bluuebunny/crossref_metadata_2025 huggingface dataset:
An N-Cadherin 2 expressing epithelial cell subpopulation predicts response to surgery, chemotherapy and immunotherapy in bladder cancer
Authors: Gouin Kenneth H. , Ing Nathan , Plummer Jasmine T. , Rosser Charles J. , Ben Cheikh Bassem , Oh Catherine , Chen Stephanie S. , Chan Keith Syson , Furuya Hideki , Tourtellotte Warren G. , Knott Simon R. V. , Theodorescu Dan
Published: August 2021

Neoadjuvant chemotherapy (NAC) prior to surgery and immune checkpoint therapy (ICT) have revolutionized bladder cancer management. However, stratification of patients that would benefit most from these modalities remains a major clinical challenge. Here, we combine single nuclei RNA sequencing with spatial transcriptomics and single-cell resolution spatial proteomic analysis of human bladder cancer to identify an epithelial subpopulation with therapeutic response prediction ability. These cells express Cadherin 12 (CDH12, N-Cadherin 2), catenins, and other epithelial markers. CDH12-enriched tumors define patients with poor outcome following surgery with or without NAC. In contrast, CDH12-enriched tumors exhibit superior response to ICT. In all settings, patient stratification by tumor CDH12 enrichment offers better prediction of outcome than currently established bladder cancer subtypes. Molecularly, the CDH12 population resembles an undifferentiated state with inherently aggressive biology including chemoresistance, likely mediated through progenitor-like gene expression and fibroblast activation. CDH12-enriched cells express PD-L1 and PD-L2 and co-localize with exhausted T-cells, possibly mediated through CD49a (ITGA1), providing one explanation for ICT efficacy in these tumors. Altogether, this study describes a cancer cell population with an intriguing diametric response to major bladder cancer therapeutics. Importantly, it also provides a compelling framework for designing biomarker-guided clinical trials.
Cryo-EM structures of the TTYH family reveal a novel architecture for lipid interactions
Authors: Sukalskaia Anastasiia , Straub Monique S. , Deneka Dawid , Sawicka Marta , Dutzler Raimund
Published: August 2021

The Tweety homologs (TTYHs) are members of a conserved family of eukaryotic membrane proteins that are abundant in the brain. The three human paralogs were assigned to function as anion channels that are either activated by Ca2+ or cell swelling. To uncover their unknown architecture and its relationship to function, we have determined the structures of human TTYH1–3 by cryo-electron microscopy. All structures display equivalent features of a dimeric membrane protein that contains five transmembrane segments and an extended extracellular domain. As none of the proteins shows attributes reminiscent of an anion channel, we revisited functional experiments and did not find any indication of ion conduction. Instead, we find density in an extended hydrophobic pocket contained in the extracellular domain that emerges from the lipid bilayer, which suggests a role of TTYH proteins in the interaction with lipid-like compounds residing in the membrane.
Ultrafast femtosecond pressure modulation of structure and exciton kinetics in 2D halide perovskites for enhanced light response and stability
Authors: Song Chunpeng , Yang Huanrui , Liu Feng , Cheng Gary J.
Published: August 2021

The carriers’ transportation between layers of two-dimensional (2D) perovskites is inhibited by dielectric confinement. Here, for the first time, we employ a femtosecond laser to introduce ultrafast shock pressure in the range of 0~15.45 GPa to reduce dielectric confinement by modulating the structure and exciton dynamics in a perovskite single crystal (PSCs), e.g. (F-PEA)2PbI4 (4-fluorophenethylammonium, F-PEA). The density functional theory (DFT) simulation and experimental results show that the inorganic framework distortion results in a bandgap reduction. It was found that the exciton-optical phonon coupling and free excitons (FEs) binding energy are minimized at 2.75 GPa shock pressure due to a reduction in dielectric confinement. The stability testing under various harsh light and humid thermal conditions shows that femtosecond laser shocking improves the stability of (F-PEA)2PbI4 PSCs. Femtosecond laser shock processing provides a new approach for regulating the structure and enhancing halide perovskite properties.
Ultra-conformal skin electrodes with synergistically enhanced conductivity for long-time and low-motion artifact epidermal electrophysiology
Authors: Zhao Yan , Zhang Song , Yu Tianhao , Zhang Yan , Ye Guo , Cui Han , He Chengzhi , Jiang Wenchao , Zhai Yu , Lu Chunming , Gu Xiaodan , Liu Nan
Published: August 2021

Accurate and imperceptible monitoring of electrophysiological signals is of primary importance for wearable healthcare. Stiff and bulky pregelled electrodes are now commonly used in clinical diagnosis, causing severe discomfort to users for long-time using as well as artifact signals in motion. Here, we report a ~100 nm ultra-thin dry epidermal electrode that is able to conformably adhere to skin and accurately measure electrophysiological signals. It showed low sheet resistance (~24 Ω/sq, 4142 S/cm), high transparency, and mechano-electrical stability. The enhanced optoelectronic performance was due to the synergistic effect between graphene and poly (3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), which induced a high degree of molecular ordering on PEDOT and charge transfer on graphene by strong π-π interaction. Together with ultra-thin nature, this dry epidermal electrode is able to accurately monitor electrophysiological signals such as facial skin and brain activity with low-motion artifact, enabling human-machine interfacing and long-time mental/physical health monitoring.
Rational design of pyrrole derivatives with aggregation-induced phosphorescence characteristics for time-resolved and two-photon luminescence imaging
Authors: Yang Jianhui , Zhang Yahui , Wu Xinghui , Dai Wenbo , Chen Dan , Shi Jianbing , Tong Bin , Peng Qian , Xie Haiyan , Cai Zhengxu , Dong Yuping , Zhang Xin
Published: August 2021

