVD mortality in the DFTJ cohort, and a separate 41% and 59% risk of total and CVD mortality in the NHANES 1999–2014. Our study suggested high SII level may increase total and CVD mortality in the general populations and physical activity exerted a beneficial effect on the above associations.
Novelty and imitation within the brain: a Darwinian neurodynamic approach to combinatorial problems
Authors: Czégel Dániel , Giaffar Hamza , Csillag Márton , Futó Bálint , Szathmáry Eörs
Published: June 2021

Efficient search in vast combinatorial spaces, such as those of possible action sequences, linguistic structures, or causal explanations, is an essential component of intelligence. Is there any computational domain that is flexible enough to provide solutions to such diverse problems and can be robustly implemented over neural substrates? Based on previous accounts, we propose that a Darwinian process, operating over sequential cycles of imperfect copying and selection of neural informational patterns, is a promising candidate. Here we implement imperfect information copying through one reservoir computing unit teaching another. Teacher and learner roles are assigned dynamically based on evaluation of the readout signal. We demonstrate that the emerging Darwinian population of readout activity patterns is capable of maintaining and continually improving upon existing solutions over rugged combinatorial reward landscapes. We also demonstrate the existence of a sharp error threshold, a neural noise level beyond which information accumulated by an evolutionary process cannot be maintained. We introduce a novel analysis method, neural phylogenies, that displays the unfolding of the neural-evolutionary process.
Omics analyses and biochemical study of Phlebiopsis gigantea elucidate its degradation strategy of wood extractives
Authors: Iwata Mana , Gutiérrez Ana , Marques Gisela , Sabat Grzegorz , Kersten Philip J. , Cullen Daniel , Bhatnagar Jennifer M. , Yadav Jagjit , Lipzen Anna , Yoshinaga Yuko , Sharma Aditi , Adam Catherine , Daum Christopher , Ng Vivian , Grigoriev Igor V. , Hori Chiaki
Published: June 2021

Wood extractives, solvent-soluble fractions of woody biomass, are considered to be a factor impeding or excluding fungal colonization on the freshly harvested conifers. Among wood decay fungi, the basidiomycete Phlebiopsis gigantea has evolved a unique enzyme system to efficiently transform or degrade conifer extractives but little is known about the mechanism(s). In this study, to clarify the mechanism(s) of softwood degradation, we examined the transcriptome, proteome, and metabolome of P. gigantea when grown on defined media containing microcrystalline cellulose and pine sapwood extractives. Beyond the conventional enzymes often associated with cellulose, hemicellulose and lignin degradation, an array of enzymes implicated in the metabolism of softwood lipophilic extractives such as fatty and resin acids, steroids and glycerides was significantly up-regulated. Among these, a highly expressed and inducible lipase is likely responsible for lipophilic extractive degradation, based on its extracellular location and our characterization of the recombinant enzyme. Our results provide insight into physiological roles of extractives in the interaction between wood and fungi.
Doublons, topology and interactions in a one-dimensional lattice
Authors: Azcona P. Martínez , Downing C. A.
Published: June 2021

We investigate theoretically the Bose–Hubbard version of the celebrated Su-Schrieffer-Heeger topological model, which essentially describes a one-dimensional dimerized array of coupled oscillators with on-site interactions. We study the physics arising from the whole gamut of possible dimerizations of the chain, including both the weakly and the strongly dimerized limiting cases. Focusing on two-excitation subspace, we systematically uncover and characterize the different types of states which may emerge due to the competition between the inter-oscillator couplings, the intrinsic topology of the lattice, and the strength of the on-site interactions. In particular, we discuss the formation of scattering bands full of extended states, bound bands full of two-particle pairs (including so-called ‘doublons’, when the pair occupies the same lattice site), and different flavors of topological edge states. The features we describe may be realized in a plethora of systems, including nanoscale architectures such as photonic cavities, optical lattices and qubits, and provide perspectives for topological two-particle and many-body physics.
Pelvic floor dysfunction one year after first childbirth in relation to perineal tear severity
Authors: Huber Malin , Malers Ellen , Tunón Katarina
Published: June 2021

