bluuebunny/crossref_metadata_2025 huggingface dataset:
A vaccine targeting mutant IDH1 in newly diagnosed glioma
Authors: Platten Michael , Bunse Lukas , Wick Antje , Bunse Theresa , Le Cornet Lucian , Harting Inga , Sahm Felix , Sanghvi Khwab , Tan Chin Leng , Poschke Isabel , Green Edward , Justesen Sune , Behrens Geoffrey A. , Breckwoldt Michael O. , Freitag Angelika , Rother Lisa-Marie , Schmitt Anita , Schnell Oliver , Hense Jörg , Misch Martin , Krex Dietmar , Stevanovic Stefan , Tabatabai Ghazaleh , Steinbach Joachim P. , Bendszus Martin , von Deimling Andreas , Schmitt Michael , Wick Wolfgang
Published: March 2021

Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma1–3. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours in syngeneic MHC-humanized mice4,6–8. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)+ astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG+ and CXCL13+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
Publisher Correction: Effects of Thymoquinone on radiation enteritis in mice
Authors: Hou Qinlian , Liu Linlin , Dong Yinping , Wu Jing , Du Liqing , Dong Hui , Li Deguan
Published: March 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Risk compensation after HIV-1 vaccination may accelerate viral adaptation and reduce cost-effectiveness: a modeling study
Authors: Peebles Kathryn , Mittler John E. , Goodreau Steven M. , Murphy James T. , Reid Molly C. , Abernethy Neil , Gottlieb Geoffrey S. , Barnabas Ruanne V. , Herbeck Joshua T.
Published: March 2021

Pathogen populations can evolve in response to selective pressure from vaccine-induced immune responses. For HIV, models predict that viral adaptation, either via strain replacement or selection on de novo mutation, may rapidly reduce the effectiveness of an HIV vaccine. We hypothesized that behavioral risk compensation after vaccination may accelerate the transmission of vaccine resistant strains, increasing the rate of viral adaptation and leading to a more rapid decline in vaccine effectiveness. To test our hypothesis, we modeled: (a) the impact of risk compensation on rates of HIV adaptation via strain replacement in response to a partially effective vaccine; and (b) the combined impact of risk compensation and viral adaptation on vaccine-mediated epidemic control. We used an agent-based epidemic model that was calibrated to HIV-1 trends in South Africa, and includes demographics, sexual network structure and behavior, and within-host disease dynamics. Our model predicts that risk compensation can increase the rate of HIV viral adaptation in response to a vaccine. In combination, risk compensation and viral adaptation can, under certain scenarios, reverse initial declines in prevalence due to vaccination, and result in HIV prevalence at 15 years equal to or greater than prevalence without a vaccine.
Measuring spatial co-occurrences of species potentially involved in Leishmania transmission cycles through a predictive and fieldwork approach
Authors: López Marla , Erazo Diana , Hoyos Juliana , León Cielo , Fuya Patricia , Lugo Ligia , Cordovez Juan Manuel , González Camila
Published: March 2021

The Leishmaniases are a group of neglected tropical diseases caused by different species of the protozoan parasiteLeishmania, transmitted to its mammalian hosts by the bites of several species of female Phlebotominae sand flies. Many factors have contributed to shifts in the disease distribution and eco epidemiological outcomes, resulting in the emergence of Cutaneous Leishmaniasis outbreaks and the incrimination of vectors in unreported regions. New research development is vital for establishing the new paradigms of the present transmission cycles, hoping to facilitate new control strategies to reduce parasite transmission. Hereafter, this work aims to model and infer the current transmission cycles of Cutaneous Leishmaniasis in Colombia defined by vector and mammal species distributed and interacting in the different regions and validate them by performing sand fly and mammal collections. Vector-host co-occurrences were computed considering five ecoregions of the Colombian territory defined by the World Wide Fund for Nature (WWF) and downloaded from The Nature Conservancy TNC Maps website. Four validation sites were selected based on Cutaneous Leishmaniasis prevalence reports. Sand flies and mammals captured in the field were processed, and species were defined using conventional taxonomic guidelines. Detection of infection byLeishmaniawas performed to identify transmission cycles in the selected areas. This study uses predictive models based on available information from international gazetteers and fieldwork to confirm sand fly and mammalian species' sustainingLeishmaniatransmission cycles. Our results show an uneven distribution of mammal samples in Colombia, possibly due to sampling bias, since only two departments contributed 50% of the available samples. Bats were the vertebrates with the highest score values, suggesting substantial spatial overlap with sand flies than the rest of the vertebrates evaluated. Fieldwork allowed identifying three circulatingLeishmaniaspecies, isolated from three sand fly species. In the Montane Forest ecosystem, one small marsupial,Gracilinanus marica, was found infected withLeishmania panamensis, constituting the first record of this species infected withLeishmania. In the same locality, an infected sand fly,Pintomyia pia,was found. The overall results could support the understanding of the current transmission cycles of Leishmaniasis in Colombia.
Abnormal upregulation of cardiovascular disease biomarker PLA2G7 induced by proinflammatory macrophages in COVID-19 patients
Authors: Li Yang , Jiang Yongzhong , Zhang Yi , Li Naizhe , Yin Qiangling , Liu Linlin , Lv Xin , Liu Yan , Li Aqian , Fang Bin , Li Jiajia , Ye Hengping , Yang Gang , Cui Xiaoxian , Liu Yang , Qu Yuanyuan , Li Chuan , Li Jiandong , Li Dexin , Gai Zhongtao , Wang Shiwen , Zhan Faxian , Liang Mifang
Published: March 2021

