bluuebunny/crossref_metadata_2025 huggingface dataset:
An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer
Authors: Lindskrog Sia Viborg , Prip Frederik , Lamy Philippe , Taber Ann , Groeneveld Clarice S. , Birkenkamp-Demtröder Karin , Jensen Jørgen Bjerggaard , Strandgaard Trine , Nordentoft Iver , Christensen Emil , Sokac Mateo , Birkbak Nicolai J. , Maretty Lasse , Hermann Gregers G. , Petersen Astrid C. , Weyerer Veronika , Grimm Marc-Oliver , Horstmann Marcus , Sjödahl Gottfrid , Höglund Mattias , Steiniche Torben , Mogensen Karin , de Reyniès Aurélien , Nawroth Roman , Jordan Brian , Lin Xiaoqi , Dragicevic Dejan , Ward Douglas G. , Goel Anshita , Hurst Carolyn D. , Raman Jay D. , Warrick Joshua I. , Segersten Ulrika , Sikic Danijel , van Kessel Kim E. M. , Maurer Tobias , Meeks Joshua J. , DeGraff David J. , Bryan Richard T. , Knowles Margaret A. , Simic Tatjana , Hartmann Arndt , Zwarthoff Ellen C. , Malmström Per-Uno , Malats Núria , Real Francisco X. , Dyrskjøt Lars
Published: April 2021

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
Deletion of CTCF sites in the SHH locus alters enhancer–promoter interactions and leads to acheiropodia
Authors: Ushiki Aki , Zhang Yichi , Xiong Chenling , Zhao Jingjing , Georgakopoulos-Soares Ilias , Kane Lauren , Jamieson Kirsty , Bamshad Michael J. , Nickerson Deborah A. ,   University of Washington Center for Mendelian Genomics, Shen Yin , Lettice Laura A. , Silveira-Lucas Elizabeth Lemos , Petit Florence , Ahituv Nadav
Published: April 2021

Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer–promoter interactions.
Structure-guided engineering of adenine base editor with minimized RNA off-targeting activity
Authors: Li Jianan , Yu Wenxia , Huang Shisheng , Wu Susu , Li Liping , Zhou Jiankui , Cao Yu , Huang Xingxu , Qiao Yunbo
Published: April 2021

Both adenine base editors (ABEs) and cytosine base editors (CBEs) have been recently revealed to induce transcriptome-wide RNA off-target editing in a guide RNA-independent manner. Here we construct a reporter system containing E.coli Hokb gene with a tRNA-like motif for robust detection of RNA editing activities as the optimized ABE, ABEmax, induces highly efficient A-to-I (inosine) editing within an E.coli tRNA-like structure. Then, we design mutations to disrupt the potential interaction between TadA and tRNAs in structure-guided principles and find that Arginine 153 (R153) within TadA is essential for deaminating RNAs with core tRNA-like structures. Two ABEmax or mini ABEmax variants (TadA* fused with Cas9n) with deletion of R153 within TadA and/or TadA* (named as del153/del153* and mini del153) are successfully engineered, showing minimized RNA off-targeting, but comparable DNA on-targeting activities. Moreover, R153 deletion in recently reported ABE8e or ABE8s can also largely reduce their RNA off-targeting activities. Taken together, we develop a strategy to generate engineered ABEs (eABEs) with minimized RNA off-targeting activities.
Nanoscale magnonic Fabry-Pérot resonator for low-loss spin-wave manipulation
Authors: Qin Huajun , Holländer Rasmus B. , Flajšman Lukáš , Hermann Felix , Dreyer Rouven , Woltersdorf Georg , van Dijken Sebastiaan
Published: April 2021

Active control of propagating spin waves on the nanoscale is essential for beyond-CMOS magnonic computing. Here, we experimentally demonstrate reconfigurable spin-wave transport in a hybrid YIG-based material structure that operates as a Fabry-Pérot nanoresonator. The magnonic resonator is formed by a local frequency downshift of the spin-wave dispersion relation in a continuous YIG film caused by dynamic dipolar coupling to a ferromagnetic metal nanostripe. Drastic downscaling of the spin-wave wavelength within the bilayer region enables programmable control of propagating spin waves on a length scale that is only a fraction of their wavelength. Depending on the stripe width, the device structure offers full nonreciprocity, tunable spin-wave filtering, and nearly zero transmission loss at allowed frequencies. Our results provide a practical route for the implementation of low-loss YIG-based magnonic devices with controllable transport properties.
The molecular pH-response mechanism of the plant light-stress sensor PsbS
Authors: Krishnan-Schmieden Maithili , Konold Patrick E. , Kennis John T. M. , Pandit Anjali
Published: April 2021