Pure organic room-temperature phosphorescent (RTP) materials have been suggested to be promising bioimaging materials due to their good biocompatibility and long emission lifetime. Herein, we report a class of RTP materials. These materials are developed through the simple introduction of an aromatic carbonyl to a tetraphenylpyrrole molecule and also exhibit aggregation-induced emission (AIE) properties. These molecules show non-emission in solution and purely phosphorescent emission in the aggregated state, which are desirable properties for biological imaging. Highly crystalline nanoparticles can be easily fabricated with a long emission lifetime (20 μs), which eliminate background fluorescence interference from cells and tissues. The prepared nanoparticles demonstrate two-photon absorption characteristics and can be excited by near infrared (NIR) light, making them promising materials for deep-tissue optical imaging. This integrated aggregation-induced phosphorescence (AIP) strategy diversifies the existing pool of bioimaging agents to inspire the development of bioprobes in the future.
Polarized X-ray scattering measures molecular orientation in polymer-grafted nanoparticles
Authors: Mukherjee Subhrangsu , Streit Jason K. , Gann Eliot , Saurabh Kumar , Sunday Daniel F. , Krishnamurthy Adarsh , Ganapathysubramanian Baskar , Richter Lee J. , Vaia Richard A. , DeLongchamp Dean M.
Published: August 2021

Polymer chains are attached to nanoparticle surfaces for many purposes, including altering solubility, influencing aggregation, dispersion, and even tailoring immune responses in drug delivery. The most unique structural motif of polymer-grafted nanoparticles (PGNs) is the high-density region in the corona where polymer chains are stretched under significant confinement, but orientation of these chains has never been measured because conventional nanoscale-resolved measurements lack sensitivity to polymer orientation in amorphous regions. Here, we directly measure local chain orientation in polystyrene grafted gold nanoparticles using polarized resonant soft X-ray scattering (P-RSoXS). Using a computational scattering pattern simulation approach, we measure the thickness of the anisotropic region of the corona and extent of chain orientation within it. These results demonstrate the power of P-RSoXS to discover and quantify orientational aspects of structure in amorphous soft materials and provide a framework for applying this emerging technique to more complex, chemically heterogeneous systems in the future.
Azobenzene-containing liquid crystalline composites for robust ultraviolet detectors based on conversion of illuminance-mechanical stress-electric signals
Authors: Zheng Xiaoxiong , Jia Yining , Chen Aihua
Published: August 2021

Wearable ultraviolet (UV) detectors have attracted considerable interest in the military and civilian realms. However, semiconductor-based UV detectors are easily interfered by elongation due to the elastic modulus incompatibility between rigid semiconductors and polymer matrix. Polymer detectors containing UV responsive moieties seriously suffer from slow response time. Herein, a UV illuminance–mechanical stress–electric signal conversion has been proposed based on well-defined ionic liquid (IL)-containing liquid crystalline polymer (ILCP) and highly elastic polyurethane (TPU) composite fabrics, to achieve a robust UV monitoring and shielding device with a fast response time of 5 s. Due to the electrostatic interactions and hydrogen bonds between ILs and LC networks, the ILCP-based device can effectively prevent the exudation of ILs and maintain stable performance upon stretching, bending, washing and 1000 testing cycles upon 365 nm UV irradiation. This work provides a generalizable approach toward the development of full polymer-based wearable electronics and soft robots.
Atomically dispersed Pb ionic sites in PbCdSe quantum dot gels enhance room-temperature NO2 sensing
Authors: Geng Xin , Li Shuwei , Mawella-Vithanage Lalani , Ma Tao , Kilani Mohamed , Wang Bingwen , Ma Lu , Hewa-Rahinduwage Chathuranga C. , Shafikova Alina , Nikolla Eranda , Mao Guangzhao , Brock Stephanie L. , Zhang Liang , Luo Long
Published: August 2021

Atmospheric NO2 is of great concern due to its adverse effects on human health and the environment, motivating research on NO2 detection and remediation. Existing low-cost room-temperature NO2 sensors often suffer from low sensitivity at the ppb level or long recovery times, reflecting the trade-off between sensor response and recovery time. Here, we report an atomically dispersed metal ion strategy to address it. We discover that bimetallic PbCdSe quantum dot (QD) gels containing atomically dispersed Pb ionic sites achieve the optimal combination of strong sensor response and fast recovery, leading to a high-performance room-temperature p-type semiconductor NO2 sensor as characterized by a combination of ultra–low limit of detection, high sensitivity and stability, fast response and recovery. With the help of theoretical calculations, we reveal the high performance of the PbCdSe QD gel arises from the unique tuning effects of Pb ionic sites on NO2 binding at their neighboring Cd sites.
Targeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma
Authors: Scagliola Alessandra , Miluzio Annarita , Ventura Gabriele , Oliveto Stefania , Cordiglieri Chiara , Manfrini Nicola , Cirino Delia , Ricciardi Sara , Valenti Luca , Baselli Guido , D’Ambrosio Roberta , Maggioni Marco , Brina Daniela , Bresciani Alberto , Biffo Stefano
Published: August 2021