High rate of cardiovascular disease (CVD) has been reported among patients with coronavirus disease 2019 (COVID-19). Importantly, CVD, as one of the comorbidities, could also increase the risks of the severity of COVID-19. Here we identified phospholipase A2 group VII (PLA2G7), a well-studied CVD biomarker, as a hub gene in COVID-19 though an integrated hypothesis-free genomic analysis on nasal swabs (n = 486) from patients with COVID-19. PLA2G7 was further found to be predominantly expressed by proinflammatory macrophages in lungs emerging with progression of COVID-19. In the validation stage, RNA level of PLA2G7 was identified in nasal swabs from both COVID-19 and pneumonia patients, other than health individuals. The positive rate of PLA2G7 were correlated with not only viral loads but also severity of pneumonia in non-COVID-19 patients. Serum protein levels of PLA2G7 were found to be elevated and beyond the normal limit in COVID-19 patients, especially among those re-positive patients. We identified and validated PLA2G7, a biomarker for CVD, was abnormally enhanced in COVID-19 at both nucleotide and protein aspects. These findings provided indications into the prevalence of cardiovascular involvements seen in patients with COVID-19. PLA2G7 could be a potential prognostic and therapeutic target in COVID-19.
Genome-wide association study of psychiatric and substance use comorbidity in Mexican individuals
Authors: Martínez-Magaña José Jaime , Genis-Mendoza Alma Delia , Villatoro Velázquez Jorge Ameth , Bustos-Gamiño Marycarmen , Juárez-Rojop Isela Esther , Tovilla-Zarate Carlos Alfonso , Sarmiento Emmanuel , Saucedo Erasmo , Rodríguez-Mayoral Oscar , Fleiz-Bautista Clara , Camarena Beatriz , Aguilar Alejandro , Gonzalez-Castro Thelma Beatriz , Medina-Mora María Elena , Nicolini Humberto
Published: March 2021

The combination of substance use and psychiatric disorders is one of the most common comorbidities. The objective of this study was to perform a genome-wide association study of this comorbidity (Com), substance use alone (Subs), and psychiatric symptomatology alone (Psych) in the Mexican population. The study included 3914 individuals of Mexican descent. Genotyping was carried out using the PsychArray microarray and genome-wide correlations were calculated. Genome-wide associations were analyzed using multiple logistic models, polygenic risk scores (PRSs) were evaluated using multinomial models, and vertical pleiotropy was evaluated by generalized summary-data-based Mendelian randomization. Brain DNA methylation quantitative loci (brain meQTL) were also evaluated in the prefrontal cortex. Genome-wide correlation and vertical pleiotropy were found between all traits. No genome-wide association signals were found, but 64 single-nucleotide polymorphism (SNPs) reached nominal associations (p < 5.00e−05). The SNPs associated with each trait were independent, and the individuals with high PRSs had a higher prevalence of tobacco and alcohol use. In the multinomial models all of the PRSs (Subs-PRS, Com-PRS, and Psych-PRS) were associated with all of the traits. Brain meQTL of the Subs-associated SNPs had an effect on the genes enriched in insulin signaling pathway, and that of the Psych-associated SNPs had an effect on the Fc gamma receptor phagocytosis pathway.
Genome-wide association study and gene network analyses reveal potential candidate genes for high night temperature tolerance in rice
Authors: Bheemanahalli Raju , Knight Montana , Quinones Cherryl , Doherty Colleen J. , Jagadish S. V. Krishna
Published: March 2021

High night temperatures (HNT) are shown to significantly reduce rice (Oryza sativa L.) yield and quality. A better understanding of the genetic architecture of HNT tolerance will help rice breeders to develop varieties adapted to future warmer climates. In this study, a diverse indica rice panel displayed a wide range of phenotypic variability in yield and quality traits under control night (24 °C) and higher night (29 °C) temperatures. Genome-wide association analysis revealed 38 genetic loci associated across treatments (18 for control and 20 for HNT). Nineteen loci were detected with the relative changes in the traits between control and HNT. Positive phenotypic correlations and co-located genetic loci with previously cloned grain size genes revealed common genetic regulation between control and HNT, particularly grain size. Network-based predictive models prioritized 20 causal genes at the genetic loci based on known gene/s expression under HNT in rice. Our study provides important insights for future candidate gene validation and molecular marker development to enhance HNT tolerance in rice. Integrated physiological, genomic, and gene network-informed approaches indicate that the candidate genes for stay-green trait may be relevant to minimizing HNT-induced yield and quality losses during grain filling in rice by optimizing source-sink relationships.
Combined cell and nanoparticle models for TOPAS to study radiation dose enhancement in cell organelles
Authors: Hahn Marc Benjamin , Zutta Villate Julián Mateo
Published: March 2021

