bluuebunny/crossref_metadata_2025 huggingface dataset:
Analytical Solution to Assess the Induced Seismicity Potential of Faults in Pressurized and Depleted Reservoirs
Authors: Wu Haiqing , Vilarrasa Victor , De Simone Silvia , Saaltink Maarten , Parisio Francesco
Published: December 2020

Displaced faults crossing the reservoir could significantly increase the induced earthquake frequency in geo‐energy projects. Understanding and predicting the stress variation in such cases is essential to minimize the risk of induced seismicity. Here, we adopt the inclusion theory to develop an analytical solution for the stress response to pore pressure variations within the reservoir for both permeable and impermeable faults with offset ranging from zero to the reservoir thickness. By analyzing fault stability changes due to reservoir pressurization/depletion under different scenarios, we find that (1) the induced seismicity potential of impermeable faults is always larger than that of permeable faults under any initial and injection conditions—the maximum size of the fault undergoing failure is 3–5 times larger for impermeable than for permeable faults; (2) stress concentration at the corners results in the occurrence of reversed slip in normal faults with a normal faulting stress regime; (3) while fault offset has no impact on the slip potential for impermeable faults, the slip potential increases with the offset for permeable faults, which indicates that non‐displaced permeable faults constitute a safer choice for site selection; (4) an impermeable fault would rupture at a lower deviatoric stress, and at a smaller pressure buildup than a permeable one; and (5) the induced seismicity potential is overestimated and the injectivity underestimated if the stress arching (i.e., the poromechanical coupling) is neglected. This analytical solution is a useful tool for site selection and for supporting decision making during the lifetime of geo‐energy projects.
Clinical relevance of extracellular vesicles in hematological neoplasms: from liquid biopsy to cell biopsy
Authors: Trino Stefania , Lamorte Daniela , Caivano Antonella , De Luca Luciana , Sgambato Alessandro , Laurenzana Ilaria
Published: December 2020

In the era of precision medicine, liquid biopsy is becoming increasingly important in oncology. It consists in the isolation and analysis of tumor-derived biomarkers, including extracellular vesicles (EVs), in body fluids. EVs are lipid bilayer-enclosed particles, heterogeneous in size and molecular composition, released from both normal and neoplastic cells. In tumor context, EVs are valuable carriers of cancer information; in fact, their amount, phenotype and molecular cargo, including proteins, lipids, metabolites and nucleic acids, mirror nature and origin of parental cells rendering EVs appealing candidates as novel biomarkers. Translation of these new potential diagnostic tools into clinical practice could deeply revolutionize the cancer field mainly for solid tumors but for hematological neoplasms, too.
Meta-neural-network for real-time and passive deep-learning-based object recognition
Authors: Weng Jingkai , Ding Yujiang , Hu Chengbo , Zhu Xue-Feng , Liang Bin , Yang Jing , Cheng Jianchun
Published: December 2020

Analyzing scattered wave to recognize object is of fundamental significance in wave physics. Recently-emerged deep learning technique achieved great success in interpreting wave field such as in ultrasound non-destructive testing and disease diagnosis, but conventionally need time-consuming computer postprocessing or bulky-sized diffractive elements. Here we theoretically propose and experimentally demonstrate a purely-passive and small-footprint meta-neural-network for real-time recognizing complicated objects by analyzing acoustic scattering. We prove meta-neural-network mimics a standard neural network despite its compactness, thanks to unique capability of its metamaterial unit-cells (dubbed meta-neurons) to produce deep-subwavelength phase shift as training parameters. The resulting device exhibits the “intelligence” to perform desired tasks with potential to overcome the current limitations, showcased by two distinctive examples of handwritten digit recognition and discerning misaligned orbital-angular-momentum vortices. Our mechanism opens the route to new metamaterial-based deep-learning paradigms and enable conceptual devices automatically analyzing signals, with far-reaching implications for acoustics and related fields.
TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts
Authors: Grauel Angelo L. , Nguyen Beverly , Ruddy David , Laszewski Tyler , Schwartz Stephanie , Chang Jonathan , Chen Julie , Piquet Michelle , Pelletier Marc , Yan Zheng , Kirkpatrick Nathaniel D. , Wu Jincheng , deWeck Antoine , Riester Markus , Hims Matt , Geyer Felipe Correa , Wagner Joel , MacIsaac Kenzie , Deeds James , Diwanji Rohan , Jayaraman Pushpa , Yu Yenyen , Simmons Quincey , Weng Shaobu , Raza Alina , Minie Brian , Dostalek Mirek , Chikkegowda Pavitra , Ruda Vera , Iartchouk Oleg , Chen Naiyan , Thierry Raphael , Zhou Joseph , Pruteanu-Malinici Iulian , Fabre Claire , Engelman Jeffrey A. , Dranoff Glenn , Cremasco Viviana
Published: December 2020

Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy.
Strong hydroclimatic controls on vulnerability to subsurface nitrate contamination across Europe
Authors: Kumar R. , Heße F. , Rao P. S. C. , Musolff A. , Jawitz J. W. , Sarrazin F. , Samaniego L. , Fleckenstein J. H. , Rakovec O. , Thober S. , Attinger S.
Published: December 2020

