bluuebunny/crossref_metadata_2025 huggingface dataset:
The Significance of the Effect of Visceral Adiposity on Left Ventricular Diastolic Function in the General Population
Authors: Sawada Naoko , Daimon Masao , Kawata Takayuki , Nakao Tomoko , Kimura Koichi , Nakanishi Koki , Kurano Makoto , Hirokawa Megumi , Xu Boqing , Yamanaka Yuko , Kato Tomoko S. , Watanabe Masafumi , Yatomi Yutaka , Komuro Issei
Published: March 2019

We evaluated the association between visceral adiposity and left ventricular (LV) diastolic function in association with plasma adiponectin levels in 213 subjects without overt cardiac diseases. Abdominal visceral fat area was quantified by computed tomography. Excessive visceral fat was significantly associated with impaired diastolic parameters including E/A, E′ and E/E′. Although serum adiponectin levels decreased with increased visceral adiposity, there was no independent association between serum adiponectin levels and diastolic parameters, which suggest that the role of adiponectin in this association might be indirect.
Integrative analysis of KIF4A, 9, 18A, and 23 and their clinical significance in low-grade glioma and glioblastoma
Authors: Cho Sang Yeon , Kim Sungha , Kim Gwanghun , Singh Parul , Kim Dong Woon
Published: March 2019

To determine the prognostic significance of kinesin superfamily gene (KIF) expression in patients with brain cancer, including low-grade glioma (LGG) and glioblastoma (GBM), we comprehensively analyzed KIFs in 515 LGG and 595 GBM patients. Among KIFs, KIF4A, 9, 18A, and 23 showed significant clinical implications in both LGG and GBM. The mRNA and protein expression levels of KIF4A, 9, 18A, and 23 were significantly increased in LGG and GBM compared with those in the normal control groups. The mRNA expression levels of KIF4A, 9, 18A, and 23 in LGG were significantly increased in the high-histologic-grade group compared with those with a low histologic grade. Genomic analysis showed that the percent of mRNA upregulation of KIF4A, 9, 18A, and 23 was higher than that of other gene alterations, including gene amplification, deep deletion, and missense mutation. In addition, LGG patients with KIF4A, 18A, and 23 gene alterations were significantly associated with a poor prognosis. In survival analysis, the group with high expression of KIF4A, 9, 18A, and 23 mRNA was significantly associated with a poor prognosis in both LGG and GBM patients. Gene Set Enrichment Analysis (GSEA) revealed that high mRNA expression of KIF4A, 18A, and 23 in LGG and GBM patients showed significant positive correlations with the cell cycle, E2F targets, G2M checkpoint, Myc target, and mitotic spindle. By contrast, high mRNA expression of KIF9 in both LGG and GBM patients was significantly negatively correlated with the cell cycle, G2M checkpoint, and mitotic spindle pathway. However, it was significantly positively correlated with EMT and angiogenesis. This study has extended our knowledge of KIF4A, 9, 18A, and 23 in LGG and GBM and shed light on their clinical relevance, which should help to improve the treatment and prognosis of LGG and GBM.
Revealing Tumor Habitats from Texture Heterogeneity Analysis for Classification of Lung Cancer Malignancy and Aggressiveness
Authors: Cherezov Dmitry , Goldgof Dmitry , Hall Lawrence , Gillies Robert , Schabath Matthew , Müller Henning , Depeursinge Adrien
Published: March 2019

We propose an approach for characterizing structural heterogeneity of lung cancer nodules using Computed Tomography Texture Analysis (CTTA). Measures of heterogeneity were used to test the hypothesis that heterogeneity can be used as predictor of nodule malignancy and patient survival. To do this, we use the National Lung Screening Trial (NLST) dataset to determine if heterogeneity can represent differences between nodules in lung cancer and nodules in non-lung cancer patients. 253 participants are in the training set and 207 participants in the test set. To discriminate cancerous from non-cancerous nodules at the time of diagnosis, a combination of heterogeneity and radiomic features were evaluated to produce the best area under receiver operating characteristic curve (AUROC) of 0.85 and accuracy 81.64%. Second, we tested the hypothesis that heterogeneity can predict patient survival. We analyzed 40 patients diagnosed with lung adenocarcinoma (20 short-term and 20 long-term survival patients) using a leave-one-out cross validation approach for performance evaluation. A combination of heterogeneity features and radiomic features produce an AUROC of 0.9 and an accuracy of 85% to discriminate long- and short-term survivors.
Assessing diversity in multiplex networks
Authors: Carpi Laura C. , Schieber Tiago A. , Pardalos Panos M. , Marfany Gemma , Masoller Cristina , Díaz-Guilera Albert , Ravetti Martín G.
Published: March 2019