Dose enhancement by gold nanoparticles (AuNP) increases the biological effectiveness of radiation damage in biomolecules and tissue. To apply them effectively during cancer therapy their influence on the locally delivered dose has to be determined. Hereby, the AuNP locations strongly influence the energy deposit in the nucleus, mitochondria, membrane and the cytosol of the targeted cells. To estimate these effects, particle scattering simulations are applied. In general, different approaches for modeling the AuNP and their distribution within the cell are possible. In this work, two newly developed continuous and discrete-geometric models for simulations of AuNP in cells are presented. These models are applicable to simulations of internal emitters and external radiation sources. Most of the current studies on AuNP focus on external beam therapy. In contrast, we apply the presented models in Monte-Carlo particle scattering simulations to characterize the energy deposit in cell organelles by radioactive 198AuNP. They emit beta and gamma rays and are therefore considered for applications with solid tumors. Differences in local dose enhancement between randomly distributed and nucleus targeted nanoparticles are compared. Hereby nucleus targeted nanoparticels showed a strong local dose enhancement in the radio sensitive nucleus. These results are the foundation for future experimental work which aims to obtain a mechanistic understanding of cell death induced by radioactive 198Au.
Additional description and genome analyses of Caenorhabditis auriculariae representing the basal lineage of genus Caenorhabditis
Authors: Dayi Mehmet , Kanzaki Natsumi , Sun Simo , Ide Tatsuya , Tanaka Ryusei , Masuya Hayato , Okabe Kimiko , Kajimura Hisashi , Kikuchi Taisei
Published: March 2021

Caenorhabditis auriculariae,which was morphologically described in 1999, was re-isolated from aPlatydemamushroom-associated beetle. Based on the re-isolated materials, some morphological characteristics were re-examined and ascribed to the species. In addition, to clarify phylogenetic relationships with otherCaenorhabditisspecies and biological features of the nematode, the whole genome was sequenced and assembled into 109.5 Mb with 16,279 predicted protein-coding genes. Molecular phylogenetic analyses based on ribosomal RNA and 269 single-copy genes revealed the species is closely related toC. sonoraeandC. monodelphisplacing them at the most basal clade of the genus.C. auriculariaehas morphological characteristics clearly differed from those two species and harbours a number of species-specific gene families, indicating its usefulness as a new outgroup species forCaenorhabditisevolutionary studies. A comparison of carbohydrate-active enzyme (CAZy) repertoires in genomes, which we found useful to speculate about the lifestyle ofCaenorhabditisnematodes, suggested thatC. auriculariaelikely has a life-cycle with tight-association with insects.
Methodological considerations for identifying multiple plasma proteins associated with all-cause mortality in a population-based prospective cohort
Authors: Drake Isabel , Hindy George , Almgren Peter , Engström Gunnar , Nilsson Jan , Melander Olle , Orho-Melander Marju
Published: March 2021

Novel methods to characterize the plasma proteome has made it possible to examine a wide range of proteins in large longitudinal cohort studies, but the complexity of the human proteome makes it difficult to identify robust protein-disease associations. Nevertheless, identification of individuals at high risk of early mortality is a central issue in clinical decision making and novel biomarkers may be useful to improve risk stratification. With adjustment for established risk factors, we examined the associations between 138 plasma proteins measured using two proximity extension assays and long-term risk of all-cause mortality in 3,918 participants of the population-based Malmö Diet and Cancer Study. To examine the reproducibility of protein-mortality associations we used a two-step random-split approach to simulate a discovery and replication cohort and conducted analyses using four different methods: Cox regression, stepwise Cox regression, Lasso-Cox regression, and random survival forest (RSF). In the total study population, we identified eight proteins that associated with all-cause mortality after adjustment for established risk factors and with Bonferroni correction for multiple testing. In the two-step analyses, the number of proteins selected for model inclusion in both random samples ranged from 6 to 21 depending on the method used. However, only three proteins were consistently included in both samples across all four methods (growth/differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide, and epididymal secretory protein E4). Using the total study population, the C-statistic for a model including established risk factors was 0.7222 and increased to 0.7284 with inclusion of the most predictive protein (GDF-15; P < 0.0001). All multiple protein models showed additional improvement in the C-statistic compared to the single protein model (all P < 0.0001). We identified several plasma proteins associated with increased risk of all-cause mortality independently of established risk factors. Further investigation into the putatively causal role of these proteins for longevity is needed. In addition, the examined methods for identifying multiple proteins showed tendencies for overfitting by including several putatively false positive findings. Thus, the reproducibility of findings using such approaches may be limited.
Morphofunctional analysis of human pancreatic cancer cell lines in 2- and 3-dimensional cultures
Authors: Minami Fuuka , Sasaki Norihiko , Shichi Yuuki , Gomi Fujiya , Michishita Masaki , Ohkusu-Tsukada Kozo , Toyoda Masashi , Takahashi Kimimasa , Ishiwata Toshiyuki
Published: March 2021

Genetic, transcriptional, and morphological differences have been reported in pancreatic ductal adenocarcinoma (PDAC) cases. We recently found that epithelial or mesenchymal features were enhanced in three-dimensional (3D) cultures compared to two-dimensional (2D) cultures. In this study, we examined the differences in the morphological and functional characteristics of eight PDAC cell lines in 2D and 3D cultures. Most PDAC cells showed similar pleomorphic morphologies in 2D culture. Under 3D culture, PDAC cells with high E-cadherin and low vimentin expression levels (epithelial) formed small round spheres encircled with flat lining cells, whereas those with high vimentin and low E-cadherin expression levels (mesenchymal) formed large grape-like spheres without lining cells and were highly proliferative. In 3D culture, gemcitabine was more effective for the spheres formed by PDAC cells with epithelial features, while abraxane was more effective on those with mesenchymal features. The expression levels of drug transporters were highest PDAC cells with high vimentin expression levels. These findings indicate that PDAC cells possess various levels of epithelial and mesenchymal characteristics. The 3D-culture method is useful for investigating the diversity of PDAC cell lines and may play important roles in the development of personalized early diagnostic methods and anticancer drugs for PDAC.
Ventilation of the abyss in the Atlantic sector of the Southern Ocean
Authors: Akhoudas Camille Hayatte , Sallée Jean-Baptiste , Haumann F. Alexander , Meredith Michael P. , Garabato Alberto Naveira , Reverdin Gilles , Jullion Loïc , Aloisi Giovanni , Benetti Marion , Leng Melanie J. , Arrowsmith Carol
Published: March 2021