Subsurface contamination due to excessive nutrient surpluses is a persistent and widespread problem in agricultural areas across Europe. The vulnerability of a particular location to pollution from reactive solutes, such as nitrate, is determined by the interplay between hydrologic transport and biogeochemical transformations. Current studies on the controls of subsurface vulnerability do not consider the transient behaviour of transport dynamics in the root zone. Here, using state-of-the-art hydrologic simulations driven by observed hydroclimatic forcing, we demonstrate the strong spatiotemporal heterogeneity of hydrologic transport dynamics and reveal that these dynamics are primarily controlled by the hydroclimatic gradient of the aridity index across Europe. Contrasting the space-time dynamics of transport times with reactive timescales of denitrification in soil indicate that ~75% of the cultivated areas across Europe are potentially vulnerable to nitrate leaching for at least one-third of the year. We find that neglecting the transient nature of transport and reaction timescale results in a great underestimation of the extent of vulnerable regions by almost 50%. Therefore, future vulnerability and risk assessment studies must account for the transient behaviour of transport and biogeochemical transformation processes.
TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation
Authors: Li Ke , Wang Feng , Yang Zhao-na , Zhang Ting-ting , Yuan Yu-fen , Zhao Chen-xi , Yeerjiang Zaiwuli , Cui Bing , Hua Fang , Lv Xiao-xi , Zhang Xiao-wei , Yu Jiao-jiao , Liu Shan-shan , Yu Jin-mei , Shang Shuang , Xiao Yang , Hu Zhuo-wei
Published: December 2020

The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation. Here, we report that high expression of tribbles homologue 3 (TRIB3) positively correlates with elevated MYC expression in lymphoma specimens; TRIB3 deletion attenuates the initiation and progression of MYC-driven lymphoma by reducing MYC expression. Mechanistically, TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which enhances MYC transcriptional activity, causing high proliferation and self-renewal of lymphoma cells. Use of a peptide to disturb the TRIB3-MYC interaction together with doxorubicin reduces the tumor burden in MycEμ mice and patient-derived xenografts. The pathophysiological relevance of UBE3B, TRIB3 and MYC is further demonstrated in human lymphoma. Our study highlights a key mechanism for controlling MYC expression and a potential therapeutic option for treating lymphomas with high TRIB3-MYC expression.
Unveiling the strong interaction among hadrons at the LHC
Authors:   ALICE Collaboration
Published: December 2020

One of the key challenges for nuclear physics today is to understand from first principles the effective interaction between hadrons with different quark content. First successes have been achieved using techniques that solve the dynamics of quarks and gluons on discrete space-time lattices1,2. Experimentally, the dynamics of the strong interaction have been studied by scattering hadrons off each other. Such scattering experiments are difficult or impossible for unstable hadrons3–6 and so high-quality measurements exist only for hadrons containing up and down quarks7. Here we demonstrate that measuring correlations in the momentum space between hadron pairs8–12 produced in ultrarelativistic proton–proton collisions at the CERN Large Hadron Collider (LHC) provides a precise method with which to obtain the missing information on the interaction dynamics between any pair of unstable hadrons. Specifically, we discuss the case of the interaction of baryons containing strange quarks (hyperons). We demonstrate how, using precision measurements of proton–omega baryon correlations, the effect of the strong interaction for this hadron–hadron pair can be studied with precision similar to, and compared with, predictions from lattice calculations13,14. The large number of hyperons identified in proton–proton collisions at the LHC, together with accurate modelling15 of the small (approximately one femtometre) inter-particle distance and exact predictions for the correlation functions, enables a detailed determination of the short-range part of the nucleon-hyperon interaction.
The prevalence of rheumatoid arthritis in Spain
Authors: Silva-Fernández Lucía , Macía-Villa Cristina , Seoane-Mato Daniel , Cortés-Verdú Raúl , Romero-Pérez Antonio , Quevedo-Vila Víctor , Fábregas-Canales Dolores , Antón-Pagés Fred , Añez Gustavo , Brandy Anahy , Martínez-Dubois Cristina , Rubio-Muñoz Paula , Sánchez-Piedra Carlos , Díaz-González Federico , Bustabad-Reyes Sagrario
Published: December 2020

Rheumatoid arthritis (RA) prevalence is believed to be around 1% worldwide, although it varies considerably among different populations. The aim of EPISER2016 study was to estimate the prevalence of RA in the general adult population in Spain. We designed a population-based cross-sectional study. A national survey was conducted between November 2016 and October 2017 involving a probabilistic sample from the general population aged 20 years or older. Subjects were randomly selected for phone screening using a computer-assisted telephone interviewer system. Positive RA screening results were evaluated by a rheumatologist. Cases fulfilled the 1987 ACR and/or the 2010 ACR/EULAR criteria; previous diagnosis established by a rheumatologist and clearly identified in medical records were also accepted regardless of the criteria used. Prevalence estimates with 95% CI were calculated taking into account the design of the sample (weighting based on age, sex, and geographic origin using as a reference the distribution of the population in Spain). 4916 subjects participated in the study and 39 RA cases were confirmed. RA estimated prevalence was 0.82% (95% CI 0.59–1.15). Mean age of RA cases was 60.48 (14.85) years, they were more frequently women (61.5%), from urban areas (74.4%), non-smokers (43.6%), and with a high body mass index (53.8% with overweight). Extrapolating to the population in Spain (approximately 37 million are ≥ 20 years old), it was estimated that there were between 220,000 and 430,000 people aged 20 years or older with RA. No undiagnosed cases were detected, which could be related to the establishment of early arthritis clinics around the country, increasing the rates of diagnosis during early phases of RA.
The hydraulic resistance paradox in rapid narrow pipe waterflow
Authors: Dvorský Richard , Svoboda Ladislav , Bednář Jiří
Published: December 2020