Plants need to protect themselves from excess light, which causes photo-oxidative damage and lowers the efficiency of photosynthesis. Photosystem II subunit S (PsbS) is a pH sensor protein that plays a crucial role in plant photoprotection by detecting thylakoid lumen acidification in excess light conditions via two lumen-faced glutamates. However, how PsbS is activated under low-pH conditions is unknown. To reveal the molecular response of PsbS to low pH, here we perform an NMR, FTIR and 2DIR spectroscopic analysis of Physcomitrella patens PsbS and of the E176Q mutant in which an active glutamate has been replaced. The PsbS response mechanism at low pH involves the concerted action of repositioning of a short amphipathic helix containing E176 facing the lumen and folding of the luminal loop fragment adjacent to E71 to a 310-helix, providing clear evidence of a conformational pH switch. We propose that this concerted mechanism is a shared motif of proteins of the light-harvesting family that may control thylakoid inter-protein interactions driving photoregulatory responses.
O-linked N-acetylglucosamine transferase is involved in fine regulation of flowering time in winter wheat
Authors: Fan Min , Miao Fang , Jia Haiyan , Li Genqiao , Powers Carol , Nagarajan Ragupathi , Alderman Phillip D. , Carver Brett F. , Ma Zhengqiang , Yan Liuling
Published: April 2021

Vernalization genes underlying dramatic differences in flowering time between spring wheat and winter wheat have been studied extensively, but little is known about genes that regulate subtler differences in flowering time among winter wheat cultivars, which account for approximately 75% of wheat grown worldwide. Here, we identify a gene encoding an O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) that differentiates heading date between winter wheat cultivars Duster and Billings. We clone this TaOGT1 gene from a quantitative trait locus (QTL) for heading date in a mapping population derived from these two bread wheat cultivars and analyzed in various environments. Transgenic complementation analysis shows that constitutive overexpression of TaOGT1b from Billings accelerates the heading of transgenic Duster plants. TaOGT1 is able to transfer an O-GlcNAc group to wheat protein TaGRP2. Our findings establish important roles for TaOGT1 in winter wheat in adaptation to global warming in the future climate scenarios.
Gallium nitride catalyzed the direct hydrogenation of carbon dioxide to dimethyl ether as primary product
Authors: Liu Chang , Kang Jincan , Huang Zheng-Qing , Song Yong-Hong , Xiao Yong-Shan , Song Jian , He Jia-Xin , Chang Chun-Ran , Ge Han-Qing , Wang Ye , Liu Zhao-Tie , Liu Zhong-Wen
Published: April 2021

The selective hydrogenation of CO2to value-added chemicals is attractive but still challenged by the high-performance catalyst. In this work, we report that gallium nitride (GaN) catalyzes the direct hydrogenation of CO2to dimethyl ether (DME) with a CO-free selectivity of about 80%. The activity of GaN for the hydrogenation of CO2is much higher than that for the hydrogenation of CO although the product distribution is very similar. The steady-state and transient experimental results, spectroscopic studies, and density functional theory calculations rigorously reveal that DME is produced as the primary product via the methyl and formate intermediates, which are formed over different planes of GaN with similar activation energies. This essentially differs from the traditional DME synthesis via the methanol intermediate over a hybrid catalyst. The present work offers a different catalyst capable of the direct hydrogenation of CO2to DME and thus enriches the chemistry for CO2transformations.
Detecting protein and DNA/RNA structures in cryo-EM maps of intermediate resolution using deep learning
Authors: Wang Xiao , Alnabati Eman , Aderinwale Tunde W. , Maddhuri Venkata Subramaniya Sai Raghavendra , Terashi Genki , Kihara Daisuke
Published: April 2021

An increasing number of density maps of macromolecular structures, including proteins and DNA/RNA complexes, have been determined by cryo-electron microscopy (cryo-EM). Although lately maps at a near-atomic resolution are routinely reported, there are still substantial fractions of maps determined at intermediate or low resolutions, where extracting structure information is not trivial. Here, we report a new computational method, Emap2sec+, which identifies DNA or RNA as well as the secondary structures of proteins in cryo-EM maps of 5 to 10 Å resolution. Emap2sec+ employs the deep Residual convolutional neural network. Emap2sec+ assigns structural labels with associated probabilities at each voxel in a cryo-EM map, which will help structure modeling in an EM map. Emap2sec+ showed stable and high assignment accuracy for nucleotides in low resolution maps and improved performance for protein secondary structure assignments than its earlier version when tested on simulated and experimental maps.
A committed fourfold increase in ocean oxygen loss
Authors: Oschlies Andreas
Published: April 2021

Less than a quarter of ocean deoxygenation that will ultimately be caused by historical CO2 emissions is already realized, according to millennial-scale model simulations that assume zero CO2 emissions from year 2021 onwards. About 80% of the committed oxygen loss occurs below 2000 m depth, where a more sluggish overturning circulation will increase water residence times and accumulation of respiratory oxygen demand. According to the model results, the deep ocean will thereby lose more than 10% of its pre-industrial oxygen content even if CO2 emissions and thus global warming were stopped today. In the surface layer, however, the ongoing deoxygenation will largely stop once CO2 emissions are stopped. Accounting for the joint effects of committed oxygen loss and ocean warming, metabolic viability representative for marine animals declines by up to 25% over large regions of the deep ocean, posing an unavoidable escalation of anthropogenic pressure on deep-ocean ecosystems.
TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation
Authors: Iizasa Ei’ichi , Chuma Yasushi , Uematsu Takayuki , Kubota Mio , Kawaguchi Hiroaki , Umemura Masayuki , Toyonaga Kenji , Kiyohara Hideyasu , Yano Ikuya , Colonna Marco , Sugita Masahiko , Matsuzaki Goro , Yamasaki Sho , Yoshida Hiroki , Hara Hiromitsu
Published: April 2021

Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, a mechanism of action is unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages respond to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages respond to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.
DUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death
Authors: Low Heng Boon , Wong Zhen Lim , Wu Bangyuan , Kong Li Ren , Png Chin Wen , Cho Yik-Lam , Li Chun-Wei , Xiao Fengchun , Xin Xuan , Yang Henry , Loo Jia Min , Lee Fiona Yi Xin , Tan Iain Bee Huat , DasGupta Ramanuj , Shen Han-Ming , Schwarz Herbert , Gascoigne Nicholas R. J. , Goh Boon Cher , Xu Xiaohong , Zhang Yongliang
Published: April 2021

Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.
multiSLIDE is a web server for exploring connected elements of biological pathways in multi-omics data
Authors: Ghosh Soumita , Datta Abhik , Choi Hyungwon
Published: April 2021

Quantitative multi-omics data are difficult to interpret and visualize due to large volume of data, complexity among data features, and heterogeneity of information represented by different omics platforms. Here, we present multiSLIDE, a web-based interactive tool for the simultaneous visualization of interconnected molecular features in heatmaps of multi-omics data sets. multiSLIDE visualizes biologically connected molecular features by keyword search of pathways or genes, offering convenient functionalities to query, rearrange, filter, and cluster data on a web browser in real time. Various querying mechanisms make it adaptable to diverse omics types, and visualizations are customizable. We demonstrate the versatility of multiSLIDE through three examples, showcasing its applicability to a wide range of multi-omics data sets, by allowing users to visualize established links between molecules from different omics data, as well as incorporate custom inter-molecular relationship information into the visualization. Online and stand-alone versions of multiSLIDE are available at https://github.com/soumitag/multiSLIDE.
Specific contribution of neurons from the Dbx1 lineage to the piriform cortex
Authors: Shabangu Thando , Chen Hung-Lun , Zhuang Zi-hui , Pierani Alessandra , Chen Chien-Fu F. , Chou Shen-Ju
Published: April 2021

The piriform cortex (PC) is a major cortical processing center for the sense of smell that receives direct inputs from the olfactory bulb. In mice, the PC consists of three neuronal layers, which are populated by cells with distinct developmental origins. One origin of PC neurons is the pool of Dbx1-expressing neural progenitors located in the ventral pallium at the pallial-subpallial boundary. Since the precise mechanisms of PC neuron development are largely unknown, we sought to define the distribution, timing of neurogenesis, morphology and projection patterns of PC neurons from the Dbx1 lineage. We found that Dbx1-lineage neurons are preferentially distributed in layer 2 and enriched in the ventral portion of the PC. Further, Dbx1 neurons are early-born neurons and contribute to most neuronal subtypes in the PC. Our data also revealed an enrichment of Dbx1-lineage neurons in the ventral anterior PC that project to the orbitofrontal cortex. These findings suggest a specific association between the developmental origin of PC neurons and their neuronal properties.
Evaluation of the C60 biodistribution in mice in a micellar ExtraOx form and in an oil solution
Authors: Semenov Konstantin N. , Ivanova Daria A. , Ageev Sergei V. , Petrov Andrey V. , Podolsky Nikita E. , Volochaeva Ekaterina M. , Fedorova Ekaterina M. , Meshcheriakov Anatolii A. , Zakharov Egor E. , Murin Igor V. , Sharoyko Vladimir V.
Published: April 2021

The article is devoted to the study of the pharmacokinetics of fullerene C60 in oil and micellar forms, analysis of its content in blood, liver, lungs, kidneys, heart, brain, adrenal glands, thymus, testicles, and spleen. The highest accumulation of C60 was found in the liver and adrenal glands. As a result of the studies carried out, it was shown that the bioavailability of C60 in the micellar form is higher than that in an oil solution.
Structural equation modeling to shed light on the controversial role of climate on the spread of SARS-CoV-2
Authors: Spada Alessia , Tucci Francesco Antonio , Ummarino Aldo , Ciavarella Paolo Pio , Calà Nicholas , Troiano Vincenzo , Caputo Michele , Ianzano Raffaele , Corbo Silvia , de Biase Marco , Fascia Nicola , Forte Chiara , Gambacorta Giorgio , Maccione Gabriele , Prencipe Giuseppina , Tomaiuolo Michele , Tucci Antonio
Published: April 2021

