bluuebunny/crossref_metadata_2025 huggingface dataset:
Aberrant dynamics of cognitive control and motor circuits predict distinct restricted and repetitive behaviors in children with autism
Authors: Supekar Kaustubh , Ryali Srikanth , Mistry Percy , Menon Vinod
Published: June 2021

Restricted and repetitive behaviors (RRBs) are a defining clinical feature of autism spectrum disorders (ASD). RRBs are highly heterogeneous with variable expression of circumscribed interests (CI), insistence of sameness (IS) and repetitive motor actions (RM), which are major impediments to effective functioning in individuals with ASD; yet, the neurobiological basis of CI, IS and RM is unknown. Here we evaluate a unified functional brain circuit model of RRBs and test the hypothesis that CI and IS are associated with aberrant cognitive control circuit dynamics, whereas RM is associated with aberrant motor circuit dynamics. Using task-free fMRI data from 96 children, we first demonstrate that time-varying cross-network interactions in cognitive control circuit are significantly reduced and inflexible in children with ASD, and predict CI and IS symptoms, but not RM symptoms. Furthermore, we show that time-varying cross-network interactions in motor circuit are significantly greater in children with ASD, and predict RM symptoms, but not CI or IS symptoms. We confirmed these results using cross-validation analyses. Moreover, we show that brain-clinical symptom relations are not detected with time-averaged functional connectivity analysis. Our findings provide neurobiological support for the validity of RRB subtypes and identify dissociable brain circuit dynamics as a candidate biomarker for a key clinical feature of ASD.
Machine-learning predicts genomic determinants of meiosis-driven structural variation in a eukaryotic pathogen
Authors: Badet Thomas , Fouché Simone , Hartmann Fanny E. , Zala Marcello , Croll Daniel
Published: June 2021

Species harbor extensive structural variation underpinning recent adaptive evolution. However, the causality between genomic features and the induction of new rearrangements is poorly established. Here, we analyze a global set of telomere-to-telomere genome assemblies of a fungal pathogen of wheat to establish a nucleotide-level map of structural variation. We show that the recent emergence of pesticide resistance has been disproportionally driven by rearrangements. We use machine learning to train a model on structural variation events based on 30 chromosomal sequence features. We show that base composition and gene density are the major determinants of structural variation. Retrotransposons explain most inversion, indel and duplication events. We apply our model toArabidopsis thalianaand show that our approach extends to more complex genomes. Finally, we analyze complete genomes of haploid offspring in a four-generation pedigree. Meiotic crossover locations are enriched for new rearrangements consistent with crossovers being mutational hotspots. The model trained on species-wide structural variation accurately predicts the position of >74% of newly generated variants along the pedigree. The predictive power highlights causality between specific sequence features and the induction of chromosomal rearrangements. Our work demonstrates that training sequence-derived models can accurately identify regions of intrinsic DNA instability in eukaryotic genomes.
Designing zero-dimensional dimer-type all-inorganic perovskites for ultra-fast switching memory
Authors: Park Youngjun , Kim Seong Hun , Lee Donghwa , Lee Jang-Sik
Published: June 2021

Resistive switching memory that uses halide perovskites (HP) has been considered as next-generation storage devices due to low operation voltage and high on/off ratio. However, the memory still faces challenges for stable operation with fast switching speed, which hinders the practical application. Thus, it should be considered from the stage of designing the HP for memory applications. Here, we design the perovskite memory using a high-throughput screening based on first-principles calculations. Total 696 compositions in four different crystal structures are investigated and essential parameters including stability, vacancy formation, and migration are considered as the descriptor. We select dimer-Cs3Sb2I9 as an optimal HP for memory; the device that uses dimer-Cs3Sb2I9 has ultra-fast switching speed (~20 ns) compared to the device that uses layer-Cs3Sb2I9 (>100 ns). The use of lead-free perovskite avoids environmental problems caused by lead in perovskite. These results demonstrate the feasibility to design the memory with ultra-fast switching speed.
A chromosome-level Camptotheca acuminata genome assembly provides insights into the evolutionary origin of camptothecin biosynthesis
Authors: Kang Minghui , Fu Rao , Zhang Pingyu , Lou Shangling , Yang Xuchen , Chen Yang , Ma Tao , Zhang Yang , Xi Zhenxiang , Liu Jianquan
Published: June 2021