In this work we present experimental results of cross-sectional speed of water flow in narrow cylindrical metal tubes at high pressure gradients up to 1.1 GPa$$\cdot$$
·
m−1. The measurement draws attention to the paradoxical behaviour of flowing water in internal diameters less than 250 $$\upmu$$
μ
m. At constant pressure gradient, its cross-section speed decreases with decreasing diameter in accordance with the classical hydrodynamic prediction for turbulent flow in rough cylindrical tube. However for very low diameters below 250 $$\upmu$$
μ
m, the cross-section speed rises again and reaches almost the maximum theoretical value of the outflow speed for the appropriate pressure without energy loss caused by contraction or hydraulic friction. Our contribution describes mainly experimental character of the new phenomenon and its motivation is to promptly provide the material for further study to the professional public.
Whole brain proton irradiation in adult Sprague Dawley rats produces dose dependent and non-dependent cognitive, behavioral, and dopaminergic effects
Authors: Williams Michael T. , Sugimoto Chiho , Regan Samantha L. , Pitzer Emily M. , Fritz Adam L. , Mascia Anthony E. , Sertorio Mathieu , Vatner Ralph E. , Perentesis John P. , Vorhees Charles V.
Published: December 2020

Proton radiotherapy causes less off-target effects than X-rays but is not without effect. To reduce adverse effects of proton radiotherapy, a model of cognitive deficits from conventional proton exposure is needed. We developed a model emphasizing multiple cognitive outcomes. Adult male rats (10/group) received a single dose of 0, 11, 14, 17, or 20 Gy irradiation (the 20 Gy group was not used because 50% died). Rats were tested once/week for 5 weeks post-irradiation for activity, coordination, and startle. Cognitive assessment began 6-weeks post-irradiation with novel object recognition (NOR), egocentric learning, allocentric learning, reference memory, and proximal cue learning. Proton exposure had the largest effect on activity and prepulse inhibition of startle 1-week post-irradiation that dissipated each week. 6-weeks post-irradiation, there were no effects on NOR, however proton exposure impaired egocentric (Cincinnati water maze) and allocentric learning and caused reference memory deficits (Morris water maze), but did not affect proximal cue learning or swimming performance. Proton groups also had reduced striatal levels of the dopamine transporter, tyrosine hydroxylase, and the dopamine receptor D1, effects consistent with egocentric learning deficits. This new model will facilitate investigations of different proton dose rates and drugs to ameliorate the cognitive sequelae of proton radiotherapy.
Gene expression data support the hypothesis that Isoetes rootlets are true roots and not modified leaves
Authors: Hetherington Alexander J. , Emms David M. , Kelly Steven , Dolan Liam
Published: December 2020

Rhizomorphic lycopsids are the land plant group that includes the first giant trees to grow on Earth and extant species in the genusIsoetes. Two mutually exclusive hypotheses account for the evolution of terminal rooting axes called rootlets among the rhizomorphic lycopsids. One hypothesis states that rootlets are true roots, like roots in other lycopsids. The other states that rootlets are modified leaves. Here we test predictions of each hypothesis by investigating gene expression in the leaves and rootlets ofIsoetes echinospora. We assembled the de novo transcriptome of axenically culturedI. echinospora. Gene expression signatures ofI. echinosporarootlets and leaves were different. Furthermore, gene expression signatures ofI. echinosporarootlets were similar to gene expression signatures of true roots ofSelaginella moellendorffiiandArabidopsis thaliana. RSL genes which positively regulate cell differentiation in roots were either exclusively or preferentially expressed in theI. echinosporarootlets, S.moellendorffiiroots andA. thalianaroots compared to the leaves of each respective species. Taken together, gene expression data from thede-novotranscriptome ofI. echinosporaare consistent with the hypothesis thatIsoetesrootlets are true roots and not modified leaves.
Multidimensional machine learning algorithms to learn liquid velocity inside a cylindrical bubble column reactor
Authors: Babanezhad Meisam , Marjani Azam , Shirazian Saeed
Published: December 2020