Climate seems to influence the spread of SARS-CoV-2, but the findings of the studies performed so far are conflicting. To overcome these issues, we performed a global scale study considering 134,871 virologic-climatic-demographic data (209 countries, first 16 weeks of the pandemic). To analyze the relation among COVID-19, population density, and climate, a theoretical path diagram was hypothesized and tested using structural equation modeling (SEM), a powerful statistical technique for the evaluation of causal assumptions. The results of the analysis showed that both climate and population density significantly influence the spread of COVID-19 (p < 0.001 and p < 0.01, respectively). Overall, climate outweighs population density (path coefficients: climate vs. incidence = 0.18, climate vs. prevalence = 0.11, population density vs. incidence = 0.04, population density vs. prevalence = 0.05). Among the climatic factors, irradiation plays the most relevant role, with a factor-loading of − 0.77, followed by temperature (− 0.56), humidity (0.52), precipitation (0.44), and pressure (0.073); for all p < 0.001. In conclusion, this study demonstrates that climatic factors significantly influence the spread of SARS-CoV-2. However, demographic factors, together with other determinants, can affect the transmission, and their influence may overcome the protective effect of climate, where favourable.
Electron guiding in macroscopic borosilicate capillaries with large bending angles
Authors: Nguyen Hai-Dang , Wulfkühler Jan-Philipp , Heisig Jörg , Tajmar Martin
Published: April 2021

This work presents experiments about the transmission of electrons with an energy of around 15 keV with beam currents up to 20 µA through macroscopic glass capillaries. A systematic study was conducted to experimentally investigate the transmission of electrons through borosilicate glass capillaries with curve angles of 90°, 180°, 270° and 360° for the first time. The focus of the work was to identify the conditions under which the injected electron current is transmitted through the capillary. It was also shown that the transmission process in the macroscopic capillaries can be optically observed by cathodoluminescence—the interaction of electrons with the capillary surface causes locally a blue glow. Different distinctive “glow states” were observed and are found to correlate with different states of electron transmission.
Multi-omic analyses in Abyssinian cats with primary renal amyloid deposits
Authors: Genova Francesca , Nonnis Simona , Maffioli Elisa , Tedeschi Gabriella , Strillacci Maria Giuseppina , Carisetti Michela , Sironi Giuseppe , Cupaioli Francesca Anna , Di Nanni Noemi , Mezzelani Alessandra , Mosca Ettore , Helps Christopher R. , Leegwater Peter A. J. , Dorso Laetitia ,   99 Lives Consortium, Buckley Reuben M. , Aberdein Danielle , Alves Paulo C. , Andersson Asa Ohlsson , Barsh Gregory S. , Bellone Rebecca R. , Bergström Tomas F. , Boyko Adam R. , Brockman Jeffrey A. , Casal Margret L. , Castelhano Marta G. , Distl Ottmar , Dodman Nicholas H. , Ellinwood N. Matthew , Fogle Jonathan E. , Forman Oliver P. , Garrick Dorian J. , Ginns Edward I. , Haase Bianca , Häggström Jens , Harvey Robert J. , Hasegawa Daisuke , Hernandez Isabel , Hytönen Marjo K. , Kaukonen Maria , Kaelin Christopher B. , Kosho Tomoki , Leclerc Emilie , Lear Teri L. , Leeb Tosso , Li Ronald H. L. , Lohi Hannes , Magnuson Mark A. , Malik Richard , Mane Shrinivasrao P. , Munday John S. , Murphy William J. , Pedersen Niels C. , Peterson-Jones Simon M. , Rothschild Max F. , Rusbridge Clare , Shapiro Beth , Stern Joshua A. , Swanson William F. , Terio Karen A. , Todhunter Rory J. , Warren Wesley C. , Wilcox Elizabeth A. , Wildschutte Julia H. , Yu Yoshihiko , Lyons Leslie A. , Longeri Maria
Published: April 2021

The amyloidoses constitute a group of diseases occurring in humans and animals that are characterized by abnormal deposits of aggregated proteins in organs, affecting their structure and function. In the Abyssinian cat breed, a familial form of renal amyloidosis has been described. In this study, multi-omics analyses were applied and integrated to explore some aspects of the unknown pathogenetic processes in cats. Whole-genome sequences of two affected Abyssinians and 195 controls of other breeds (part of the 99 Lives initiative) were screened to prioritize potential disease-associated variants. Proteome and miRNAome from formalin-fixed paraffin-embedded kidney specimens of fully necropsied Abyssinian cats, three affected and three non-amyloidosis-affected were characterized. While the trigger of the disorder remains unclear, overall, (i) 35,960 genomic variants were detected; (ii) 215 and 56 proteins were identified as exclusive or overexpressed in the affected and control kidneys, respectively; (iii) 60 miRNAs were differentially expressed, 20 of which are newly described. With omics data integration, the general conclusions are: (i) the familial amyloid renal form in Abyssinians is not a simple monogenic trait; (ii) amyloid deposition is not triggered by mutated amyloidogenic proteins but is a mix of proteins codified by wild-type genes; (iii) the form is biochemically classifiable as AA amyloidosis.
Functional disability is related to serum chemerin levels in rheumatoid arthritis
Authors: Vazquez-Villegas Maria Luisa , Gamez-Nava Jorge I. , Saldaña-Cruz A. Miriam , Celis Alfredo , Sanchez-Rodriguez Esther N. , Perez-Guerrero Edsaul Emilio , Ramirez-Villafaña Melissa , Nava-Valdivia Cesar Arturo , Contreras-Haro Betsabe , Vasquez-Jimenez Jose C. , Ponce-Guarneros Juan M. , Barocio-Ramirez Ana K. , Cerpa-Cruz Sergio , Alcaraz-Lopez Miriam F. , Gonzalez-Lopez Laura
Published: April 2021