Diversity, understood as the variety of different elements or configurations that an extensive system has, is a crucial property that allows maintaining the system’s functionality in a changing environment, where failures, random events or malicious attacks are often unavoidable. Despite the relevance of preserving diversity in the context of ecology, biology, transport, finances, etc., the elements or configurations that more contribute to the diversity are often unknown, and thus, they can not be protected against failures or environmental crises. This is due to the fact that there is no generic framework that allows identifying which elements or configurations have crucial roles in preserving the diversity of the system. Existing methods treat the level of heterogeneity of a system as a measure of its diversity, being unsuitable when systems are composed of a large number of elements with different attributes and types of interactions. Besides, with limited resources, one needs to find the best preservation policy, i.e., one needs to solve an optimization problem. Here we aim to bridge this gap by developing a metric between labeled graphs to compute the diversity of the system, which allows identifying the most relevant components, based on their contribution to a global diversity value. The proposed framework is suitable for large multiplex structures, which are constituted by a set of elements represented as nodes, which have different types of interactions, represented as layers. The proposed method allows us to find, in a genetic network (HIV-1), the elements with the highest diversity values, while in a European airline network, we systematically identify the companies that maximize (and those that less compromise) the variety of options for routes connecting different airports.
High-throughput screening and classification of chemicals and their effects on neuronal gene expression using RASL-seq
Authors: Simon Jeremy M. , Paranjape Smita R. , Wolter Justin M. , Salazar Gabriela , Zylka Mark J.
Published: March 2019

We previously used RNA-seq to identify chemicals whose effects on neuronal gene expression mimicked transcriptional signatures of autism, aging, and neurodegeneration. However, this approach was costly and time consuming, which limited our study to testing a single chemical concentration on mixed sex cortical neuron cultures. Here, we adapted a targeted transcriptomic method (RASL-seq, similar to TempO-seq) to interrogate changes in expression of a set of 56 signature genes in response to a library of 350 chemicals and chemical mixtures at four concentrations in male and female mouse neuronal cultures. This enabled us to replicate and expand our previous classifications, and show that transcriptional responses were largely equivalent between sexes. Overall, we found that RASL-seq can be used to accelerate the pace at which chemicals and mixtures that transcriptionally mimic autism and other neuropsychiatric diseases can be identified, and provides a cost-effective way to quantify gene expression with a panel of marker genes.
A new oligonucleotide array for the detection of multidrug and extensively drug-resistance tuberculosis
Authors: Chen Ching-Yu , Weng Jui-Yun , Huang Hsin-Hui , Yen Wen-Chun , Tsai Yu-Han , Cheng Tsung Chain , Jou Ruwen
Published: March 2019

Drug-resistant tuberculosis (TB) is a global crisis and a threat to health security. Since conventional drug susceptibility testing (DST) takes several weeks, we herein described a molecular assay to rapidly identify multidrug-resistant (MDR) and extensively drug-resistant (XDR) and reveal transmission associated-mutations of Mycobacterium tuberculosis complex (MTBC) isolates in 6 to 7 hours. An array was designed with 12 pairs of primers and 60 single nucleotide polymorphisms of 9 genes: rpoB, katG, inhA, ahpC, embB, rpsL, gyrA, rrs and eis. We assessed the performance of the array using 176 clinical MTBC isolates. The results of culture-based DST were used as the gold standard, the GenoType MTBDRplus and MTBDRsl tests were used for parallel comparison, and gene sequencing was performed to resolve the discordance. The sensitivities and specificities of the array are comparable to those of the MTBDRplus test for resistance to isoniazid (INH) (100.0%, 96.7%) and rifampicin (RIF) (99.4%, 96.7%) and of the MTBDRsl test for resistance to fluoroquinolones (FQs) (100%, 100%) and second-line injectable drugs (SLIDs) (98.3%, 100%). The sensitivities of the array for detecting resistance to ethambutol and streptomycin were 79.3% and 64.9%, respectively. The array has potential as a powerful tool for clinical diagnosis and epidemiological investigations.
The effects of fatigue and oxidation on contractile function of intact muscle fibers and myofibrils isolated from the mouse diaphragm
Authors: Bagni M. Angela , Colombini Barbara , Nocella Marta , Pregno Claudio , S. Cornachione Anabelle , Rassier Dilson E.
Published: March 2019