For understanding the complex behavior of fluids in a multiphase chemical bubble column reactor, a combination of the computational fluid dynamic (CFD) method and the adaptive network-based fuzzy inference system (ANFIS) method is used to predict bubble flow inside a reactor based on the function of column height. In this study, the Euler–Euler model is employed as a CFD method. In the Eulerian method, continuity and momentum governing equations are mathematically computed for each phase, while the equations are connected together by source terms. After calculating the flow pattern and turbulence flow in the reactor, all data sets are used to prepare a fully artificial method for further prediction. This algorithm contains different learning dimensions such as learning in different directions of reactor or large amount of input parameters and data set representing “big data”. The ANFIS method was evaluated in three steps by using one, two, and three inputs in each one to predict the liquid velocity in the x-direction (Ux). The x, y, and z coordinates of the location of the node of the liquid were considered as the inputs. Different percentages of data and various iterations and membership functions were used for training in the ANFIS method. The ANFIS method showed the best prediction using three inputs. This combination also shows the ability of computer science and computational methods in learning physical and chemical phenomena.
Large-scale resculpting of cortical circuits in children after surgical resection
Authors: Maallo Anne Margarette S. , Granovetter Michael C. , Freud Erez , Kastner Sabine , Pinsk Mark A. , Glen Daniel , Patterson Christina , Behrmann Marlene
Published: December 2020

Despite the relative successes in the surgical treatment of pharmacoresistant epilepsy, there is rather little research on the neural (re)organization that potentially subserves behavioral compensation. Here, we examined the post-surgical functional connectivity (FC) in children and adolescents who have undergone unilateral cortical resection and, yet, display remarkably normal behavior. Conventionally, FC has been investigated in terms of the mean correlation of the BOLD time courses extracted from different brain regions. Here, we demonstrated the value of segregating the voxel-wise relationships into mutually exclusive populations that were either positively or negatively correlated. While, relative to controls, the positive correlations were largely normal, negative correlations among networks were increased. Together, our results point to reorganization in the contralesional hemisphere, possibly suggesting competition for cortical territory due to the demand for representation of function. Conceivably, the ubiquitous negative correlations enable the differentiation of function in the reduced cortical volume following a unilateral resection.
Rapid microbial identification and colistin resistance detection via MALDI-TOF MS using a novel on-target extraction of membrane lipids
Authors: Sorensen Matthew , Chandler Courtney E. , Gardner Francesca M. , Ramadan Salma , Khot Prasanna D. , Leung Lisa M. , Farrance Christine E. , Goodlett David R. , Ernst Robert K. , Nilsson Erik
Published: December 2020

Rapid infection diagnosis is critical to improving patient treatment and outcome. Recent studies have shown microbial lipids to be sensitive and selective biomarkers for identifying bacterial and fungal species and antimicrobial resistance. Practical procedures for microbial lipid biomarker analysis will therefore improve patient outcomes and antimicrobial stewardship. However, current lipid extraction methods require significant hands-on time and are thus not suited for direct adoption as a clinical assay for microbial identification. Here, we have developed a method for lipid extraction directly on the surface of stainless-steel matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) plates, termed fast lipid analysis technique or FLAT, which facilitates the identification of bacterial and fungal species using a sub-60-minute workflow. Additionally, our method detects lipid A modifications in Gram-negative bacteria that are associated with antimicrobial resistance, including to colistin.
Metabolic activation and toxicological evaluation of polychlorinated biphenyls in Drosophila melanogaster
Authors: Idda T. , Bonas C. , Hoffmann J. , Bertram J. , Quinete N. , Schettgen T. , Fietkau K. , Esser A. , Stope M. B. , Leijs M. M. , Baron J. M. , Kraus T. , Voigt A. , Ziegler P.
Published: December 2020

Degradation of polychlorinated biphenyls (PCBs) is initiated by cytochrome P450 (CYP) enzymes and includes PCB oxidation to OH-metabolites, which often display a higher toxicity than their parental compounds. In search of an animal model reflecting PCB metabolism and toxicity, we tested Drosophila melanogaster, a well-known model system for genetics and human disease. Feeding Drosophila with lower chlorinated (LC) PCB congeners 28, 52 or 101 resulted in the detection of a human-like pattern of respective OH-metabolites in fly lysates. Feeding flies high PCB 28 concentrations caused lethality. Thus we silenced selected CYPs via RNA interference and analyzed the effect on PCB 28-derived metabolite formation by assaying 3-OH-2′,4,4′-trichlorobiphenyl (3-OHCB 28) and 3′-OH-4′,4,6′-trichlorobiphenyl (3′-OHCB 28) in fly lysates. We identified several drosophila CYPs (dCYPs) whose knockdown reduced PCB 28-derived OH-metabolites and suppressed PCB 28 induced lethality including dCYP1A2. Following in vitro analysis using a liver-like CYP-cocktail, containing human orthologues of dCYP1A2, we confirm human CYP1A2 as a PCB 28 metabolizing enzyme. PCB 28-induced mortality in flies was accompanied by locomotor impairment, a common phenotype of neurodegenerative disorders. Along this line, we show PCB 28-initiated caspase activation in differentiated fly neurons. This suggested the loss of neurons through apoptosis. Our findings in flies are congruent with observation in human exposed to high PCB levels. In plasma samples of PCB exposed humans, levels of the neurofilament light chain increase after LC-PCB exposure, indicating neuronal damage. In summary our findings demonstrate parallels between Drosophila and the human systems with respect to CYP mediated metabolism and PCB mediated neurotoxicity.
Memory guidance of value-based decision making at an abstract level of representation
Authors: Liashenko Anna , Dizaji Aslan S. , Melloni Lucia , Schwiedrzik Caspar M.
Published: December 2020

