bluuebunny/crossref_metadata_2025 huggingface dataset:
PLAU directs conversion of fibroblasts to inflammatory cancer-associated fibroblasts, promoting esophageal squamous cell carcinoma progression via uPAR/Akt/NF-κB/IL8 pathway
Authors: Fang Lingling , Che Yun , Zhang Chaoqi , Huang Jianbing , Lei Yuanyuan , Lu Zhiliang , Sun Nan , He Jie
Published: February 2021

Cancer-associated fibroblasts (CAFs) plays an important role in the tumor microenvironment. The heterogeneity of CAFs affects the effect of CAFs on promoting or inhibiting tumors, which can be regulated by other cells in the tumor microenvironment through paracrine methods. The urokinase-type plasminogen activator (PLAU) system mediates cell proliferation, migration, adhesion, and other functions through the proteolytic system, intracellular signal transduction, and chemokine activation. PLAU promotes tumor progression in many tumors. We explored the function of PLAU in ESCC and the influence of PLAU secreted by tumor cells on the heterogeneity of CAFs. We found that PLAU is highly expressed in ESCC, which is related to poor prognosis and can be used as a prognostic marker for ESCC. Through loss-of function and gain-of function experiments, we found that PLAU promoted ESCC proliferation and clone formation via MAPK pathway, and promotes migration by upregulating Slug and MMP9, which can be reversed by the MEK 1/2 inhibitor U0126. At the same time, through sequencing, cytokine detection, and RT-qPCR verification, we found that tumor cells secreted PLAU promoted the conversion of fibroblasts to inflammatory CAFs, which upregulated expression and secretion of IL8 via the uPAR/Akt/NF-κB pathway. The IL8 secreted by CAFs in turn promotes the high expression of PLAU in tumor cells and further promoted the progression of ESCC. In summary, PLAU was not only a prognostic marker of ESCC, which promoted tumor cell proliferation and migration, but also promoted the formation of inflammatory CAFs by the PLAU secreted by tumor cells.
Cas9-directed immune tolerance in humans—a model to evaluate regulatory T cells in gene therapy?
Authors: Wagner Dimitrios Laurin , Peter Lena , Schmueck-Henneresse Michael
Published: February 2021

The dichotomic nature of the adaptive immune response governs the outcome of clinical gene therapy. On the one hand, neutralizing antibodies and cytotoxic T cells can have a dramatic impact on the efficacy and safety of human gene therapies. On the other hand, regulatory T cells (Treg) can promote tolerance toward transgenes thereby enabling long-term benefits of in vivo gene therapy after a single administration. Pre-existing antibodies and T cell immunity has been a major obstacle for in vivo gene therapies with viral vectors. As CRISPR-Cas9 gene editing advances toward the clinics, the technology’s inherent immunogenicity must be addressed in order to guide clinical treatment decisions. This review summarizes the recent evidence on Cas9-specific immunity in humans—including early results from clinical trials—and discusses the risks for in vivo gene therapies. Finally, we focus on solutions and highlight the potential role of Cas9-specific Treg cells to promote immune tolerance. As a “beneficial alliance” beyond Cas9-immunity, antigen-specific Treg cells may serve as a living and targeted immunosuppressant to increase safety and efficacy of gene therapy.
Genome sequence and evolution ofBetula platyphylla
Authors: Chen Su , Wang Yucheng , Yu Lili , Zheng Tao , Wang Sui , Yue Zhen , Jiang Jing , Kumari Sapna , Zheng Chunfang , Tang Haibao , Li Jun , Li Yuqi , Chen Jiongjiong , Zhang Wenbo , Kuang Hanhui , Robertson Jon S , Zhao Patrick X , Li Huiyu , Shu Shengqiang , Yordanov Yordan S , Huang Haijiao , Goodstein David M , Gai Ying , Qi Qi , Min JiuMeng , Xu ChunYan , Wang SongBo , Qu Guan-Zheng , Paterson Andrew H , Sankoff David , Wei Hairong , Liu Guifeng , Yang Chuanping
Published: February 2021

Betula L. (birch) is a pioneer hardwood tree species with ecological, economic, and evolutionary importance in the Northern Hemisphere. We sequenced the Betula platyphylla genome and assembled the sequences into 14 chromosomes. The Betula genome lacks evidence of recent whole-genome duplication and has the same paleoploidy level as Vitis vinifera and Prunus mume. Phylogenetic analysis of lignin pathway genes coupled with tissue-specific expression patterns provided clues for understanding the formation of higher ratios of syringyl to guaiacyl lignin observed in Betula species. Our transcriptome analysis of leaf tissues under a time-series cold stress experiment revealed the presence of the MEKK1–MKK2–MPK4 cascade and six additional mitogen-activated protein kinases that can be linked to a gene regulatory network involving many transcription factors and cold tolerance genes. Our genomic and transcriptome analyses provide insight into the structures, features, and evolution of the B. platyphylla genome. The chromosome-level genome and gene resources of B. platyphylla obtained in this study will facilitate the identification of important and essential genes governing important traits of trees and genetic improvement of B. platyphylla.
Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism
Authors: Cheng Yurong , Schlosser Pascal , Hertel Johannes , Sekula Peggy , Oefner Peter J. , Spiekerkoetter Ute , Mielke Johanna , Freitag Daniel F. , Schmidts Miriam ,   GCKD Investigators, Oefner Peter J. , Kronenberg Florian , Eckardt Kai-Uwe , Kronenberg Florian , Eckardt Kai-Uwe , Thiele Ines , Li Yong , Köttgen Anna
Published: February 2021

Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e−7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.
Exciton–phonon coupling strength in single-layer MoSe2 at room temperature
Authors: Li Donghai , Trovatello Chiara , Dal Conte Stefano , Nuß Matthias , Soavi Giancarlo , Wang Gang , Ferrari Andrea C. , Cerullo Giulio , Brixner Tobias
Published: February 2021

Single-layer transition metal dichalcogenides are at the center of an ever increasing research effort both in terms of fundamental physics and applications. Exciton–phonon coupling plays a key role in determining the (opto)electronic properties of these materials. However, the exciton–phonon coupling strength has not been measured at room temperature. Here, we use two-dimensional micro-spectroscopy to determine exciton–phonon coupling of single-layer MoSe2. We detect beating signals as a function of waiting time induced by the coupling between A excitons and A′1 optical phonons. Analysis of beating maps combined with simulations provides the exciton–phonon coupling. We get a Huang–Rhys factor ~1, larger than in most other inorganic semiconductor nanostructures. Our technique offers a unique tool to measure exciton–phonon coupling also in other heterogeneous semiconducting systems, with a spatial resolution ~260 nm, and provides design-relevant parameters for the development of optoelectronic devices.
GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
Authors: Eriksson Daniel , Røyrvik Ellen Christine , Aranda-Guillén Maribel , Berger Amund Holte , Landegren Nils , Artaza Haydee , Hallgren Åsa , Grytaas Marianne Aardal , Ström Sara , Bratland Eirik , Botusan Ileana Ruxandra , Oftedal Bergithe Eikeland , Breivik Lars , Vaudel Marc , Helgeland Øyvind , Falorni Alberto , Jørgensen Anders Palmstrøm , Hulting Anna-Lena , Svartberg Johan , Ekwall Olov , Fougner Kristian Johan , Wahlberg Jeanette , Nedrebø Bjørn Gunnar , Dahlqvist Per ,   The Norwegian Addison Registry Study Group, Ræder Helge , Jovanovic Nevena , Reisegg Sigfrid Christine , Hølleland Geir , Carlsen Siri , Berg Tore Julsrud , Eggesbø Jan Bertil , Svendsen Thomas , Lima Kari , Nermoen Ingrid , Whitfield Rolf , Sollid Stina , Aarskog Dagfinn , Korsgaard Elin , Sæta Solveig , Finnes Trine , Valland Susanna Fonneland , Fossum Christian , Brevik Eli , Moe Ragnar Bekkhus , Svendsen Margrethe , Debowska Aleksandra , Milova Petya , Holte Synnøve , Tomkowicz Aneta Eva , Sørmo Dag Eirik , Svare Anders , Rensvik Marthe Landsverk , Revheim Randi , Haug Thor , Blix Ivar , Jensen Lars Petter ,   The Swedish Addison Registry Study Group, Åkerman Anna-Karin , Hulting Anna-Lena , Lindberg Bengt , Kriström Berit , Waldenström Erik , Johannsson Gudmundur , Skov Jakob , Wahlberg Jeanette , Duchen Karel , Isaksson Magnus , Elfving Maria , Stenlid Maria Halldin , Nilsson Ola , Kämpe Olle , Ekwall Olov , Dahlqvist Per , Bergthorsdottir Ragnhildur , Nergårdh Ricard , Björnsdottir Sigridur , Bensing Sophie , Olsson Tommy , Knappskog Per Morten , Wolff Anette Susanne Bøe , Bensing Sophie , Johansson Stefan , Kämpe Olle , Husebye Eystein Sverre
Published: February 2021

Autoimmune Addison’s disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10−8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10−25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35–41% of heritability (h2).
Multi-level quantum noise spectroscopy
Authors: Sung Youngkyu , Vepsäläinen Antti , Braumüller Jochen , Yan Fei , Wang Joel I-Jan , Kjaergaard Morten , Winik Roni , Krantz Philip , Bengtsson Andreas , Melville Alexander J. , Niedzielski Bethany M. , Schwartz Mollie E. , Kim David K. , Yoder Jonilyn L. , Orlando Terry P. , Gustavsson Simon , Oliver William D.
Published: February 2021

System noise identification is crucial to the engineering of robust quantum systems. Although existing quantum noise spectroscopy (QNS) protocols measure an aggregate amount of noise affecting a quantum system, they generally cannot distinguish between the underlying processes that contribute to it. Here, we propose and experimentally validate a spin-locking-based QNS protocol that exploits the multi-level energy structure of a superconducting qubit to achieve two notable advances. First, our protocol extends the spectral range of weakly anharmonic qubit spectrometers beyond the present limitations set by their lack of strong anharmonicity. Second, the additional information gained from probing the higher-excited levels enables us to identify and distinguish contributions from different underlying noise mechanisms.
Regulatory inter-domain interactions influence Hsp70 recruitment to the DnaJB8 chaperone
Authors: Ryder Bryan D. , Matlahov Irina , Bali Sofia , Vaquer-Alicea Jaime , van der Wel Patrick C. A. , Joachimiak Lukasz A.
Published: February 2021