The goal of this study was to investigate the effects of repetitive stimulation and the oxidant H2O2 on fatigue of diaphragm intact fibers and in myofibrils measured with different Ca2+ concentrations. Intact fibers were isolated from mice diaphragm, and twitch and tetanic contractions (500 ms duration) were performed at different frequencies of stimulation ranging from 15 Hz to 150 Hz to establish a force-frequency relation before and after a fatigue and recovery protocol, without or after a treatment with H2O2. Fatigue was induced with isometric contractions (500 ms, 40 Hz) evoked every 0.8 seconds, with a total of 625 tetani. After the fatigue, the force recovery was followed by invoking tetanic contractions (500 ms, 40 Hz) every 1 min, with a total duration of 30 min. Individual myofibrils were also isolated from the mouse diaphragm and were tested for isometric contractions before and after treatment with H2O2 and NAC. In a second series of experiments, myofibrils were activated at different pCa (pCa = −log10 [Ca2+]), before and after H2O2 treatment. After 15 minutes of H2O2 treatment, the myofibrillar force was decreased to 54 ± 12% of its control, maximal value, and a result that was reversed by NAC treatment. The force was also decreased after myofibrils were treated with H2O2 and activated in pCa ranging between 4.5 and 5.7. These results suggest that fatigue in diaphragm intact fibers and at the myofibrils level is caused partially by oxidation of the contractile proteins that may be responsible for changing the force in various levels of Ca2+ activation.
Epidermal Growth Factor Like-domain 7 and miR-126 are abnormally expressed in diffuse Systemic Sclerosis fibroblasts
Authors: Liakouli Vasiliki , Cipriani Paola , Di Benedetto Paola , Panzera Noemi , Ruscitti Piero , Pantano Ilenia , Berardicurti Onorina , Carubbi Francesco , Esteves Filomena , Mavria Georgia , Del Galdo Francesco , Giacomelli Roberto
Published: March 2019

Systemic sclerosis (SSc) is characterized by microangiopathy with impaired reparative angiogenesis and fibrosis. Epidermal Growth Factor Like-domain 7 (EGFL7), firstly described in endothelial cells plays a pivotal role in angiogenesis. Fibroblasts (FBs) are involved in vascular remodeling, under physiological and pathological conditions. In this study, we investigated: (i) the expression of EGFL7 and its miR-126 in patients affected by diffuse cutaneous SSc (dcSSc); (ii) the ability of Transforming Growth Factor-beta (TGF-β) to modulate EGFL7 expression; (iii) the ability of EGFL7 to modulate COL1A1 expression and proliferation/migration, and (iv) the functional role of EGFL7 on angiogenesis. Patients were divided in 2 subsets: patients fulfilling the classification criteria in less than one year from Raynaud’s Phenomenon onset (Early Onset Subset–EOS), and all the others (Long Standing Subset–LSS). We show that EGFL7 expression is increased in EOS dcSSc skin and cultured FBs. EGFL7 is inducible by TGF-β on Healthy Controls (HC) FBs but not in SSc-FBs. EGFL7 decreases COL1A1 expression in EOS SSc-FBs while EGFL7 silencing up-regulates COL1A1 expression. EGFL7 promotes migration/invasion of EOS SSc-FBs but not proliferation. Finally, SSc-FBs, partially inhibit angiogenesis in organotypic coculture assays, and this is reversed by treatment with human recombinant (rh)EGFL7. We conclude that EGFL7 and its specific microRNA miR-126 may be involved in the pathogenesis of SSc vasculopathy and fibrosis.
The R229Q mutation of Rag2 does not characterize severe immunodeficiency in mice
Authors: Jin Young , Lee Ara , Oh Ja Hyun , Lee Han-Woong , Ha Sang-Jun
Published: March 2019