Value-based decisions about alternatives we have never experienced can be guided by associations between current choice options and memories of prior reward. A critical question is how similar memories need to be to the current situation to effectively guide decisions. We address this question in the context of associative learning of faces using a sensory preconditioning paradigm. We find that memories of reward spread along established associations between faces to guide decision making. While memory guidance is specific for associated facial identities, it does not only occur for the specific images that were originally encountered. Instead, memory guidance generalizes across different images of the associated identities. This suggests that memory guidance does not rely on a pictorial format of representation but on a higher, view-invariant level of abstraction. Thus, memory guidance operates on a level of representation that neither over- nor underspecifies associative relationships in the context of obtaining reward.
Metabolomics analysis of plasma and adipose tissue samples from mice orally administered with polydextrose and correlations with cecal microbiota
Authors: Saarinen Markku Tapani , Kärkkäinen Olli , Hanhineva Kati , Tiihonen Kirsti , Hibberd Ashley , Mäkelä Kari Antero , Raza Ghulam Shere , Herzig Karl-Heinz , Anglenius Heli
Published: December 2020

Polydextrose (PDX) is a branched glucose polymer, utilized as a soluble dietary fiber. Recently, PDX was found to have hypolipidemic effects and effects on the gut microbiota. To investigate these findings more closely, a non-targeted metabolomics approach, was exploited to determine metabolic alterations in blood and epididymal adipose tissue samples that were collected from C57BL/6 mice fed with a Western diet, with or without oral administration of PDX. Metabolomic analyses revealed significant differences between PDX- and control mice, which could be due to differences in diet or due to altered microbial metabolism in the gut. Some metabolites were found in both plasma and adipose tissue, such as the bile acid derivative deoxycholic acid and the microbiome-derived tryptophan metabolite indoxyl sulfate, both of which increased by PDX. Additionally, PDX increased the levels of glycine betaine and l-carnitine in plasma samples, which correlated negatively with plasma TG and positively correlated with bacterial genera enriched in PDX mice. The results demonstrated that PDX caused differential metabolite patterns in blood and adipose tissues and that one-carbon metabolism, associated with glycine betaine and l-carnitine, and bile acid and tryptophan metabolism are associated with the hypolipidemic effects observed in mice that were given PDX.
Biomarkers of cardiometabolic complications in survivors of childhood acute lymphoblastic leukemia
Authors: Morel Sophia , Léveillé Pauline , Samoilenko Mariia , Franco Anita , England Jade , Malaquin Nicolas , Tu Véronique , Cardin Guillaume B. , Drouin Simon , Rodier Francis , Lippé Sarah , Krajinovic Maja , Laverdière Caroline , Sinnett Daniel , Lefebvre Geneviève , Levy Emile , Marcil Valérie
Published: December 2020

Survivors of childhood acute lymphoblastic leukemia (cALL) are at higher risk of developing cardiometabolic complications. We aimed at exploring the associations between biomarkers of inflammation, oxidative stress, endothelial function, endotoxemia and cardiometabolic risk factors. We conducted a cross-sectional analysis in 246 cALL survivors (mean age, 22.1 ± 6.3 years; mean time since diagnosis, 15.5 ± 5.2 years) and evaluated the associations using a series of logistic regressions. Using structural equation models, we also tested if the relationship between endotoxemia and cardiometabolic complications was mediated by the latent (unobserved) variable inflammation inferred from the observed biomarkers CRP, TNF-α and IL-6. High leptin-adiponectin ratio was associated with obesity [adjusted OR = 15.7; 95% CI (6.2–39.7)], insulin resistance [20.6 (5.2–82.1)] and the metabolic syndrome [11.2 (2.6–48.7)]. Higher levels of plasminogen activator inhibitor-1 and tumor necrosis factor-α were associated with obesity [3.37 (1.6–7.1) and 2.34 (1.3–4.2), respectively] whereas high C-reactive protein levels were associated with insulin resistance [3.3 (1.6–6.8)], dyslipidemia [2.6 (1.4–4.9)] and MetS [6.5 (2.4–17.9)]. Our analyses provided evidence for a directional relationship between lipopolysaccharide binding protein, related to metabolic endotoxemia, inflammation and cardiometabolic outcomes. Identification of biomarkers and biological mechanisms could open new avenues for prevention strategies to minimize the long-term sequelae, improve follow-up and optimize the quality of life of this high-risk population.
A comparison of AAV-vector production methods for gene therapy and preclinical assessment
Authors: Davidsson Marcus , Negrini Matilde , Hauser Swantje , Svanbergsson Alexander , Lockowandt Marcus , Tomasello Giuseppe , Manfredsson Fredric P. , Heuer Andreas
Published: December 2020