Camptothecin and its derivatives are widely used for treating malignant tumors. Previous studies revealed only a limited number of candidate genes for camptothecin biosynthesis in Camptotheca acuminata, and it is still poorly understood how its biosynthesis of camptothecin has evolved. Here, we report a high-quality, chromosome-level C. acuminata genome assembly. We find that C. acuminata experiences an independent whole-genome duplication and numerous genes derive from it are related to camptothecin biosynthesis. Comparing with Catharanthus roseus, the loganic acid O-methyltransferase (LAMT) in C. acuminata fails to convert loganic acid into loganin. Instead, two secologanic acid synthases (SLASs) convert loganic acid to secologanic acid. The functional divergence of the LAMT gene and positive evolution of two SLAS genes, therefore, both contribute greatly to the camptothecin biosynthesis in C. acuminata. Our results emphasize the importance of high-quality genome assembly in identifying genetic changes in the evolutionary origin of a secondary metabolite.
Viral infiltration of pancreatic islets in patients with COVID-19
Authors: Steenblock Charlotte , Richter Stefanie , Berger Ilona , Barovic Marko , Schmid Janine , Schubert Undine , Jarzebska Natalia , von Mässenhausen Anne , Linkermann Andreas , Schürmann Annette , Pablik Jessica , Dienemann Thomas , Evert Katja , Rodionov Roman N. , Semenova Natalia Y. , Zinserling Vsevolod A. , Gainetdinov Raul R. , Baretton Gustavo , Lindemann Dirk , Solimena Michele , Ludwig Barbara , Bornstein Stefan R.
Published: June 2021

Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19.
Exploring the link between molecular cloud ices and chondritic organic matter in laboratory
Authors: Danger G. , Vinogradoff V. , Matzka M. , Viennet J-C. , Remusat L. , Bernard S. , Ruf A. , Le Sergeant d’Hendecourt L. , Schmitt-Kopplin P.
Published: June 2021

Carbonaceous meteorites are fragments of asteroids rich in organic material. In the forming solar nebula, parent bodies may have accreted organic materials resulting from the evolution of icy grains observed in dense molecular clouds. The major issues of this scenario are the secondary processes having occurred on asteroids, which may have modified the accreted matter. Here, we explore the evolution of organic analogs of protostellar/protoplanetary disk material once accreted and submitted to aqueous alteration at 150 °C. The evolution of molecular compounds during up to 100 days is monitored by high resolution mass spectrometry. We report significant evolution of the molecular families, with the decreases of H/C and N/C ratios. We find that the post-aqueous products share compositional similarities with the soluble organic matter of the Murchison meteorite. These results give a comprehensive scenario of the possible link between carbonaceous meteorites and ices of dense molecular clouds.
Order–disorder transition of a rigid cage cation embedded in a cubic perovskite
Authors: Shi Zhifang , Fang Zheng , Wu Jingshu , Chen Yi , Mi Qixi
Published: June 2021

The structure and properties of organic–inorganic hybrid perovskites are impacted by the order–disorder transition, whose driving forces from the organic cation and the inorganic framework cannot easily be disentangled. Herein, we report the design, synthesis and properties of a cage-in-framework perovskite AthMn(N3)3, where Ath+ is an organic cation 4-azatricyclo[2.2.1.02,6]heptanium. Ath+ features a rigid and spheroidal profile, such that its molecular reorientation does not alter the cubic lattice symmetry of the Mn(N3)3− host framework. This order–disorder transition is well characterized by NMR, crystallography, and calorimetry, and associated with the realignment of Ath+ dipole from antiferroelectric to paraelectric. As a result, an abrupt rise in the dielectric constant was observed during the transition. Our work introduces a family of perovskite structures and provides direct insights to the order–disorder transition of hybrid materials.
Large Stokes shift fluorescence activation in an RNA aptamer by intermolecular proton transfer to guanine
Authors: Mieczkowski Mateusz , Steinmetzger Christian , Bessi Irene , Lenz Ann-Kathrin , Schmiedel Alexander , Holzapfel Marco , Lambert Christoph , Pena Vladimir , Höbartner Claudia
Published: June 2021

Fluorogenic RNA aptamers are synthetic functional RNAs that specifically bind and activate conditional fluorophores. The Chili RNA aptamer mimics large Stokes shift fluorescent proteins and exhibits high affinity for 3,5-dimethoxy-4-hydroxybenzylidene imidazolone (DMHBI) derivatives to elicit green or red fluorescence emission. Here, we elucidate the structural and mechanistic basis of fluorescence activation by crystallography and time-resolved optical spectroscopy. Two co-crystal structures of the Chili RNA with positively charged DMHBO+ and DMHBI+ ligands revealed a G-quadruplex and a trans-sugar-sugar edge G:G base pair that immobilize the ligand by π-π stacking. A Watson-Crick G:C base pair in the fluorophore binding site establishes a short hydrogen bond between the N7 of guanine and the phenolic OH of the ligand. Ultrafast excited state proton transfer (ESPT) from the neutral chromophore to the RNA was found with a time constant of 130 fs and revealed the mode of action of the large Stokes shift fluorogenic RNA aptamer.
Cu2Se-based thermoelectric cellular architectures for efficient and durable power generation
Authors: Choo Seungjun , Ejaz Faizan , Ju Hyejin , Kim Fredrick , Lee Jungsoo , Yang Seong Eun , Kim Gyeonghun , Kim Hangeul , Jo Seungki , Baek Seongheon , Cho Soyoung , Kim Keonkuk , Kim Ju-Young , Ahn Sangjoon , Chae Han Gi , Kwon Beomjin , Son Jae Sung
Published: June 2021