RAG1 or RAG2 mutations are associated with defects in V(D)J recombination activity, causing severe immunodeficiency with a wide spectrum of clinical phenotypes. A R229Q mutation of RAG2 was identified in patients with severe combined immunodeficiency (SCID) or Omenn syndrome (OS). Although some factors determining the clinical features between SCID and OS were not clear, the molecular mechanism of OS was studied in a mouse model in which an EGFP tag is fused to Rag2 with the R229Q mutation. To design the human disease model mimicking severe immunodeficiency, we generated Rag2-R229Q knock-in mice without an epitope tag. Mutant mice showed impaired T and B cell differentiation with reduced V(D)J recombination activity; however, the extent to which the R229Q mutation affects severe immunodeficiency was not severe. While Rag2-R229Q mutation under some conditions may cause severe immunological and clinical phenotypes similar to human SCID or OS, R229Q mutation per se did not cause severe immunodeficiency in mice, suggesting that additional factors other than R229Q mutation are required to induce severe immunodeficiency. Thus, our report implies that the effects of genetic background and/or a tagged protein sequence may alter the mouse immune system, revealing the mechanism of phenotypic heterogeneity arising from an identical mutation.
Observation of a superconducting glass state in granular superconducting diamond
Authors: Klemencic G. M. , Fellows J. M. , Werrell J. M. , Mandal S. , Giblin S. R. , Smith R. A. , Williams O. A.
Published: March 2019

The magnetic field dependence of the superconductivity in nanocrystalline boron doped diamond thin films is reported. Evidence of a superconducting glass state is presented, as demonstrated by the observation of a quasi de Almeida-Thouless line in the phase diagram and a logarithmic time dependence of the magnetism. The position of the phase boundary in the H-T plane is determined from electrical transport data by detailed fitting to quasi-zero-dimensional fluctuation conductivity theory. This allows determination of the boundary between resistive and non-resistive behaviour to be made with greater precision than the standard ad hoc onset/midpoint/offset criterion. We attribute the glassy superconductivity to the morphological granularity of the diamond films.
CHD4 regulates the DNA damage response and RAD51 expression in glioblastoma
Authors: McKenzie Lisa D. , LeClair John W. , Miller Kayla N. , Strong Averey D. , Chan Hilda L. , Oates Edward L. , Ligon Keith L. , Brennan Cameron W. , Chheda Milan G.
Published: March 2019

Glioblastoma (GBM) is a lethal brain tumour. Despite therapy with surgery, radiation, and alkylating chemotherapy, most people have recurrence within 6 months and die within 2 years. A major reason for recurrence is resistance to DNA damage. Here, we demonstrate that CHD4, an ATPase and member of the nucleosome remodelling and deactetylase (NuRD) complex, drives a component of this resistance. CHD4 is overexpressed in GBM specimens and cell lines. Based on The Cancer Genome Atlas and Rembrandt datasets, CHD4 expression is associated with poor prognosis in patients. While it has been known in other cancers that CHD4 goes to sites of DNA damage, we found CHD4 also regulates expression of RAD51, an essential component of the homologous recombination machinery, which repairs DNA damage. Correspondingly, CHD4 suppression results in defective DNA damage response in GBM cells. These findings demonstrate a mechanism by which CHD4 promotes GBM cell survival after DNA damaging treatments. Additionally, we found that CHD4 suppression, even in the absence of extrinsic treatment, cumulatively increases DNA damage. Lastly, we found that CHD4 is dispensable for normal human astrocyte survival. Since standard GBM treatments like radiation and temozolomide chemotherapy create DNA damage, these findings suggest an important resistance mechanism that has therapeutic implications.
Exploring designability of electrostatic complementarity at an antigen-antibody interface directed by mutagenesis, biophysical analysis, and molecular dynamics simulations
Authors: Yoshida Kouhei , Kuroda Daisuke , Kiyoshi Masato , Nakakido Makoto , Nagatoishi Satoru , Soga Shinji , Shirai Hiroki , Tsumoto Kouhei
Published: March 2019

Antibodies protect organisms from a huge variety of foreign antigens. Antibody diversity originates from both genetic and structural levels. Antigen recognition relies on complementarity between antigen-antibody interfaces. Recent methodological advances in structural biology and the accompanying rapid increase of the number of crystal structures of proteins have enabled atomic-level manipulation of protein structures to effect alterations in function. In this study, we explored the designability of electrostatic complementarity at an antigen-antibody interface on the basis of a crystal structure of the complex. We designed several variants with altered charged residues at the interface and characterized the designed variants by surface plasmon resonance, circular dichroism, differential scanning calorimetry, and molecular dynamics simulations. Both successes and failures of the structure-based design are discussed. The variants that compensate electrostatic interactions can restore the interface complementarity, enabling the cognate antigen-antibody binding. Retrospectively, we also show that these mutational effects could be predicted by the simulations. Our study demonstrates the importance of charged residues on the physical properties of this antigen-antibody interaction and suggests that computational approaches can facilitate design of antibodies that recognize a weakly immunogenic antigen.
Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and cognitive capability at older ages: individual participant meta-analysis of five cohorts
Authors: Gardner Michael , Lightman Stafford , Kuh Diana , Comijs Hannie , Deeg Dorly , Gallacher John , Geoffroy Marie-Claude , Kivimaki Mika , Kumari Meena , Power Chris , Hardy Rebecca , Richards Marcus , Ben-Shlomo Yoav
Published: March 2019