A postprandial increase of translation mediated by eukaryotic Initiation Factor 6 (eIF6) occurs in the liver. Its contribution to steatosis and disease is unknown. In this study we address whether eIF6-driven translation contributes to disease progression. eIF6 levels increase throughout the progression from Non-Alcoholic Fatty Liver Disease (NAFLD) to hepatocellular carcinoma. Reduction of eIF6 levels protects the liver from disease progression. eIF6 depletion blunts lipid accumulation, increases fatty acid oxidation (FAO) and reduces oncogenic transformation in vitro. In addition, eIF6 depletion delays the progression from NAFLD to hepatocellular carcinoma, in vivo. Mechanistically, eIF6 depletion reduces the translation of transcription factor C/EBPβ, leading to a drop in biomarkers associated with NAFLD progression to hepatocellular carcinoma and preserves mitochondrial respiration due to the maintenance of an alternative mTORC1-eIF4F translational branch that increases the expression of transcription factor YY1. We provide proof-of-concept that in vitro pharmacological inhibition of eIF6 activity recapitulates the protective effects of eIF6 depletion. We hypothesize the existence of a targetable, evolutionarily conserved translation circuit optimized for lipid accumulation and tumor progression.
Optimization of C-to-G base editors with sequence context preference predictable by machine learning methods
Authors: Yuan Tanglong , Yan Nana , Fei Tianyi , Zheng Jitan , Meng Juan , Li Nana , Liu Jing , Zhang Haihang , Xie Long , Ying Wenqin , Li Di , Shi Lei , Sun Yongsen , Li Yongyao , Li Yixue , Sun Yidi , Zuo Erwei
Published: August 2021

Efficient and precise base editors (BEs) for C-to-G transversion are highly desirable. However, the sequence context affecting editing outcome largely remains unclear. Here we report engineered C-to-G BEs of high efficiency and fidelity, with the sequence context predictable via machine-learning methods. By changing the species origin and relative position of uracil-DNA glycosylase and deaminase, together with codon optimization, we obtain optimized C-to-G BEs (OPTI-CGBEs) for efficient C-to-G transversion. The motif preference of OPTI-CGBEs for editing 100 endogenous sites is determined in HEK293T cells. Using a sgRNA library comprising 41,388 sequences, we develop a deep-learning model that accurately predicts the OPTI-CGBE editing outcome for targeted sites with specific sequence context. These OPTI-CGBEs are further shown to be capable of efficient base editing in mouse embryos for generating Tyr-edited offspring. Thus, these engineered CGBEs are useful for efficient and precise base editing, with outcome predictable based on sequence context of targeted sites.
Deep learning-based transformation of H&E stained tissues into special stains
Authors: de Haan Kevin , Zhang Yijie , Zuckerman Jonathan E. , Liu Tairan , Sisk Anthony E. , Diaz Miguel F. P. , Jen Kuang-Yu , Nobori Alexander , Liou Sofia , Zhang Sarah , Riahi Rana , Rivenson Yair , Wallace W. Dean , Ozcan Aydogan
Published: August 2021

Pathology is practiced by visual inspection of histochemically stained tissue slides. While the hematoxylin and eosin (H&E) stain is most commonly used, special stains can provide additional contrast to different tissue components. Here, we demonstrate the utility of supervised learning-based computational stain transformation from H&E to special stains (Masson’s Trichrome, periodic acid-Schiff and Jones silver stain) using kidney needle core biopsy tissue sections. Based on the evaluation by three renal pathologists, followed by adjudication by a fourth pathologist, we show that the generation of virtual special stains from existing H&E images improves the diagnosis of several non-neoplastic kidney diseases, sampled from 58 unique subjects (P = 0.0095). A second study found that the quality of the computationally generated special stains was statistically equivalent to those which were histochemically stained. This stain-to-stain transformation framework can improve preliminary diagnoses when additional special stains are needed, also providing significant savings in time and cost.
Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters
Authors: Parker Seth J. , Encarnación-Rosado Joel , Hollinshead Kate E. R. , Hollinshead David M. , Ash Leonard J. , Rossi Juan A. K. , Lin Elaine Y. , Sohn Albert S. W. , Philips Mark R. , Jones Drew R. , Kimmelman Alec C.
Published: August 2021

α-ketoglutarate (KG), also referred to as 2-oxoglutarate, is a key intermediate of cellular metabolism with pleiotropic functions. Cell-permeable esterified analogs are widely used to study how KG fuels bioenergetic and amino acid metabolism and DNA, RNA, and protein hydroxylation reactions, as cellular membranes are thought to be impermeable to KG. Here we show that esterified KG analogs rapidly hydrolyze in aqueous media, yielding KG that, in contrast to prevailing assumptions, imports into many cell lines. Esterified KG analogs exhibit spurious KG-independent effects on cellular metabolism, including extracellular acidification, arising from rapid hydrolysis and de-protonation of α-ketoesters, and significant analog-specific inhibitory effects on glycolysis or mitochondrial respiration. We observe that imported KG decarboxylates to succinate in the cytosol and contributes minimally to mitochondrial metabolism in many cell lines cultured in normal conditions. These findings demonstrate that nuclear and cytosolic KG-dependent reactions may derive KG from functionally distinct subcellular pools and sources.
Unsupervised discovery of thin-film photovoltaic materials from unlabeled data
Authors: Wang Zhilong , Cai Junfei , Wang Qingxun , Wu SiCheng , Li Jinjin
Published: August 2021

