bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractNovel 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

AbstractGenetic, 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

AbstractThe 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$$^{-3}$$

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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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractIce-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

AbstractThe 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

AbstractPrognosis 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

AbstractMycoplasma 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

AbstractDevelopment 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

AbstractTiming 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

AbstractMultiple 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.