Evidence on the association between functioning of the hypothalamic pituitary adrenal (HPA) axis and cognitive capability at older ages is mixed. We undertook a systematic review (until October 2016) and individual participant data (IPD) meta-analysis to test if dysregulation of the HPA axis is associated with worse cognitive capability. Five cohort studies were included in the IPD meta-analysis of diurnal cortisol patterns with crystallised and fluid cognitive ability. Higher night time cortisol was associated with worse fluid ability (standardised coefficient per SD increase −0.063, 95% CI −0.124, −0.002,P = 0.04; I2 = 79.9%; age and gender adjusted). A larger diurnal drop was associated with better fluid ability (standardised coefficient per SD increase 0.037, 95% CI 0.008, 0.065,P = 0.01; I2 = 49.2%; age and gender adjusted). A bigger cortisol awakening response (CAR) was weakly associated with better fluid (P = 0.09; I2 = 0.0%; age and gender adjusted) and crystallised (P = 0.10; I2 = 0.0%; age and gender adjusted) ability. There is weak evidence that a greater diurnal decline of the HPA axis and a larger CAR are associated with improvements in cognition at older ages. As associations are cross-sectional, we cannot rule out reverse causation.
Immutable heavy metal pollution before and after change in industrial waste treatment procedure
Authors: Ozaki Hirokazu , Ichise Hiroshi , Kitaura Emi , Yaginuma Yuki , Yoda Masaaki , Kuno Katsuji , Watanabe Izumi
Published: March 2019

This study compared state of pollution around an intermediate treatment plant of industrial wastes before and after the change of its treatment procedure. Bulk atmospheric deposition, surface soil, suspended particulate matter and groundwater were collected after the plant changed main operation to waste crushing and volume reduction. Their heavy metals content were comparatively investigated with the previous results obtained when it was burning wastes. The bulk heavy metals deposition showed a clear distance-related attenuation both in burning and crushing periods, indicating that the plant was the main emissions source in either case. High concentrations of heavy metals in suspended particles, soil, and groundwater during the crushing period indicated their diffusion to water environment over time. The bulk atmospheric heavy metals deposition decreased significantly, 0.20~ 0.49 times for Cu, Zn, Cd and Pb and 0.69~0.94 times for Cr, during the crushing period than burning period. However, change of their enrichment factors was not significant. It may indicate that the pollution state did not change qualitatively in a bulk deposition basis and quantitatively in a depositing particle basis. The results showed that heavy metals deposition is dominated by suspended and precipitated particulate matters that adsorb and transport the metals.
Robust $${\bf{P}}{\bf{T}}$$ symmetry of two-dimensional fundamental and vortex solitons supported by spatially modulated nonlinearity
Authors: Luz Eitam , Lutsky Vitaly , Granot Er’el , Malomed Boris A.
Published: March 2019