Quaternary chalcogenide semiconductors (I2-II-IV-X4) are key materials for thin-film photovoltaics (PVs) to alleviate the energy crisis. Scaling up of PVs requires the discovery of I2-II-IV-X4 with good photoelectric properties; however, the structure search space is significantly large to explore exhaustively. The scarcity of available data impedes even many machine learning (ML) methods. Here, we employ the unsupervised learning (UL) method to discover I2-II-IV-X4 that alleviates the challenge of data scarcity. We screen all the I2-II-IV-X4 from the periodic table as the initial data and finally select eight candidates through UL. As predicted by ab initio calculations, they exhibit good optical conversion efficiency, strong optical responses, and good thermal stabilities at room temperatures. This typical case demonstrates the potential of UL in material discovery, which overcomes the limitation of data scarcity, and shortens the computational screening cycle of I2-II-IV-X4 by ~12.1 years, providing a research avenue for rapid material discovery.
Functional comparison of exome capture-based methods for transcriptomic profiling of formalin-fixed paraffin-embedded tumors
Authors: Shohdy Kyrillus S. , Bareja Rohan , Sigouros Michael , Wilkes David C. , Dorsaint Princesca , Manohar Jyothi , Bockelman Daniel , Xiang Jenny Z. , Kim Rob , Ohara Kentaro , Eng Kenneth , Mosquera Juan Miguel , Elemento Olivier , Sboner Andrea , Alonso Alicia , Faltas Bishoy M.
Published: August 2021

The availability of fresh frozen (FF) tissue is a barrier for implementing RNA sequencing (RNA-seq) in the clinic. The majority of clinical samples are stored as formalin-fixed, paraffin-embedded (FFPE) tissues. Exome capture platforms have been developed for RNA-seq from FFPE samples. However, these methods have not been systematically compared. We performed transcriptomic analysis of 32 FFPE tumor samples from 11 patients using three exome capture-based methods: Agilent SureSelect V6, TWIST NGS Exome, and IDT XGen Exome Research Panel. We compared these methods to the TruSeq RNA-seq of fresh frozen (FF-TruSeq) tumor samples from the same patients. We assessed the recovery of clinically relevant biological features. The Spearman’s correlation coefficients between the global expression profiles of the three capture-based methods from FFPE and matched FF-TruSeq were high (rho = 0.72–0.9,p < 0.05). A significant correlation between the expression of key immune genes between individual capture-based methods and FF-TruSeq (rho = 0.76-0.88,p < 0.05) was observed. All exome capture-based methods reliably detected outlier expression of actionable gene transcripts, includingERBB2, MET, NTRK1, andPPARG. In urothelial cancer samples, the Agilent assay was associated with the highest molecular subtype concordance with FF-TruSeq (Cohen’sk = 0.7,p < 0.01). The Agilent and IDT assays detected all the clinically relevant fusions that were initially identified in FF-TruSeq. All FFPE exome capture-based methods had comparable performance and concordance with FF-TruSeq. Our findings will enable the implementation of RNA-seq in the clinic to guide precision oncology approaches.
Dog colour patterns explained by modular promoters of ancient canid origin
Authors: Bannasch Danika L. , Kaelin Christopher B. , Letko Anna , Loechel Robert , Hug Petra , Jagannathan Vidhya , Henkel Jan , Roosje Petra , Hytönen Marjo K. , Lohi Hannes , Arumilli Meharji ,   DoGA consortium, Lohi Hannes , Kere Juha , Daub Carsten , Hytönen Marjo , Araujo César L. , Quintero Ileana B. , Kyöstilä Kaisa , Kaukonen Maria , Arumilli Meharji , Salonen Milla , Sarviaho Riika , Niskanen Julia , Hundi Sruthi , Puurunen Jenni , Sulkama Sini , Karjalainen Sini , Sukura Antti , Syrjä Pernilla , Airas Niina , Pekkarinen Henna , Kareinen Ilona , Knuuttila Anna , Nordgren Heli , Hagner Karoliina , Pääkkönen Tarja , Iivanainen Antti , Krjutskov Kaarel , Ezer Sini , Saarinen Auli , Katayama Shintaro , Yoshihara Masahito , Hörtenhuber Matthias , Aljelaify Rasha Fahad , Ross Fiona , Raman Amitha , Stevens Irene , Gusev Oleg , Bannasch Danika L. , Schoenebeck Jeffrey J. , Minor Katie M. , Mickelson James R. , Drögemüller Cord , Barsh Gregory S. , Leeb Tosso
Published: August 2021