The Atlantic sector of the Southern Ocean is the world’s main production site of Antarctic Bottom Water, a water-mass that is ventilated at the ocean surface before sinking and entraining older water-masses—ultimately replenishing the abyssal global ocean. In recent decades, numerous attempts at estimating the rates of ventilation and overturning of Antarctic Bottom Water in this region have led to a strikingly broad range of results, with water transport-based calculations (8.4–9.7 Sv) yielding larger rates than tracer-based estimates (3.7–4.9 Sv). Here, we reconcile these conflicting views by integrating transport- and tracer-based estimates within a common analytical framework, in which bottom water formation processes are explicitly quantified. We show that the layer of Antarctic Bottom Water denser than 28.36 kg m$$^{-3}$$

-
3

$$\gamma _{n}$$

γ
n

is exported northward at a rate of 8.4 ± 0.7 Sv, composed of 4.5 ± 0.3 Sv of well-ventilated Dense Shelf Water, and 3.9 ± 0.5 Sv of old Circumpolar Deep Water entrained into cascading plumes. The majority, but not all, of the Dense Shelf Water (3.4 ± 0.6 Sv) is generated on the continental shelves of the Weddell Sea. Only 55% of AABW exported from the region is well ventilated and thus draws down heat and carbon into the deep ocean. Our findings unify traditionally contrasting views of Antarctic Bottom Water production in the Atlantic sector, and define a baseline, process-discerning target for its realistic representation in climate models.
A nationwide population-based study in South Korea on a relationship between height and anosmia
Authors: Kang Jeong Wook , Lee Young Chan , Han Kyung Do , Lee Kun Hee
Published: March 2021

The relationship between anosmia and anthropometric factor has not been investigated sufficiently yet. Thus, the purpose of this study was to evaluate anthropometric risk factors of anosmia in an Asian population. Claims data of subjects over 20 years old who underwent a national health examination conducted by the Korean National Insurance Program between 2005 and 2008 were analyzed. They were followed up through the Korean National Insurance Service database. Individuals newly diagnosed with anosmia were identified after the initial health examination until the last follow-up date (December 31, 2016). The incidence of anosmia was high in females younger than 70 years old. The hazard ratio of anosmia was found to be higher in taller groups. The tallest quintile had higher risk than the shortest quintile (hazard ratio = 1.185, 95% confidence interval: 1.147–1.225) after adjusting for age, sex, BMI, income, smoking status, alcohol consumption, regular physical activity, hypertension, diabetes mellitus, and dyslipidemia. This study showed that the incidence of anosmia had a positive association with height. However, careful interpretation is needed to generalize our result because of the limitation of the study population. Further studies are needed to clarify the genetic or environmental causes of anosmia.
A network meta-analysis for neoadjuvant and adjuvant treatments for resectable squamous cell carcinoma of esophagus
Authors: Zhao Yunpeng , Wang Yongqiang , Shan Lei , Peng Chuanliang , Zhang Wenhao , Zhao Xiaogang
Published: March 2021

The optimal treatment for resectable esophageal squamous cell carcinoma (ESCC) is still a debatable point; however, randomized trials for strategies including neoadjuvant or adjuvant chemotherapy (CT), radiotherapy, or chemoradiotherapy (CRT) are not always available. This network meta-analysis aimed to identify an effective approach through indirect comparisons. An extensive literature search comparing multimodality treatment and surgery was performed, and a network meta-analysis was conducted with the frequentist method. Twenty-three trials including a total of 3636 ESCC patients were included. Neoadjuvant CRT and neoadjuvant CT, which were recommended by most guidelines for esophageal cancer, were associated with an overall survival advantage compared with surgery alone (HR = 0.43, 95% CI 0.26–0.73; HR = 0.71, 95% CI 0.32–1.59). A statistically significant survival benefit from neoadjuvant CRT compared with neoadjuvant CT could not be demonstrated in our study (HR = 0.61, 95% CI 0.32–1.17, P = 0.08). Our network meta-analysis showed that both neoadjuvant CRT and neoadjuvant CT were effective in improving the survival of patients with ESCC. Individual clinical decisions need further study in the future.
Mining of high throughput screening database reveals AP-1 and autophagy pathways as potential targets for COVID-19 therapeutics
Authors: Zhu Hu , Chen Catherine Z. , Sakamuru Srilatha , Zhao Jinghua , Ngan Deborah K. , Simeonov Anton , Hall Mathew D. , Xia Menghang , Zheng Wei , Huang Ruili
Published: March 2021

