bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal, Moisture, and Solute Transport Responses Effects on Unsaturated Soil Hydraulic Parameters Estimation
Authors: Lemoubou Ernest Léontin , Tagne Kamdem Hervé Thierry , Bogning Jean Roger , Zefack Tonnang Edouard Henri
Published: December 2019

This paper studies the estimation of unsaturated soil parameters based on thermal, moisture, and solute characteristics, which are important factors that affect productivity and the environment. The objective of this investigation was to determine optimal hydraulic parameters in unsaturated soil. The soil thermal, moisture, and solute transport processes are approached using one‐dimensional isothermal models characterized with nonlinear permeability effects, sorption, and reaction that generally cause considerable experimental and numerical difficulties. The spectral element method is presented for space discretization while the time scheme is constructed along the fully implicit approach with the modified Picard iterative procedure. The iterative Levenberg‐Marquardt optimization algorithm is adopted for the inverse process. The reliability and performance of the studied model is conducted using refinement indicators based on error, residual, and variance analyses, which allow drawing more representative uncertainty of model parameters estimation. Good agreement with the nonlinear optimization of soil hydraulic parameters estimated and true values is obtained. The estimated responses from respective shape curves show relatively small variability. A consideration of ionic diffusional and average temperature effects was revealed, indicating that the change of one of these factors might not necessarily improve parameter identification responses. For soil moisture content ranges between 0.04 and 0.5 cm3 cm−3, average temperature input from 20 to 40 ° C as well as when the ionic molecular diffusion coefficient is greater than 10 cm2 hr−1, a rough representation of moisture, thermal, and hydrochemical characteristics might be sufficient to estimate soil hydraulic parameters.
Hydrological Spaces of Long‐Term Catchment Water Balance
Authors: Daly Edoardo , Calabrese Salvatore , Yin Jun , Porporato Amilcare
Published: December 2019

Land and water management often relies upon relationships describing the catchment‐scale water balance using only a few parameters. The classic Budyko and Turc frameworks are examples of these relationships applicable to large catchments, where the effect of climatic variables on the water balance overshadows that of catchment characteristics, including the catchment ability to store water to supply evapotranspiration. To account for the latter in the list of variables driving evapotranspiration, here we introduce a new framework that includes Budyko and Turc as particular cases. The four variables in this framework are combined to form dimensionless groups, the choice of which leads to the definition of hydrological spaces highlighting different features of the long‐term hydrological partitioning. In addition to the Budyko and Turc spaces, suitable for water‐ and energy‐limited catchments, respectively, a new space ensues; this is especially apt to describe catchments where evapotranspiration is mainly controlled by catchment characteristics. An existing stochastic model for the soil water balance is used to specify the relationship between the variables in these different hydrological spaces. This framework, successfully tested here against about 400 catchments in the continental United States, provides a concise yet realistic description of long‐term catchment‐scale water balance and overcomes some limitations of current models for the estimation of long‐term evapotranspiration and runoff in ungauged catchments.
Stochastic Analysis of the Soil Water Content Standard Deviation‐Mean Value Relationships: On the Physical Significance of the Critical Mean Soil Water Content
Authors: Russo David
Published: December 2019

The spatial heterogeneity in the soil hydraulic properties was considered here as the main cause of the spatial variability in soil water content, θ. The aim of the study was (i) to identify the critical mean soil water content, Θcr, below which the standard deviation of the soil water content, σθ, can only diminish, and (ii) to provide a mathematical tool capable of linking Θcr to inherent soil hydraulic properties. The relationships between σθ and the mean value of θ, Θ, were analyzed by a first‐order analysis, based on a stochastic continuum presentation of steady‐state flow in 3‐D, spatially hetrogeneous, unsaturated soils, using the Gardner‐Russo model to describe the constitutive relations locally. Novel results of the study suggested that the mean pressure head, H, associated with Θcr, Hcr = H (Θcr), is an inflection point of the mean soil water capacity function, C(H) = dΘ/dH. Results of numerical simulations of flow in 3‐D, spatially heterogeneous, unsaturated soils, using the van Genuchten (1980, https://doi.org/10.2136/sssaj1980.03615995004400050002x) model to describe the constitutive relations locally, suggested that the results of the first‐order analysis might be applicable to more realistic situations, involving transient, nonmonotonous flows and more complicated descriptions of the local constitutive relations.
Intracellular sensing of viral genomes and viral evasion
Authors: Lee Hyun-Cheol , Chathuranga Kiramage , Lee Jong-Soo
Published: December 2019

During viral infection, virus-derived cytosolic nucleic acids are recognized by host intracellular specific sensors. The efficacy of this recognition system is crucial for triggering innate host defenses, which then stimulate more specific adaptive immune responses against the virus. Recent studies show that signal transduction pathways activated by sensing proteins are positively or negatively regulated by many modulators to maintain host immune homeostasis. However, viruses have evolved several strategies to counteract/evade host immune reactions. These systems involve viral proteins that interact with host sensor proteins and prevent them from detecting the viral genome or from initiating immune signaling. In this review, we discuss key regulators of cytosolic sensor proteins and viral proteins based on experimental evidence.
Monkeys mutant for PKD1 recapitulate human autosomal dominant polycystic kidney disease
Authors: Tsukiyama Tomoyuki , Kobayashi Kenichi , Nakaya Masataka , Iwatani Chizuru , Seita Yasunari , Tsuchiya Hideaki , Matsushita Jun , Kitajima Kahoru , Kawamoto Ikuo , Nakagawa Takahiro , Fukuda Koji , Iwakiri Teppei , Izumi Hiroyuki , Itagaki Iori , Kume Shinji , Maegawa Hiroshi , Nishinakamura Ryuichi , Nishio Saori , Nakamura Shinichiro , Kawauchi Akihiro , Ema Masatsugu
Published: December 2019