Adeno Associated Virus (AAV)-mediated gene expression in the brain is widely applied in the preclinical setting to investigate the therapeutic potential of specific molecular targets, characterize various cellular functions, and model central nervous system (CNS) diseases. In therapeutic applications in the clinical setting, gene therapy offers several advantages over traditional pharmacological based therapies, including the ability to directly manipulate disease mechanisms, selectively target disease-afflicted regions, and achieve long-term therapeutic protein expression in the absence of repeated administration of pharmacological agents. Next to the gold-standard iodixanol-based AAV vector production, we recently published a protocol for AAV production based on chloroform-precipitation, which allows for fast in-house production of small quantities of AAV vector without the need for specialized equipment. To validate our recent protocol, we present here a direct side-by-side comparison between vectors produced with either method in a series of in vitro and in vivo assays with a focus on transgene expression, cell loss, and neuroinflammatory responses in the brain. We do not find differences in transduction efficiency nor in any other parameter in our in vivo and in vitro panel of assessment. These results suggest that our novel protocol enables most standardly equipped laboratories to produce small batches of high quality and high titer AAV vectors for their experimental needs.
Rapid reduction of nitroarenes photocatalyzed by an innovative Mn3O4/α-Ag2WO4 nanoparticles
Authors: Mohamed Mohamed Mokhtar , El-Farsy Hassan
Published: December 2020

A novel photocatalyst based on the design of P-N heterojunction between hollow spherical Mn3O4 and nanorods shape of α-Ag2WO4 is synthesized using a sonication-deposition–precipitation route. The nanocomposite Mn3O4/α-Ag2WO4(60%) exhibits a great potential towards nitroarenes (including 4-nitrophenol, 4-nitro-aniline and 4-Nitro-acetanilide) reduction under visible light irradiation exceeding that of Mn3O4/α-Ag2WO4(40%) as well as their individual counterparts (3–5%). The Mn3O4/α-Ag2WO4(60%) catalyst exhibited an excellent photo-reduction activity comprised of 0.067 s−1 towards 4-nitrophenol (0.001 M) in only 60 s reaction time using NaBH4 (0.2 M). This was due to the successful formation of the Mn3O4/α-Ag2WO4 composite as validated by XRD, TEM-SAED, XPS, FTIR, UV–Vis diffuse reflectance and PL techniques. Decreasing the Eg value into 2.7 eV, the existence of a new (151) plane in the composite beside enhancement of the composite electrical conductivity (1.66 × 10–7 Ω−1 cm−1) helps the facile nitroarenes adsorption and hydrogenation. Transient photocurrent response and linear sweep voltammetry results prove the facilitation of photogenerated charge carriers separation and transport via improving electron lifetime and lessening recombination rate. The composite photocatalyst produced higher amounts of H2 production, when inserted in a typical reaction medium containing NaBH4, comprised of 470 µ mole/g exceeding those of the counterparts (35 µ mole/g). This photocatalyst is strikingly hydrogenated 4-nitrophenol under mild conditions (25 °C and 0.35 MPa pressure of H2) with magnificent rate constant equal 34.9 × 10−3 min−1 with 100% selectivity towards 4-aminophenol.
Dysgraphia detection through machine learning
Authors: Drotár Peter , Dobeš Marek
Published: December 2020

Dysgraphia, a disorder affecting the written expression of symbols and words, negatively impacts the academic results of pupils as well as their overall well-being. The use of automated procedures can make dysgraphia testing available to larger populations, thereby facilitating early intervention for those who need it. In this paper, we employed a machine learning approach to identify handwriting deteriorated by dysgraphia. To achieve this goal, we collected a new handwriting dataset consisting of several handwriting tasks and extracted a broad range of features to capture different aspects of handwriting. These were fed to a machine learning algorithm to predict whether handwriting is affected by dysgraphia. We compared several machine learning algorithms and discovered that the best results were achieved by the adaptive boosting (AdaBoost) algorithm. The results show that machine learning can be used to detect dysgraphia with almost 80% accuracy, even when dealing with a heterogeneous set of subjects differing in age, sex and handedness.
Transcriptome analysis of wheat spikes in response to Tilletia controversa Kühn which cause wheat dwarf bunt
Authors: Ren Zhaoyu , Liu Jianjian , Din Ghulam Muhae Ud , Zhang Han , Du Zhenzhen , Chen Wanquan , Liu Taiguo , Zhang Jianmin , Zhao Sifeng , Gao Li
Published: December 2020

Wheat dwarf bunt is caused by Tilletia controversa Kühn, which is one of the most destructive diseases of wheat worldwide. To explore the interaction of T. controversa and wheat, we analysed the transcriptome profile of spikes of the susceptible wheat cultivar Dongxuan 3, which was subjected to a T. controversa infection and a mock infection. The results obtained from a differential expression analysis of T. controversa-infected plants compared with mock-infected ones showed that 10,867 out of 21,354 genes were upregulated, while 10,487 genes were downregulated, and these genes were enriched in 205 different pathways. Our findings demonstrated that the genes associated with defence against diseases, such as PR-related genes, WRKY transcription factors and mitogen-activated protein kinase genes, were more highly expressed in response to T. controversa infection. Additionally, a number of genes related to physiological attributes were expressed during infection. Three pathways were differentiated based on the characteristics of gene ontology classification. KEGG enrichment analysis showed that twenty genes were expressed differentially during the infection of wheat with T. controversa. Notable changes were observed in the transcriptomes of wheat plants after infection. The results of this study may help to elucidate the mechanism governing the interactions between this pathogen and wheat plants and may facilitate the development of new methods to increase the resistance level of wheat against T. controversa, including the overexpression of defence-related genes.
Deep learning reveals 3D atherosclerotic plaque distribution and composition
Authors: Jurtz Vanessa Isabell , Skovbjerg Grethe , Salinas Casper Gravesen , Roostalu Urmas , Pedersen Louise , Hecksher-Sørensen Jacob , Rolin Bidda , Nyberg Michael , van de Bunt Martijn , Ingvorsen Camilla
Published: December 2020