The recent global pandemic of the Coronavirus disease 2019 (COVID-19) caused by the new coronavirus SARS-CoV-2 presents an urgent need for the development of new therapeutic candidates. Many efforts have been devoted to screening existing drug libraries with the hope to repurpose approved drugs as potential treatments for COVID-19. However, the antiviral mechanisms of action of the drugs found active in these phenotypic screens remain largely unknown. In an effort to deconvolute the viral targets in pursuit of more effective anti-COVID-19 drug development, we mined our in-house database of approved drug screens against 994 assays and compared their activity profiles with the drug activity profile in a cytopathic effect (CPE) assay of SARS-CoV-2. We found that the autophagy and AP-1 signaling pathway activity profiles are significantly correlated with the anti-SARS-CoV-2 activity profile. In addition, a class of neurology/psychiatry drugs was found to be significantly enriched with anti-SARS-CoV-2 activity. Taken together, these results provide new insights into SARS-CoV-2 infection and potential targets for COVID-19 therapeutics, which can be further validated by in vivo animal studies and human clinical trials.
Seismic behaviour analysis of a wind turbine tower affected by sea ice based on a simplified model
Authors: Huang Shuai , Qi Qingjie , Zhai Shufeng , Liu Wengang , Liu Jianzhong
Published: March 2021

Ice-structure interaction threatens the safety of the offshore structure; however, dynamic seismic action even renders this process more sophisticated. This research constructed a simplified calculation model for the wind turbine tower, ice, and water under seismic loading, which could avoid solving the complex non-linear equations. Then, the seismic behaviour of the structure, i.e. wind turbine tower, in the presence and absence of influences of the sea ice was investigated, and we found the remarkable effect of sea ice upon the wind turbine tower when its mass is within a range; the wind turbine tower is found to have reduced capacity in energy dissipation, and thickness of tower walls or stiffening ribs is supposed to be enlarged for making the structure more ductile. Affected by the sea ice, the shear force and bending moment of the tower showed significant increases, and more attention needs to be paid to the tower bottom and action position of the sea ice. According to the dynamic similarity principle, finally paraffin was used to simulate sea ice, and shaking-table tests were performed for simulating dynamic ice-structure-water interactions. Results of shaking-table tests verified the rationality of our proposed simplified model.
Absence of evidence for Palaeoproterozoic eclogite-facies metamorphism in East Antarctica: no record of subduction orogenesis during Nuna development
Authors: Brown Dillon A. , Morrissey Laura J. , Goodge John W. , Hand Martin
Published: March 2021

The cratonic elements of proto-Australia, East Antarctica, and Laurentia constitute the nucleus of the Palaeo-Mesoproterozoic supercontinent Nuna, with the eastern margin of the Mawson Continent (South Australia and East Antarctica) positioned adjacent to the western margin of Laurentia. Such reconstructions of Nuna fundamentally rely on palaeomagnetic and geological evidence. In the geological record, eclogite-facies rocks are irrefutable indicators of subduction and collisional orogenesis, yet occurrences of eclogites in the ancient Earth (> 1.5 Ga) are rare. Models for Palaeoproterozoic amalgamation between Australia, East Antarctica, and Laurentia are based in part on an interpretation that eclogite-facies metamorphism and, therefore, collisional orogenesis, occurred in the Nimrod Complex of the central Transantarctic Mountains at c. 1.7 Ga. However, new zircon petrochronological data from relict eclogite preserved in the Nimrod Complex indicate that high-pressure metamorphism did not occur in the Palaeoproterozoic, but instead occurred during early Palaeozoic Ross orogenesis along the active convergent margin of East Gondwana. Relict c. 1.7 Ga zircons from the eclogites have trace-element characteristics reflecting the original igneous precursor, thereby casting doubt on evidence for a Palaeoproterozoic convergent plate boundary along the current eastern margin of the Mawson Continent. Therefore, rather than a Palaeoproterozoic (c. 1.7 Ga) history involving subduction-related continental collision, a pattern of crustal shortening, magmatism, and high thermal gradient metamorphism connected cratons in Australia, East Antarctica, and western Laurentia at that time, leading eventually to amalgamation of Nuna at c. 1.6 Ga.
Cardiac mitofusin-1 is reduced in non-responding patients with idiopathic dilated cardiomyopathy
Authors: Hsiao Yung Ting , Shimizu Ippei , Wakasugi Takayuki , Yoshida Yohko , Ikegami Ryutaro , Hayashi Yuka , Suda Masayoshi , Katsuumi Goro , Nakao Masaaki , Ozawa Takuya , Izumi Daisuke , Kashimura Takeshi , Ozaki Kazuyuki , Soga Tomoyoshi , Minamino Tohru
Published: March 2021

Prognosis of severe heart failure remains poor. Urgent new therapies are required. Some heart failure patients do not respond to established multidisciplinary treatment and are classified as “non-responders”. The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Mitofusin-1 (Mfn1), a mitochondrial fusion protein, is significantly reduced in non-responding patients. This study aimed to elucidate the role of Mfn1 in the failing heart. Twenty-two idiopathic dilated cardiomyopathy (IDCM) patients who underwent endomyocardial biopsy of intraventricular septum were included. Of the 22 patients, 8 were non-responders (left ventricular (LV) ejection fraction (LVEF) of < 10% improvement at late phase follow-up). Electron microscopy (EM), quantitative PCR, and immunofluorescence studies were performed to explore the biological processes and molecules involved in failure to respond. Studies in cardiac specific Mfn1 knockout mice (c-Mfn1 KO), and in vitro studies with neonatal rat ventricular myocytes (NRVMs) were also conducted. A significant reduction in mitochondrial size in cardiomyocytes, and Mfn1, was observed in non-responders. A LV pressure overload with thoracic aortic constriction (TAC) c-Mfn1 KO mouse model was generated. Systolic function was reduced in c-Mfn1 KO mice, while mitochondria alteration in TAC c-Mfn1 KO mice increased. In vitro studies in NRVMs indicated negative regulation of Mfn1 by the β-AR/cAMP/PKA/miR-140-5p pathway resulting in significant reduction in mitochondrial respiration of NRVMs. The level of miR140-5p was increased in cardiac tissues of non-responders. Mfn1 is a biomarker of heart failure in non-responders. Therapies targeting mitochondrial dynamics and homeostasis are next generation therapy for non-responding heart failure patients.
Protein cleavage influences surface protein presentation in Mycoplasma pneumoniae
Authors: Berry Iain J. , Widjaja Michael , Jarocki Veronica M. , Steele Joel R. , Padula Matthew P. , Djordjevic Steven P.
Published: March 2021