The Hsp40/Hsp70 chaperone families combine versatile folding capacity with high substrate specificity, which is mainly facilitated by Hsp40s. The structure and function of many Hsp40s remain poorly understood, particularly oligomeric Hsp40s that suppress protein aggregation. Here, we used a combination of biochemical and structural approaches to shed light on the domain interactions of the Hsp40 DnaJB8, and how they may influence recruitment of partner Hsp70s. We identify an interaction between the J-Domain (JD) and C-terminal domain (CTD) of DnaJB8 that sequesters the JD surface, preventing Hsp70 interaction. We propose a model for DnaJB8-Hsp70 recruitment, whereby the JD-CTD interaction of DnaJB8 acts as a reversible switch that can control the binding of Hsp70. These findings suggest that the evolutionarily conserved CTD of DnaJB8 is a regulatory element of chaperone activity in the proteostasis network.
Probing electronic structure in berkelium and californium via an electron microscopy nanosampling approach
Authors: Müller Alexander , Deblonde Gauthier J.-P. , Ercius Peter , Zeltmann Steven E. , Abergel Rebecca J. , Minor Andrew M.
Published: February 2021

Due to their rarity and radioactive nature, comparatively little is known about the actinides, particularly those with atomic numbers higher than that of plutonium, and their compounds. In this work, we describe how transmission electron microscopy can provide comprehensive, safe, and cost-effective characterization using only single nanogram amounts of highly-radioactive, solid compounds. Chlorides of the rare elements berkelium and californium are dropcast and then converted in situ to oxides using the electron beam. The f-band occupancies are probed using electron energy loss spectroscopy and an unexpectedly weak spin-orbit-coupling is identified for berkelium. In contrast, californium follows a jj coupling scheme. These results have important implications for the chemistries of these elements and solidify the status of californium as a transitional element in the actinide series.
RNA secondary structure prediction using deep learning with thermodynamic integration
Authors: Sato Kengo , Akiyama Manato , Sakakibara Yasubumi
Published: February 2021

Accurate predictions of RNA secondary structures can help uncover the roles of functional non-coding RNAs. Although machine learning-based models have achieved high performance in terms of prediction accuracy, overfitting is a common risk for such highly parameterized models. Here we show that overfitting can be minimized when RNA folding scores learnt using a deep neural network are integrated together with Turner’s nearest-neighbor free energy parameters. Training the model with thermodynamic regularization ensures that folding scores and the calculated free energy are as close as possible. In computational experiments designed for newly discovered non-coding RNAs, our algorithm (MXfold2) achieves the most robust and accurate predictions of RNA secondary structures without sacrificing computational efficiency compared to several other algorithms. The results suggest that integrating thermodynamic information could help improve the robustness of deep learning-based predictions of RNA secondary structure.
A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry
Authors: Zhu Yunkai , Feng Fei , Hu Gaowei , Wang Yuyan , Yu Yin , Zhu Yuanfei , Xu Wei , Cai Xia , Sun Zhiping , Han Wendong , Ye Rong , Qu Di , Ding Qiang , Huang Xinxin , Chen Hongjun , Xu Wei , Xie Youhua , Cai Qiliang , Yuan Zhenghong , Zhang Rong
Published: February 2021

The global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses.
Structural mechanism of bivalent histone H3K4me3K9me3 recognition by the Spindlin1/C11orf84 complex in rRNA transcription activation
Authors: Du Yongming , Yan Yinxia , Xie Si , Huang Hao , Wang Xin , Ng Ray Kit , Zhou Ming-Ming , Qian Chengmin
Published: February 2021

Spindlin1 is a unique multivalent epigenetic reader that facilitates ribosomal RNA transcription. In this study, we provide molecular and structural basis by which Spindlin1 acts in complex with C11orf84 to preferentially recognize non-canonical bivalent mark of trimethylated lysine 4 and lysine 9 present on the same histone H3 tail (H3K4me3K9me3). We demonstrate that C11orf84 binding stabilizes Spindlin1 and enhances its association with bivalent H3K4me3K9me3 mark. The functional analysis suggests that Spindlin1/C11orf84 complex can displace HP1 proteins from H3K4me3K9me3-enriched rDNA loci, thereby facilitating the conversion of these poised rDNA repeats from the repressed state to the active conformation, and the consequent recruitment of RNA Polymerase I for rRNA transcription. Our study uncovers a previously unappreciated mechanism of bivalent H3K4me3K9me3 recognition by Spindlin1/C11orf84 complex required for activation of rRNA transcription.
Addressable nanoantennas with cleared hotspots for single-molecule detection on a portable smartphone microscope
Authors: Trofymchuk Kateryna , Glembockyte Viktorija , Grabenhorst Lennart , Steiner Florian , Vietz Carolin , Close Cindy , Pfeiffer Martina , Richter Lars , Schütte Max L. , Selbach Florian , Yaadav Renukka , Zähringer Jonas , Wei Qingshan , Ozcan Aydogan , Lalkens Birka , Acuna Guillermo P. , Tinnefeld Philip
Published: February 2021