Complications of atherosclerosis are the leading cause of morbidity and mortality worldwide. Various genetically modified mouse models are used to investigate disease trajectory with classical histology, currently the preferred methodology to elucidate plaque composition. Here, we show the strength of light-sheet fluorescence microscopy combined with deep learning image analysis for characterising and quantifying plaque burden and composition in whole aorta specimens. 3D imaging is a non-destructive method that requires minimal ex vivo handling and can be up-scaled to large sample sizes. Combined with deep learning, atherosclerotic plaque in mice can be identified without any ex vivo staining due to the autofluorescent nature of the tissue. The aorta and its branches can subsequently be segmented to determine how anatomical position affects plaque composition and progression. Here, we find the highest plaque accumulation in the aortic arch and brachiocephalic artery. Simultaneously, aortas can be stained for markers of interest (for example the pan immune cell marker CD45) and quantified. In ApoE−/− mice we observe that levels of CD45 reach a plateau after which increases in plaque volume no longer correlate to immune cell infiltration. All underlying code is made publicly available to ease adaption of the method.
Age and sex specific target of blood pressure for the prevention of cardiovascular event among the treatment naive hypertensive patients
Authors: Kim Hyoungnae , Lee Seulbi , Ha Eunhee , Kwon Soon Hyo , Jeon Jin Seok , Noh Hyunjin , Han Dong Cheol , Oh Hyung Jung , Ryu Dong-Ryeol
Published: December 2020

The time at which hypertension treatment should be initiated for different age groups and sexes remains controversial. We aimed to determine whether the association between blood pressure (BP) and major adverse cardiovascular events (MACE) varies with age and sex. This study enrolled 327,328 subjects who had not taken antihypertensive medication in the Korean National Health Service-National Health Screening Cohort between 2002 and 2003. Participants were categorized into four groups according to 2017 American College of Cardiology/American Heart Association hypertension guideline. Primary outcome was MACE characterized by cardiovascular mortality, myocardial infarction, unstable angina, and stroke. During a 10-year follow-up, a significant increase in MACE risk was observed from the stage 1 hypertension group (hazard ratio [HR], 1.23; 95% CI 1.15–1.32; P < 0.001) in time-varying Cox analysis. This relationship was persistent in subjects aged < 70 years, but increased MACE risk was observed only in the stage 2 hypertension group in ≥ 70 years (HR, 1.52; 95% CI 1.32–1.76, P < 0.001). When categorized as per sex, both men and women showed significant MACE risk from stage 1 hypertension. However, on comparing the sexes after stratifying by age, a significantly increased risk of MACE was shown from stage 1 hypertension in men aged < 50 years, but from stage 2 hypertension in men aged ≥ 50 years. Meanwhile, increased MACE risk was observed from stage 2 hypertension in women aged < 60 years, but from stage 1 hypertension in women aged ≥ 60 years. Thus, young male subjects had higher MACE risk than young female subjects, but this difference gradually decreased with age and there was no difference between sexes in subjects aged ≥ 70 years. Therefore, our results suggest that hypertension treatment initiation may need to be individualized depending on age and sex.
Diet and life history reduce interspecific and intraspecific competition among three sympatric Arctic cephalopods
Authors: Golikov Alexey V. , Ceia Filipe R. , Sabirov Rushan M. , Batalin Georgii A. , Blicher Martin E. , Gareev Bulat I. , Gudmundsson Gudmundur , Jørgensen Lis L. , Mingazov Gazinur Z. , Zakharov Denis V. , Xavier José C.
Published: December 2020

Trophic niche and diet comparisons among closely sympatric marine species are important to understand complex food webs, particularly in regions most affected by climate change. Using stable isotope analyses, all ontogenetic stages of three sympatric species of Arctic cephalopods (genusRossia) were studied to assess inter- and intraspecific competition with niche and diet overlap and partitioning in West Greenland and the Barents Sea. Seven traits related to resource and habitat utilization were identified inRossia: no trait was shared by all three species. High borealR. megapteraand Arctic endemicR. moellerishared three traits with each other, while bothR. megapteraandR. moellerishared only two unique traits each with widespread boreal-ArcticR. palpebrosa. Thus all traits formed fully uncrossing pattern with each species having unique strategy of resource and habitat utilization. Predicted climate changes in the Arctic would have an impact on competition amongRossiawith one potential ‘winner’ (R. megapterain the Barents Sea) but no potential ‘losers’.
Structural and biochemical analyses of an aminoglycoside 2′-N-acetyltransferase from Mycolicibacterium smegmatis
Authors: Jeong Chang-Sook , Hwang Jisub , Do Hackwon , Cha Sun-Shin , Oh Tae-Jin , Kim Hak Jun , Park Hyun Ho , Lee Jun Hyuck
Published: December 2020