Thermoelectric power generation offers a promising way to recover waste heat. The geometrical design of thermoelectric legs in modules is important to ensure sustainable power generation but cannot be easily achieved by traditional fabrication processes. Herein, we propose the design of cellular thermoelectric architectures for efficient and durable power generation, realized by the extrusion-based 3D printing process of Cu2Se thermoelectric materials. We design the optimum aspect ratio of a cuboid thermoelectric leg to maximize the power output and extend this design to the mechanically stiff cellular architectures of hollow hexagonal column- and honeycomb-based thermoelectric legs. Moreover, we develop organic binder-free Cu2Se-based 3D-printing inks with desirable viscoelasticity, tailored with an additive of inorganic Se82− polyanion, fabricating the designed topologies. The computational simulation and experimental measurement demonstrate the superior power output and mechanical stiffness of the proposed cellular thermoelectric architectures to other designs, unveiling the importance of topological designs of thermoelectric legs toward higher power and longer durability.
Tumor microenvironmental cytokines bound to cancer exosomes determine uptake by cytokine receptor-expressing cells and biodistribution
Authors: Lima Luize G. , Ham Sunyoung , Shin Hyunku , Chai Edna P. Z. , Lek Erica S. H. , Lobb Richard J. , Müller Alexandra F. , Mathivanan Suresh , Yeo Belinda , Choi Yeonho , Parker Belinda S. , Möller Andreas
Published: June 2021

Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings.
Accelerated design and discovery of perovskites with high conductivity for energy applications through machine learning
Authors: Priya Pikee , Aluru N. R.
Published: June 2021

We use machine learning tools for the design and discovery of ABO3-type perovskite oxides for various energy applications, using over 7000 data points from the literature. We demonstrate a robust learning framework for efficient and accurate prediction of total conductivity of perovskites and their classification based on the type of charge carrier at different conditions of temperature and environment. After evaluating a set of >100 features, we identify average ionic radius, minimum electronegativity, minimum atomic mass, minimum formation energy of oxides for all B-site, and B-site dopant ions of the perovskite as the crucial and relevant predictors for determining conductivity and the type of charge carriers. The models are validated by predicting the conductivity of compounds absent in the training set. We screen 1793 undoped and 95,832 A-site and B-site doped perovskites to report the perovskites with high conductivities, which can be used for different energy applications, depending on the type of the charge carriers.
Non-uniform tropical forest responses to the ‘Columbian Exchange’ in the Neotropics and Asia-Pacific
Authors: Hamilton Rebecca , Wolfhagen Jesse , Amano Noel , Boivin Nicole , Findley David Max , Iriarte José , Kaplan Jed O. , Stevenson Janelle , Roberts Patrick
Published: June 2021

It has been suggested that Iberian arrival in the Americas in 1492 and subsequent dramatic depopulation led to forest regrowth that had global impacts on atmospheric CO2 concentrations and surface temperatures. Despite tropical forests representing the most important terrestrial carbon stock globally, systematic examination of historical afforestation in these habitats in the Neotropics is lacking. Additionally, there has been no assessment of similar depopulation–afforestation dynamics in other parts of the global tropics that were incorporated into the Spanish Empire. Here, we compile and semi-quantitatively analyse pollen records from the regions claimed by the Spanish in the Atlantic and Pacific to provide pan-tropical insights into European colonial impacts on forest dynamics. Our results suggest that periods of afforestation over the past millennium varied across space and time and depended on social, economic and biogeographic contexts. We argue that this reveals the unequal and divergent origins of the Anthropocene as a socio-political and biophysical process, highlighting the need for higher-resolution, targeted analyses to fully elucidate pre-colonial and colonial era human–tropical landscape interactions.
Cric searchable image database as a public platform for conventional pap smear cytology data
Authors: Rezende Mariana T. , Silva Raniere , Bernardo Fagner de O. , Tobias Alessandra H. G. , Oliveira Paulo H. C. , Machado Tales M. , Costa Caio S. , Medeiros Fatima N. S. , Ushizima Daniela M. , Carneiro Claudia M. , Bianchi Andrea G. C.
Published: June 2021

Amidst the current health crisis and social distancing, telemedicine has become an important part of mainstream of healthcare, and building and deploying computational tools to support screening more efficiently is an increasing medical priority. The early identification of cervical cancer precursor lesions by Pap smear test can identify candidates for subsequent treatment. However, one of the main challenges is the accuracy of the conventional method, often subject to high rates of false negative. While machine learning has been highlighted to reduce the limitations of the test, the absence of high-quality curated datasets has prevented strategies development to improve cervical cancer screening. The Center for Recognition and Inspection of Cells (CRIC) platform enables the creation of CRIC Cervix collection, currently with 400 images (1,376 × 1,020 pixels) curated from conventional Pap smears, with manual classification of 11,534 cells. This collection has the potential to advance current efforts in training and testing machine learning algorithms for the automation of tasks as part of the cytopathological analysis in the routine work of laboratories.
Interactions between polyphenolic antioxidants quercetin and naringenin dictate the distinctive redox-related chemical and biological behaviour of their mixtures
Authors: Baranowska Monika , Koziara Zuzanna , Suliborska Klaudia , Chrzanowski Wojciech , Wormstone Michael , Namieśnik Jacek , Bartoszek Agnieszka
Published: June 2021