The advent of highly sensitive photodetectors and the development of photostabilization strategies made detecting the fluorescence of single molecules a routine task in many labs around the world. However, to this day, this process requires cost-intensive optical instruments due to the truly nanoscopic signal of a single emitter. Simplifying single-molecule detection would enable many exciting applications, e.g., in point-of-care diagnostic settings, where costly equipment would be prohibitive. Here, we introduce addressable NanoAntennas with Cleared HOtSpots (NACHOS) that are scaffolded by DNA origami nanostructures and can be specifically tailored for the incorporation of bioassays. Single emitters placed in NACHOS emit up to 461-fold (average of 89 ± 7-fold) brighter enabling their detection with a customary smartphone camera and an 8-US-dollar objective lens. To prove the applicability of our system, we built a portable, battery-powered smartphone microscope and successfully carried out an exemplary single-molecule detection assay for DNA specific to antibiotic-resistant Klebsiella pneumonia on the road.
Post-exposure protection of SARS-CoV-2 lethal infected K18-hACE2 transgenic mice by neutralizing human monoclonal antibody
Authors: Rosenfeld Ronit , Noy-Porat Tal , Mechaly Adva , Makdasi Efi , Levy Yinon , Alcalay Ron , Falach Reut , Aftalion Moshe , Epstein Eyal , Gur David , Chitlaru Theodor , Vitner Einat B. , Melamed Sharon , Politi Boaz , Zauberman Ayelet , Lazar Shirley , Beth-Din Adi , Evgy Yentl , Yitzhaki Shmuel , Shapira Shmuel C. , Israely Tomer , Mazor Ohad
Published: February 2021

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits high levels of mortality and morbidity and has dramatic consequences on human life, sociality and global economy. Neutralizing antibodies constitute a highly promising approach for treating and preventing infection by this novel pathogen. In the present study, we characterize and further evaluate the recently identified human monoclonal MD65 antibody for its ability to provide protection against a lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice. Eighty percent of the untreated mice succumbed 6–9 days post-infection, while administration of the MD65 antibody as late as 3 days after exposure rescued all infected animals. In addition, the efficiency of the treatment is supported by prevention of morbidity and ablation of the load of infective virions in the lungs of treated animals. The data demonstrate the therapeutic value of human monoclonal antibodies as a life-saving treatment for severe COVID-19 infection.
Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy
Authors: Li Ying , Cong Yanni , Jia Mingming , He Qianqian , Zhong Haiqing , Zhao Yun , Li Hang , Yan Meining , You Jia , Liu Jia , Chen Lieping , Hang Haiying , Wang Shengdian
Published: February 2021

T cell rejuvenation by PD-1/PD-L1 blockade, despite emerging as a highly promising therapy for advanced cancers, is only beneficial for a minority of treated patients. There is evidence that a lack of efficient T cell activation may be responsible for the failure. Here, we demonstrate that IL-21 can be targeted to tumor-reactive T cells by fusion of IL-21 to anti-PD-1 antibody. To our surprise, the fusion protein PD-1Ab21 promotes the generation of memory stem T cells (TSCM) with enhanced cell proliferation. PD-1Ab21 treatment show potent antitumor effects in established tumor-bearing mice accompanied with an increased frequency of TSCM and robust expansion of tumor-specific CD8+ T cells with a memory phenotype, and is superior to a combination of PD-1 blockade and IL-21 infusion. Therefore, we have developed a potential strategy to improve the therapeutic effects of immune checkpoint blockade by simultaneously targeting cytokines to tumor-reactive T cells.
Diagnostic accuracy of cytology for the detection of endometrial cancer in urine and vaginal samples
Authors: O’Flynn Helena , Ryan Neil A. J. , Narine Nadira , Shelton David , Rana Durgesh , Crosbie Emma J.
Published: February 2021

Postmenopausal bleeding triggers urgent investigation by sequential invasive tests that are avoidable for the 90–95% of women who do not have endometrial cancer. A simple, non-invasive tool that accurately identifies cancer and safely reassures healthy women could transform patient care. Here we report, in a cross-sectional diagnostic accuracy study of 103 women with known cancer and 113 with unexplained postmenopausal bleeding, that urine and vaginal cytology has a combined sensitivity of 91.7% (95% CI 85.0%, 96.1%) and specificity of 88.8% (81.2%, 94.1%) for gynecological cancer detection. Cytology identifies 91 endometrial, two fallopian tube and one cervical cancer from 103 known cancer cases. In women with unexplained postmenopausal bleeding, cytology identifies all four endometrial cancers and three others (cervical, ovarian and bladder), for a 12/107 (11.2%) false positive rate. We show proof-of-principle that endometrial cancer can be detected in urine and vaginal fluid. Prospective validation of these findings will support incorporation of this non-invasive test into clinical practice.
Deciphering the interactions between single arm dislocation sources and coherent twin boundary in nickel bi-crystal
Authors: Samaee Vahid , Dupraz Maxime , Pardoen Thomas , Van Swygenhoven Helena , Schryvers Dominique , Idrissi Hosni
Published: February 2021