Distinctive colour patterns in dogs are an integral component of canine diversity. Colour pattern differences are thought to have arisen from mutation and artificial selection during and after domestication from wolves but important gaps remain in understanding how these patterns evolved and are genetically controlled. In other mammals, variation at the ASIP gene controls both the temporal and spatial distribution of yellow and black pigments. Here, we identify independent regulatory modules for ventral and hair cycle ASIP expression, and we characterize their action and evolutionary origin. Structural variants define multiple alleles for each regulatory module and are combined in different ways to explain five distinctive dog colour patterns. Phylogenetic analysis reveals that the haplotype combination for one of these patterns is shared with Arctic white wolves and that its hair cycle-specific module probably originated from an extinct canid that diverged from grey wolves more than 2 million years ago. Natural selection for a lighter coat during the Pleistocene provided the genetic framework for widespread colour variation in dogs and wolves.
OPERA tau neutrino charged current interactions
Authors: Agafonova N. , Alexandrov A. , Anokhina A. , Aoki S. , Ariga A. , Ariga T. , Bertolin A. , Bozza C. , Brugnera R. , Buonaura A. , Buontempo S. , Chernyavskiy M. , Chukanov A. , Consiglio L. , D’Ambrosio N. , De Lellis G. , De Serio M. , del Amo Sanchez P. , Di Crescenzo A. , Di Ferdinando D. , Di Marco N. , Dmitrievsky S. , Dracos M. , Duchesneau D. , Dusini S. , Dzhatdoev T. , Ebert J. , Ereditato A. , Fini R. A. , Fornari F. , Fukuda T. , Galati G. , Garfagnini A. , Gentile V. , Goldberg J. , Gorbunov S. , Gornushkin Y. , Grella G. , Guler A. M. , Gustavino C. , Hagner C. , Hara T. , Hayakawa T. , Hollnagel A. , Ishiguro K. , Iuliano A. , Jakovčić K. , Jollet C. , Kamiscioglu C. , Kamiscioglu M. , Kim S. H. , Kitagawa N. , Kliček B. , Kodama K. , Komatsu M. , Kose U. , Kreslo I. , Laudisio F. , Lauria A. , Lavasa A. , Longhin A. , Loverre P. , Malgin A. , Mandrioli G. , Matsuo T. , Matveev V. , Mauri N. , Medinaceli E. , Meregaglia A. , Mikado S. , Miyanishi M. , Mizutani F. , Monacelli P. , Montesi M. C. , Morishima K. , Muciaccia M. T. , Naganawa N. , Naka T. , Nakamura M. , Nakano T. , Niwa K. , Ogawa S. , Okateva N. , Ozaki K. , Paoloni A. , Park B. D. , Pasqualini L. , Pastore A. , Patrizii L. , Pessard H. , Podgrudkov D. , Polukhina N. , Pozzato M. , Pupilli F. , Roda M. , Roganova T. , Rokujo H. , Rosa G. , Ryazhskaya O. , Sato O. , Shakirianova I. , Schembri A. , Shchedrina T. , Shibayama E. , Shibuya H. , Shiraishi T. , Šimko T. , Simone S. , Sirignano C. , Sirri G. , Sotnikov A. , Spinetti M. , Stanco L. , Starkov N. , Stellacci S. M. , Stipčević M. , Strolin P. , Takahashi S. , Tenti M. , Terranova F. , Tioukov V. , Tsanaktsidis I. , Tufanli S. , Ustyuzhanin A. , Vasina S. , Vidal García M. , Vilain P. , Voevodina E. , Votano L. , Vuilleumier J. L. , Wilquet G. , Yoon C. S.
Published: August 2021

The OPERA experiment was designed to discover the vτ appearance in a vμ beam, due to neutrino oscillations. The detector, located in the underground Gran Sasso Laboratory, consisted of a nuclear photographic emulsion/lead target with a mass of about 1.25 kt, complemented by electronic detectors. It was exposed from 2008 to 2012 to the CNGS beam: an almost pure vμ beam with a baseline of 730 km, collecting a total of 1.8·1020 protons on target. The OPERA Collaboration eventually assessed the discovery of vμ→vτ oscillations with a statistical significance of 6.1 σ by observing ten vτ CC interaction candidates. These events have been published on the Open Data Portal at CERN. This paper provides a detailed description of the vτ data sample to make it usable by the whole community.
A new CAM6 + DART reanalysis with surface forcing from CAM6 to other CESM models
Authors: Raeder Kevin , Hoar Timothy J. , El Gharamti Mohamad , Johnson Benjamin K. , Collins Nancy , Anderson Jeffrey L. , Steward Jeff , Coady Mick
Published: August 2021

An ensemble Kalman filter reanalysis has been archived in the Research Data Archive at the National Center for Atmospheric Research. It used a CAM6 configuration of the Community Earth System Model (CESM), several million observations per day, and the Data Assimilation Research Testbed (DART). The data saved from this global, $$\sim 1^\circ $$

∼

1
∘

resolution, 80 member ensemble span 2011–2019. They include ensembles of: sub-daily, real world, atmospheric forcing for use by all of the nonatmospheric models of CESM; weekly, CAM6, restart file sets; 6 hourly, prior hindcast estimates of the assimilated observations; 6 hourly, land model, plant growth variables, and 6 hourly, ensemble mean, gridded, atmospheric analyses. This data can be used for hindcast studies and data assimilation using component models of CESM; CAM6, CLM5, CICE5, POP2. MOM6, MOSART, and CISM; and non-CESM Earth system models. This large dataset (~ 120 Tb) has a unique combination of a large ensemble, high frequency, and multiyear time span, which provides opportunities for robust statistical analysis and use as a machine learning training dataset.
Moisture variation inferred from tree rings in north central China and its links with the remote oceans
Authors: Zheng Zeyu , Jin Liya , Li Jinjian , Chen Jie , Zhang Xiaojian , Wang Zhenqian
Published: August 2021