The real spectrum of bound states produced by $${\bf{P}}{\bf{T}}$$
P
T
-symmetric Hamiltonians usually suffers breakup at a critical value of the strength of gain-loss terms, i.e., imaginary part of the complex potential. The breakup essentially impedes the use of $${\bf{P}}{\bf{T}}$$
P
T
-symmetric systems for various applications. On the other hand, it is known that the $${\bf{P}}{\bf{T}}$$
P
T
symmetry can be made unbreakable in a one-dimensional (1D) model with self-defocusing nonlinearity whose strength grows fast enough from the center to periphery. The model is nonlinearizable, i.e., it does not have a linear spectrum, while the (unbreakable) $${\bf{P}}{\bf{T}}$$
P
T
symmetry in it is defined by spectra of continuous families of nonlinear self-trapped states (solitons). Here we report results for a 2D nonlinearizable model whose $${\bf{P}}{\bf{T}}$$
P
T
symmetry remains unbroken for arbitrarily large values of the gain-loss coefficient. Further, we introduce an extended 2D model with the imaginary part of potential ~xy in the Cartesian coordinates. The latter model is not a $${\bf{P}}{\bf{T}}$$
P
T
-symmetric one, but it also supports continuous families of self-trapped states, thus suggesting an extension of the concept of the $${\bf{P}}{\bf{T}}$$
P
T
symmetry. For both models, universal analytical forms are found for nonlinearizable tails of the 2D modes, and full exact solutions are produced for particular solitons, including ones with the unbreakable $${\bf{P}}{\bf{T}}$$
P
T
symmetry, while generic soliton families are found in a numerical form. The $${\bf{P}}{\bf{T}}$$
P
T
-symmetric system gives rise to generic families of stable single- and double-peak 2D solitons (including higher-order radial states of the single-peak solitons), as well as families of stable vortex solitons with m = 1, 2, and 3. In the model with imaginary potential ~xy, families of single- and multi-peak solitons and vortices are stable if the imaginary potential is subject to spatial confinement. In an elliptically deformed version of the latter model, an exact solution is found for vortex solitons with m = 1.
Complement component 1q subcomponent binding protein in the brain of the rat
Authors: Barna János , Dimén Diána , Puska Gina , Kovács Dávid , Csikós Vivien , Oláh Szilvia , Udvari Edina B. , Pál Gabriella , Dobolyi Árpád
Published: March 2019

Complement component 1q subcomponent binding protein (C1qbp) is a multifunctional protein involved in immune response, energy homeostasis of cells as a plasma membrane receptor, and a nuclear, cytoplasmic or mitochondrial protein. Recent reports suggested its neuronal function, too, possibly in axon maintenance, synaptic function, and neuroplasticity. Therefore, we addressed to identify C1qbp in the rat brain using in situ hybridization histochemistry and immunolabelling at light and electron microscopic level. C1qbp has a topographical distribution in the brain established by the same pattern of C1qbp mRNA-expressing and protein-containing neurons with the highest abundance in the cerebral cortex, anterodorsal thalamic nucleus, hypothalamic paraventricular (PVN) and arcuate nuclei, spinal trigeminal nucleus. Double labelling of C1qbp with the neuronal marker NeuN, with the astrocyte marker S100, and the microglia marker Iba1 demonstrated the presence of C1qbp in neurons but not in glial cells in the normal brain, while C1qbp appeared in microglia following their activation induced by focal ischemic lesion. Only restricted neurons expressed C1qbp, for example, in the PVN, magnocellular neurons selectively contained C1qbp. Further double labelling by using the mitochondria marker Idh3a antibody suggested the mitochondrial localization of C1qbp in the brain, confirmed by correlated light and electron microscopy at 3 different brain regions. Post-embedding immunoelectron microscopy also suggested uneven C1qbp content of mitochondria in different brain areas but also heterogeneity within single neurons. These data suggest a specific function of C1qbp in the brain related to mitochondria, such as the regulation of local energy supply in neuronal cells.
Linear and circular-polarization conversion in X-band using anisotropic metasurface
Authors: Khan M. Ismail , Khalid Zobaria , Tahir Farooq A.
Published: March 2019

An ultrathin single-layer metasurface manifesting both linear cross-polarization conversion (CPC) and linear-to-circular polarization (LP-to-CP) conversion in X-band is presented in this research. The designed metasurface acts as a multifunctional metasurface achieving CPC over a fractional bandwidth of 31.6% (8–11 GHz) with more than 95% efficiency while linear-to-circular polarization conversion is realized over two frequency bands from 7.5–7.7 GHz and 11.5–11.9 GHz. Moreover, the overall optimized structure of the unit cell results in a stable polarization transformation against changes in the incidence angle up to 45° both for transverse-electric (TE) and transverse-magnetic (TM) polarizations. The proposed metasurface with simple structure, compact size, angular stability and multifunctional capability qualifies for many applications in communication and polarization manipulating devices.
Predictors of Initial Smear-Negative Active Pulmonary Tuberculosis with Acute Early Stage Lung Injury by High-Resolution Computed Tomography and Clinical Manifestations: An Auxiliary Model in Critical Patients
Authors: Yeh Jun-Jun
Published: March 2019

This study evaluated the diagnostic use of high-resolution computed tomography (HRCT), chest X-ray (CXR), and clinical manifestations (CM) to identify initial smear-negative (iSN) active pulmonary tuberculosis (aPTB) [iSN-aPTB] in patients with iSN-pulmonary diseases (PD) and acute lung injury (ALI). In the derivation cohort, the [iSN-PD] with ALI patients were divided into the [iSN-aPTB] (G1, n = 26) and [non-aPTB-PD] (G2, n = 233) groups. Lung morphology, number, and lobar (segmental) distribution were evaluated using CXR and HRCT. A multivariate analysis was performed to identify independent variables associated with G1, which were used to generate predictive score models for G1. The predictive model was validated in a separate population of patients (n = 372) with [iSN-PD] and (ALI). The validated model for [HRCT (CXR + Hypoalbuminemia)] had 93.5% (25.8%) sensitivity, 99.5% (89.4%) specificity, and a negative predictive value of 99.5% (93.0%). For [iSN-aPTB], the post-test probability in the derivation cohort (prevalence = 10%), validation cohort (prevalence = 8.3%), and the given prevalence (prevalence = 1%) was 88.7%, 94.4%, and 41.5%, respectively. The HRCT model effectively identified the [iSN-aPTB] subjects among the [iSN-PD] with ALI, regardless of CM. The [non-aPTB-PD] were also correctly classified by the HRCT and [CXR + Hypoalbuminemia] models.
Timing Information Propagation in Interactive Networks
Authors: Hafnaoui Imane , Nicolescu Gabriela , Beltrame Giovanni
Published: March 2019

Animal behavior is greatly influenced by interaction between peers as well as with the environment. Understanding the flow of information between individuals can help decipher their behavior. This applies to both the microscopic and macroscopic levels, from cellular communication to coordinated actions by humans. The aim of this work is to provide a simple but sufficient model of information propagation to learn from natural coordinated behavior, and apply this knowledge to engineered systems. We develop a probabilistic model to infer the information propagation in a network of communicating agents with different degrees of interaction affinity. Another focus of the work is estimating the time needed to reach an agreement between all agents. We experiment using swarms of robots to emulate the communication of biological and social media groups for which we are able to provide upper bounds for the time needed to reach a global consensus, as well as to identify individuals that are responsible for slow convergence.
The Parkinson’s disease-linked Leucine-rich repeat kinase 2 (LRRK2) is required for insulin-stimulated translocation of GLUT4
Authors: Funk Natalja , Munz Marita , Ott Thomas , Brockmann Kathrin , Wenninger-Weinzierl Andrea , Kühn Ralf , Vogt-Weisenhorn Daniela , Giesert Florian , Wurst Wolfgang , Gasser Thomas , Biskup Saskia
Published: March 2019

Mutations within Leucine-rich repeat kinase 2 (LRRK2) are associated with late-onset Parkinson’s disease. The physiological function of LRRK2 and molecular mechanism underlying the pathogenic role of LRRK2 mutations remain uncertain. Here, we investigated the role of LRRK2 in intracellular signal transduction. We find that deficiency of Lrrk2 in rodents affects insulin-dependent translocation of glucose transporter type 4 (GLUT4). This deficit is restored during aging by prolonged insulin-dependent activation of protein kinase B (PKB, Akt) and Akt substrate of 160 kDa (AS160), and is compensated by elevated basal expression of GLUT4 on the cell surface. Furthermore, we find a crucial role of Rab10 phosphorylation by LRRK2 for efficient insulin signal transduction. Translating our findings into human cell lines, we find comparable molecular alterations in fibroblasts from Parkinson’s patients with the known pathogenic G2019S LRRK2 mutation. Our results highlight the role of LRRK2 in insulin-dependent signalling with potential therapeutic implications.
Links between physical and chemical weathering inferred from a 65-m-deep borehole through Earth’s critical zone
Authors: Holbrook W. Steven , Marcon Virginia , Bacon Allan R. , Brantley Susan L. , Carr Bradley J. , Flinchum Brady A. , Richter Daniel D. , Riebe Clifford S.
Published: March 2019