The introduction of a well-controlled population of coherent twin boundaries (CTBs) is an attractive route to improve the strength ductility product in face centered cubic (FCC) metals. However, the elementary mechanisms controlling the interaction between single arm dislocation sources (SASs), often present in nanotwinned FCC metals, and CTB are still not well understood. Here, quantitative in-situ transmission electron microscopy (TEM) observations of these mechanisms under tensile loading are performed on submicron Ni bi-crystal. We report that the absorption of curved screw dislocations at the CTB leads to the formation of constriction nodes connecting pairs of twinning dislocations at the CTB plane in agreement with large scale 3D atomistic simulations. The coordinated motion of the twinning dislocation pairs due to the presence of the nodes leads to a unique CTB sliding mechanism, which plays an important role in initiating the fracture process at a CTB ledge. TEM observations of the interactions between non-screw dislocations and the CTB highlight the importance of the synergy between the repulsive force of the CTB and the back stress from SASs when the interactions occur in small volumes.
Renal metabolism and hypertension
Authors: Tian Zhongmin , Liang Mingyu
Published: February 2021

Hypertension is a leading risk factor for disease burden worldwide. The kidneys, which have a high specific metabolic rate, play an essential role in the long-term regulation of arterial blood pressure. In this review, we discuss the emerging role of renal metabolism in the development of hypertension. Renal energy and substrate metabolism is characterized by several important and, in some cases, unique features. Recent advances suggest that alterations of renal metabolism may result from genetic abnormalities or serve initially as a physiological response to environmental stressors to support tubular transport, which may ultimately affect regulatory pathways and lead to unfavorable cellular and pathophysiological consequences that contribute to the development of hypertension.
Publisher Correction: Few keystone plant genera support the majority of Lepidoptera species
Authors: Narango Desiree L. , Tallamy Douglas W. , Shropshire Kimberley J.
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21304-2
Predicting intraocular pressure using systemic variables or fundus photography with deep learning in a health examination cohort
Authors: Ishii Kaori , Asaoka Ryo , Omoto Takashi , Mitaki Shingo , Fujino Yuri , Murata Hiroshi , Onoda Keiichi , Nagai Atsushi , Yamaguchi Shuhei , Obana Akira , Tanito Masaki
Published: February 2021

The purpose of the current study was to predict intraocular pressure (IOP) using color fundus photography with a deep learning (DL) model, or, systemic variables with a multivariate linear regression model (MLM), along with least absolute shrinkage and selection operator regression (LASSO), support vector machine (SVM), and Random Forest: (RF). Training dataset included 3883 examinations from 3883 eyes of 1945 subjects and testing dataset 289 examinations from 289 eyes from 146 subjects. With the training dataset, MLM was constructed to predict IOP using 35 systemic variables and 25 blood measurements. A DL model was developed to predict IOP from color fundus photographs. The prediction accuracy of each model was evaluated through the absolute error and the marginal R-squared (mR2), using the testing dataset. The mean absolute error with MLM was 2.29 mmHg, which was significantly smaller than that with DL (2.70 dB). The mR2with MLM was 0.15, whereas that with DL was 0.0066. The mean absolute error (between 2.24 and 2.30 mmHg) and mR2(between 0.11 and 0.15) with LASSO, SVM and RF were similar to or poorer than MLM. A DL model to predict IOP using color fundus photography proved far less accurate than MLM using systemic variables.
Anti-icing performance on aluminum surfaces and proposed model for freezing time calculation
Authors: Nguyen Van-Huy , Nguyen Ba Duc , Pham Hien Thu , Lam Su Shiung , Vo Dai-Viet N. , Shokouhimehr Mohammadreza , Vu Thi Hong Hanh , Nguyen Thanh-Binh , Kim Soo Young , Le Quyet Van
Published: February 2021

In this work, we proposed a facile approach to fabricate a superhydrophobic surface for anti-icing performance in terms of adhesive strength and freezing time. A hierarchical structure was generated on as-received Al plates using a wet etching method and followed with a low energy chemical compound coating. Surfaces after treatment exhibited the great water repellent properties with a high contact angle and extremely low sliding angle. An anti-icing investigation was carried out by using a custom-built apparatus and demonstrated the expected low adhesion and freezing time for icephobic applications. In addition, we proposed a model for calculating the freezing time. The experimented results were compared with theoretical calculation and demonstrated the good agreement, illustrating the importance of theoretical contribution in design icephobic surfaces. Therefore, this study provides a guideline for the understanding of icing phenomena and designing of icephobic surfaces.
Population epidemiology and concordance for plasma amino acids and precursors in 11–12-year-old children and their parents
Authors: Andraos Stephanie , Lange Katherine , Clifford Susan A. , Jones Beatrix , Thorstensen Eric B. , Wake Melissa , Burgner David P. , Saffery Richard , O’Sullivan Justin M.
Published: February 2021