In this study we presented a composite standard chronology, spanning 1635–2018 to reconstruct May–July moisture variation in north central China. Our reconstruction revealed four severe dry epochs and five pronounced wet epochs. Additionally, spatial correlation analysis of our reconstruction with the actual self-calibrating Palmer drought severity index showed that our reconstruction was representative of large-scale May–July moisture changes. Both the severe dry and pronounced wet epochs showed one-to-one correspondence with other reconstructions nearby during their common periods, which demonstrated the reliability of our reconstruction backwards in time. Spectral analysis showed that significant spectral peaks were found at 2.1–3.8 years, which fell within the overall bandwidth of the El Niño-Southern Oscillations (ENSO). The spatial correlation patterns between our reconstruction and sea surface temperature (SST) in the equatorial eastern Pacific further confirmed the link between regional moisture and ENSO, with warm-phase ENSO resulting in low moisture and vice-versa. However, this link was time-dependent during the past four centuries, and was modulated by different phases of SST in the tropical Indian Ocean. Additionally, significant peaks at 24.9–46.5 years and spatial correlation patterns indicated that the Pacific Decadal Oscillation and the North Atlantic Oscillation may be the possible forcing factors of regional moisture at lower frequencies.
The first dinosaurs from the Early Cretaceous Hami Pterosaur Fauna, China
Authors: Wang Xiaolin , Bandeira Kamila L. N. , Qiu Rui , Jiang Shunxing , Cheng Xin , Ma Yingxia , Kellner Alexander W. A.
Published: August 2021

The Early Cretaceous Hami Pterosaur Fauna in Northwest China preserves a large number of specimens of the sexually dimorphic pteranodontoid pterosaurHamipterus tianshanensis, including 3D eggs and embryos. During the last decade, several more fossils have been collected in this area, including three somphospondylan sauropod specimens. The first isSilutitan sinensisgen. et sp. nov., which consists of an articulated middle to posterior cervical vertebrae series. The second,Hamititan xinjiangensisgen. et sp. nov., consists of an incomplete articulated caudal sequence that could be assigned to lithostrotian titanosaurs based on the strongly procoelous caudal vertebrae with lateral concave surface, as well as marked ventrolateral ridges. The third specimen consists of four sacral vertebral elements, apparently unfused, with exposed camellate internal bone and regarded as somphospondylan. Cladistic analyses based on different datasets recoveredSilutitan sinensisas an euhelopodid closely related toEuhelopusandHamititan xinjiangensisas a titanosaur. Besides the pterosaurHamipterusand one theropod tooth,these dinosaurs are the first vertebrates reported in this region, increasing the diversity of the fauna as well as the information on Chinese sauropods, further supporting a widespread diversification of somphospondylans during the Early Cretaceous of Asia.
JNK activation in TA and EDL muscle is load-dependent in rats receiving identical excitation patterns
Authors: Eftestøl Einar , Franchi Martino V. , Kasper Stephanie , Flück Martin
Published: August 2021

As the excitation–contraction coupling is inseparable during voluntary exercise, the relative contribution of the mechanical and neural input on hypertrophy-related molecular signalling is still poorly understood. Herein, we use a rat in-vivo strength exercise model with an electrically-induced standardized excitation pattern, previously shown to induce a load-dependent increase in myonuclear number and hypertrophy, to study acute effects of load on molecular signalling. We assessed protein abundance and specific phosphorylation of the four protein kinases FAK, mTOR, p70S6K and JNK after 2, 10 and 28 min of a low- or high-load contraction, in order to assess the effects of load, exercise duration and muscle-type on their response to exercise. Specific phosphorylation of mTOR, p70S6K and JNK was increased after 28 min of exercise under the low- and high-load protocol. Elevated phosphorylation of mTOR and JNK was detectable already after 2 and 10 min of exercise, respectively, but greatest after 28 min of exercise, and JNK phosphorylation was highly load-dependent. The abundance of all four kinases was higher in TA compared to EDL muscle, p70S6K abundance was increased after exercise in a load-independent manner, and FAK and JNK abundance was reduced after 28 min of exercise in both the exercised and control muscles. In conclusion, the current study shows that JNK activation after a single resistance exercise is load-specific, resembling the previously reported degree of myonuclear accrual and muscle hypertrophy with repetition of the exercise stimulus.
Predicted limited redistribution of T cells to secondary lymphoid tissue correlates with increased risk of haematological malignancies in asplenic patients
Authors: Kmieciak Aleksandra E. , Brown Liam V. , Coles Mark C. , Wagg Jonathan , Phipps Alex , Gaffney Eamonn A.
Published: August 2021

The spleen, a secondary lymphoid tissue (SLT), has an important role in generation of adaptive immune responses. Although splenectomy remains a common procedure, recent studies reported poor prognosis and increased risk of haematological malignancies in asplenic patients. The high baseline trafficking of T lymphocytes to splenic tissue suggests splenectomy may lead to loss of blood-borne malignant immunosurveillance that is not compensated for by the remaining SLT. To date, no quantitative analysis of the impact of splenectomy on the human T cell trafficking dynamics and tissue localisation has been reported. We developed a quantitative computational model that describes organ distribution and trafficking of human lymphocytes to explore the likely impact of splenectomy on immune cell distributions. In silico splenectomy resulted in an average reduction of T cell numbers in SLT by 35% (95%CI 0.12–0.97) and a comparatively lower, 9% (95%CI 0.17–1.43), mean decrease of T cell concentration in SLT. These results suggest that the surveillance capacity of the remaining SLT insufficiently compensates for the absence of the spleen. This may, in part, explain haematological malignancy risk in asplenic patients and raises the question of whether splenectomy has a clinically meaningful impact on patient responses to immunotherapy.
Transcriptomic profiling of Gh/Igf system reveals a prompted tissue-specific differentiation and novel hypoxia responsive genes in gilthead sea bream
Authors: Naya-Català F. , Simó-Mirabet P. , Calduch-Giner J. , Pérez-Sánchez J.
Published: August 2021