Autosomal dominant polycystic kidney disease (ADPKD) caused by PKD1 mutations is one of the most common hereditary disorders. However, the key pathological processes underlying cyst development and exacerbation in pre-symptomatic stages remain unknown, because rodent models do not recapitulate critical disease phenotypes, including disease onset in heterozygotes. Here, using CRISPR/Cas9, we generate ADPKD models with PKD1 mutations in cynomolgus monkeys. As in humans and mice, near-complete PKD1 depletion induces severe cyst formation mainly in collecting ducts. Importantly, unlike in mice, PKD1 heterozygote monkeys exhibit cyst formation perinatally in distal tubules, possibly reflecting the initial pathology in humans. Many monkeys in these models survive after cyst formation, and cysts progress with age. Furthermore, we succeed in generating selective heterozygous mutations using allele-specific targeting. We propose that our models elucidate the onset and progression of ADPKD, which will serve as a critical basis for establishing new therapeutic strategies, including drug treatments.
Normalization governs attentional modulation within human visual cortex
Authors: Bloem Ilona M. , Ling Sam
Published: December 2019

Although attention is known to increase the gain of visuocortical responses, its underlying neural computations remain unclear. Here, we use fMRI to test the hypothesis that a neural population’s ability to be modulated by attention is dependent on divisive normalization. To do so, we leverage the feature-tuned properties of normalization and find that visuocortical responses to stimuli sharing features normalize each other more strongly. Comparing these normalization measures to measures of attentional modulation, we demonstrate that subpopulations which exhibit stronger normalization also exhibit larger attentional benefits. In a converging experiment, we reveal that attentional benefits are greatest when a subpopulation is forced into a state of stronger normalization. Taken together, these results suggest that the degree to which a subpopulation exhibits normalization plays a role in dictating its potential for attentional benefits.
Giant single molecule chemistry events observed from a tetrachloroaurate(III) embedded Mycobacterium smegmatis porin A nanopore
Authors: Cao Jiao , Jia Wendong , Zhang Jinyue , Xu Xiumei , Yan Shuanghong , Wang Yuqin , Zhang Panke , Chen Hong-Yuan , Huang Shuo
Published: December 2019

Biological nanopores are capable of resolving small analytes down to a monoatomic ion. In this research, tetrachloroaurate(III), a polyatomic ion, is discovered to bind to the methionine residue (M113) of a wild-type α-hemolysin by reversible Au(III)-thioether coordination. However, the cylindrical pore geometry of α-hemolysin generates shallow ionic binding events (~5–6 pA) and may have introduced other undesired interactions. Inspired by nanopore sequencing, a Mycobacterium smegmatis porin A (MspA) nanopore, which possesses a conical pore geometry, is mutated to bind tetrachloroaurate(III). Subsequently, further amplified blockage events (up to ~55 pA) are observed, which report the largest single ion binding event from a nanopore measurement. By taking the embedded Au(III) as an atomic bridge, the MspA nanopore is enabled to discriminate between different biothiols from single molecule readouts. These phenomena suggest that MspA is advantageous for single molecule chemistry investigations and has applications as a hybrid biological nanopore with atomic adaptors.
Palladium-bearing intermetallic electride as an efficient and stable catalyst for Suzuki cross-coupling reactions
Authors: Ye Tian-Nan , Lu Yangfan , Xiao Zewen , Li Jiang , Nakao Takuya , Abe Hitoshi , Niwa Yasuhiro , Kitano Masaaki , Tada Tomofumi , Hosono Hideo
Published: December 2019

Suzuki cross-coupling reactions catalyzed by palladium are powerful tools for the synthesis of functional organic compounds. Excellent catalytic activity and stability require negatively charged Pd species and the avoidance of metal leaching or clustering in a heterogeneous system. Here we report a Pd-based electride material, Y3Pd2, in which active Pd atoms are incorporated in a lattice together with Y. As evidenced from detailed characterization and density functional theory (DFT) calculations, Y3Pd2 realizes negatively charged Pd species, a low work function and a high carrier density, which are expected to be beneficial for the efficient Suzuki coupling reaction of activated aryl halides with various coupling partners under mild conditions. The catalytic activity of Y3Pd2 is ten times higher than that of pure Pd and the activation energy is lower by nearly 35%. The Y3Pd2 intermetallic electride catalyst also exhibited extremely good catalytic stability during long-term coupling reactions.
Probable basal allosauroid from the early Middle Jurassic Cañadón Asfalto Formation of Argentina highlights phylogenetic uncertainty in tetanuran theropod dinosaurs
Authors: Rauhut Oliver W. M. , Pol Diego
Published: December 2019

Tetanurae, the most successful clade of theropod dinosaurs, including modern birds, split into three major clades early in their evolutionary history: Megalosauroidea, Coelurosauria, and Allosauroidea. The oldest tetanurans occur in the earliest Middle Jurassic, but the early fossil record of the clade is still poor. Here we report one of the oldest known and most complete pre-Late Jurassic tetanuran, the probable allosauroid Asfaltovenator vialidadi gen. et sp. nov., which has an unusual character combination, uniting features currently considered to be apomorphic of different tetanuran lineages. A phylogenetic analysis resulted in a monophyletic Carnosauria (Allosauroidea + Megalosauroidea), and the inclusion of the new taxon significantly changes topology within carnosaurs. The analysis shows concentrated homoplasy in proximal nodes at the base of Tetanurae, and a temporal peak at the Pliensbachian-Toarcian extinction event, recently identified as a potential driver of tetanuran radiation. These results highlight the complex morphological evolution in the early radiation of tetanuran theropods, in which convergences and parallelisms were extremely common. This pattern seems to be a common feature in rapid radiation events of major clades of vertebrates and might explain the common difficulties to unravel phylogenetic relationships of important lineages at the base of major clades.
The green peach aphid gut contains host plant microRNAs identified by comprehensive annotation of Brassica oleracea small RNA data
Authors: Thompson Max C. , Feng Honglin , Wuchty Stefan , Wilson Alex C. C.
Published: December 2019

Like all organisms, aphids, plant sap-sucking insects that house a bacterial endosymbiont called Buchnera, are members of a species interaction network. Ecological interactions across such networks can result in phenotypic change in network members mediated by molecular signals, like microRNAs. Here, we interrogated small RNA data from the aphid, Myzus persicae, to determine the source of reads that did not map to the aphid or Buchnera genomes. Our analysis revealed that the pattern was largely explained by reads that mapped to the host plant, Brassica oleracea, and a facultative symbiont, Regiella. To start elucidating the function of plant small RNA in aphid gut, we annotated 213 unique B. oleracea miRNAs; 32/213 were present in aphid gut as mature and star miRNAs. Next, we predicted targets in the B. oleracea and M. persicae genomes for these 32 plant miRNAs. We found that plant targets were enriched for genes associated with transcription, while the distribution of targets in the aphid genome was similar to the functional distribution of all genes in the aphid genome. We discuss the potential of plant miRNAs to regulate aphid gene expression and the mechanisms involved in processing, export and uptake of plant miRNAs by aphids.
Biomechanical investigation of extragraft bone formation influences on the operated motion segment after anterior cervical spinal discectomy and fusion
Authors: Park Won Man , Jin Yong Jun
Published: December 2019

Although the clinical importance of extragraft bone formation (ExGBF) and bridging (ExGBB) has been reported, few studies have investigated the biomechanical influences of ExGBF on the motion segment. In this study, ExGBF was simulated at the C5-C6 motion segment after anterior cervical discectomy and fusion using a developed finite element model and a sequential bone-remodelling algorithm in flexion and extension. The computer simulation results showed that extragraft bone was primarily formed in the extension motion and grew to form ExGBB. A stepwise decrease in the intersegmental rotation angle, maximum von Mises stress and strain energy density on the trabecular bone with ExGBF were predicted in extension. When ExGBB was formed in the trabecular bone region, the intersegmental rotation angle slightly decreased with additional bone formation. However, the stress and strain energy density on the trabecular bone region decreased until ExGBB reached the peripheral cortical margin. The results offer a rationale supporting the hypothesis that mechanical stimuli influence ExGBF. ExGBF was helpful in increasing the stability of the motion segment and decreasing the fracture risk of trabecular bones, even in cases in which ExGBB was not formed. ExGBB can be classified as either soft or hard bridging based on a biomechanical point of view.
Improving the odds of drug development success through human genomics: modelling study
Authors: Hingorani Aroon D. , Kuan Valerie , Finan Chris , Kruger Felix A. , Gaulton Anna , Chopade Sandesh , Sofat Reecha , MacAllister Raymond J. , Overington John P. , Hemingway Harry , Denaxas Spiros , Prieto David , Casas Juan Pablo
Published: December 2019

Lack of efficacy in the intended disease indication is the major cause of clinical phase drug development failure. Explanations could include the poor external validity of pre-clinical (cell, tissue, and animal) models of human disease and the high false discovery rate (FDR) in preclinical science. FDR is related to the proportion of true relationships available for discovery (γ), and the type 1 (false-positive) and type 2 (false negative) error rates of the experiments designed to uncover them. We estimated the FDR in preclinical science, its effect on drug development success rates, and improvements expected from use of human genomics rather than preclinical studies as the primary source of evidence for drug target identification. Calculations were based on a sample space defined by all human diseases – the ‘disease-ome’ – represented as columns; and all protein coding genes – ‘the protein-coding genome’– represented as rows, producing a matrix of unique gene- (or protein-) disease pairings. We parameterised the space based on 10,000 diseases, 20,000 protein-coding genes, 100 causal genes per disease and 4000 genes encoding druggable targets, examining the effect of varying the parameters and a range of underlying assumptions, on the inferences drawn. We estimated γ, defined mathematical relationships between preclinical FDR and drug development success rates, and estimated improvements in success rates based on human genomics (rather than orthodox preclinical studies). Around one in every 200 protein-disease pairings was estimated to be causal (γ = 0.005) giving an FDR in preclinical research of 92.6%, which likely makes a major contribution to the reported drug development failure rate of 96%. Observed success rate was only slightly greater than expected for a random pick from the sample space. Values for γ back-calculated from reported preclinical and clinical drug development success rates were also close to the a priori estimates. Substituting genome wide (or druggable genome wide) association studies for preclinical studies as the major information source for drug target identification was estimated to reverse the probability of late stage failure because of the more stringent type 1 error rate employed and the ability to interrogate every potential druggable target in the same experiment. Genetic studies conducted at much larger scale, with greater resolution of disease end-points, e.g. by connecting genomics and electronic health record data within healthcare systems has the potential to produce radical improvement in drug development success rate.
Host phylogeny, diet, and habitat differentiate the gut microbiomes of Darwin’s finches on Santa Cruz Island
Authors: Loo Wesley T. , García-Loor Jefferson , Dudaniec Rachael Y. , Kleindorfer Sonia , Cavanaugh Colleen M.
Published: December 2019

Darwin’s finches are an iconic example of an adaptive radiation with well-characterized evolutionary history, dietary preferences, and biogeography, offering an unparalleled opportunity to disentangle effects of evolutionary history on host microbiome from other factors like diet and habitat. Here, we characterize the gut microbiome in Darwin’s finches, comparing nine species that occupy diverse ecological niches on Santa Cruz island. The finch phylogeny showed moderate congruence with the microbiome, which was comprised mostly of the bacterial phyla Firmicutes, Actinobacteria, and Proteobacteria. Diet, as measured with stable isotope values and foraging observations, also correlated with microbiome differentiation. Additionally, each gut microbial community could easily be classified by the habitat of origin independent of host species. Altogether, these findings are consistent with a model of microbiome assembly in which environmental filtering via diet and habitat are primary determinants of the bacterial taxa present with lesser influence from the evolutionary history between finch species.
Fingerprints of slingshot non-sequential double ionization on two-electron probability distributions
Authors: Katsoulis G. P. , Emmanouilidou A.
Published: December 2019

We study double ionization of He driven by near-single-cycle laser pulses at low intensities at 400 nm. Using a three-dimensional semiclassical model, we identify the pathways that prevail non-sequential double ionization (NSDI). We focus mostly on the delayed pathway, where one electron ionizes with a time-delay after recollision. We have recently shown that the mechanism that prevails the delayed pathway depends on intensity. For low intensities slingshot-NSDI is the dominant mechanism. Here, we identify the differences in two-electron probability distributions of the prevailing NSDI pathways. This allows us to identify properties of the two-electron escape and thus gain significant insight into slingshot-NSDI. Interestingly, we find that an observable fingerpint of slingshot-NSDI is the two electrons escaping with large and roughly equal energies.
Association of circulating miR-20a, miR-27a, and miR-126 with non-alcoholic fatty liver disease in general population
Authors: Ando Yoshitaka , Yamazaki Mirai , Yamada Hiroya , Munetsuna Eiji , Fujii Ryosuke , Mizuno Genki , Ichino Naohiro , Osakabe Keisuke , Sugimoto Keiko , Ishikawa Hiroaki , Ohashi Koji , Teradaira Ryoji , Ohta Yoshiji , Hamajima Nobuyuki , Hashimoto Shuji , Suzuki Koji
Published: December 2019

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity, metabolic syndrome, and type II diabetes mellitus. Recently, circulating microRNAs (miRNAs) have been proposed as useful disease biomarkers. We examined whether circulating miRNAs, such as miR-20a, miR-27a, and miR-126, were useful biomarkers for NAFLD. We conducted a cross-sectional analysis of 527 subjects aged 39 years or older who had undergone a health examination in the Yakumo Study. Of the residents, 92 were diagnosed with NAFLD using a registered medical sonographer. Serum miR-20a, miR-27a and miR-126 levels were measured by quantitative real-time PCR. We then calculated the odds ratios for serum miRNA level changes according to the severity of NAFLD using normal liver status as the reference group. Serum levels of miR-20a and 27a, but not miR-126, were significantly lower in NAFLD subjects than normal subjects. Serum miR-20a and miR-27a levels were significantly lower in both male and female severe NAFLD subjects. Logistic regression analysis showed a significant relationship between low circulating miR-20a and 27a levels and severe NAFLD. Down-regulated circulating miR-20a and 27a levels were significantly associated with severe NAFLD in the general population. Circulating miR-20a and miR-27a may be useful biomarkers for severe NAFLD.
Fission of Lipid-Vesicles by Membrane Phase Transitions in Thermal Convection
Authors: Kudella Patrick W. , Preißinger Katharina , Morasch Matthias , Dirscherl Christina F. , Braun Dieter , Wixforth Achim , Westerhausen Christoph
Published: December 2019

Unilamellar lipid vesicles can serve as model for protocells. We present a vesicle fission mechanism in a thermal gradient under flow in a convection chamber, where vesicles cycle cold and hot regions periodically. Crucial to obtain fission of the vesicles in this scenario is a temperature-induced membrane phase transition that vesicles experience multiple times. We model the temperature gradient of the chamber with a capillary to study single vesicles on their way through the temperature gradient in an external field of shear forces. Starting in the gel-like phase the spherical vesicles are heated above their main melting temperature resulting in a dumbbell-deformation. Further downstream a temperature drop below the transition temperature induces splitting of the vesicles without further physical or chemical intervention. This mechanism also holds for less cooperative systems, as shown here for a lipid alloy with a broad transition temperature width of 8 K. We find a critical tether length that can be understood from the transition width and the locally applied temperature gradient. This combination of a temperature-induced membrane phase transition and realistic flow scenarios as given e.g. in a white smoker enable a fission mechanism that can contribute to the understanding of more advanced protocell cycles.
The perceptual continuity field is retinotopic
Authors: Collins Thérèse
Published: December 2019

Visual perception is systematically biased towards input from the recent past: perceived orientation, numerosity, and face identity are pulled towards previously seen stimuli. To better understand the brain level at which serial dependence occurs, the present study examined its spatial tuning. In three experiments, serial dependence occurred between stimuli occupying the same retinal position. Serial dependence between stimuli at distant retinal locations was smaller, even when the stimuli occupied the same location in external space. The spatial window over which serial dependence occurs is thus retinotopic, but wide, suggesting that serial dependence occurs at late stages of visual processing.
High efficiency DBR assisted grating chirp generators for silicon nitride fiber-chip coupling
Authors: Nambiar Siddharth , Ranganath Praveen , Kallega Rakshitha , Selvaraja Shankar Kumar
Published: December 2019

Silicon Nitride (SiN) is emerging as a promising material for a variety of integrated photonic applications. Given its low index contrast however, a key challenge remains to design efficient couplers for the numerous platforms in SiN photonics portfolio. Using a combination of bottom reflector and a chirp generating algorithm, we propose and demonstrate high efficiency, grating couplers on two distinct SiN platforms. For a partially etched grating on 500 nm thick SiN, a calculated peak efficiency of −0.5 dB/coupler is predicted, while for a fully etched grating on 400 nm thick SiN, an efficiency of −0.4 dB/coupler is predicted. Experimentally measured coupling efficiencies are observed to be −1.17 and −1.24 dB/coupler for the partial and fully etched grating couplers respectively in the C-L band region. Furthermore, through numerical simulations, it is shown that the chirping algorithm can be implemented in eight additional combinations comprising SiN film thickness between 300–700 nm as well as alternate claddings, to achieve a per coupler loss between −0.33 to −0.65 dB.
A higher throughput assay for quantification of melphalan-induced DNA damage in peripheral blood mononuclear cells
Authors: van Kan Maia , Burns Kathryn E. , Browett Peter , Helsby Nuala A.
Published: December 2019

Inter-individual differences in DNA adduct formation and repair influence the response to melphalan treatment, however, further clinical investigation of this variability requires a logistically feasible and reproducible bioassay. Our improved fluorescence-based QPCR-block assay is robust, has good precision, and improved throughput. It also incorporates direct PCR amplification from melphalan exposed PBMC using commercially available blood tubes and extraction kits to maximise the utility of this assay for future clinical studies. Using this assay we have demonstrated reproducible inter-individual differences in melphalan-induced QPCR-block across individual PBMC donors. As proof-of-principle we assessed nine healthy donors and found a 7.8 fold range in sensitivity following exposure of PBMC ex vivo. This likely reflects differences in melphalan transport into cells as well as differences in DNA adduct repair proficiency. This improved bioassay may be useful for assessment of these processes in patients about to receive melphalan treatment.
Population relationships based on 170 ancestry SNPs from the combined Kidd and Seldin panels
Authors: Pakstis Andrew J. , Speed William C. , Soundararajan Usha , Rajeevan Haseena , Kidd Judith R. , Li Hui , Kidd Kenneth K.
Published: December 2019

The benefits of ancestry informative SNP (AISNP) panels can best accrue and be properly evaluated only as sufficient reference population data become readily accessible. Ideally the set of reference populations should approximate the genetic diversity of human populations worldwide. The Kidd and Seldin AISNP sets are two panels that have separately accumulated thus far the largest and most diverse collections of data on human reference populations from the major continental regions. A recent tally in the ALFRED allele frequency database finds 164 reference populations available for all the 55 Kidd AISNPs and 132 reference populations for all the 128 Seldin AISNPs. Although much more of the genetic diversity in human populations around the world still needs to be documented, 81 populations have genotype data available for all 170 AISNPs in the union of the Kidd and Seldin panels. In this report we examine admixture and principal component analyses on these 81 worldwide populations and some regional subsets of these reference populations to determine how well the combined panel illuminates population relationships. Analyses of this dataset that focused on Native American populations revealed very strong cluster patterns associated with many of the individual populations studied.
VAS2870 and VAS3947 attenuate platelet activation and thrombus formation via a NOX-independent pathway downstream of PKC
Authors: Lu Wan Jung , Li Jiun Yi , Chen Ray Jade , Huang Li Ting , Lee Tzu Yin , Lin Kuan Hung
Published: December 2019

NADPH oxidase (NOX) enzymes are involved in a various physiological and pathological processes such as platelet activation and inflammation. Interestingly, we found that the pan-NOX inhibitors VAS compounds (VAS2870 and its analog VAS3947) exerted a highly potent antiplatelet effect. Unlike VAS compounds, concurrent inhibition of NOX1, 2, and 4 by treatment with ML171, GSK2795039, and GKT136901/GKT137831 did not affect thrombin and U46619-induced platelet aggregation. These findings suggest that VAS compounds may inhibit platelet aggregation via a NOX-independent manner. Thus, we aimed to investigate the detailed antiplatelet mechanisms of VAS compounds. The data revealed that VAS compounds blocked various agonist-induced platelet aggregation, possibly via blocking PKC downstream signaling, including IKKβ and p38 MAPK, eventually reducing platelet granule release, calcium mobilization, and GPIIbIIIa activation. In addition, VAS compounds inhibited mouse platelet aggregation-induced by collagen and thrombin. The in vivo study also showed that VAS compounds delayed thrombus formation without affecting normal hemostasis. This study is the first to demonstrate that, in addition to inhibiting NOX activity, VAS compounds reduced platelet activation and thrombus formation through a NOX-independent pathway downstream of PKC. These findings also indicate that VAS compounds may be safe and potentially therapeutic agents for treating patients with cardiovascular diseases.
Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation
Authors: Fujiwara Hiroaki , Tateishi Keisuke , Misumi Kento , Hayashi Akimasa , Igarashi Kaori , Kato Hiroyuki , Nakatsuka Takuma , Suzuki Nobumi , Yamamoto Keisuke , Kudo Yotaro , Hayakawa Yoku , Nakagawa Hayato , Tanaka Yasuo , Ijichi Hideaki , Kogure Hirofumi , Nakai Yosuke , Isayama Hiroyuki , Hasegawa Kiyoshi , Fukayama Masashi , Soga Tomoyoshi , Koike Kazuhiko
Published: December 2019

Metabolism is a critical regulator of cell fate determination. Recently, the significance of metabolic reprogramming in environmental adaptation during tumorigenesis has attracted much attention in cancer research. Recurrent mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes have been identified in several cancers, including intrahepatic cholangiocarcinoma (ICC). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which affects the activity of multiple α-KG-dependent dioxygenases including histone lysine demethylases. Although mutant IDH can be detected even in the early stages of neoplasia, how IDH mutations function as oncogenic drivers remains unclear. In this study, we aimed to address the biological effects of IDH1 mutation using intrahepatic biliary organoids (IBOs). We demonstrated that mutant IDH1 increased the formation of IBOs as well as accelerated glucose metabolism. Gene expression analysis and ChIP results revealed the upregulation of platelet isoform of phosphofructokinase-1 (PFKP), which is a rate-limiting glycolytic enzyme, through the alteration of histone modification. Knockdown of the Pfkp gene alleviated the mutant IDH1-induced increase in IBO formation. Notably, the high expression of PFKP was observed more frequently in patients with IDH-mutant ICC compared to in those with wild-type IDH (p < 0.01, 80.9% vs. 42.5%, respectively). Furthermore, IBOs expressing mutant IDH1 survived the suppression of ATP production caused by growth factor depletion and matrix detachment by retaining high ATP levels through 5ʹ adenosine monophosphate-activated protein kinase (AMPK) activation. Our findings provide a systematic understanding as to how mutant IDH induces tumorigenic preconditioning by metabolic rewiring in intrahepatic cholangiocytes.
Differential regulation of TRP channel gene and protein expression by intervertebral disc degeneration and back pain
Authors: Sadowska A. , Hitzl W. , Karol A. , Jaszczuk P. , Cherif H. , Haglund L. , Hausmann O. N. , Wuertz-Kozak K.
Published: December 2019

Intervertebral disc (IVD) degeneration and consequent low back pain (LBP) are common and costly pathological processes that require improved treatment strategies. Transient Receptor Potential (TRP) channels constitute a family of multimodal ion channels that have recently emerged as contributors to disc pathologies and were thus proposed as potential therapeutic targets, although limited data on their presence and function in the IVD exist. The purpose of this study was to determine the mRNA and protein expression of TRP channels in non-degenerated and degenerated human IVD tissue (with different pain intensity and chronicity) using gene array, conventional qPCR and immunohistochemistry. We could demonstrate that 26 out of 28 currently known TRP channels are expressed in the IVD on the mRNA level, thereby revealing novel therapeutic candidates from the TRPC, TRPM and TRPML subfamilies. TRPC6, TRPM2 and TRPML1 displayed enhanced gene and protein expression in degenerated IVDs as compared to non-degenerated IVDs. Additionally, the gene expression of TRPC6 and TRPML1 was influenced by the IVD degeneration grade. Pain intensity and/or chronicity influenced the gene and/or protein expression of TRPC6, TRPM2 and TRML1. Interestingly, decreased gene expression of TRPM2 was observed in patients treated with steroids. This study supports the importance of TRP channels in IVD homeostasis and pathology and their possible application as pharmacological targets for the treatment of IVD degeneration and LBP. However, the exact function and activation of the highlighted TRP channels will have to be determined in future studies.
Unmixing noisy co-registered spectrum images of multicomponent nanostructures
Authors: Braidy Nadi , Gosselin Ryan
Published: December 2019

Analytical electron microscopy plays a key role in the development of novel nanomaterials. Electron energy-loss spectroscopy (EELS) and energy-dispersive X-ray spectroscopy (EDX) datasets are typically processed to isolate the background-subtracted elemental signal. Multivariate tools have emerged as powerful methods to blindly map the components, which addresses some of the shortcomings of the traditional methods. Here, we demonstrate the superior performance of a new multivariate optimization method using a challenging EELS and EDX dataset. The dataset was recorded from a spectrum image P-type metal-oxide-semiconductor stack with 7 components exhibiting heavy spectral overlap and a low signal-to-noise ratio. Compared to peak integration, independent component analysis, Baysian Linear Unmixing and Non-negative matrix factorization, the method proposed was the only one to identify the EELS spectra of all 7 components with the corresponding abundance profiles. Using the abundance of each component, it was possible to retrieve the EDX spectra of all the components, which were otherwise impossible to isolate, regardless of the method used. We expect that this robust method will bring a significant improvement for the chemical analysis of nanomaterials, especially for weak signals, dose-sensitive specimen or signals suffering heavy spectral overlap.
A comparative study on droplet characteristics and specific charge of ethanol in two small-scale electrospray systems
Authors: Gan Yunhua , Jiang Zhengwei , Li Haige , Luo Yanlai , Chen Xiaowen , Shi Yanling , Yan Yuying , Yan Yunfei
Published: December 2019

An investigation on the droplet characteristics of ethanol in small-scale combustors with two different systems was conducted experimentally and theoretically. The classical capillary-mesh electrode arrangement was applied in Type A electrospray system, and for Type B, an additional ring electrode is included. The droplet size and velocity were measured by a Phase Doppler Anemometer. The electric filed intensity was theoretically calculated in the two electrospray systems. Compared with Type A, Type B system has smaller droplet size and velocity in the same spraying mode. Meanwhile the electrospray process in Type B system is more stable than that in Type A with its smaller root mean square velocity. By measuring the spraying current, the average specific charge of the droplets for the two systems was obtained in different spraying modes. And it was found that the addition of the ring electrode can help to increase the droplet charge, which is the fundamental reason for Type B electrospray system to perform better. The corona charge of the droplets was theoretically calculated for the two electrospray systems. It was found that the calculated specific charge generated by corona charging was in good agreement with the experimental results.
Performance of tropical forest seedlings under shade and drought: an interspecific trade-off in demographic responses
Authors: Kupers Stefan J. , Wirth Christian , Engelbrecht Bettina M. J. , Hernández Andrés , Condit Richard , Wright S. Joseph , Rüger Nadja
Published: December 2019

Seedlings in moist tropical forests must cope with deep shade and seasonal drought. However, the interspecific relationship between seedling performance in shade and drought remains unsettled. We quantified spatiotemporal variation in shade and drought in the seasonal moist tropical forest on Barro Colorado Island (BCI), Panama, and estimated responses of naturally regenerating seedlings as the slope of the relationship between performance and shade or drought intensity. Our performance metrics were relative height growth and first-year survival. We investigated the relationship between shade and drought responses for up to 63 species. There was an interspecific trade-off in species responses to shade versus species responses to dry season intensity; species that performed worse in the shade did not suffer during severe dry seasons and vice versa. This trade-off emerged in part from the absence of species that performed particularly well or poorly in both drought and shade. If drought stress in tropical forests increases with climate change and as solar radiation is higher during droughts, the trade-off may reinforce a shift towards species that resist drought but perform poorly in the shade by releasing them from deep shade.
Structural studies of the MMP-3 interaction with triple-helical collagen introduce new roles for the enzyme in tissue remodelling
Authors: Manka Szymon W. , Bihan Dominique , Farndale Richard W.
Published: December 2019

Matrix metalloproteinase-3 (MMP-3) participates in normal extracellular matrix turnover during embryonic development, organ morphogenesis and wound healing, and in tissue-destruction associated with aneurysm, cancer, arthritis and heart failure. Despite its inability to cleave triple-helical collagens, MMP-3 can still bind to them, but the mechanism, location and role of binding are not known. We used the Collagen Toolkits, libraries of triple-helical peptides that embrace the entire helical domains of collagens II and III, to map MMP-3 interaction sites. The enzyme recognises five sites on collagen II and three sites on collagen III. They share a glycine-phenylalanine-hydroxyproline/alanine (GFO/A) motif that is recognised by the enzyme in a context-dependent manner. Neither MMP-3 zymogen (proMMP-3) nor the individual catalytic (Cat) and hemopexin (Hpx) domains of MMP-3 interact with the peptides, revealing cooperative binding of both domains to the triple helix. The Toolkit binding data combined with molecular modelling enabled us to deduce the putative collagen-binding mode of MMP-3, where all three collagen chains make contacts with the enzyme in the valley running across both Cat and Hpx domains. The observed binding pattern casts light on how MMP-3 could regulate collagen turnover and compete with various collagen-binding proteins regulating cell adhesion and proliferation.
Preparation and Characterization of Microencapsulated Ethylenediamine with Epoxy Resin for Self-healing Composites
Authors: Yuan Liye , Sun Tongqing , Hu Honglin , Yuan Shuxia , Yang Yu , Wang Rongguo , Lyu Chunxiang , Yang Fan , Lyu Xiaoxuan
Published: December 2019

Healing agent microcapsules have been used to realize self-healing for polymeric composites. In this work a novel kind of microcapsules encapsulating ethylenediamine (EDA) with epoxy resin as shell material were prepared by interfacial polymerization technology. The oil phase was epoxy resin prepolymer and carbon tetrachloride, and the water phase was EDA and deionized water. Under the action of emulsifier, a stable water-in-oil emulsion was formed. Then the emulsion was added to dimethyl silicone oil, stirred and dispersed, to prepare microcapsules. In addition, the factors affecting the preparation of microcapsules were studied. In this study, Fourier transform infrared(FTIR) was carried out to demonstrate the chemical structure of ethylenediamine microcapsules. Optical microscope(OM) and scanning electron microscope(SEM) were used to observe the morphology of microcapsules. Thermogravimetric analysis and differential scanning calorimetry were done to investigate the thermal properties of microcapsules. Permeability experiment and isothermal aging test were executed to verify the environment resistance of microcapsules. Results showed that EDA was successfully coated in epoxy resin and the microcapsule size was in the range of 50~630 μm. The synthesized microcapsules were thermally stable below 75 °C and perfect permeability resistance to ethanol solvent.
Differences in the intestinal microbiome of healthy children and patients with newly diagnosed Crohn’s disease
Authors: Kowalska-Duplaga Kinga , Gosiewski Tomasz , Kapusta Przemysław , Sroka-Oleksiak Agnieszka , Wędrychowicz Andrzej , Pieczarkowski Stanisław , Ludwig-Słomczyńska Agnieszka H. , Wołkow Paweł P. , Fyderek Krzysztof
Published: December 2019

The aetiology of inflammatory bowel diseases (IBD) seems to be strongly connected to changes in the enteral microbiome. The dysbiosis pattern seen in Crohn’s disease (CD) differs among published studies depending on patients’ age, disease phenotype and microbiome research methods. The aims was to investigate microbiome in treatment-naive paediatric patients to get an insight into its structure at the early stage of the disease in comparison to healthy. Stool samples were obtained from controls and newly diagnosed patients prior to any intervention. Microbiota was analysed by 16SrRNAnext-generation-sequencing (NGS). Differences in the within-sample phylotype richness and evenness (alpha diversity) were detected between controls and patients. Statistically significant dissimilarities between samples were present for all used metrics. We also found a significant increase in the abundance of OTUs of theEnterococcusgenus and reduction in, among others,Bifidobacterium(B. adolescentis),Roseburia (R.faecis), Faecalibacterium (F. prausnitzii), Gemmiger (G. formicilis), Ruminococcus (R. bromii) and Veillonellaceae (Dialister). Moreover, differences in alpha and beta diversities in respect to calprotectin and PCDAI were observed: patients with calprotectin <100 µg/g and with PCDAI below 10 points vs those with calprotectin >100 µg/g and mild (10–27.7 points), moderate (27.5–40 points) or severe (>40 points) CD disease activity had higher richness and diversity of gut microbiota. The results of our study highlight reduced diversity and dysbiosis at the earliest stage of the disease. Microbial imbalance and low abundance of butyrate-producing bacteria, includingBifidobacterium adolescentis, may suggest benefits of microbial modification therapy.
Overexpression of LAPTM4B-35 is a negative prognostic factor in head and neck squamous cell carcinoma
Authors: Kotowski Ulana , Kadletz Lorenz , Schneider Sven , Oberndorfer Felicitas , Schnoell Julia , Gurnhofer Elisabeth , Kenner Lukas , Lucas Trevor , Heiduschka Gregor
Published: December 2019

Overexpression of LAPTM4B-35 (lysosomal-associated transmembrane protein 4β-35) is associated with a poor prognosis in numerous malignant tumours. Expression patterns and effects of LAPTM4B-35 on head and neck squamous cell carcinomas (HNSCC) are unknown. The aim of this study was to investigate the prognostic relevance of LAPTM4B-35 in HNSCC. Tissue microarrays were constructed with primary tumours and associated lymph node metastases isolated from 127 patients. The expression of LAPTM4B-35 was investigated by immunohistochemistry and the results were correlated with survival data. LAPTM4B-35 in the primary tumour was highly expressed in 47.2% of the patients (60/127). LAPTM4B-35 expression was significantly associated with tumour stage. Moreover, overexpression of LAPTM4B-35 correlated with a significantly worse disease-free survival (10.23 years vs. not reached) and a higher recurrence rate (40.7% vs. 25%). High expression of LAPTM4B-35 in lymph node metastasis was found in 29.2% of cases. In 19.4% of cases, high LAPTM4B-35 expression was observed in both the primary tumour and corresponding lymph node metastases. In conclusion, our data indicates that overexpression of LAPTM4B-35 is associated with poor prognosis and may therefore serve as a new prognostic marker in HNSCC.
3D-printed biological cell phantom for testing 3D quantitative phase imaging systems
Authors: Ziemczonok Michał , Kuś Arkadiusz , Wasylczyk Piotr , Kujawińska Małgorzata
Published: December 2019

As the 3D quantitative phase imaging (QPI) methods mature, their further development calls for reliable tools and methods to characterize and compare their metrological parameters. We use refractive index engineering during two-photon laser photolithography to fabricate a life-scale phantom of a biological cell with internal structures that mimic optical and structural properties of mammalian cells. After verification with a number of reference techniques, the phantom is used to characterize the performance of a limited-angle holographic tomography microscope.