Amino acid (AA) concentrations are influenced by both exogenous (e.g. diet, lifestyle) and endogenous factors (e.g. genetic, transcriptomic, epigenetic, and metabolomic). Fasting plasma AA profiles in adulthood are predictive of diabetes risk over periods of up to 12 years. Data on AA profiles in cross-generational cohorts, including individuals from shared gene-environment settings are scarce, but would allow the identification of the contribution of heritable and environmental factors characterising the levels of circulating AAs. This study aimed to investigate parent–child (familial dyad) concordance, absolute differences between generations- (children versus adults), age- (in adults: 28–71 years), and sex-dependent differences in plasma AA concentrations. Plasma AA concentrations were measured by UHPLC/MS–MS in 1166 children [mean (SD) age 11 (0.5) years, 51% female] and 1324 of their parents [44 (5.1) years, 87% female]. AA concentrations were variably concordant between parents and their children (5–41% of variability explained). Most AA concentrations were higher in adults than children, except for the non-essential AAs arginine, aspartic acid, glutamine, hydroxy-proline, proline, and serine. Male adults and children typically had higher AA concentrations than females. The exceptions were alanine, glutamine, glycine, hydroxy-proline, serine, and threonine in girls; and glycine and serine in women. Age, sex, and shared familial factors are important determinants of plasma AA concentrations.
Correlation of staging and risk factors with cardiovascular autonomic neuropathy in patients with type II diabetes mellitus
Authors: Dhumad Muhanad M. , Hamdan Farqad B. , Khudhair Mahmood S. , Al-Matubsi Hisham Y.
Published: February 2021

The impairment of cardiovascular autonomic control among the underdiagnosed complication of diabetes mellitus (DM) with a high prevalence rate of up to 60% in type 2 DM (T2DM). Cardiac autonomic neuropathy (CAN) is an independent risk factor for cardiovascular mortality, arrhythmia, silent ischemia, any major cardiovascular event, and heart failure. We aimed to evaluate cardiovascular autonomic activity by different physiological maneuvers, study risk factors for diabetic CAN including age, gender, duration of diabetes, body mass index (BMI), and glycemic control, and correlate CAN stage with risk factors. One hundred and forty-two T2DM patients consisted of 62 males and 80 females and 100 volunteers as a control sample. Cardiac autonomic functions were assessed by Ewing's tests. Glycated hemoglobin (HbA1c), body weight, height, body mass index (BMI), and waist-hip ratio (WHR) were also measured. Cardiovascular autonomic functions and Ewing scores were significantly different in people with diabetes when compared with control healthy subjects. Ewings test values and Ewing scores were significantly different between diabetics with and without CAN and within patients with different CAN staging. People with diabetes with CAN have a significantly longer duration of disease when compared to those without CAN. A strong association has been found between CAN severity and patient age, duration of disease, HbA1c severity, and the WHR (P < 0.001) but not with BMI. The duration of disease and HbA1c level appear to be associated with the development of CAN (P = 0.001 and P = 0.008, respectively). The poorer glycemic control and the longer the duration of the disease, the higher the prevalence of CAN in T2DM. Age, duration of disease, WHR, and HbA1c are well correlated with the severity of CAN. Parasympathetic impairment is more sensitive to the detection of autonomic dysfunctions than do sympathetic impairment.
Using head-mounted eye tracking to examine visual and manual exploration during naturalistic toy play in children with and without autism spectrum disorder
Authors: Yurkovic Julia R. , Lisandrelli Grace , Shaffer Rebecca C. , Dominick Kelli C. , Pedapati Ernest V. , Erickson Craig A. , Kennedy Daniel P. , Yu Chen
Published: February 2021

Multimodal exploration of objects during toy play is important for a child’s development and is suggested to be abnormal in children with autism spectrum disorder (ASD) due to either atypical attention or atypical action. However, little is known about how children with ASD coordinate their visual attention and manual actions during toy play. The current study aims to understand if and in what ways children with ASD generate exploratory behaviors to toys in natural, unconstrained contexts by utilizing head-mounted eye tracking to quantify moment-by-moment attention. We found no differences in how 24- to 48-mo children with and without ASD distribute their visual attention, generate manual action, or coordinate their visual and manual behaviors during toy play with a parent. Our findings suggest an intact ability and willingness of children with ASD to explore toys and suggest that context is important when studying child behavior.
On the optimal certification of von Neumann measurements
Authors: Lewandowska Paulina , Krawiec Aleksandra , Kukulski Ryszard , Pawela Łukasz , Puchała Zbigniew
Published: February 2021

In this report we study certification of quantum measurements, which can be viewed as the extension of quantum hypotheses testing. This extension involves also the study of the input state and the measurement procedure. Here, we will be interested in two-point (binary) certification scheme in which the null and alternative hypotheses are single element sets. Our goal is to minimize the probability of the type II error given some fixed statistical significance. In this report, we begin with studying the two-point certification of pure quantum states and unitary channels to later use them to prove our main result, which is the certification of von Neumann measurements in single-shot and parallel scenarios. From our main result follow the conditions when two pure states, unitary operations and von Neumann measurements cannot be distinguished perfectly but still can be certified with a given statistical significance. Moreover, we show the connection between the certification of quantum channels or von Neumann measurements and the notion of q-numerical range.
Expression of Cyr61 in ApoE−/− mice with chronic unilateral renal artery ligation
Authors: Pathak Alokkumar S. , Rojas Mauricio , Stouffer George A.
Published: February 2021