Food synergy concept is suggested to explain observations that isolated antioxidants are less bioactive than real foods containing them. However, mechanisms behind this discrepancy were hardly studied. Here, we demonstrate the profound impact of interactions between two common food flavonoids (individual: aglycones quercetin—Q and naringenin—N− or their glycosides rutin—R and naringin—N+ vs. mixed: QN− and RN+) on their electrochemical properties and redox-related bioactivities. N− and N+ seemed weak antioxidants individually, yet in both chemical and cellular tests (DPPH and CAA, respectively), they increased reducing activity of mixtures synergistically. In-depth measurements (differential pulse voltammetry) pointed to kinetics of oxidation reaction as decisive factor for antioxidant power. In cellular (HT29 cells) tests, the mixtures exhibited properties of a new substance rather than those of components. Pure flavonoids did not influence proliferation; mixtures stimulated cell growth. Individual flavonoids tended to decrease global DNA methylation with growing concentration; this effect was more pronounced for mixtures, but not concentration-dependent. In nutrigenomic studies, expression of gene set affected by QN− differed entirely from common genes modulated by individual components. These results question the current approach of predicting bioactivity of mixtures based on research with isolated antioxidants.
Proteomic and genomic analysis of acid dentin lysate with focus on TGF-β signaling
Authors: Nasirzade Jila , Kargarpour Zahra , Mitulović Goran , Strauss Franz Josef , Panahipour Layla , Schwarz Frank , Gruber Reinhard
Published: June 2021

Particulate autologous tooth roots are increasingly used for alveolar bone augmentation; however, the proteomic profile of acid dentin lysate and the respective cellular response have not been investigated. Here we show that TGF-β1 is among the 226 proteins of acid dentin lysate (ADL) prepared from porcine teeth. RNA sequencing identified 231 strongly regulated genes when gingival fibroblasts were exposed to ADL. Out of these genes, about one third required activation of the TGF-β receptor type I kinase including interleukin 11 (IL11) and NADPH oxidase 4 (NOX4). Reverse transcription-quantitative polymerase chain reaction and immunoassay confirmed the TGF-β-dependent expression of IL11 and NOX4. The activation of canonical TGF-β signaling by ADL was further confirmed by the phosphorylation of Smad3 and translocation of Smad2/3, using Western blot and immunofluorescence staining, respectively. Finally, we showed that TGF-β activity released from dentin by acid lysis adsorbs to titanium and collagen membranes. These findings suggest that dentin particles are a rich source of TGF-β causing a major response of gingival fibroblasts.
External ears for non-invasive and stable monitoring of volatile organic compounds in human blood
Authors: Toma Koji , Suzuki Shota , Arakawa Takahiro , Iwasaki Yasuhiko , Mitsubayashi Kohji
Published: June 2021

Volatile organic compounds (VOCs) released through skin (transcutaneous gas) has been increasing in importance for the continuous and real-time assessment of diseases or metabolisms. For stable monitoring of transcutaneous gas, finding a body part with little interference on the measurement is essential. In this study, we have investigated the possibility of external ears for stable and real-time measurement of ethanol vapour by developing a monitoring system that consisted with an over-ear gas collection cell and a biochemical gas sensor (bio-sniffer). The high sensitivity with the broad dynamic range (26 ppb–554 ppm), the high selectivity to ethanol, and the capability of the continuous measurement of the monitoring system uncovered three important characteristics of external ear-derived ethanol with alcohol intake for the first time: there is little interference from sweat glands to a sensor signal at the external ear; similar temporal change in ethanol concentration to that of breath with delayed peak time (avg. 13 min); relatively high concentration of ethanol relative to other parts of a body (external ear-derived ethanol:breath ethanol = 1:590). These features indicated the suitability of external ears for non-invasive monitoring of blood VOCs.
Optical quantum technologies with hexagonal boron nitride single photon sources
Authors: Shaik Akbar Basha Dhu-al-jalali-wal-ikram , Palla Penchalaiah
Published: June 2021

Single photon quantum emitters are important building blocks of optical quantum technologies. Hexagonal boron nitride (hBN), an atomically thin wide band gap two dimensional material, hosts robust, optically active luminescent point defects, which are known to reduce phonon lifetimes, promises as a stable single-photon source at room temperature. In this Review, we present the recent advances in hBN quantum light emission, comparisons with other 2D material based quantum sources and analyze the performance of hBN quantum emitters. We also discuss state-of-the-art stable single photon emitter’s fabrication in UV, visible and near IR regions, their activation, characterization techniques, photostability towards a wide range of operating temperatures and harsh environments, Density-functional theory predictions of possible hBN defect structures for single photon emission in UV to IR regions and applications of single photon sources in quantum communication and quantum photonic circuits with associated potential obstacles.
High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation
Authors: Sibley Laura , White Andrew D. , Gooch Karen E. , Stevens Lisa M. , Tanner Rachel , Jacobs Ashley , Daykin-Pont Owen , Gleeson Fergus , McIntyre Anthony , Basaraba Randall , Clark Simon , Hall Graham , Pearson Geoff , Rayner Emma , McShane Helen , Williams Ann , Dennis Mike , Marsh Philip D. , Sharpe Sally
Published: June 2021