The aims of this study were to evaluate pelvic floor dysfunction symptoms one year after delivery and investigate whether adverse functional outcomes after childbirth were related to the degree of perineal injury. A prospective cohort of 776 primiparas were included. Self-reported pelvic floor function data were obtained using a web-based questionnaire. Women with no/first-degree injuries, second-degree injuries, third-/fourth-degree injuries (obstetric anal sphincter injury, OASI) and cesarean section were compared. A total of 511 women (66%) responded. Second-degree tears were a risk factor for stress incontinence (aOR 2.6 (95% CI 1.3–5.1)). Cesarean section was protective against stress incontinence (aOR 0.2 (95% CI 0.1–0.9)). OASI was a risk factor for urge incontinence (aOR 4.8 (95% CI 1.6–15)), prolapse (aOR 7.7 (95% CI 2.1–29)) and pelvic pain (OR 3.3 (95% CI 1.1–10)). Dyspareunia was reported by 38% of women, 63% of women in the OASI group (aOR 3.1 (95% CI 1.1–9.0)). Women with OASI reported that the injury affected daily life (OR 18 (95% CI 5.1–59)). Pelvic floor dysfunction is common after childbirth, even in women with moderate injury. Women with OASI had significantly higher risks of symptoms of prolapse, urge urinary incontinence, pain, dyspareunia and impacts on daily life.
A dose response model for Staphylococcus aureus
Authors: Chandrasekaran Srikiran , Jiang Sunny C.
Published: June 2021

Dose-response models (DRMs) are used to predict the probability of microbial infection when a person is exposed to a given number of pathogens. In this study, we propose a new DRM forStaphylococcus aureus(SA), which causes skin and soft-tissue infections. The current approach to SA dose-response is only partially mechanistic and assumes that individual bacteria do not interact with each other. Our proposed two-compartment (2C) model assumes that bacteria that have not adjusted to the host environment decay. After adjusting to the host, they exhibit logistic/cooperative growth, eventually causing disease. The transition between the adjusted and un-adjusted states is a stochastic process, which the 2C DRM explicitly models to predict response probabilities. By fitting the 2C model to SA pathogenesis data, we show that cooperation between individual SA bacteria is sufficient (and, within the scope of the 2C model, necessary) to characterize the dose-response. This is a departure from the classical single-hit theory of dose-response, where complete independence is assumed between individual pathogens. From a quantitative microbial risk assessment standpoint, the mechanistic basis of the 2C DRM enables transparent modeling of dose-response of antibiotic-resistant SA that has not been possible before. It also enables the modeling of scenarios having multiple/non-instantaneous exposures, with minimal assumptions.
Cytokine signatures of end organ injury in COVID-19
Authors: Gómez-Escobar Luis G. , Hoffman Katherine L. , Choi Justin J. , Borczuk Alain , Salvatore Steven , Alvarez-Mulett Sergio L. , Galvan Manuel D. , Zhao Zhen , Racine-Brzostek Sabrina E. , Yang He S. , Stout-Delgado Heather W. , Choi Mary E. , Choi Augustine M. K. , Cho Soo Jung , Schenck Edward J.
Published: June 2021