Cyr61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions and regulated by angiotensin II. It is unknown whether renal artery stenosis (RAS) increases Cyr61 expression. Male ApoE−/− mice were randomized to surgically induced RAS, RAS + treatment with either irbesartan, aliskiren or amlodipine or sham-surgery. RAS resulted in increased plasma angiotensin II levels, a mild, sustained increase in systolic blood pressure and increased aortic lipid deposition compared to sham-surgery. Surgically induced RAS led to the formation of atheroma in the infrarenal aorta and there was consistent and intense staining for Cyr61 within the atheroma. Treatment with irbesartan, aliskiren and amlodipine were associated with decreased aortic lipid deposition and decreased staining for Cyr61 in aortic atheroma. Serum levels of Cyr61 were not increased in mice or humans with RAS. In summary, Cyr61 expression in aortic atheroma but not serum is increased by RAS in ApoE−/− mice and is reduced by agents that lower blood pressure.
Ultrasound shearwave elastography to characterize muscles of healthy and cerebral palsy children
Authors: Lallemant-Dudek Pauline , Vergari Claudio , Dubois Guillaume , Forin Véronique , Vialle Raphaël , Skalli Wafa
Published: February 2021

Shear wave elastography (SWE) is an ultrasound technique to obtain soft tissue mechanical properties. The aim of this study was to establish the reliability of SWE in young children, define reference data on healthy ones and compare the shear modulus of healthy and spastic muscles from cerebral palsy (CP). The reproducibility is evaluated: at rest, on 7 children without any musculoskeletal pathology by 3 different operators, on 2 muscles: biceps brachii long head and medial gastrocnemius. The comparison study was made, on the same 2 muscles, at rest and under passive stretching, with a control group (29 healthy children), a spastic group (spastic muscles of 16 children from CP) and a non-spastic group (non-spastic muscles of 14 children from CP). The intra-operator reliability and inter-operator reliability, in terms of standard deviation, were 0.6 kPa (11.2% coefficient of variation (CV)) and 0.8 kPa (14.9% CV) for the biceps, respectively, and 0.4 kPa (11.5% CV) and 0.5 kPa (13.8% CV) for the gastrocnemius. At rest, no significant difference was found. Under passive stretching, the non-spastic CP biceps were significantly stiffer than the control ones (p = 0.033). Spastic gastrocnemius had a higher shear modulus than in the control muscles (p = 0.0003) or the non-spastic CP muscles (p = 0.017). CP stretched medial gastrocnemius presented an abnormally high shear moduli for 50% of patients.
Peaks in bat activity at turbines and the implications for mitigating the impact of wind energy developments on bats
Authors: Richardson Suzanne M. , Lintott Paul R. , Hosken David J. , Economou Theo , Mathews Fiona
Published: February 2021

Wind turbines are a relatively new threat to bats, causing mortalities worldwide. Reducing these fatalities is essential to ensure that the global increase in wind-energy facilities can occur with minimal impact on bat populations. Although individual bats have been observed approaching wind turbines, and fatalities frequently reported, it is unclear whether bats are actively attracted to, indifferent to, or repelled by, the turbines at large wind-energy installations. In this study, we assessed bat activity at paired turbine and control locations at 23 British wind farms. The research focussed on Pipistrellus species, which were by far the most abundant bats recorded at these sites. P. pipistrellus activity was 37% higher at turbines than at control locations, whereas P. pygmaeus activity was consistent with no attraction or repulsion by turbines. Given that more than 50% of bat fatalities in Europe are P. pipistrellus, these findings help explain why Environmental Impact Assessments conducted before the installation of turbines are poor predictors of actual fatality rates. They also suggest that operational mitigation (minimising blade rotation in periods of high collision risk) is likely to be the most effective way to reduce collisions because the presence of turbines alters bat activity.
Transcriptome analysis of genes involved in starch biosynthesis in developing Chinese chestnut (Castanea mollissima Blume) seed kernels
Authors: Shi Lingling , Wang Jia , Liu Yujun , Ma Chao , Guo Sujuan , Lin Shanzhi , Wang Jianzhong
Published: February 2021

Chinese chestnut (Castanea mollissimaBlume) seed kernels (CCSK) with high quality and quantity of starch has emerged as a potential raw material for food industry, but the molecular regulatory mechanism of starch accumulation in developing CCSK is still unclear. In this study, we firstly analyzed the fruit development, starch accumulation, and microscopic observation of dynamic accumulation of starch granules of developing CCSK from 10 days after flowering (DAF) to 100 DAF, of which six representative CCSK samples (50–100 DAF) were selected for transcriptome sequencing analysis. Approximately 40 million valid reads were obtained, with an average length of 124.95 bp, which were searched against a reference genome, returning 38,146 unigenes (mean size = 1164.19 bp). Using the DESeq method, 1968, 1573, 1187, 1274, and 1494 differentially expressed unigenes were identified at 60:50, 70:60, 80:70, 90:80 and 100:90 DAF, respectively. The relationship between the unigene transcriptional profiles and starch dynamic patterns in developing CCSK was comparatively analyzed, and the specific unigenes encoding for metabolic enzymes (SUSY2, PGM, PGI, GPT, NTT, AGP3, AGP2, GBSS1, SS1, SBE1, SBE2.1, SBE2.2, ISA1, ISA2, ISA3, and PHO) were characterized to be involved potentially in the biosynthesis of G-1-P, ADPG, and starch. Finally, the temporal transcript profiles of genes encoding key enzymes (susy2,pgi2,gpt1,agp2,agp3,gbss1,ss1, sbe1, sbe2.1, sbe2.2, isa1, isa2, isa3,and pho) were validated by quantitative real-time PCR (qRT-PCR). Our findings could help to reveal the molecular regulatory mechanism of starch accumulation in developing CCSK and may also provide potential candidate genes for increasing starch content in Chinese chestnut or other starchy crops.
Two dominant patterns of low anterior resection syndrome and their effects on patients’ quality of life
Authors: Kim Min Jung , Park Ji Won , Lee Mi Ae , Lim Han-Ki , Kwon Yoon-Hye , Ryoo Seung-Bum , Park Kyu Joo , Jeong Seung-Yong
Published: February 2021