This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within 10 weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.
The short-term safety and efficacy of TANDEM microspheres of various sizes and doxorubicin loading concentrations for hepatocellular carcinoma treatment
Authors: Lin Chia-Ying , Liu Yi-Sheng , Pan Kuang-Tse , Chen Chia-Bang , Hung Chein-Fu , Chou Chen-Te
Published: June 2021

Drug-eluting bead transarterial chemoembolization (DEB-TACE) is the most common treatment for unresectable hepatocellular carcinoma (HCC). However, the effect of drug loading concentration and microsphere size on treatment outcomes remains unclear. This retrospective study compares the outcomes of 87 HCC patients who underwent DEB-TACE with half-loaded or full-loaded doxorubicin (maximum capacity 50 mg/mL) in 75-µm or 100-µm microspheres. Treatment with 100-μm microspheres resulted in significantly lower rates of procedure-related complications (6.6% vs. 26.9%; P < 0.05), post-embolization syndrome (32.8% vs. 61.5%, P < 0.05), SIR complications (32.8% vs. 61.5%; P < 0.01) and adverse events involving abdominal pain (19.7% vs. 42.3%; P < 0.05). Half-load doxorubicin microspheres resulted in greater treatment response (OR, 4.00; 95% CI 1.06–15.13; P, 0.041) and shorter hospital stays (OR, − 1.72; 95% CI − 2.77–0.68; P, 0.001) than did microspheres loaded to full capacity. Stratified analysis further showed that patients treated with 100-μm half-load doxorubicin microspheres had a higher CR (63.6% vs 18.0%) and ORR (90.9 vs 54.0%) and a shorter hospital stay (1.6 ± 1.3 vs 4.2 ± 2.3 days) than did those treated with full-load microspheres (P < 0.05). Thus, the drug-loading concentration of microspheres in DEB-TACE should be carefully considered.
Redefining the oceanic distribution of Atlantic salmon
Authors: Rikardsen Audun H. , Righton David , Strøm John Fredrik , Thorstad Eva B. , Gargan Patrick , Sheehan Timothy , Økland Finn , Chittenden Cedar M. , Hedger Richard D. , Næsje Tor F. , Renkawitz Mark , Sturlaugsson Johannes , Caballero Pablo , Baktoft Henrik , Davidsen Jan G. , Halttunen Elina , Wright Serena , Finstad Bengt , Aarestrup Kim
Published: June 2021

Determining the mechanisms driving range-wide reductions in Atlantic salmon marine survival is hindered by an insufficient understanding of their oceanic ecology and distribution. We attached 204 pop-up satellite archival tags to post-spawned salmon when they migrated to the ocean from seven European areas and maiden North American salmon captured at sea at West Greenland. Individuals migrated further north and east than previously reported and displayed increased diving activity near oceanographic fronts, emphasizing the importance of these regions as feeding areas. The oceanic distribution differed among individuals and populations, but overlapped more between geographically proximate than distant populations. Dissimilarities in distribution likely contribute to variation in growth and survival within and among populations due to spatio-temporal differences in environmental conditions. Climate-induced changes in oceanographic conditions will alter the location of frontal areas and may have stock-specific effects on Atlantic salmon population dynamics, likely having the largest impacts on southern populations.
Author Correction: Realization of tunable artificial synapse and memory based on amorphous oxide semiconductor transistor
Authors: Dai Mingzhi , Wang Weiliang , Wang Pengjun , Iqbal Muhammad Zahir , Annabi Nasim , Amin Nasir
Published: June 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Impact of interstitial impurities on the trapping of dislocation loops in tungsten
Authors: Bakaev Alexander , Bonny Giovanni , Castin Nicolas , Terentyev Dmitry , Bakaev Viktor A.
Published: June 2021

Ab initio simulations are employed to assess the interaction of typical interstitial impurities with self-interstitial atoms, dislocation loops and edge dislocation lines in tungsten. These impurities are present in commercial tungsten grades and are also created as a result of neutron transmutation or the plasma in-take process. The relevance of the study is determined by the application of tungsten as first wall material in fusion reactors. For the defects with dislocation character, the following ordering of the interaction strength was established: H < N < C < O < He. The magnitude of the interaction energy was rationalized by decomposing it into elastic (related to the lattice strain) and chemical (related to local electron density) contributions. To account for the combined effect of impurity concentration and pinning strength, the impact of the presence of these impurities on the mobility of isolated dislocation loops was studied for DEMO relevant conditions in the non-elastic and dilute limit.
Cobalamin is present in cells of non-tuberculous mycobacteria, but not in Mycobacterium tuberculosis
Authors: Minias Alina , Gąsior Filip , Brzostek Anna , Jagielski Tomasz , Dziadek Jarosław
Published: June 2021