A customized PCR-array was used for the simultaneous gene expression of the Gh/Igf system and related markers of muscle growth, and lipid and energy metabolism during early life stages of gilthead sea bream (60–127 days posthatching). Also, transcriptional reprogramming by mild hypoxia was assessed in fingerling fish with different history trajectories on O2 availability during the same time window. In normoxic fish, the expression of almost all the genes in the array varied over time with a prompted liver and muscle tissue-specific differentiation, which also revealed temporal changes in the relative expression of markers of the full gilthead sea bream repertoire of Gh receptors, Igfs and Igf-binding proteins. Results supported a different contribution through development of ghr and igf subtypes on the type of action of GH via systemic or direct effects at the local tissue level. This was extensive to Igfbp1/2/4 and Igfbp3/5/6 clades that clearly evolved through development as hepatic and muscle Igfbp subtypes, respectively. This trade-off is however very plastic to cope changes in the environment, and ghr1 and igfbp1/3/4/5 emerged as hypoxic imprinting genes during critical early developmental windows leading to recognize individuals with different history trajectories of oxygen availability and metabolic capabilities later in life.
Direct numerical simulations of three-dimensional surface instability patterns in thin film-compliant substrate structures
Authors: Nikravesh Siavash , Ryu Donghyeon , Shen Yu-Lin
Published: August 2021

A comprehensive numerical study of three-dimensional surface instability patterns is presented. The formation of wrinkles is a consequence of deformation instability when a thin film, bonded to a compliant substrate, is subject to in-plane compressive loading. We apply a recently developed computational approach to directly simulate complex surface wrinkling from pre-instability to post-instability in a straightforward manner, covering the entire biaxial loading spectrum from pure uniaxial to pure equi-biaxial compression. The simulations use embedded imperfections with perturbed material properties at the film-substrate interface. This approach not only triggers the first bifurcation mode but also activates subsequent post-buckling states, thus capable of predicting the temporal evolution of wrinkle patterns in one simulation run. The state of biaxiality is found to influence the surface pattern significantly, and each bifurcation mode can be traced back to certain abrupt changes in the overall load–displacement response. Our systematic study reveals how the loading condition dictates the formation of various instability modes including one-dimensional (1D) sinusoidal wrinkles, herringbone, labyrinth, and checkerboard.
Fatty liver index as a predictor for type 2 diabetes in subjects with normoglycemia in a nationwide cohort study
Authors: García-Escobar E. , Valdés S. , Soriguer F. , Vendrell J. , Urrutia-Etxebarria I. M. , Maldonado-Araque C. , Ortega E. , Ocón P. , Montanya E. , Menéndez E. , Lago-Sampedro A. , González-Frutos T. , Gomis R. , Goday A. , García-Serrano S. , Galán-García J. L. , Castell C. , Bordiú E. , Badía R. , Aguilera-Venegas G. , Girbés J. , Gaztambide S. , Delgado E. , Chaves F. J. , Castaño L. , Calle-Pascual A. , Rojo-Martínez G. , Franch-Nadal J.
Published: August 2021

Our aim was to evaluate whether fatty liver index (FLI) is associated with the risk of type 2 diabetes (T2DM) development within the Spanish adult population and according to their prediabetes status; additionally, to examine its incremental predictive value regarding traditional risk factors. A total of 2260 subjects (Prediabetes: 641 subjects, normoglycemia: 1619 subjects) from the Di@bet.es cohort study were studied. Socio-demographic, anthropometric, clinical data and survey on habits were recorded. An oral glucose tolerance test was performed and fasting determinations of glucose, lipids and insulin were made. FLI was calculated and classified into three categories: Low (< 30), intermediate (30–60) and high (> 60). In total, 143 people developed diabetes at follow-up. The presence of a high FLI category was in all cases a significant independent risk factor for the development of diabetes. The inclusion of FLI categories in prediction models based on different conventional T2DM risk factors significantly increase the prediction power of the models when all the population was considered. According to our results, FLI might be considered an early indicator of T2DM development even under normoglycemic condition. The data also suggest that FLI could provide additional information for the prediction of T2DM in models based on conventional risk factors.
Extended in vivo transcriptomes of two ascoviruses with different tissue tropisms reveal alternative mechanisms for enhancing virus reproduction in hemolymph
Authors: Zaghloul Heba A. H. , Hice Robert H. , Arensburger Peter , Bideshi Dennis K. , Federici Brian A.
Published: August 2021

Ascoviruses are large dsDNA viruses characterized by the extraordinary changes they induce in cellular pathogenesis and architecture whereby after nuclear lysis and extensive hypertrophy, each cell is cleaved into numerous vesicles for virion reproduction. However, the level of viral replication and transcription in vesicles compared to other host tissues remains uncertain. Therefore, we applied RNA-Sequencing to compare the temporal transcriptome of Spodoptera frugiperda ascovirus (SfAV) and Trichoplusia ni ascovirus (TnAV) at 7, 14, and 21 days post-infection (dpi). We found most transcription occurred in viral vesicles, not in initial tissues infected, a remarkably novel reproduction mechanism compared to all other viruses and most other intracellular pathogens. Specifically, the highest level of viral gene expression occurred in hemolymph, for TnAV at 7 dpi, and SfAV at 14 dpi. Moreover, we found that host immune genes were partially down-regulated in hemolymph, where most viral replication occurred in highly dense accumulations of vesicles.
Effects of Transcranial Direct Current Stimulation on effort during a working-memory task
Authors: Framorando David , Cai Tianlan , Wang Yi , Pegna Alan J.
Published: August 2021