Increasing evidence has shown that Coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunologic response. We aimed to assess the differences in inflammatory cytokines in COVID-19 patients compared to contemporaneously hospitalized controls and then analyze the relationship between these cytokines and the development of Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI) and mortality. In this cohort study of hospitalized patients, done between March third, 2020 and April first, 2020 at a quaternary referral center in New York City we included adult hospitalized patients with COVID-19 and negative controls. Serum specimens were obtained on the first, second, and third hospital day and cytokines were measured by Luminex. Autopsies of nine cohort patients were examined. We identified 90 COVID-19 patients and 51 controls. Analysis of 48 inflammatory cytokines revealed upregulation of macrophage induced chemokines, T-cell related interleukines and stromal cell producing cytokines in COVID-19 patients compared to the controls. Moreover, distinctive cytokine signatures predicted the development of ARDS, AKI and mortality in COVID-19 patients. Specifically, macrophage-associated cytokines predicted ARDS, T cell immunity related cytokines predicted AKI and mortality was associated with cytokines of activated immune pathways, of which IL-13 was universally correlated with ARDS, AKI and mortality. Histopathological examination of the autopsies showed diffuse alveolar damage with significant mononuclear inflammatory cell infiltration. Additionally, the kidneys demonstrated glomerular sclerosis, tubulointerstitial lymphocyte infiltration and cortical and medullary atrophy. These patterns of cytokine expression offer insight into the pathogenesis of COVID-19 disease, its severity, and subsequent lung and kidney injury suggesting more targeted treatment strategies.
Attractive and repulsive residue fragments at the interface of SARS-CoV-2 and hACE2
Authors: Rodriguez Jorge H.
Published: June 2021

The initial stages of SARS-CoV-2 coronavirus attachment to human cells are mediated by non-covalent interactions of viral spike (S) protein receptor binding domains (S-RBD) with human ACE2 receptors (hACE2). Structural characterization techniques, such as X-ray crystallography (XRC) and cryoelectron microscopy (cryo-EM), previously identified SARS-CoV-2 spike protein conformations and their surface residues in contact with hACE2. However, recent quantum-biochemical calculations on the structurally related S-RBD of SARS-CoV-1 identified some contact-residue fragments as intrinsically attractive and others as repulsive. This indicates that not all surface residues are equally important for hACE2 attachment. Here, using similar quantum-biochemical methods, we report some four-residue fragments (i.e quartets) of the SARS-CoV-2 S-RBD as intrinsically attractive towards hACE2 and, therefore, directly promoting host–virus non-covalent binding. Other fragments are found to be repulsive although involved in intermolecular recognition. By evaluation of their respective intermolecular interaction energies we found two hACE2 fragments that include contact residues (ASP30, LYS31, HIS34) and (ASP38, TYR41, GLN42), respectively, behaving as important SARS-CoV-2 attractors. LYS353 also promotes viral binding via several mechanisms including dispersion van der Waals forces. Similarly, among others, three SARS-CoV-2 S-RBD fragments that include residues (GLN498, THR500, ASN501), (GLU484, PHE486, ASN487) and (LYS417), respectively, were identified as hACE2 attractors. In addition, key hACE2 quartets identified as weakly-repulsive towards the S-RBD of SARS-CoV-1 were found strongly attractive towards SARS-CoV-2 explaining, in part, the stronger binding affinity of hACE2 towards the latter coronavirus. These findings may guide the development of synthetic antibodies or identify potential viral epitopes.
Natural nutrient subsidies alter demographic rates in a functionally important coral-reef fish
Authors: Benkwitt Cassandra E. , Taylor Brett M. , Meekan Mark G. , Graham Nicholas A. J.
Published: June 2021

By improving resource quality, cross-ecosystem nutrient subsidies may boost demographic rates of consumers in recipient ecosystems, which in turn can affect population and community dynamics. However, empirical studies on how nutrient subsidies simultaneously affect multiple demographic rates are lacking, in part because humans have disrupted the majority of these natural flows. Here, we compare the demographics of a sex-changing parrotfish (Chlorurus sordidus) between reefs where cross-ecosystem nutrients provided by seabirds are available versus nearby reefs where invasive, predatory rats have removed seabird populations. For this functionally important species, we found evidence for a trade-off between investing in growth and fecundity, with parrotfish around rat-free islands with many seabirds exhibiting 35% faster growth, but 21% lower size-based fecundity, than those around rat-infested islands with few seabirds. Although there were no concurrent differences in population-level density or biomass, overall mean body size was 16% larger around rat-free islands. Because the functional significance of parrotfish as grazers and bioeroders increases non-linearly with size, the increased growth rates and body sizes around rat-free islands likely contributes to higher ecosystem function on coral reefs that receive natural nutrient subsidies. More broadly, these results demonstrate additional benefits, and potential trade-offs, of restoring natural nutrient pathways for recipient ecosystems.