Adipokines, especially chemerin, can interact with cytokines and other molecules in inflammation. To date, there is insufficient information regarding a possible correlation between functional disability and chemerin and other pro-inflammatory molecules in rheumatoid arthritis (RA). To identify the association of functional disability with serum chemerin and other pro-inflammatory molecules, including other adipokines, cytokines and E-selectin, in patients with RA. Cross-sectional study. Assessment: disease activity (DAS28-ESR) and functional disability (HAQ-DI). We compared the adipokines (chemerin, leptin, adiponectin, resistin, and visfatin), cytokines (TNF-α, IL-6, IL-1β, and IL-18) and E-selectin levels between RA with functional disability and RA non-disabled patients. Of 82 patients with RA, 43 (52%) had functional disability. The RA with functional disability group had higher chemerin (140 vs. 112 ng/mL, p = 0.007) than the non-disabled RA group. Chemerin correlated with the HAQ-DI (rho = 0.27, p = 0.02) and DAS28-ESR (rho = 0.21, p = 0.05). Severe activity correlated with IL-6 (rho = 0.33, p = 0.003) and E-selectin (rho = 0.23, p = 0.03) but not with disability. No other pro-inflammatory molecules correlated with HAQ-DI. High chemerin levels were associated with functional disability in RA, whereas no other molecules correlated with loss of function. These results encourage further studies assessing new roles of chemerin as a marker of impairment in RA.
The neurodevelopment of delay discounting for monetary rewards in pre-adolescent children
Authors: Yu Mei , Liu Tongran , Shangguan Fangfang , Sui Jingxin , Shi Jiannong
Published: April 2021

Children are found to exhibit high degrees of delay discounting compared with adults in many delay discounting studies, which might be due to the asynchronous development of “bottom-up” and “top-down” neural systems. However, the temporal dynamics associated with the two systems in the development of delay discounting processes are not well known. In this study, we chose two age groups of participants and adopted event-related potential (ERP) techniques to investigate the neural dynamic differences between children and adults during delay discounting processes. Behavioral findings showed that children discounted more than adults and chose more immediate choices. Electrophysiological findings revealed that children exhibited longer neural processing (longer P2 latency) than adults during the early detection and identification phase. Children showed less cognitive control (smaller N2 amplitude) than adults over the middle frontal areas, and they devoted more neural effort (larger P3 amplitudes) to making final choices than adults. The factors of reward amount and time delay could influence the development of delay discounting in children.
Long-term demise of sub-Antarctic glaciers modulated by the Southern Hemisphere Westerlies
Authors: Bakke Jostein , Paasche Øyvind , Schaefer Joerg M , Timmermann Axel
Published: April 2021

The accelerated melting of ice on the Antarctic Peninsula and islands in the sub-Antarctic suggests that the cryosphere is edging towards an irreversible tipping point. How unusual is this trend of ice loss within the frame of natural variability, and to what extent can it be explained by underlying climate dynamics? Here, we present new high-resolution reconstructions of long-term changes in the extents of three glaciers on the island of South Georgia (54°S, 36°W), combining detailed analyses of glacial-derived sediments deposited in distal glacier-fed lakes and cosmogenic exposure dating of moraines. We document that the glaciers of South Georgia have gradually retracted since the Antarctic cold reversal (ACR, 14.5–12.8 ka), culminating in the disappearance of at least one of the reconstructed glaciers. The glacier retreat pattern observed in South Georgia suggests a persistent link to summer insolation at 55°S, which intensified during the period from the ACR to approximately 2 ka. It also reveals multi-decadal to centennial climate shifts superimposed on this long-term trend that have resulted in at least nine glacier readvances during the last 10.5 ka. Accompanying meridional changes in the Southern Hemisphere westerlies and their interconnection with local topography may explain these glacier readvances.
Establishment and characterization of a new spontaneously immortalized ER−/PR−/HER2+ human breast cancer cell line, DHSF-BR16
Authors: Nobili Stefania , Mannini Antonella , Parenti Astrid , Raggi Chiara , Lapucci Andrea , Chiorino Giovanna , Paccosi Sara , Di Gennaro Paola , Vezzosi Vania , Romagnoli Paolo , Susini Tommaso , Coronnello Marcella
Published: April 2021

Invasive ductal carcinoma (IDC) constitutes the most frequent malignant cancer endangering women’s health. In this study, a new spontaneously immortalized breast cancer cell line, DHSF-BR16 cells, was isolated from the primary IDC of a 74-years old female patient, treated with neoadjuvant chemotherapy and disease-free 5-years after adjuvant chemotherapy. Primary breast cancer tissue surgically removed was classified as ER−/PR−/HER2+, and the same phenotype was maintained by DHSF-BR16 cells. We examined DHSF-BR16 cell morphology and relevant biological and molecular markers, as well as their response to anticancer drugs commonly used for breast cancer treatment. MCF-7 cells were used for comparison purposes. The DHSF-BR16 cells showed the ability to form spheroids and migrate. Furthermore, DHSF-BR16 cells showed a mixed stemness phenotype (i.e. CD44+/CD24−/low), high levels of cytokeratin 7, moderate levels of cytokeratin 8 and 18, EpCAM and E-Cadh. Transcriptome analysis showed 2071 differentially expressed genes between DHSF-BR16 and MCF-7 cells (logFC > 2, p-adj < 0.01). Several genes were highly upregulated or downregulated in the new cell line (log2 scale fold change magnitude within − 9.6 to + 12.13). A spontaneous immortalization signature, mainly represented by extracellular exosomes-, plasma membrane- and endoplasmic reticulum membrane pathways (GO database) as well as by metabolic pathways (KEGG database) was observed in DHSF-BR16 cells. Also, these cells were more resistant to anthracyclines compared with MCF-7 cells. Overall, DHSF-BR16 cell line represents a relevant model useful to investigate cancer biology, to identify both novel prognostic and drug response predictive biomarkers as well as to assess new therapeutic strategies.
Origin and hydrodynamics of xylem sap in tree stems, and relationship to root uptake of soil water
Authors: Mahara Yasunori , Ohta Tomoko , Ohshima Jyunichi , Iizuka Kazuya
Published: April 2021

Although 10 years have passed since Japan’s Fukushima nuclear accident, the future radiation risk from 137Cs contamination of wood via root uptake is a serious concern. We estimated the depth at which the roots of evergreen coniferous sugi (Cryptomeria japonica) and broadleaf deciduous konara (Quercus serrata) trees actively take up soil water by using positive δD values from the artificial D2O tracer and seasonal changes in the δ18O values of soil water as a natural environmental tracer. We compared the tracer concentration changes in xylem sap with those in the soil water and ascertained that both tree species primarily took up water from a depth of 20 cm, though with mixing of water from other depths. Using sap hydrodynamics in tree stems, we found that water circulation was significantly slower in heartwood than in sapwood. Heartwood water was not supplied by direct root uptake of soil water. The measured diffusion coefficients for D2O, K+, Cs+, and I− in xylem stems were greater in sapwood than in heartwood, and their magnitude was inversely correlated with their molecular weights. The distribution of D2O and 137Cs concentrations along the radial stem could be explained by simulations using the simple advective diffusion model.
Self-organization and culture of Mesenchymal Stem Cell spheroids in acoustic levitation
Authors: Jeger-Madiot Nathan , Arakelian Lousineh , Setterblad Niclas , Bruneval Patrick , Hoyos Mauricio , Larghero Jérôme , Aider Jean-Luc
Published: April 2021

In recent years, 3D cell culture models such as spheroid or organoid technologies have known important developments. Many studies have shown that 3D cultures exhibit better biomimetic properties compared to 2D cultures. These properties are important for in-vitro modeling systems, as well as for in-vivo cell therapies and tissue engineering approaches. A reliable use of 3D cellular models still requires standardized protocols with well-controlled and reproducible parameters. To address this challenge, a robust and scaffold-free approach is proposed, which relies on multi-trap acoustic levitation. This technology is successfully applied to Mesenchymal Stem Cells (MSCs) maintained in acoustic levitation over a 24-h period. During the culture, MSCs spontaneously self-organized from cell sheets to cell spheroids with a characteristic time of about 10 h. Each acoustofluidic chip could contain up to 30 spheroids in acoustic levitation and four chips could be ran in parallel, leading to the production of 120 spheroids per experiment. Various biological characterizations showed that the cells inside the spheroids were viable, maintained the expression of their cell surface markers and had a higher differentiation capacity compared to standard 2D culture conditions. These results open the path to long-time cell culture in acoustic levitation of cell sheets or spheroids for any type of cells.
Pore-scale modelling and sensitivity analyses of hydrogen-brine multiphase flow in geological porous media
Authors: Hashemi Leila , Blunt Martin , Hajibeygi Hadi
Published: April 2021

Underground hydrogen storage (UHS) in initially brine-saturated deep porous rocks is a promising large-scale energy storage technology, due to hydrogen’s high specific energy capacity and the high volumetric capacity of aquifers. Appropriate selection of a feasible and safe storage site vitally depends on understanding hydrogen transport characteristics in the subsurface. Unfortunately there exist no robust experimental analyses in the literature to properly characterise this complex process. As such, in this work, we present a systematic pore-scale modelling study to quantify the crucial reservoir-scale functions of relative permeability and capillary pressure and their dependencies on fluid and reservoir rock conditions. To conduct a conclusive study, in the absence of sufficient experimental data, a rigorous sensitivity analysis has been performed to quantify the impacts of uncertain fluid and rock properties on these upscaled functions. The parameters are varied around a base-case, which is obtained through matching to the existing experimental study. Moreover, cyclic hysteretic multiphase flow is also studied, which is a relevant aspect for cyclic hydrogen-brine energy storage projects. The present study applies pore-scale analysis to predict the flow of hydrogen in storage formations, and to quantify the sensitivity to the micro-scale characteristics of contact angle (i.e., wettability) and porous rock structure.
LRTM effect and electronic crystal imaging on silicon surface
Authors: Huang Zhong-Mei , Liu Shi-Rong , Peng Hong-yan , Li Xin , Huang Wei-Qi
Published: April 2021

Some interesting phenomena have been observed in the laser reflecting Talbot magnification (LRTM) effect discovered at first, in which the high-order nonlinear imaging and the plasmonic structures imaging occur. The LRTM effect images were obtained on the 1D and 2D photonic crystals fabricated by using nanosecond pulsed laser etching on silicon surface, where the high-order nonlinear imaging on the 1D and 2D photonic crystals was observed interestingly. The theory result is consistent with the experimental one, which exhibits that the suitable wave-front shape of injection beam selected in optical route can effectively enlarge the magnification rate and elevate the resolution of the Talbot image. Especially the periodic plasmonic structures on silicon surface have been observed in the LRTM effect images, which have a good application in the online detection of pulsed laser etching process. The temporary reflecting Talbot images exhibit that the electrons following with photonic frequency float on plasma surface to form electronic crystal observed on silicon at first, which is similar with the Wigner crystal structure.
Superradiance of bacteriochlorophyll c aggregates in chlorosomes of green photosynthetic bacteria
Authors: Malina Tomáš , Koehorst Rob , Bína David , Pšenčík Jakub , van Amerongen Herbert
Published: April 2021

Chlorosomes are the main light-harvesting complexes of green photosynthetic bacteria that are adapted to a phototrophic life at low-light conditions. They contain a large number of bacteriochlorophyll c, d, or e molecules organized in self-assembling aggregates. Tight packing of the pigments results in strong excitonic interactions between the monomers, which leads to a redshift of the absorption spectra and excitation delocalization. Due to the large amount of disorder present in chlorosomes, the extent of delocalization is limited and further decreases in time after excitation. In this work we address the question whether the excitonic interactions between the bacteriochlorophyll c molecules are strong enough to maintain some extent of delocalization even after exciton relaxation. That would manifest itself by collective spontaneous emission, so-called superradiance. We show that despite a very low fluorescence quantum yield and short excited state lifetime, both caused by the aggregation, chlorosomes indeed exhibit superradiance. The emission occurs from states delocalized over at least two molecules. In other words, the dipole strength of the emissive states is larger than for a bacteriochlorophyll c monomer. This represents an important functional mechanism increasing the probability of excitation energy transfer that is vital at low-light conditions. Similar behaviour was observed also in one type of artificial aggregates, and this may be beneficial for their potential use in artificial photosynthesis.
SARS-CoV-2 seroprevalence in healthcare workers at a frontline hospital in Tokyo
Authors: Fukuda Hiroshi , Seyama Kuniaki , Ito Kanami , Ai Tomohiko , Nojiri Shuko , Hori Satoshi , Wakita Mitsuru , Saito Kaori , Shida Yuka , Nagura Rie , Hasegawa Mayu , Kanemoto Chiaki , Tokuhara Mayumi , Okajima Katsunobu , Yoshikawa Yukio , Katsuta Narimasa , Yamamoto Takamasa , Idei Mayumi , Horiuchi Yuki , Yamatani Kotoko , Misawa Shigeki , Naito Toshio , Miida Takashi , Sato Hiroyuki , Hattori Nobutaka , Tabe Yoko , Takahashi Kazuhisa
Published: April 2021

Healthcare workers (HCWs) are highly exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The actual coronavirus disease (COVID-19) situation, especially in regions that are less affected, has not yet been determined. This study aimed to assess the seroprevalence of SARS-CoV-2 in HCWs working in a frontline hospital in Tokyo, Japan. In this cross-sectional observational study, screening was performed on consented HCWs, including medical, nursing, and other workers, as part of a mandatory health checkup. The screening test results and clinical characteristics of the participants were recorded. The antibody seroprevalence rate among the 4147 participants screened between July 6 and August 21, 2020, was 0.34% (14/4147). There was no significant difference in the seroprevalence rate between frontline HCWs with a high exposure risk and HCWs working in other settings with a low exposure risk. Of those seropositive for SARS-CoV-2, 64% (9/14) were not aware of any symptoms and had not previously been diagnosed with COVID-19. In conclusion, this study provides insights into the extent of infection and immune status in HCWs in Japan, which has a relatively low prevalence of COVID-19. Our findings aid in formulating public health policies to control virus spread in regions with low-intensity COVID-19.
An ERP study on proactive and reactive response inhibition in individuals with schizotypy
Authors: Jia Lu-xia , Qin Xiao-jing , Cui Ji-fang , Zheng Qi , Yang Tian-xiao , Wang Ya , Chan Raymond C. K.
Published: April 2021