Mycoplasma pneumoniae is a significant cause of pneumonia and post infection sequelae affecting organ sites distant to the respiratory tract are common. It is also a model organism where extensive ‘omics’ studies have been conducted to gain insight into how minimal genome self-replicating organisms function. An N-terminome study undertaken here identified 4898 unique N-terminal peptides that mapped to 391 (56%) predicted M. pneumoniae proteins. True N-terminal sequences beginning with the initiating methionine (iMet) residue from the predicted Open Reading Frame (ORF) were identified for 163 proteins. Notably, almost half (317; 46%) of the ORFS derived from M. pneumoniae strain M129 are post-translationally modified, presumably by proteolytic processing, because dimethyl labelled neo-N-termini were characterised that mapped beyond the predicted N-terminus. An analysis of the N-terminome describes endoproteolytic processing events predominately targeting tryptic-like sites, though cleavages at negatively charged residues in P1′ (D and E) with lysine or serine/alanine in P2′ and P3′ positions also occurred frequently. Surfaceome studies identified 160 proteins (23% of the proteome) to be exposed on the extracellular surface of M. pneumoniae. The two orthogonal methodologies used to characterise the surfaceome each identified the same 116 proteins, a 72% (116/160) overlap. Apart from lipoproteins, transporters, and adhesins, 93/160 (58%) of the surface proteins lack signal peptides and have well characterised, canonical functions in the cell. Of the 160 surface proteins identified, 134 were also targets of endo-proteolytic processing. These processing events are likely to have profound implications for how the host immune system recognises and responds to M. pneumoniae.
Prevalence of pathogenic copy number variants among children conceived by donor oocyte
Authors: Monfort Sandra , Orellana Carmen , Oltra Silvestre , Rosello Mónica , Caro-Llopis Alfonso , Martinez Francisco
Published: March 2021

Development of assisted reproductive technologies to address infertility has favored the birth of many children in the last years. The majority of children born with these treatments are healthy, but some concerns remain on the safety of these medical procedures. We have retrospectively analyzed both the fertilization method and the microarray results in all those children born between 2010 and 2019 with multiple congenital anomalies, developmental delay and/or autistic spectrum disorder (n = 486) referred for array study in our center. This analysis showed a significant excess of pathogenic copy number variants among those patients conceived after in vitro fertilization with donor oocyte with respect to those patients conceived by natural fertilization (p = 0.0001). On the other hand, no significant excess of pathogenic copy number variants was observed among patients born by autologous oocyte in vitro fertilization. Further studies are necessary to confirm these results and in order to identify the factors that may contribute to an increased risk of genomic rearrangements, as well as consider the screening for genomic alterations after oocyte donation in prenatal diagnosis.
Finding Nemo’s clock reveals switch from nocturnal to diurnal activity
Authors: Schalm Gregor , Bruns Kristina , Drachenberg Nina , Geyer Nathalie , Foulkes Nicholas S. , Bertolucci Cristiano , Gerlach Gabriele
Published: March 2021

Timing mechanisms play a key role in the biology of coral reef fish. Typically, fish larvae leave their reef after hatching, stay for a period in the open ocean before returning to the reef for settlement. During this dispersal, larvae use a time-compensated sun compass for orientation. However, the timing of settlement and how coral reef fish keep track of time via endogenous timing mechanisms is poorly understood. Here, we have studied the behavioural and genetic basis of diel rhythms in the clown anemonefish Amphiprion ocellaris. We document a behavioural shift from nocturnal larvae to diurnal adults, while juveniles show an intermediate pattern of activity which potentially indicates flexibility in the timing of settlement on a host anemone. qRTPCR analysis of six core circadian clock genes (bmal1, clocka, cry1b, per1b, per2, per3) reveals rhythmic gene expression patterns that are comparable in larvae and juveniles, and so do not reflect the corresponding activity changes. By establishing an embryonic cell line, we demonstrate that clown anemonefish possess an endogenous clock with similar properties to that of the zebrafish circadian clock. Furthermore, our study provides a first basis to study the multi-layered interaction of clocks from fish, anemones and their zooxanthellae endosymbionts.
Added value of computed tomography fractional flow reserve in the diagnosis of coronary artery disease
Authors: Peper J. , Schaap J. , Kelder J. C. , Rensing B. J. W. M. , Grobbee D. E. , Leiner T. , Swaans M. J.
Published: March 2021