Transcranial Direct Current Stimulation (tDCS) has shown that stimulation of Dorsolateral Prefrontal Cortex (DLPFC) facilitates task performance in working-memory tasks. However, little is known about its potential effects on effort. This study examined whether tDCS affects effort during a working-memory task. Participants received anodal, cathodal and sham stimulation over DLPFC across three sessions before carrying out a 2-back task. During the task, effort-related cardiovascular measures were recorded—especially the Initial Systolic Time Interval (ISTI). Results showed that anodal stimulation produced a shorter ISTI, indicating a greater effort compared to cathodal and sham conditions, where effort was lower. These findings demonstrate that anodal stimulation helps participants to maintain engagement in a highly demanding task (by increasing task mastery), without which they would otherwise disengage. This study is the first to show that tDCS impacts the extent of effort engaged by individuals during a difficult task.
Comparing the COVID-19 pandemic in space and over time in Europe, using numbers of deaths, crude rates and adjusted mortality trend ratios
Authors: Gallo Valentina , Chiodini Paolo , Bruzzese Dario , Kondilis Elias , Howdon Dan , Mierau Jochen , Bhopal Raj
Published: August 2021

Comparison of COVID-19 trends in space and over time is essential to monitor the pandemic and to indirectly evaluate non-pharmacological policies aimed at reducing the burden of disease. Given the specific age- and sex- distribution of COVID-19 mortality, the underlying sex- and age-distribution of populations need to be accounted for. The aim of this paper is to present a method for monitoring trends of COVID-19 using adjusted mortality trend ratios (AMTRs). Age- and sex-mortality distribution of a reference European population (N = 14,086) was used to calculate age- and sex-specific mortality rates. These were applied to each country to calculate the expected deaths. Adjusted Mortality Trend Ratios (AMTRs) with 95% confidence intervals (C.I.) were calculated for selected European countries on a daily basis from 17th March 2020 to 29th April 2021 by dividing observed cumulative mortality, by expected mortality, times the crude mortality of the reference population. These estimated the sex- and age-adjusted mortality for COVID-19 per million population in each country. United Kingdom experienced the highest number of COVID-19 related death in Europe. Crude mortality rates were highest Hungary, Czech Republic, and Luxembourg. Accounting for the age-and sex-distribution of the underlying populations with AMTRs for each European country, four different patterns were identified: countries which experienced a two-wave pandemic, countries with almost undetectable first wave, but with either a fast or a slow increase of mortality during the second wave; countries with consistently low rates throughout the period. AMTRs were highest in Eastern European countries (Hungary, Czech Republic, Slovakia, and Poland). Our methods allow a fair comparison of mortality in space and over time. These might be of use to indirectly estimating the efficacy of non-pharmacological health policies. The authors urge the World Health Organisation, given the absence of age and sex-specific mortality data for direct standardisation, to adopt this method to estimate the comparative mortality from COVID-19 pandemic worldwide.
Dietary intake of tocopherols and risk of incident disabling dementia
Authors: Aoki Shoko , Yamagishi Kazumasa , Maruyama Koutatsu , Kishida Rie , Ikeda Ai , Umesawa Mitsumasa , Renzhe Cui , Kubota Yasuhiko , Hayama-Terada Mina , Shimizu Yuji , Muraki Isao , Imano Hironori , Sankai Tomoko , Okada Takeo , Kitamura Akihiko , Kiyama Masahiko , Iso Hiroyasu
Published: August 2021

Tocopherols, strong antioxidants, may be useful in preventing dementia, but the epidemiological evidence is insufficient. We performed a community-based follow-up study of Japanese, the Circulatory Risk in Community Study, involving 3739 people aged 40–64 years at baseline (1985–1999). Incident disabling dementia was followed up from 1999 through 2020. For subtype analysis, we classified disabling dementia into that with and that without a history of stroke. Dietary intake of tocopherols (total, α, β, γ, and δ) were estimated using 24-h recall surveys. During a median follow-up of 19.7 years, 670 cases of disabling dementia developed. Total tocopherol intake was inversely associated with risk of disabling dementia with multivariable hazard ratios (95% confidence intervals) of 0.79 (0.63–1.00) for the highest versus lowest quartiles of total tocopherol intake (P for trend = 0.05). However, the association was strengthened when further adjusted for α-linolenic acid intake (Spearman correlation with total tocopherol intake = 0.93), with multivariable hazard ratios of 0.50 (0.34–0.74) (P for trend = 0.001) but was weakened and nonsignificant when further adjusted for linoleic acid intake (Spearman correlation with total tocopherol intake = 0.92), with multivariable hazard ratios of 0.69 (0.47–1.01) (P for trend = 0.05). Similar but nonsignificant inverse associations were observed for α-, γ-, and δ-tocopherols but not for β-tocopherol. These results were similar regardless of the presence of a history of stroke. Dietary tocopherol intake was inversely associated with risk of disabling dementia, but its independent effect was uncertain owing to a high intercorrelation of α-linolenic linoleic acids with total tocopherol intake. Even with such confounding, a diet high in tocopherols may help prevent the onset of dementia.
NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice
Authors: Guo Fangfei , Seldin Marcus , Péterfy Miklós , Charugundla Sarada , Zhou Zhiqiang , Lee Stephen D. , Mouton Alice , Rajbhandari Prashant , Zhang Wenchao , Pellegrini Matteo , Tontonoz Peter , Lusis Aldons J. , Shih Diana M.
Published: August 2021

We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A β3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C–C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A’s effects on upregulation of TGF-β signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling.