bluuebunny/crossref_metadata_2025 huggingface dataset:
Large-scale electron microscopy database for human type 1 diabetes
Authors: de Boer Pascal , Pirozzi Nicole M. , Wolters Anouk H. G. , Kuipers Jeroen , Kusmartseva Irina , Atkinson Mark A. , Campbell-Thompson Martha , Giepmans Ben N. G.
Published: May 2020

Autoimmune β-cell destruction leads to type 1 diabetes, but the pathophysiological mechanisms remain unclear. To help address this void, we created an open-access online repository, unprecedented in its size, composed of large-scale electron microscopy images (‘nanotomy’) of human pancreas tissue obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD; www.nanotomy.org). Nanotomy allows analyses of complete donor islets with up to macromolecular resolution. Anomalies we found in type 1 diabetes included (i) an increase of ‘intermediate cells’ containing granules resembling those of exocrine zymogen and endocrine hormone secreting cells; and (ii) elevated presence of innate immune cells. These are our first results of mining the database and support recent findings that suggest that type 1 diabetes includes abnormalities in the exocrine pancreas that may induce endocrine cellular stress as a trigger for autoimmunity.
Switching of band inversion and topological surface states by charge density wave
Authors: Mitsuishi N. , Sugita Y. , Bahramy M. S. , Kamitani M. , Sonobe T. , Sakano M. , Shimojima T. , Takahashi H. , Sakai H. , Horiba K. , Kumigashira H. , Taguchi K. , Miyamoto K. , Okuda T. , Ishiwata S. , Motome Y. , Ishizaka K.
Published: May 2020

Topologically nontrivial materials host protected edge states associated with the bulk band inversion through the bulk-edge correspondence. Manipulating such edge states is highly desired for developing new functions and devices practically using their dissipation-less nature and spin-momentum locking. Here we introduce a transition-metal dichalcogenide VTe2, that hosts a charge density wave (CDW) coupled with the band inversion involving V3d and Te5p orbitals. Spin- and angle-resolved photoemission spectroscopy with first-principles calculations reveal the huge anisotropic modification of the bulk electronic structure by the CDW formation, accompanying the selective disappearance of Dirac-type spin-polarized topological surface states that exist in the normal state. Thorough three dimensional investigation of bulk states indicates that the corresponding band inversion at the Brillouin zone boundary dissolves upon the CDW formation, by transforming into anomalous flat bands. Our finding provides a new insight to the topological manipulation of matters by utilizing CDWs’ flexible characters to external stimuli.
Manipulating the fluorescence lifetime at the sub-cellular scale via photo-switchable barcoding
Authors: Xie Yujie , Arno Maria C. , Husband Jonathan T. , Torrent-Sucarrat Miquel , O’Reilly Rachel K.
Published: May 2020

Fluorescent barcoding is a pivotal technique for the investigation of the microscale world, from information storage to the monitoring of dynamic biochemical processes. Using fluorescence lifetime as the readout modality offers more reproducible and quantitative outputs compared to conventional fluorescent barcoding, being independent of sample concentration and measurement methods. However, the use of fluorescence lifetime in this area has been limited by the lack of strategies that provide spatiotemporal manipulation of the coding process. In this study, we design a two-component photo-switchable nanogel that exhibits variable fluorescence lifetime upon photoisomerization-induced energy transfer processes through light irradiation. This remotely manipulated fluorescence lifetime property could be visually mapped using fluorescence lifetime imaging microscopy (FLIM), allowing selective storage and display of information at the microscale. Most importantly, the reversibility of this system further provides a strategy for minimizing the background influence in fluorescence lifetime imaging of live cells and sub-cellular organelles.
TFEB regulates murine liver cell fate during development and regeneration
Authors: Pastore Nunzia , Huynh Tuong , Herz Niculin J. , Calcagni’ Alessia , Klisch Tiemo J. , Brunetti Lorenzo , Kim Kangho Ho , De Giorgi Marco , Hurley Ayrea , Carissimo Annamaria , Mutarelli Margherita , Aleksieva Niya , D’Orsi Luca , Lagor William R. , Moore David D. , Settembre Carmine , Finegold Milton J. , Forbes Stuart J. , Ballabio Andrea
Published: May 2020

It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show thatSox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.
Ecological drivers of global gradients in avian dispersal inferred from wing morphology
Authors: Sheard Catherine , Neate-Clegg Montague H. C. , Alioravainen Nico , Jones Samuel E. I. , Vincent Claire , MacGregor Hannah E. A. , Bregman Tom P. , Claramunt Santiago , Tobias Joseph A.
Published: May 2020

An organism’s ability to disperse influences many fundamental processes, from speciation and geographical range expansion to community assembly. However, the patterns and underlying drivers of variation in dispersal across species remain unclear, partly because standardised estimates of dispersal ability are rarely available. Here we present a global dataset of avian hand-wing index (HWI), an estimate of wing shape widely adopted as a proxy for dispersal ability in birds. We show that HWI is correlated with geography and ecology across 10,338 (>99%) species, increasing at higher latitudes and with migration, and decreasing with territoriality. After controlling for these effects, the strongest predictor of HWI is temperature variability (seasonality), with secondary effects of diet and habitat type. Finally, we also show that HWI is a strong predictor of geographical range size. Our analyses reveal a prominent latitudinal gradient in HWI shaped by a combination of environmental and behavioural factors, and also provide a global index of avian dispersal ability for use in community ecology, macroecology, and macroevolution.
Author Correction: Structural basis of astrocytic Ca2+ signals at tripartite synapses
Authors: Arizono Misa , Inavalli V. V. G. Krishna , Panatier Aude , Pfeiffer Thomas , Angibaud Julie , Levet Florian , Veer Mirelle J. T. Ter , Stobart Jillian , Bellocchio Luigi , Mikoshiba Katsuhiko , Marsicano Giovanni , Weber Bruno , Oliet Stéphane H. R. , Nägerl U. Valentin
Published: May 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Low-temperature spin dynamics of ferromagnetic molecular ring {Cr8Y8}
Authors: Fu Zhendong , Qin Lei , Sun Kai , Hao Lijie , Zheng Yan-Zhen , Lohstroh Wiebke , Günther Gerrit , Russina Margarita , Liu Yuntao , Xiao Yinguo , Jin Wentao , Chen Dongfeng
Published: May 2020

The spin dynamics of {Cr8Y8}, a rare example of ferromagnetic molecular rings, has been studied by inelastic neutron scattering (INS) and heat capacity (HC) methods. Clear evidence of low-lying magnetic excitation has been found. Magnetic Schottky anomalies are observed in low-temperature (low-T) HC curves measured under various fields and can be well fitted with a multi-level Schottky term, giving important information on the energy gaps between spin levels. The INS results obtained on TOFTOF and NEAT time-of-flight spectrometers show INS peaks corresponding to the transitions within S = 12 ground states and between the S = 12 ground state and the S = 11 excited state. The single-J model with a unique exchange constant J = 0.151 meV can well reproduce the low-lying energy levels and their Zeeman splitting upon applied magnetic fields. This work shows that the single-J model can be a good approach for the low-T spin dynamics of {Cr8Y8} and may have general significance for other weak ferromagnetic molecular rings. Determination of the Cr3+-Cr3+ exchange constant in {Cr8Y8} will benefit the study on the complicated magnetic interactions in chromium lanthanide complexes. The zero-field splitting which is suggested by HC data still calls for EPR or high-resolution INS technique to verify.
Using the force: STEM knowledge and experience construct shared neural representations of engineering concepts
Authors: Cetron Joshua S. , Connolly Andrew C. , Diamond Solomon G. , May Vicki V. , Haxby James V. , Kraemer David J. M.
Published: May 2020

How does STEM knowledge learned in school change students’ brains? Using fMRI, we presented photographs of real-world structures to engineering students with classroom-based knowledge and hands-on lab experience, examining how their brain activity differentiated them from their “novice” peers not pursuing engineering degrees. A data-driven MVPA and machine-learning approach revealed that neural response patterns of engineering students were convergent with each other and distinct from novices’ when considering physical forces acting on the structures. Furthermore, informational network analysis demonstrated that the distinct neural response patterns of engineering students reflected relevant concept knowledge: learned categories of mechanical structures. Information about mechanical categories was predominantly represented in bilateral anterior ventral occipitotemporal regions. Importantly, mechanical categories were not explicitly referenced in the experiment, nor does visual similarity between stimuli account for mechanical category distinctions. The results demonstrate how learning abstract STEM concepts in the classroom influences neural representations of objects in the world.
Identifying inhibitors of epithelial–mesenchymal plasticity using a network topology-based approach
Authors: Hari Kishore , Sabuwala Burhanuddin , Subramani Balaram Vishnu , La Porta Caterina A. M. , Zapperi Stefano , Font-Clos Francesc , Jolly Mohit Kumar
Published: May 2020

Metastasis is the cause of over 90% of cancer-related deaths. Cancer cells undergoing metastasis can switch dynamically between different phenotypes, enabling them to adapt to harsh challenges, such as overcoming anoikis and evading immune response. This ability, known as phenotypic plasticity, is crucial for the survival of cancer cells during metastasis, as well as acquiring therapy resistance. Various biochemical networks have been identified to contribute to phenotypic plasticity, but how plasticity emerges from the dynamics of these networks remains elusive. Here, we investigated the dynamics of various regulatory networks implicated in Epithelial–mesenchymal plasticity (EMP)—an important arm of phenotypic plasticity—through two different mathematical modelling frameworks: a discrete, parameter-independent framework (Boolean) and a continuous, parameter-agnostic modelling framework (RACIPE). Results from either framework in terms of phenotypic distributions obtained from a given EMP network are qualitatively similar and suggest that these networks are multi-stable and can give rise to phenotypic plasticity. Neither method requires specific kinetic parameters, thus our results emphasize that EMP can emerge through these networks over a wide range of parameter sets, elucidating the importance of network topology in enabling phenotypic plasticity. Furthermore, we show that the ability to exhibit phenotypic plasticity correlates positively with the number of positive feedback loops in a given network. These results pave a way toward an unorthodox network topology-based approach to identify crucial links in a given EMP network that can reduce phenotypic plasticity and possibly inhibit metastasis—by reducing the number of positive feedback loops.
Compound Opening Arrow Mixture exerts anti-tumor effects in a mouse model of breast cancer
Authors: Zhou Zhen , Peng Yanfang , Ai Wang , Li Qi , Ye Taisheng , Wu Chaoyan , Ke Haoliang , Wang Xiuping , Zhang Yingwen
Published: May 2020

Compound Opening Arrow Mixture (COAM) has demonstrated therapeutic effects in patients with breast cancer. We explored the underlying molecular mechanisms of COAM using a mouse model of breast cancer. Luciferase-labeled 4T1-Luc2 cells were inoculated into the breast pad of BALB/c-nu mice, which were divided into model group (saline), COAM (6 g/ml high-dose, 3 g/ml medium-dose, and 1.5 g/ml low-dose) groups, and low-molecular-weight heparin (LMWH, 1500 U/Kg) group. The number and distribution of 4T1-luc2 tumors were measured by an in vivo imaging system. Tumor cell apoptosis was measured through TUNEL and quantitating the expression of Caspase-3 mRNA and protein. Compared with the model group, in vivo tumor growth was lower in the LMWH- and COAM-treated groups. Tumor apoptosis was time-dependent and dose-dependent, as shown by a higher TUNEL apoptotic index and higher Caspase-3 mRNA and Caspase-3/cleaved-Caspase-3 proteins levels on the 14th day than the 7th day. The COAM high-dose group had the highest apoptotic index and the most activation of Caspase-3. Collectively, COAM significantly inhibits the growth of 4T1-luc2 breast cancer in mice and induces tumor apoptosis by activating Caspase-3, which provides a preliminary explanation of therapeutic effects of COAM.
Slip rates along the narrow Magallanes Fault System, Tierra Del Fuego Region, Patagonia
Authors: Sandoval Francisca B. , De Pascale Gregory P.
Published: May 2020

The up to 1000 km-long Magallanes Fault System (MFS) is the southernmost onshore strike-slip plate boundary and located between the South American and Scotia Plates. Slip-rates, a key factor for understanding neotectonics and seismic hazard are only available there from geodetic models. In this study, we present the first direct geologic evidence of MFS slip rates. Late-Cenozoic slip rates along the main MF is 5.4 ± 3.3 mm/yr based on lithologic geological separations found in regional mapping. Late-Quaternary deformation from offset geomorphologic markers was documented along the MFS in Chile and Argentina based on a combination of satellite mapping, fieldwork, and Structure from Motion (SfM) models developed from drone photography. By combining displacements observed in SfM models with regional Late-Quaternary dating, sinistral slip rates are 10.5 ± 1.5 mm/yr (Chile) and 7.8 ± 1.3 mm/yr (Argentina). By comparing our results with regional models, contemporary plate boundary deformation is narrow, approximately ~20–50 km wide from Tierra Del Fuego (TdF) and east (one of the narrowest on Earth), which widens and becoming more diffuse from Cabo Froward north and west (>100 km wide). In addition to the tectonic implications, these faults should be considered important sources of fault rupture and seismic hazard.
Generation of a conditional transgenic mouse model expressing human Phospholipase A2 Receptor 1
Authors: Jaber Sara , Goehrig Delphine , Bertolino Philippe , Massemin Amélie , Bihl Franck , Chabry Joëlle , Lambeau Gérard , Vindrieux David , Bernard David
Published: May 2020

The Phospholipase A2 Receptor 1 (PLA2R1) was first identified for its ability to bind some secreted PLA2s (sPLA2s). It belongs to the C-type lectin superfamily and it binds different types of proteins. It is likely a multifunctional protein that plays a role i) in inflammation and inflammatory diseases, ii) in cellular senescence, a mechanism participating in aging and age-related diseases including cancer, and iii) in membranous nephropathy (MN), a rare autoimmune kidney disease where PLA2R1 is the major autoantigen. To help study the role of PLA2R1 in these pathophysiological conditions, we have generated a versatile NeoR-hPLA2R1 conditional transgenic mice which will allow the specific expression of human PLA2R1 (hPLA2R1) in relevant organs and cells following Cre recombinase-driven excision of the NeoR-stop cassette flanked by LoxP sites. Proof-of-concept breeding of NeoR-hPLA2R1 mice with the ubiquitous adenoviral EIIa promoter-driven Cre mouse line resulted in the expected excision of the NeoR-stop cassette and the expression of hPLA2R1 in all tested tissues. These Tg-hPLA2R1 animals breed normally, with no reproduction or apparent growth defect. These models, especially the NeoR-hPLA2R1 conditional transgenic mouse line, will facilitate the future investigation of PLA2R1 functions in relevant pathophysiological contexts, including inflammatory diseases, age-related diseases and MN.
Upregulation of follistatin and low apoptotic activity in intraductal oncocytic papillary neoplasm of the pancreatobiliary system
Authors: Nakahodo Jun , Fukumura Yuki , Saito Tsuyoshi , Hirabayashi Kenichi , Doi Reiko , Hayashi Takuo , Yao Takashi
Published: May 2020

Intraductal oncocytic papillary neoplasm (IOPN) is a rare intraductal tumor of the pancreatobiliary system. Currently, little is known about its distinct characteristics, unlike intraductal papillary mucinous neoplasms (IPMN) and intraductal papillary neoplasms of the bile duct (IPNB). The present study compared 22 IOPNs (18 pancreatic and 4 biliary) with those of 61 IPMNs/8 IPNBs. IOPNs were classified into pure and combined types, depending on the coexistence of IPMN/IPNB. Multiple gene expression analysis (nCounter system) was performed, and hierarchical clustering analysis separated IOPNs(n = 4) and IPMNs(n = 3)/ IPNBs(n = 3), and pathway score analysis supported the result. Volcano plot identified follistatin (FST) as the most upregulated mRNA in IOPN in comparison to the gastric subtype (log2 fold change of 5.34) and the intestinal subtype (that of 5.81) of IPMN/IPNB. The expression of FST in IOPN was also high in quantitative polymerase chain reaction and immunohistochemical analysis. We also found lower apoptotic activity in IOPN, particularly in pure type, compared to high-grade or invasive IPMN/IPNB using immunohistochemistry for cleaved caspase 3. But, combined type IOPN was more similar to IPMN/IPNB than pure IOPN. In conclusion, we proved that IOPN, particularly pure IOPN, is distinct from IPMN/IPNB in FST mRNA overexpression and exhibits lower apoptotic activity.
A mobile MRI field study of the biochemical cartilage reaction of the knee joint during a 4,486 km transcontinental multistage ultra-marathon using T2* mapping
Authors: Schütz Uwe , Ehrhardt Martin , Göd Sabine , Billich Christian , Beer Meinrad , Trattnig Siegfried
Published: May 2020

Nearly nothing is known about the consequences of ultra-long-distance running on knee cartilage. In this mobile MRI field study, we analysed the biochemical effects of a 4,486 km transcontinental multistage ultra-marathon on femorotibial joint (FTJ) cartilage. Serial MRI data were acquired from 22 subjects (20 male, 18 finisher) using a 1.5 T MR scanner mounted on a 38-ton trailer, travelling with the participants of the TransEurope FootRace (TEFR) day by day over 64 stages. The statistical analyses focused on intrachondral T2* behaviour during the course of the TEFR as the main outcome variable of interest. T2* mapping (sagittal FLASH T2* weighted gradient echo) is a validated and highly accurate method for quantitative compositional cartilage analysis of specific weightbearing areas of the FTJ. T2* mapping is sensitive to changes in the equilibrium of free intrachondral water, which depends on the content and orientation of collagen and the proteoglycan content in the extracellular cartilage matrix. Within the first 1,100 km, a significant running load-induced T2* increase occurred in all joint regions: 44.0% femoral-lateral, 42.9% tibial-lateral, 34.9% femoral-medial, and 25.1% tibial-medial. Osteochondral lesions showed no relevant changes or new occurrence during the TEFR. The reasons for stopping the race were not associated with knee problems. As no further T2* elevation was found in the second half of the TEFR but a decreasing T2* trend (recovery) was observed after the 3,500 km run, we assume that no further softening of the cartilage occurs with ongoing running burden over ultra-long distances extending 4,500 km. Instead, we assume the ability of the FTJ cartilage matrix to reorganize and adapt to the load.
Regularized selection indices for breeding value prediction using hyper-spectral image data
Authors: Lopez-Cruz Marco , Olson Eric , Rovere Gabriel , Crossa Jose , Dreisigacker Susanne , Mondal Suchismita , Singh Ravi , Campos Gustavo de los
Published: May 2020

High-throughput phenotyping (HTP) technologies can produce data on thousands of phenotypes per unit being monitored. These data can be used to breed for economically and environmentally relevant traits (e.g., drought tolerance); however, incorporating high-dimensional phenotypes in genetic analyses and in breeding schemes poses important statistical and computational challenges. To address this problem, we developed regularized selection indices; the methodology integrates techniques commonly used in high-dimensional phenotypic regressions (including penalization and rank-reduction approaches) into the selection index (SI) framework. Using extensive data from CIMMYT’s (International Maize and Wheat Improvement Center) wheat breeding program we show that regularized SIs derived from hyper-spectral data offer consistently higher accuracy for grain yield than those achieved by standard SIs, and by vegetation indices commonly used to predict agronomic traits. Regularized SIs offer an effective approach to leverage HTP data that is routinely generated in agriculture; the methodology can also be used to conduct genetic studies using high-dimensional phenotypes that are often collected in humans and model organisms including body images and whole-genome gene expression profiles.
Metagenomic analysis of an urban resistome before and after wastewater treatment
Authors: Lira Felipe , Vaz-Moreira Ivone , Tamames Javier , Manaia Célia M. , Martínez José Luis
Published: May 2020

Determining the effect of wastewater treatment in water resistome is a topic of interest for water quality, mainly under re-use and One-Health perspectives. The resistome, the plasmidome, and the bacterial community composition of samples from influents and treated effluents from a wastewater treatment plant located in Northern Portugal were studied using metagenomic techniques. Wastewater treatment contributed to reduce the abundance of resistance genes and of plasmid replicons, coinciding with a decline in the number of intrinsic resistance genes from Enterobacteriaceae, as well as with a reduction in the relative abundance of Firmicutes and Proteobacteria after treatment. These taxons comprise bacterial pathogens, including those belonging to the ESKAPE group, which encompasses bacteria with the highest risk of acquiring antibiotic resistance, being the most relevant hosts of resistance genes acquired through horizontal gene transfer. Our results support that wastewater treatment efficiently removes the hosts of antibiotic resistance genes and, consequently, the harboured antibiotic resistance genes. Principal component analysis indicates that the resistome and the bacterial composition clustered together in influent samples, while did not cluster in final effluent samples. Our results suggest that wastewater treatment mitigates the environmental dissemination of urban resistome, through the removal of the hosts harbouring mobile resistance genes.
Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity
Authors: Gupta Vijay , Salim Safa , Hmila Issam , Vaikath Nishant N. , Sudhakaran Indulekha P. , Ghanem Simona S. , Majbour Nour K. , Abdulla Sara A. , Emara Mohamed M. , Abdesselem Houari B. , Lukacsovich Tamas , Erskine Daniel , El-Agnaf Omar M. A.
Published: May 2020

Synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibody-based immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative disease-relevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities.
Circulating lymphocytes and monocytes transcriptomic analysis of patients with type 2 diabetes mellitus, dyslipidemia and periodontitis
Authors: Corbi Sâmia C. T. , de Vasconcellos Jaira F. , Bastos Alliny S. , Bussaneli Diego Girotto , da Silva Bárbara Roque , Santos Raquel Alves , Takahashi Catarina S. , de S. Rocha Cristiane , Carvalho Benilton de Sá , Maurer-Morelli Cláudia V. , Orrico Silvana R. P. , Barros Silvana P. , Scarel-Caminaga Raquel M.
Published: May 2020

Type 2 diabetes mellitus (T2DM), dyslipidemia and periodontitis are frequently associated pathologies; however, there are no studies showing the peripheral blood transcript profile of these combined diseases. Here we identified the differentially expressed genes (DEGs) of circulating lymphocytes and monocytes to reveal potential biomarkers that may be used as molecular targets for future diagnosis of each combination of these pathologies (compared to healthy patients) and give insights into the underlying molecular mechanisms of these diseases. Study participants (n = 150) were divided into groups: (H) systemically and periodontal healthy (control group); (P) with periodontitis, but systemically healthy; (DL-P) with dyslipidemia and periodontitis; (T2DMwell-DL-P) well-controlled type 2 diabetes mellitus with dyslipidemia and periodontitis; and (T2DMpoorly-DL-P) poorly-controlled type 2 diabetes mellitus with dyslipidemia and periodontitis. We preprocessed the microarray data using the Robust Multichip Average (RMA) strategy, followed by the RankProd method to identify candidates for DEGs. Furthermore, we performed functional enrichment analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis. DEGs were submitted to pairwise comparisons, and selected DEGs were validated by quantitative polymerase chain reaction. Validated DEGs verified from T2DMpoorly-DL-P versus H were: TGFB1I1, VNN1, HLADRB4 and CXCL8; T2DMwell-DL-P versus H: FN1, BPTF and PDE3B; DL-P versus H: DAB2, CD47 and HLADRB4; P versus H: IGHDL-P, ITGB2 and HLADRB4. In conclusion, we identified that circulating lymphocytes and monocytes of individuals simultaneously affected by T2DM, dyslipidemia and periodontitis, showed an altered molecular profile mainly associated to inflammatory response, immune cell trafficking, and infectious disease pathways. Altogether, these results shed light on novel potential targets for future diagnosis, monitoring or development of targeted therapies for patients sharing these conditions.
Optimization of cultivation techniques improves the agronomic behavior of Agaricus subrufescens
Authors: Pardo-Giménez Arturo , Pardo José Emilio , Dias Eustáquio Souza , Rinker Danny Lee , Caitano Cinthia Elen Cardoso , Zied Diego Cunha
Published: May 2020

New species of medicinal mushrooms have emerged over the past several decades, such as the Sun mushroom, Agaricus subrufescens. Horticultural improvements are required to shift its cultivation from small-scale local production to large-scale international production. The research reported here evaluated the agronomic behavior and the chemical characteristics of the Sun mushroom as a function of i) nutritional supplementation ii) ruffling of the casing layer and iii) the temperature management on the primordia induction and reduction of the crop cycle. Supplementation was beneficial for yield, unit mushroom weigh and decrease in time to first harvest. Supplementation improved biological efficiency with Champfood providing a yield increase of 15% over the non-supplemented compost. Among the supplements only Promycel increased the individual mushroom weight. Ruffling overall improved the yield in the 2nd and 4th flush. Already biological efficiency was greater by 21%. The highest yield harvested in any single day in the crop occurred in 3rd flush with the amount of 2.484 kg of mushrooms per m2 for the rapid induction method. Still the biological efficiency was not significantly affected by the mushroom induction temperature method. Only the fat content of the mushrooms was positively affected by the rapid induction of primordia. Champfood supplement promotes a reduction in the value of earliness and an increase of 1st flush yield. The ruffling technique provided an increase in biological efficiency due to the great number of mushrooms harvested. Rapid primordia induction allowed the crop cycle to end 3 days earlier than the slow primordia induction, providing a higher production rate.
A single variant sequencing method for sensitive and quantitative detection of HIV-1 minority variants
Authors: Sidhu Gurjit , Schuster Layla , Liu Lin , Tamashiro Ryan , Li Eric , Langaee Taimour , Wagner Richard , Wang Gary P.
Published: May 2020

HIV drug resistance is a major threat to achieving long-term viral suppression in HIV-positive individuals. Drug resistant HIV variants, including minority variants, can compromise response to antiretroviral therapy. Many studies have investigated the clinical relevance of drug resistant minority variants, but the level at which minority variants become clinically relevant remains unclear. A combination of Primer-ID and deep sequencing is a promising approach that may quantify minority variants more accurately compared to standard deep sequencing. However, most studies that used the Primer-ID method have analyzed clinical samples directly. Thus, its sensitivity and quantitative accuracy have not been adequately validated using known controls. Here, we constructed defined proportions of artificial RNA and virus quasispecies and measured their relative proportions using the Primer-ID based, quantitative single-variant sequencing (qSVS) assay. Our results showed that minority variants present at 1% of quasispecies were detected reproducibly with minimal variations between technical replicates. In addition, the measured frequencies were comparable to the expected frequencies. These data validate the accuracy and reproducibility of the qSVS assay in quantifying authentic HIV minority variants, and support the use of this approach to examine the impacts of minority HIV variants on virologic response and clinical outcome.
Immunorthodontics: in vivo gene expression of orthodontic tooth movement
Authors: Klein Yehuda , Fleissig Omer , Polak David , Barenholz Yechezkel , Mandelboim Ofer , Chaushu Stella
Published: May 2020

Orthodontic tooth movement (OTM) is a “sterile” inflammatory process. The present study aimed to reveal the underlying biological mechanisms, by studying the force associated-gene expression changes, in a time-dependent manner. Ni-Ti springs were set to move the upper 1st-molar in C57BL/6 mice. OTM was measured by μCT. Total-RNA was extracted from tissue blocks at 1,3,7 and 14-days post force application, and from two control groups: naïve and inactivated spring. Gene-expression profiles were generated by next-generation-RNA-sequencing. Gene Set Enrichment Analysis, K-means algorithm and Ingenuity pathway analysis were used for data interpretation. Genes of interest were validated with qRT-PCR. A total of 3075 differentially expressed genes (DEGs) were identified, with the greatest number at day 3. Two distinct clusters patterns were recognized: those in which DEGs peaked in the first days and declined thereafter (tissue degradation, phagocytosis, leukocyte extravasation, innate and adaptive immune system responses), and those in which DEGs were initially down-regulated and increased at day 14 (cell proliferation and migration, cytoskeletal rearrangement, tissue homeostasis, angiogenesis). The uncovering of novel innate and adaptive immune processes in OTM led us to propose a new term “Immunorthodontics”. This genomic data can serve as a platform for OTM modulation future approaches.
Risk of cancer in patients with glaucoma: A nationwide population-based cohort study
Authors: Jung Younhea , Han Kyungdo , Na Kyung-sun , Kim Gee-hyun , Ha Minji , Paik Ji-Sun , Moon Jung Il
Published: May 2020

To compare the risk of cancer development between patients with glaucoma and those without, we conducted a nationwide population-based cohort study using the Korean National Health Insurance Database. Individuals with diagnosis of glaucoma between 2007 and 2016 were identified, and controls were 1:1 matched based on age and sex. We calculated the incidence rates(IR) and hazard ratios(HR) before and after adjusting for age, gender, diabetes, smoking history, and body mass index. A total of 107,536 individuals with glaucoma and the same number of individuals without glaucoma were included. The IR of overall cancer were 12.23 and 11.62 per 1,000 individuals in the glaucoma and control groups, respectively. The HR of overall cancer was significantly higher in the glaucoma group before(HR: 1.053) and after adjusting for confounding factors(adjusted HR: 1.049) compared to that in the control group. The risk of overall cancer and specific cancers varied depending on gender and age groups, and the association was stronger in women and those under 65 years of age. Our study revealed that individuals with glaucoma showed higher risk of overall cancer and higher risk of specific cancers than those without glaucoma.
Denser Markers and Advanced Statistical Method Identified More Genetic Loci Associated with Husk Traits in Maize
Authors: Cui Zhenhai , Dong Haixiao , Zhang Ao , Ruan Yanye , Jiang Siqi , He Yan , Zhang Zhiwu
Published: May 2020

The husk—the leaf-like outer covering of maize ear—has multiple functions, including protecting the ear from diseases infection and dehydration. In previous studies, we genotyped an association panel of 508 inbred lines genotyped with a total of ~550,000 SNPs (Illumina 50 K SNP Chip and RNA-seq). Genome-Wide Association Studies (GWAS) were conducted on four husk traits: husk length (HL), husk layer number (HN), husk thickness (HT), and husk width (HW). Minimal associations were identified and none of them passed the P-value threshold after a Bonferroni multiple-test correction using a single locus test in framework of mixed linear model. In this study, we doubled the number of SNPs (~1,250,000 in total) by adding GBS and 600 K SNP Chip. GWAS, performed with the recently developed multiple loci model (BLINK), revealed six genetic loci associated with HN and HT above the Bonferroni multiple-test threshold. Five candidate genes were identified based on the linkage disequilibrium with these loci, including GRMZM2G381691 and GRMZM2G012416. These two genes were up-regulation and down-regulation in all husk related tissues, respectively. GRMZM2G381691 associated with HT encoded a CCT domain protein, which expressed higher in tropical than temperate maize. GRMZM2G012416 associated with HN encoded an Armadillo (ARM) repeat protein, which regulated GA signal pathway. These associated SNPs and candidate genes paved a path to understand the genetic architecture of husk in maize.
Maternal administration of probiotics promotes brain development and protects offspring’s brain from postnatal inflammatory insults in C57/BL6J mice
Authors: Lu Jing , Lu Lei , Yu Yueyue , Baranowski Jillian , Claud Erika C.
Published: May 2020

Neonatal morbidities are associated with long term neurological deficits in life and have also been associated with dysbiosis. We tested whether optimizing the neonate’s microbiome through maternal probiotic supplementation can improve offspring’s neurodevelopmental outcomes. Maternal LB supplementation, carried out by givingLactobacillus acidophilusandBifidobacterium infantis(LB) to pregnant C57/BL6J mice daily from E16 to weaning, significantly suppressed postnatal peripheral proinflammatory insult-induced systemic inflammation and normalized compromised blood-brain barrier permeability and tight junction protein expression in the offspring at pre-weaned age. Maternal LB exposure also regulated markers associated with leukocyte transendothelial migration, extracellular matrix injury and neuroinflammation. The suppressed neuroinflammation by maternal LB supplementation was associated with reduced astrocyte/microglia activation and downregulation of the transcriptional regulators CEBPD and IκBα. Furthermore, maternal LB supplementation promoted neuronal and oligodendrocyte progenitor cell development. Our study demonstrates the efficacy of maternal LB supplementation in modulating systemic and central nervous system inflammation as well as promoting neural/oligodendrocyte progenitor development in the offspring. This evidence suggests that maternal probiotic supplementation may be a safe and effective strategy to improve neurological outcomes in the offspring.
Relationship between dementia and gut microbiome-associated metabolites: a cross-sectional study in Japan
Authors: Saji Naoki , Murotani Kenta , Hisada Takayoshi , Kunihiro Tadao , Tsuduki Tsuyoshi , Sugimoto Taiki , Kimura Ai , Niida Shumpei , Toba Kenji , Sakurai Takashi
Published: May 2020

Dysregulation of the gut microbiome is associated with dementia. However, the relationship between microbiome-associated metabolites and dementia has yet to be identified. Outpatients visiting a memory clinic in Japan enrolled in this cross-sectional study; 107 subjects were eligible for the study, 25 of which had dementia. We collected demographics, activities of daily living, risk factors, cognitive function, and brain imaging data. The gut microbiome was assessed using terminal restriction fragment length polymorphism analysis. Concentrations of faecal metabolite were measured. We used multivariable logistic regression analyses to identify whether metabolites were independently related to dementia. The concentrations of metabolites were significantly different between subjects with and those without dementia. Every 1 standard deviation increment in faecal ammonia concentration was associated with around a 1.6-fold risk for the presence of dementia. A higher faecal lactic acid concentration was related to a lower risk of dementia, by around 60%. A combination of higher faecal ammonia and lactic acid concentrations was indicative of the presence of dementia, and had a similar predictive value as traditional biomarkers of dementia. Thus, faecal ammonia and lactic acid are related to dementia, independently of the other risk factors for dementia and dysregulation of the gut microbiome.
Clinical significance of combined circulating TERT promoter mutations and miR-122 expression for screening HBV-related hepatocellular carcinoma
Authors: Trung Ngo Tat , Hoan Nghiem Xuan , Trung Pham Quang , Binh Mai Thanh , Van Tong Hoang , Toan Nguyen Linh , Bang Mai Hong , Song Le Huu
Published: May 2020

Telomerase reverse-transcriptase (TERT) gene promoter mutations in circulating cell-free DNA (cfDNA) as well as the levels of circulating microRNA-122 (miR-122) have been reported as potential noninvasive biomarkers for several. This study evaluates the diagnostic performance of potent biomarker-based panels composing of serological AFP, miR-122 and circulating TERT promoter mutations for screening HBV-related HCC. TERT promoter mutations (C228T and C250T) and miR-122 expression were assessed in the plasma samples from 249 patients with HBV-related liver diseases by nested PCR and qRT-PCR assays, respectively. The diagnostic values of TERT promoter mutations, miR-122 expression and biomarker-based panels were assessed by computation of the area under the curve (AUC). Nested-PCR assays were optimized to detect C228T and C250T mutations in TERT promoter with detection limit of 1%. The common hotspot C228T was observed in 22 HCC cases. The triple combinatory panel (AFP@TERT@miR-122) acquired the best diagnostic value to distinguish HCC from CHB (AUC = 0.98), LC (AUC = 0.88) or non-HCC (LC + CHB, AUC = 0.94) compared to the performance of double combinations or single biomarkers, respectively. Notably, among patients with AFP levels≤20 ng/μl, the double combination panel (TERT@miR-122) retains satisfactory diagnostic performance in discriminating HCC from the others (HCC vs. CHB, AUC = 0.96; HCC vs. LC, AUC = 0.88, HCC vs. non-HCC, AUC = 0.94). The triple combination panel AFP@TERT@miR-122 shows a better diagnostic performance for screening HCC in HBV patients, regardless of AFP levels. The newly established panels can be a potential application in clinical practice in Vietnamese setting.
Warming and acidification threaten glass sponge Aphrocallistes vastus pumping and reef formation
Authors: Stevenson A. , Archer S. K. , Schultz J. A. , Dunham A. , Marliave J. B. , Martone P. , Harley C. D. G.
Published: May 2020

The glass sponge Aphrocallistes vastus contributes to the formation of large reefs unique to the Northeast Pacific Ocean. These habitats have tremendous filtration capacity that facilitates flow of carbon between trophic levels. Their sensitivity and resilience to climate change, and thus persistence in the Anthropocene, is unknown. Here we show that ocean acidification and warming, alone and in combination have significant adverse effects on pumping capacity, contribute to irreversible tissue withdrawal, and weaken skeletal strength and stiffness of A. vastus. Within one month sponges exposed to warming (including combined treatment) ceased pumping (50–60%) and exhibited tissue withdrawal (10–25%). Thermal and acidification stress significantly reduced skeletal stiffness, and warming weakened it, potentially curtailing reef formation. Environmental data suggests conditions causing irreversible damage are possible in the field at +0.5 °C above current conditions, indicating that ongoing climate change is a serious and immediate threat to A. vastus, reef dependent communities, and potentially other glass sponges.
Author Correction: Spatio-temporal expression of ANK2 promotes cytokinesis in oocytes
Authors: Tetkova Anna , Jansova Denisa , Susor Andrej
Published: May 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Large area chemical vapour deposition grown transition metal dichalcogenide monolayers automatically characterized through photoluminescence imaging
Authors: Severs Millard Toby , Genco Armando , Alexeev Evgeny M. , Randerson Sam , Ahn Seongjoon , Jang A-Rang , Suk Shin Hyeon , Tartakovskii Alexander I.
Published: May 2020

Chemical vapour deposition (CVD) growth is capable of producing multiple single-crystal islands of atomically thin transition metal dichalcogenides (TMDs) over large areas. Subsequent merging of perfectly epitaxial domains can lead to single-crystal monolayer sheets, a step towards scalable production of high quality TMDs. For CVD growth to be effectively harnessed for such production it is necessary to be able to rapidly assess the quality of material across entire large area substrates. To date, characterisation has been limited to sub-0.1-mm2 areas, where the properties measured are not necessarily representative of an entire sample. Here, we apply photoluminescence (PL) imaging and computer vision techniques to create an automated analysis for large area samples of monolayer TMDs, measuring the properties of island size, density of islands, relative PL intensity and homogeneity, and orientation of triangular domains. The analysis is applied to ×20 magnification optical microscopy images that completely map samples of WSe2 on hBN, 5.0 mm × 5.0 mm in size, and MoSe2–WS2 on SiO2/Si, 11.2 mm × 5.8 mm in size. Two prevailing orientations of epitaxial growth were observed in WSe2 grown on hBN and four predominant orientations were observed in MoSe2, initially grown on c-plane sapphire. The proposed analysis will greatly reduce the time needed to study freshly synthesised material over large area substrates and provide feedback to optimise growth conditions, advancing techniques to produce high quality TMD monolayer sheets for commercial applications.
AI-doscopist: a real-time deep-learning-based algorithm for localising polyps in colonoscopy videos with edge computing devices
Authors: Poon Carmen C. Y. , Jiang Yuqi , Zhang Ruikai , Lo Winnie W. Y. , Cheung Maggie S. H. , Yu Ruoxi , Zheng Yali , Wong John C. T. , Liu Qing , Wong Sunny H. , Mak Tony W. C. , Lau James Y. W.
Published: May 2020

We have designed a deep-learning model, an “Artificial Intelligent Endoscopist (a.k.a. AI-doscopist)”, to localise colonic neoplasia during colonoscopy. This study aims to evaluate the agreement between endoscopists and AI-doscopist for colorectal neoplasm localisation. AI-doscopist was pre-trained by 1.2 million non-medical images and fine-tuned by 291,090 colonoscopy and non-medical images. The colonoscopy images were obtained from six databases, where the colonoscopy images were classified into 13 categories and the polyps’ locations were marked image-by-image by the smallest bounding boxes. Seven categories of non-medical images, which were believed to share some common features with colorectal polyps, were downloaded from an online search engine. Written informed consent were obtained from 144 patients who underwent colonoscopy and their full colonoscopy videos were prospectively recorded for evaluation. A total of 128 suspicious lesions were resected or biopsied for histological confirmation. When evaluated image-by-image on the 144 full colonoscopies, the specificity of AI-doscopist was 93.3%. AI-doscopist were able to localise 124 out of 128 polyps (polyp-based sensitivity = 96.9%). Furthermore, after reviewing the suspected regions highlighted by AI-doscopist in a 102-patient cohort, an endoscopist has high confidence in recognizing four missed polyps in three patients who were not diagnosed with any lesion during their original colonoscopies. In summary, AI-doscopist can localise 96.9% of the polyps resected by the endoscopists. If AI-doscopist were to be used in real-time, it can potentially assist endoscopists in detecting one more patient with polyp in every 20–33 colonoscopies.
The emerging role of microfluidics in multi-material 3D bioprinting
Authors: Richard Cynthia , Neild Adrian , Cadarso Victor J.
Published: May 2020

To assist the transition of 3D bioprinting technology from simple lab-based tissue fabrication, to fully functional and implantable organs, the technology must not only provide shape control, but also functional control.
Expedient green-chemistry approaches for a one-pot synthesis of two series of novel 1,5-benzodiazepines via domino reactions
Authors: Wu Hai-tao , Wang Lan-zhi
Published: May 2020

Unique green-chemistry approaches have been developed for the one-pot synthesis of two series of novel 1,5-benzodiazepines 4 and 5.