Multiple non-invasive tests are performed to diagnose coronary artery disease (CAD), but all are limited to either anatomical or functional assessments. Computed tomography derived Fractional Flow Reserve (CT-FFR) based on patient-specific lumped parameter models is a new test combining both characteristics simulating invasive FFR. This study aims to evaluate the added value of CT-FFR over other non-invasive tests to diagnose CAD. Patients with clinical suspicion of angina pectoris between 2010 and 2011 were included in this cross-sectional study. All underwent stress electrocardiography (X-ECG), SPECT, CT coronary angiography (CCTA) and CT-FFR. Invasive coronary angiography (ICA) and FFR were used as reference standard. Five models mimicking the clinical workflow were fitted and the area under receiver operating characteristic (AUROC) curve was used for comparison. 44% of the patients included in the analysis had a FFR of ≤ 0.80. The basic model including pre-test-likelihood and X-ECG had an AUROC of 0.79. The SPECT-strategy had an AUROC of 0.90 (p = 0.008), CCTA-strategy of 0.88 (p < 0.001), 0.93 when adding CT-FFR (p = 0.40) compared to 0.94 when combining CCTA and SPECT. This study shows adding on-site CT-FFR based on patient-specific lumped parameter models leads to an increased AUROC compared to the basic model. It improves the diagnostic work-up beyond SPECT or CCTA and is non-inferior to the combined strategy of SPECT and CCTA in the diagnosis of hemodynamically relevant CAD.
Detrimental effects of long-term elevated serum uric acid on cognitive function in rats
Authors: Tian Tian , Liu Xi-run , Li Ting-ting , Nie Zhi-chao , Li Shuang-jing , Tang Yan , Gu Cong-wei , Xu Wang-dong , Jia Hong
Published: March 2021

Uric acid is a powerful antioxidant. However, its elevated levels in association with cardiovascular diseases predispose individuals to cognitive impairment. Uric acid’s effects on cognition may be related to its concentration and exposure period. We aimed to explore the effects of long-term elevated serum uric acid on cognitive function and hippocampus. Rats were randomly divided into four groups: NC, M1, M2 and M3 groups. Hyperuricemia was established in rats at week 6 and maintained until week 48 in groups M1, M2 and M3. The rats’ spatial learning and memory abilities were assessed by the Morris Water Maze test at weeks 0, 6, 16, 32, and 48. After week 48, we observed pathological changes in right hippocampal CA1 and CA3 regions, and measured levels of oxidative stress, inflammatory cytokines, and β-amyloid peptide of left hippocampus. Starting from week 6, the serum uric acid level of M3 group > M2 group, the serum uric acid level of M2 group > M1 group, and the serum uric acid level of M1 group > NC group. The rats in M3 and M2 groups had longer escape latencies, longer mean distances to the platform, more extensive pathological damage, stronger inflammation response, higher oxidative stress and β-amyloid peptide levels than those in NC group. No significant differences were observed between M1 and NC groups. In addition, we also found that oxidative stress significantly correlated with tumour necrosis factor-α and β-amyloid peptide. Long-term elevated serum uric acid was significantly associated with cognitive impairment risk. Oxidative stress, tumour necrosis factor-α and β-amyloid peptide may mediate the pathogenesis of the cognitive impairment induced by uric acid. The detrimental effect of elevated serum uric acid on cognitive function was probably expressed when the serum uric acid concentration reached a certain level.
Location of ischemia and ischemic pain intensity affect spatiotemporal parameters and leg muscles activity during walking in patients with intermittent claudication
Authors: Guilleron Céline , Abraham Pierre , Beaune Bruno , Pouliquen Camille , Henni Samir , Durand Sylvain
Published: March 2021

The ways in which locations of ischemia and ischemic pain affect spatiotemporal gait parameters and leg electromyographic activity during walking have never been investigated in patients with peripheral arterial disease presenting intermittent claudication. Two groups were classified according to unilateral location of ischemia (distal, n = 10, or proximo-distal, n = 12). Patients described pain and three gait phases—initial pain-free, onset of pain and maximum pain—were analyzed. Patients with proximo-distal ischemia walked less (230 ± 111 m vs 384 ± 220 m), with increased step length, step time (+ 5.4% and + 5.8%) and reduced cadence (− 8.2%), than patients with distal ischemia. In both, the peaks of vertical ground reaction force were reduced in maximum pain (Peak1-distal: − 11.4%, Peak1-proximo-distal: − 10.3%; Peak2-distal: − 11.8%, Peak2-proximo-distal: − 9.0%). In the proximo-distal group, tibialis anterior activation peak and time were lower than in the distal group (− 4.5% and − 19.7%). During the maximum pain phase, this peak decreased only in the proximo-distal group (− 13.0%), and gastrocnemius medialis activation peak and time decreased in both groups (− 2.5% in distal and − 4.5% in proximo-distal). Thus, proximo-distal ischemia leads to more adverse consequences in gait than distal ischemia only. Increasing ischemic pain until maximum, but not onset of pain, induced gait adaptations.
Classification algorithm for congenital Zika Syndrome: characterizations, diagnosis and validation
Authors: Veiga Rafael V. , Schuler-Faccini Lavinia , França Giovanny V. A. , Andrade Roberto F. S. , Teixeira Maria Glória , Costa Larissa C. , Paixão Enny S. , Costa Maria da Conceição N. , Barreto Maurício L. , Oliveira Juliane F. , Oliveira Wanderson K. , Cardim Luciana L. , Rodrigues Moreno S.
Published: March 2021

Zika virus was responsible for the microcephaly epidemic in Brazil which began in October 2015 and brought great challenges to the scientific community and health professionals in terms of diagnosis and classification. Due to the difficulties in correctly identifying Zika cases, it is necessary to develop an automatic procedure to classify the probability of a CZS case from the clinical data. This work presents a machine learning algorithm capable of achieving this from structured and unstructured available data. The proposed algorithm reached 83% accuracy with textual information in medical records and image reports and 76% accuracy in classifying data without textual information. Therefore, the proposed algorithm has the potential to classify CZS cases in order to clarify the real effects of this epidemic, as well as to contribute to health surveillance in monitoring possible future epidemics.
Author Correction: Development of an integrated peri-urban wetland degradation assessment approach for the Chatra Wetland in eastern India
Authors: Basu Tirthankar , Das Arijit , Pham Quoc Bao , Al-Ansari Nadhir , Linh Nguyen Thi Thuy , Lagerwall Gareth
Published: March 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Heterogeneous alkane dehydrogenation catalysts investigated via a surface organometallic chemistry approach
Authors: Docherty Scott R. , Rochlitz Lukas , Payard Pierre-Adrien , Copéret Christophe
Published: March 2021

Alkane dehydrogenation over heterogeneous catalysts has attracted renewed attention in recent years. Here, well-defined catalysts based on isolated metal sites and supported Pt-alloys prepared via SOMC are discussed and compared to classical systems.
Synthesis of ruthenium complexes functionalized with benzothiophene and their antibacterial activity against Staphylococcus aureus
Authors: Liao Xiangwen , Liu Lianghong , Tan Yanhui , Jiang Guijuan , Fang Haihong , Xiong Yanshi , Duan Xuemin , Jiang Guangbin , Wang Jintao
Published: March 2021

Ruthenium complex Ru(II)-3 functionalized with benzothiophene showed good antimicrobial activity against Staphylococcus aureus in vivo.
Trace xenon detection in helium environment via laser-induced breakdown spectroscopy
Authors: Burger M. , Garrett L. , Burak A. J. , Petrov V. , Manera A. , Sabharwall P. , Sun X. , Jovanovic I.
Published: March 2021

We assess the sensitivity of LIBS for trace xenon detection in a helium buffer and its suitability for online monitoring of reactor fuel integrity.
Novel microwell with a roof capable of buoyant spheroid culture
Authors: Kim Daehan , Kim Kideok , Park Joong Yull
Published: March 2021

Our unique microwell in the shape of the Greek letter sigma (σ) with a roof can culture floating spheroids.
Two models to estimate the density of organic cocrystals
Authors: Zhou Jun-Hong , Zhao Li , Shi Liang-Wei , Pei-Cheng Luo
Published: March 2021

Taking the organic cocrystals as the datasets, an artificial neural network was built based on six input parameters (Ms, RTm, E1u), and a model was also built based on the surface electrostatic potential correction method.
Recent progress in the shape deformation of polymeric hydrogels from memory to actuation
Authors: Wu Baoyi , Lu Huanhuan , Le Xiaoxia , Lu Wei , Zhang Jiawei , Théato Patrick , Chen Tao
Published: March 2021

Shape deformation hydrogels, which are one of the most promising and essential classes of stimuli-responsive polymers, could provide large-scale and reversible deformation under external stimuli.
Simultaneous determination of the concentration and enantiomeric excess of amino acids with a coumarin-derived achiral probe
Authors: Yang Lamei , Luo Feng , Wei Weili
Published: March 2021

An achiral easy-to-synthesize coumarin aldehyde probe was designed and synthesized for chiral analysis of amino acids.
Controlled synthesis of conjugated polymers in dendritic mesoporous silica nanoparticles
Authors: Wu Yusen , Wang Jie , Zhu Yanchao , Yu Xiaowang , Shang Zhikun , Ding Yun , Hu Aiguo
Published: March 2021

A controlled polymerization strategy is developed by confining the step-growth polycondensation to take place exclusively in the nanochannels of dendritic mesoporous silica nanoparticles.
Valveless flow reversal by a pH responsive supramolecular micropump
Authors: Alam Mujeeb , Varshney Rohit , Agashe Chinmayee , Gill Arshdeep Kaur , Patra Debabrata
Published: March 2021

Flow reversal in a valveless micropump was achieved via dynamic supramolecular interaction between beta-cyclodextrin (β-CD) and benzimidazole (BzI).
Photo-initiated oxidation of C–H bonds by diimine complexes of vanadium(v)
Authors: Zhang Rui , Zhou Wen , Warren Jeffrey J.
Published: March 2021

The photochemical activation of carbon–hydrogen bonds by vanadium(v)–dioxo and vanadium(v)–oxo–peroxo diimine complexes is described.
Three dimensional isophlorinoid tetrapodal molecular cage
Authors: Basavarajappa Ashokkumar , Ambhore Madan D. , Anand Venkataramanarao G.
Published: March 2021

A cage-like structure bearing sixteen thiophene units is synthesized by the acid assisted condensation of bithiophene and tetrathiophene units. It represents a three dimensional isophlorinoid with a weak antiaromatic character.
Sodium citrate as a self-sacrificial sodium compensation additive for sodium-ion batteries
Authors: Zhang Rui , Tang Zheng , Sun Dan , Li Ruiyi , Yang Wenhao , Zhou Siyu , Xie Zhiyong , Tang Yougen , Wang Haiyan
Published: March 2021

Sodium citrate is proposed as a promising cathode additive to compensate the first cycle Na loss in sodium ion batteries.