The expression of aminoglycoside-modifying enzymes represents a survival strategy of antibiotic-resistant bacteria. Aminoglycoside 2′-N-acetyltransferase [AAC(2′)] neutralizes aminoglycoside drugs by acetylation of their 2′ amino groups in an acetyl coenzyme A (CoA)-dependent manner. To understand the structural features and molecular mechanism underlying AAC(2′) activity, we overexpressed, purified, and crystallized AAC(2′) from Mycolicibacterium smegmatis [AAC(2′)-Id] and determined the crystal structures of its apo-form and ternary complexes with CoA and four different aminoglycosides (gentamicin, sisomicin, neomycin, and paromomycin). These AAC(2′)-Id structures unraveled the binding modes of different aminoglycosides, explaining the broad substrate specificity of the enzyme. Comparative structural analysis showed that the α4-helix and β8–β9 loop region undergo major conformational changes upon CoA and substrate binding. Additionally, structural comparison between the present paromomycin-bound AAC(2′)-Id structure and the previously reported paromomycin-bound AAC(6′)-Ib and 30S ribosome structures revealed the structural features of paromomycin that are responsible for its antibiotic activity and AAC binding. Taken together, these results provide useful information for designing AAC(2′) inhibitors and for the chemical modification of aminoglycosides.
Multilayered salt water with high optical transparency for EMI shielding applications
Authors: Phan Duy Tung , Jung Chang Won
Published: December 2020

Electromagnetic interference (EMI) shielding for visual observation applications, such as windows utilized in military or aerospace, is important but difficult to realize due to conventional materials having difficulty in achieving sufficient transparency and EMI shielding simultaneously. In this paper, we present multilayered structures based on salt water for simultaneous highly optical transparency (OT) and EM shielding effectiveness (SE) performance. In the proposed structures, planar acrylic and glass were used as two types of clear substrates to hold salt water. The measured OT of both acrylic/salt water/acrylic and glass/salt water/glass structures was higher than 90% with a nearly uniform light transmission, which introduced a negligible impact on optical observation. Furthermore, both simulations and experimental results demonstrated that the SE of the multilayer structure was higher than 20 dB in the X-band from 7.5 to 8.5 GHz. Moreover, the SE was significantly enhanced by increasing the thickness of the salt water layer. Especially, both OT and SE of the multilayered structures were improved simultaneously by increasing the salinity of the salt water. These proposed structures demonstrate great potential in EMI shielding observation applications.
Molecular phenotypes of circulating tumor cells and efficacy of nivolumab treatment in patients with head and neck squamous cell carcinoma
Authors: Tada Hiroe , Takahashi Hideyuki , Kawabata-Iwakawa Reika , Nagata Yurino , Uchida Miho , Shino Masato , Ida Shota , Mito Ikko , Matsuyama Toshiyuki , Chikamatsu Kazuaki
Published: December 2020

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Biomarkers of the therapeutic efficacy of ICIs have been extensively investigated. In this study, we aimed to analyze whether molecular phenotypes of circulating tumor cells (CTCs) are associated with treatment responses and clinical outcomes in patients with R/M HNSCC treated with nivolumab. Peripheral blood samples were collected before treatment initiation and after four infusions of nivolumab. CTCs isolated by depletion of CD45-positive cells were analyzed to determine the expression of EPCAM, MET, KRT19, and EGFR using real-time quantitative polymerase chain reaction. CTC-positive samples were analyzed to determine the expression of PIK3CA, CCND1, SNAI1, VIM, ZEB2, CD44, NANOG, ALDH1A1, CD47, CD274, and PDCD1LG2. Of 30 patients treated with nivolumab, 28 (93.3%) were positive for CTCs. In 20 CTC-positive patients, molecular alterations in CTCs before and after nivolumab treatment were investigated. Patients with MET-positive CTCs had significantly shorter overall survival than those with MET-negative CTCs (p = 0.027). The expression level of CCND1 in CTCs of disease-controlled patients was significantly higher than that of disease-progressed patients (p = 0.034). In disease-controlled patients, the expression level of CCND1 in CTCs significantly decreased after nivolumab treatment (p = 0.043). The NANOG expression in CTCs was significantly increased in disease-controlled patients after nivolumab treatment (p = 0.036). Our findings suggest that the molecular profiling of CTCs is a promising tool to predict the treatment efficacy of nivolumab.
Hyperpolarized 15N-labeled, deuterated tris(2-pyridylmethyl)amine as an MRI sensor of freely available Zn2+
Authors: Suh Eul Hyun , Park Jae Mo , Lumata Lloyd , Sherry A. Dean , Kovacs Zoltan
Published: December 2020

Dynamic nuclear polarization (DNP) coupled with15N magnetic resonance imaging (MRI) provides an opportunity to image quantitative levels of biologically important metal ions such as Zn2+, Mg2+or Ca2+using appropriately designed15N enriched probes. For example, a Zn-specific probe could prove particularly valuable for imaging the tissue distribution of freely available Zn2+ions, an important known metal ion biomarker in the pancreas, in prostate cancer, and in several neurodegenerative diseases. In the present study, we prepare the cell-permeable,15N-enriched, d6-deuterated version of the well-known Zn2+chelator, tris(2-pyridylmethyl)amine (TPA) and demonstrate that the polarized ligand had favorable T1and linewidth characteristics for15N MRI. Examples of how polarized TPA can be used to quantify freely available Zn2+in homogenized human prostate tissue and intact cells are presented.