Schizotypy, a subclinical group at risk for schizophrenia, has been found to show impairments in response inhibition. However, it remains unclear whether this impairment is accompanied by outright stopping (reactive inhibition) or preparation for stopping (proactive inhibition). We recruited 20 schizotypy and 24 non-schizotypy individuals to perform a modified stop-signal task with electroencephalographic (EEG) data recorded. This task consists of three conditions based on the probability of stop signal: 0% (no stop trials, only go trials), 17% (17% stop trials), and 33% (33% stop trials), the conditions were indicated by the colour of go stimuli. For proactive inhibition (go trials), individuals with schizotypy exhibited significantly lesser increase in go response time (RT) as the stop signal probability increasing compared to non-schizotypy individuals. Individuals with schizotypy also exhibited significantly increased N1 amplitude on all levels of stop signal probability and increased P3 amplitude in the 17% stop condition compared with non-schizotypy individuals. For reactive inhibition (stop trials), individuals with schizotypy exhibited significantly longer stop signal reaction time (SSRT) in both 17% and 33% stop conditions and smaller N2 amplitude on stop trials in the 17% stop condition than non-schizotypy individuals. These findings suggest that individuals with schizotypy were impaired in both proactive and reactive response inhibition at behavioural and neural levels.
Artificial intelligence-assisted analysis of endoscopic retrograde cholangiopancreatography image for identifying ampulla and difficulty of selective cannulation
Authors: Kim Taesung , Kim Jinhee , Choi Hyuk Soon , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Lee Hong Sik , Chun Hoon Jai , Han Sung Yong , Kim Dong Uk , Kwon Soonwook , Choo Jaegul , Lee Jae Min
Published: April 2021

The advancement of artificial intelligence (AI) has facilitated its application in medical fields. However, there has been little research for AI-assisted endoscopy, despite the clinical significance of the efficiency and safety of cannulation in the endoscopic retrograde cholangiopancreatography (ERCP). In this study, we aim to assist endoscopists performing ERCP through automatic detection of the ampulla and the identification of cannulation difficulty. We developed a novel AI-assisted system based on convolutional neural networks that predict the location of the ampulla and the difficulty of cannulation to the ampulla. ERCP data of 531 and 451 patients were utilized in the evaluation of our model for each task. Our model detected the ampulla with mean intersection-over-union 64.1%, precision 76.2%, recall 78.4%, and centroid distance 0.021. In classifying the cannulation difficulty, it achieved the recall of 71.9% for the class of easy cases and that of 61.1% for that of difficult cases. Remarkably, our model accurately detected AOV with varying morphological shape, size, and texture on par with the level of a human expert and showed promising results for recognizing cannulation difficulty. It demonstrated its potential to improve the quality of ERCP by assisting endoscopists.
Utility of prophylactic antibiotics for preventing febrile neutropenia during cabazitaxel therapy for castration-resistant prostate cancer
Authors: Watanabe Keitaro , Kosaka Takeo , Hongo Hiroshi , Oya Mototsugu
Published: April 2021

The aim was to investigate the efficacy of prophylactic antibiotics for the prevention of febrile neutropenia (FN) during cabazitaxel therapy for castration-resistant prostate cancer (CRPC) with G-CSF. We retrospectively studied 443 cycles of cabazitaxel therapy given to 56 patients with CRPC at Keio University Hospital between May 2012 and August 2018. Statistical analysis was conducted to determine whether the combination of prophylactic G-CSF and antibiotics was more effective in preventing FN, compared with prophylactic G-CSF alone. Prophylactic PEG-G-CSF or G-CSF was administered in all 443 cycles. Only fluoroquinolones were used as prophylactic antibiotics and were administered in 328 cycles (74.0%). FN occurred in 5 cycles (1.1%). Prophylactic antibiotics were administered in 327 cycles (74.6%) in the FN-negative group and in only 1 cycle (20.0%) in the FN-positive group. Chi-square test indicated the incidence of FN was significantly lower in the group that received prophylactic antibiotics compared with the group that did not receive prophylactic antibiotics (P = 0.017). Compared with prophylactic G-CSF alone, prophylactic G-CSF and antibiotics significantly suppressed the occurrence of FN.
Ensemble forecasting of a continuously decreasing trend in bladder cancer incidence in Taiwan
Authors: Hsiao Bo-Yu , Su Shih-Yung , Jhuang Jing-Rong , Chiang Chun-Ju , Yang Ya-Wen , Lee Wen-Chung
Published: April 2021

Bladder cancer is one of the most common malignancies involving the urinary system of about 1.65 million cases worldwide. To attain the 25 by 25 goal set by the World Health Organization (25% reduction in non-communicable diseases between 2015 and 2025), developing strategies to reduce cancer burdens is essential. The data of the study comprised the age-specific bladder cancer cases and total population numbers from age 25 to 85 and above from 1997 to 2016 in Taiwan. An ensemble age–period–cohort model was used to estimate bladder cancer incidence trends and forecast the trends to 2025. For men, the projected age-standardized incidence rates per 100,000 people in 2020 and 2025 are 13.0 and 10.4, respectively, with a 16.1% and 32.9% decrease projected from 2016 to 2020 and 2025, respectively. For women, the projected age-standardized incidence rates per 100,000 people in 2020 and 2025 are 4.7 and 3.7, respectively, with a 16.1% and 33.9% decrease projected from 2016 to 2020 and 2025, respectively. The age-specific bladder cancer incidence rates demonstrated a consistently downward trend after 2003 for all ages and both sexes. This study projects that the incidence rates of bladder cancer in Taiwan will continue to decrease, and more than a 25% reduction can be achieved from 2016 to 2025.