Cobalamin (vitamin B12) is a structurally complex molecule that acts as a cofactor for enzymes and regulates gene expression through so-called riboswitches. The existing literature on the vitamin B12 synthesis capacity in Mycobacterium tuberculosis is ambiguous, while in non-tuberculous mycobacteria (NTM) is rather marginal. Here we present the results of our investigation into the occurrence of vitamin B12 in mycobacteria. For detection purposes, immunoassay methods were applied to cell lysates of NTM and M. tuberculosis clinical and laboratory strains grown under different conditions. We show that whereas vitamin B12 is present in cells of various NTM species, it cannot be evidenced in strains of differently cultured M. tuberculosis, even though the genes responsible for vitamin B12 synthesis are actively expressed based on RNA-Seq data. In summary, we conclude that the production of vitamin B12 does occur in mycobacteria, with the likely exception of M. tuberculosis. Our results provide direct evidence of vitamin B12 synthesis in a clinically important group of bacteria.
Automated home-cage for the evaluation of innate non-reflexive pain behaviors in a mouse model of inflammatory pain
Authors: Hasriadi  , Wasana Peththa Wadu Dasuni , Vajragupta Opa , Rojsitthisak Pornchai , Towiwat Pasarapa
Published: June 2021

The failure to develop analgesic drugs is attributed not only to the complex and diverse pathophysiology of pain in humans but also to the poor experimental design and poor preclinical assessment of pain. Although considerable efforts have been devoted to overcoming the relevant problems, many features of the behavioral pain assessment remain to be characterized. For example, a decreased locomotor activity as a common presentation of pain-like behavior has yet to be described. Studies on mice experimentally induced with carrageenan have provided opportunities to explore pain-related behaviors in automated home-cage monitoring. Through this approach, the locomotor activities of mice with carrageenan-induced inflammatory pain can be precisely and objectively captured. Here, we found that the mobile behaviors of mice reduced, and their immobility increased, indicating that carrageenan induction in mice caused a significant decrease in locomotor activity. These non-reflexive pain behaviors were strongly correlated with the reflexive pain behaviors measured via von Frey and plantar tests. Furthermore, the pharmacological intervention using indomethacin improved the locomotor activity of mice with carrageenan-induced pain. Thus, the analysis of the locomotor activity in automated home-cage monitoring is useful for studying the behavioral analgesia and the pharmacological screening of analgesic drugs. The combined evaluation of reflexive and non-reflexive pain behaviors enhances the translational utility of preclinical pain research in rodents.
Host specific endophytic microbiome diversity and associated functions in three varieties of scented black rice are dependent on growth stage
Authors: Singha K. Malabika , Singh Brahmanand , Pandey Piyush
Published: June 2021

The compositional and functional role of the endophytic bacterial community, associated with black scented rice, in correlation with its antioxidant property has been elucidated. Community dissimilarity analysis confirmed the overlapping of community in shoot and root tissues at the young stage, but not in mature plants. Proteobacteria was the most abundant phylum, in which Agrobacterium, Pleomorphomonas, Bradyrhizobium, Novasphingobium, Caulobacter were the most abundant genera, followed by Cyanobacteria and Planctomycetes in all three different varieties of the black rice. The antioxidant activity of mature plants was found to be higher in comparison to young plants. Intrinsically, the relative abundance of Pleomorphomonas and Streptomyces was positively correlated with total phenol content, while Gemmata, unclassified Pirellulaceae, unclassified Stramenopiles positively correlated with total flavonoid content and negatively correlated with Free radical scavenging activity. Accordingly, functional metagenome analysis of the endophytic microbiome revealed that naringenin -3-dioxygenase and anthocyanidin 3-O-glucosyltransferase for phenylpropanoid (flavonoid and anthocyanin) synthesis were abundant in the endophytic microbiome of mature plants. Specific enrichment of the antioxidant producing genes in the mature plant endophytic microbiome was assigned to some bacteria such as Streptomyces, Pantoea which might have contributed to the common pathway of flavonoid synthesis. The genomes of endophytic isolates Kluyvera sp.PO2S7, Bacillus subtilis AMR1 and Enterobacter sp. SES19 were sequenced and annotated, and were found to have genes for phenylpropanoid synthesis in their genomes.
Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis
Authors: Hassan Mubashir , Zahid Sara , Alashwal Hany , Kloczkowski Andrzej , Moustafa Ahmed A.
Published: June 2021