To identify low anterior resection syndrome (LARS) patterns and their associations with risk factors and quality of life (QOL). This cross-sectional study analyzed patients who underwent restorative anterior resection for left-sided colorectal cancer at Seoul National University Hospital, Seoul, Republic of Korea. We administered LARS questionnaires to assess bowel dysfunction and quality of life between April 2017 and November 2019. LARS patterns were classified based on factor analyses. Variable effects on LARS patterns were estimated using logistic regression analysis. The risk factors and quality of life associated with dominant LARS patterns were analyzed. Data of 283 patients with a median follow-up duration of 24 months were analyzed. Major LARS was observed in 123 (43.3%) patients. Radiotherapy (odds ratio [OR]: 2.851, 95% confidence interval [95% CI]: 2.504–43.958, p = 0.002), low anastomosis (OR: 10.492, 95% CI: 2.504–43.958, p = 0.001), and complications (OR: 2.163, 95% CI: 1.100–4.255, p = 0.025) were independently associated with major LARS. LARS was classified into incontinence- or frequency-dominant types. Risk factors for incontinence-dominant LARS were radiotherapy and complications, whereas those for frequency-dominant LARS included low tumor location. Patients with incontinence-dominant patterns showed lower emotional function, whereas those with frequency-dominant patterns showed lower global health QOL, lower emotional, cognitive, and social functions, and higher incidence of pain and diarrhea. Frequency-dominant LARS had a greater negative effect on QOL than incontinence-dominant LARS. These patterns could be used for preoperative prediction and postoperative treatment of LARS.
Clinical data mining reveals analgesic effects of lapatinib in cancer patients
Authors: Zhou Shuo , Zheng Fang , Zhan Chang-Guo
Published: February 2021

Microsomal prostaglandin E2 synthase 1 (mPGES-1) is recognized as a promising target for a next generation of anti-inflammatory drugs that are not expected to have the side effects of currently available anti-inflammatory drugs. Lapatinib, an FDA-approved drug for cancer treatment, has recently been identified as an mPGES-1 inhibitor. But the efficacy of lapatinib as an analgesic remains to be evaluated. In the present clinical data mining (CDM) study, we have collected and analyzed all lapatinib-related clinical data retrieved from clinicaltrials.gov. Our CDM utilized a meta-analysis protocol, but the clinical data analyzed were not limited to the primary and secondary outcomes of clinical trials, unlike conventional meta-analyses. All the pain-related data were used to determine the numbers and odd ratios (ORs) of various forms of pain in cancer patients with lapatinib treatment. The ORs, 95% confidence intervals, and P values for the differences in pain were calculated and the heterogeneous data across the trials were evaluated. For all forms of pain analyzed, the patients received lapatinib treatment have a reduced occurrence (OR 0.79; CI 0.70–0.89; P = 0.0002 for the overall effect). According to our CDM results, available clinical data for 12,765 patients enrolled in 20 randomized clinical trials indicate that lapatinib therapy is associated with a significant reduction in various forms of pain, including musculoskeletal pain, bone pain, headache, arthralgia, and pain in extremity, in cancer patients. Our CDM results have demonstrated the significant analgesic effects of lapatinib, suggesting that lapatinib may be repurposed as a novel type of analgesic.
Shallow seamounts represent speciation islands for circumglobal yellowtail Seriola lalandi
Authors: Kerwath Sven , Roodt-Wilding Rouvay , Samaai Toufiek , Winker Henning , West Wendy , Surajnarayan Sheroma , Swart Belinda , Bester-van der Merwe Aletta , Götz Albrecht , Lamberth Stephen , Wilke Christopher
Published: February 2021

Phenotypic plasticity in life-history traits in response to heterogeneous environments has been observed in a number of fishes. Conversely, genetic structure has recently been detected in even the most wide ranging pelagic teleost fish and shark species with massive dispersal potential, putting into question previous expectations of panmixia. Shallow oceanic seamounts are known aggregation sites for pelagic species, but their role in genetic structuring of widely distributed species remains poorly understood. The yellowtail kingfish (Seriola lalandi), a commercially valuable, circumglobal, epipelagic fish species occurs in two genetically distinct Southern Hemisphere populations (South Pacific and southern Africa) with low levels of gene-flow between the regions. Two shallow oceanic seamounts exist in the ocean basins around southern Africa; Vema and Walters Shoal in the Atlantic and Indian oceans, respectively. We analysed rare samples from these remote locations and from the South African continental shelf to assess genetic structure and population connectivity inS. lalandiand investigated life-history traits by comparing diet, age, growth and maturation among the three sites. The results suggest that yellowtail from South Africa and the two seamounts are genetically and phenotypically distinct. Rather than mere feeding oases, we postulate that these seamounts represent islands of breeding populations with site-specific adaptations.