Proteins are tiny players involved in the activation and deactivation of multiple signaling cascades through interactions in cells. The TNFR1 and MADD interact with each other and mediate downstream protein signaling pathways which cause neuronal cell death and Alzheimer’s disease. In the current study, a molecular docking approach was employed to explore the interactive behavior of TNFR1 and MADD proteins and their role in the activation of downstream signaling pathways. The computational sequential and structural conformational results revealed that Asp400, Arg58, Arg59 were common residues of TNFR1 and MADD which are involved in the activation of downstream signaling pathways. Aspartic acid in negatively charged residues is involved in the biosynthesis of protein. However, arginine is a positively charged residue with the potential to interact with oppositely charged amino acids. Furthermore, our molecular dynamic simulation results also ensured the stability of the backbone of TNFR1 and MADD death domains (DDs) in binding interactions. This DDs interaction mediates some conformational changes in TNFR1 which leads to the activation of mediators proteins in the cellular signaling pathways. Taken together, a better understanding of TNFR1 and MADD receptors and their activated signaling cascade may help treat Alzheimer’s disease. The death domains of TNFR1 and MADD could be used as a novel pharmacological target for the treatment of Alzheimer’s disease by inhibiting the MAPK pathway.
Residual limb volume fluctuations in transfemoral amputees
Authors: Paternò Linda , Ibrahimi Michele , Rosini Elisa , Menfi Giuseppe , Monaco Vito , Gruppioni Emanuele , Ricotti Leonardo , Menciassi Arianna
Published: June 2021

This study constitutes the first attempt to systematically quantify residual limb volume fluctuations in transfemoral amputees. The study was carried out on 24 amputees to investigate variations due to prosthesis doffing, physical activity, and testing time. A proper experimental set-up was designed, including a 3D optical scanner to improve precision and acceptability by amputees. The first test session aimed at measuring residual limb volume at 7 time-points, with 10 min intervals, after prosthesis doffing. This allowed for evaluating the time required for volume stabilization after prosthesis removal, for each amputee. In subsequent sessions, 16 residual limb scans in a day for each amputee were captured to evaluate volume fluctuations due to prosthesis removal and physical activity, in two times per day (morning and afternoon). These measurements were repeated in three different days, a week apart from each other, for a total of 48 scans for each amputee. Volume fluctuations over time after prosthesis doffing showed a two-term decay exponential trend (R2 = 0.97), with the highest variation in the initial 10 min and an average stabilization time of 30 min. A statistically significant increase in residual limb volume following both prosthesis removal and physical activity was verified. No differences were observed between measures collected in the morning and in the afternoon.

Clinical Trials.gov ID: NCT04709367.
Results of the IROCA international clinical audit in prostate cancer radiotherapy at six comprehensive cancer centres
Authors: Lopes de Castro Carla , Fundowicz Magdalena , Roselló Alvar , Jové Josep , Deantonio Letizia , Aguiar Artur , Pisani Carla , Villà Salvador , Boladeras Anna , Konstanty Ewelina , Kruszyna-Mochalska Marta , Milecki Piotr , Jurado-Bruggeman Diego , Lencart Joana , Modolell Ignasi , Muñoz-Montplet Carles , Aliste Luisa , Torras Maria Gloria , Puigdemont Montserrat , Carvalho Luísa , Krengli Marco , Guedea Ferran , Malicki Julian
Published: June 2021

To assess adherence to standard clinical practice for the diagnosis and treatment of patients undergoing prostate cancer (PCa) radiotherapy in four European countries using clinical audits as part of the international IROCA project. Multi-institutional, retrospective cohort study of 240 randomly-selected patients treated for PCa (n = 40/centre) in the year 2015 at six European hospitals. Clinical indicators applicable to general and PCa-specific radiotherapy processes were evaluated. All data were obtained directly from medical records. The audits were performed in the year 2017. Adherence to clinical protocols and practices was satisfactory, but with substantial inter-centre variability in numerous variables, as follows: staging MRI (range 27.5–87.5% of cases); presentation to multidisciplinary tumour board (2.5–100%); time elapsed between initial visit to the radiation oncology department and treatment initiation (42–102.5 days); number of treatment interruptions ≥ 1 day (7.5–97.5%). The most common deviation from standard clinical practice was inconsistent data registration, mainly failure to report data related to diagnosis, treatment, and/or adverse events. This clinical audit detected substantial inter-centre variability in adherence to standard clinical practice, most notably inconsistent record keeping. These findings confirm the value of performing clinical audits to detect deviations from standard clinical practices and procedures.
Insulin resistance is linked to a specific profile of immune activation in human subjects
Authors: Cezar Renaud , Desigaud Delphine , Pastore Manuela , Kundura Lucy , Dupuy Anne-Marie , Cognot Chantal , Vincent Thierry , Reynes Christelle , Sabatier Robert , Maggia Elisabeth , Corbeau Pierre
Published: June 2021

We tested the hypothesis that a particular immune activation profile might be correlated with insulin resistance in a general population. By measuring 43 markers of immune, endothelial, and coagulation activation, we have previously shown that five different immune activation profiles may be distinguished in 150 volunteers. One of these profiles, Profile 2, characterized by CD4+ T cell senescence, inflammation, monocyte, B cell, and endothelial activation, presented elevated insulinemia, glycemia, triglyceridemia, and γ-glutamyl transferase, a marker of liver injury, in comparison with other profiles. Our data are compatible with a model in which a particular immune activation profile might favor the development of insulin resistance and metabolic syndrome. In this hypothesis, identification of this profile, that is feasible with only 3 markers with an error rate of 5%, might allow to personalize the screening and prevention of metabolic syndrome-driven morbidities as liver steatosis.
Author Correction: Identifcation, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A
Authors: Matabaro Emmanuel , Kaspar Hannelore , Dahlin Paul , Bader Daniel L. V. , Murar Claudia E. , Staubli Florian , Field Christopher M. , Bode Jeffrey W. , Künzler Markus
Published: June 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Heparanase inhibition preserves the endothelial glycocalyx in lung grafts and improves lung preservation and transplant outcomes
Authors: Noda Kentaro , Philips Brian J. , Snyder Mark E. , Phillippi Julie A. , Sullivan Mara , Stolz Donna B. , Ren Xi , Luketich James D. , Sanchez Pablo G.
Published: June 2021

The endothelial glycocalyx (eGC) is considered a key regulator of several mechanisms that prevent vascular injury and disease. Degradation of this macromolecular layer may be associated with post-transplant graft dysfunction. In this study, we aimed to demonstrate the benefits of eGC protection via heparanase inhibition on graft quality. We established rat models of lung grafts with damaged or preserved eGC using ischemic insult and transplanted the grafts into recipients. Lung grafts were also subjected to normothermic ex vivo lung perfusion for detailed assessment under isolated conditions. Physiologic parameters and eGC-associated cellular events were assessed in grafts before and after reperfusion. Structurally degraded eGC and highly activated heparanase were confirmed in lungs with ischemic insult. After transplant, lungs with damaged eGC exhibited impaired graft function, inflammation, edema, and inflammatory cell migration. Increased eGC shedding was evident in the lungs after reperfusion both in vivo and ex vivo. These reperfusion-related deficiencies were significantly attenuated in lungs with preserved eGC following heparanase inhibition. Our studies demonstrated that eGC plays a key role in maintaining lung graft quality and function. Heparanase inhibition may serve as a potential therapeutic to preserve eGC integrity, leading to improved post-transplant outcomes.
Extracellular vesicle-shuttled miRNAs as a diagnostic and prognostic biomarker and their potential roles in gallbladder cancer patients
Authors: Ueta Eijiro , Tsutsumi Koichiro , Kato Hironari , Matsushita Hiroshi , Shiraha Hidenori , Fujii Masakuni , Matsumoto Kazuyuki , Horiguchi Shigeru , Okada Hiroyuki
Published: June 2021

Circulating microRNAs (miRNAs) in serum extracellular vesicles (EVs) are a promising biomarker in cancer. We aimed to elucidate the serum EVs miRNA biomarkers to identify patients with gallbladder cancer (GBC) and to clarify their potential roles. One hundred nineteen serum EVs from GBC and non-GBC individuals were isolated by pure-EVs-yieldable size-exclusion chromatography, and then were analyzed using a comprehensive miRNAs array and RT-qPCR-based validation. The functional roles of the identified miRNAs were also investigated using GBC cell lines. Serum EVs miR-1246 and miR-451a were significantly upregulated and downregulated, respectively in GBC patients (P = 0.005 and P = 0.001), in line with their expression levels in cancer tissue according to an in silico analysis. The combination of CEA and CA19-9 with miR-1246 showed the highest diagnostic power (AUC, 0.816; Sensitivity, 72.0%; Specificity, 90.8%), and miR-1246 was an independent prognostic marker of GBC (Hazard ratio, 3.05; P = 0.017) according to a Cox proportional hazards model. In vitro, miR-1246 promoted cell proliferation and invasion, while miR-451a inhibited cell proliferation and induced apoptosis with the targeting of MIF, PSMB8 and CDKN2D. Taken together, miR-1246 in serum EVs has potential application as a diagnostic and prognostic marker and miR-451a may be a novel therapeutic target in GBC.
Identifying molecular targets for reverse aging using integrated network analysis of transcriptomic and epigenomic changes during aging
Authors: Lee Hwang-Yeol , Jeon Yeonsu , Kim Yeon Kyung , Jang Jae Young , Cho Yun Sung , Bhak Jong , Cho Kwang-Hyun
Published: June 2021

Aging is associated with widespread physiological changes, including skeletal muscle weakening, neuron system degeneration, hair loss, and skin wrinkling. Previous studies have identified numerous molecular biomarkers involved in these changes, but their regulatory mechanisms and functional repercussions remain elusive. In this study, we conducted next-generation sequencing of DNA methylation and RNA sequencing of blood samples from 51 healthy adults between 20 and 74 years of age and identified aging-related epigenetic and transcriptomic biomarkers. We also identified candidate molecular targets that can reversely regulate the transcriptomic biomarkers of aging by reconstructing a gene regulatory network model and performing signal flow analysis. For validation, we screened public experimental data including gene expression profiles in response to thousands of chemical perturbagens. Despite insufficient data on the binding targets of perturbagens and their modes of action, curcumin, which reversely regulated the biomarkers in the experimental dataset, was found to bind and inhibit JUN, which was identified as a candidate target via signal flow analysis. Collectively, our results demonstrate the utility of a network model for integrative analysis of omics data, which can help elucidate inter-omics regulatory mechanisms and develop therapeutic strategies against aging.