As bedrock weathers to regolith – defined here as weathered rock, saprolite, and soil – porosity grows, guides fluid flow, and liberates nutrients from minerals. Though vital to terrestrial life, the processes that transform bedrock into soil are poorly understood, especially in deep regolith, where direct observations are difficult. A 65-m-deep borehole in the Calhoun Critical Zone Observatory, South Carolina, provides unusual access to a complete weathering profile in an Appalachian granitoid. Co-located geophysical and geochemical datasets in the borehole show a remarkably consistent picture of linked chemical and physical weathering processes, acting over a 38-m-thick regolith divided into three layers: soil; porous, highly weathered saprolite; and weathered, fractured bedrock. The data document that major minerals (plagioclase and biotite) commence to weather at 38 m depth, 20 m below the base of saprolite, in deep, weathered rock where physical, chemical and optical properties abruptly change. The transition from saprolite to weathered bedrock is more gradational, over a depth range of 11–18 m. Chemical weathering increases steadily upward in the weathered bedrock, with intervals of more intense weathering along fractures, documenting the combined influence of time, reactive fluid transport, and the opening of fractures as rock is exhumed and transformed near Earth’s surface.
Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis
Authors: Rabionet Raquel , Remesal Agustín , Mensa-Vilaró Anna , Murías Sara , Alcobendas Rosa , González-Roca Eva , Ruiz-Ortiz Estibaliz , Antón Jordi , Iglesias Estibaliz , Modesto Consuelo , Comas David , Puig Anna , Drechsel Oliver , Ossowski Stephan , Yagüe Jordi , Merino Rosa , Estivill Xavier , Arostegui Juan I.
Published: March 2019

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease with both autoimmune and autoinflammatory components. Recently, familial cases of systemic-onset JIA have been attributed to mutations in LACC1/FAMIN. We describe three affected siblings from a Moroccan consanguineous family with an early-onset chronic, symmetric and erosive arthritis previously diagnosed as rheumatoid factor (RF)-negative polyarticular JIA. Autozygosity mapping identified four homozygous regions shared by all patients, located in chromosomes 3, 6 (n:2) and 13, containing over 330 genes. Subsequent whole exome sequencing identified two potential candidate variants within these regions (in FARS2 and LACC1/FAMIN). Genotyping of a cohort of healthy Moroccan individuals (n: 352) and bioinformatics analyses finally supported the frameshift c.128_129delGT mutation in the LACC1/FAMIN gene, leading to a truncated protein (p.Cys43Tyrfs*6), as the most probable causative gene defect. Additional targeted sequencing studies performed in patients with systemic-onset JIA (n:23) and RF-negative polyarticular JIA (n: 44) revealed no pathogenic LACC1/FAMIN mutations. Our findings support the homozygous genotype in the LACC1/FAMIN gene as the defect underlying the family here described with a recessively inherited severe inflammatory joint disease. Our evidences provide further support to the involvement of LACC1/FAMIN deficiency in different types of JIA in addition to the initially described systemic-onset JIA.
Conjugated linoleic acid (CLA)-induced milk fat depression: application of RNA-Seq technology to elucidate mammary gene regulation in dairy ewes
Authors: Suárez-Vega Aroa , Gutiérrez-Gil Beatriz , Toral Pablo G. , Hervás Gonzalo , Arranz Juan José , Frutos Pilar
Published: March 2019

Milk fat depression (MFD) is characterized by a reduction in the content of milk fat, presumably caused by the anti-lipogenic effects of rumen biohydrogenation intermediates, such as trans-10 cis-12 conjugated linoleic acid (CLA). In this study, RNA-Seq technology was used to help elucidate the mammary responses involved in CLA-induced MFD in lactating ewes. To this end, we compared the milk somatic cell transcriptome of ewes suffering from CLA-induced MFD with control ewes (i.e., those without MFD), as well as with ewes fed a diet supplemented with fish oil (FO-MFD) that we previously reported affects the mammary transcriptome. In the differential expression analysis between CLA-MFD and controls, we identified 1,524 differentially expressed genes (DEGs), whereas 653 were detected between CLA- and FO-MFD groups. Although this article focuses on lipid metabolism, CLA affected the expression of many genes related to other biological processes, especially immunity. Among the 55 genes shared by both MFD conditions, some genes linked to fatty acid synthesis, such as ACACA, AACS, ACSS2, or ACSS3, were downregulated. In addition, this study provides a list of candidate genes that are not usually considered in the nutrigenomics of MFD but that may act as key regulators of this syndrome in dairy ewes.
Thermochemistry and Kinetics of the Thermal Degradation of 2-Methoxyethanol as Possible Biofuel Additives
Authors: Abdel-Rahman Mohamed A. , Al-Hashimi Nessreen , Shibl Mohamed F. , Yoshizawa Kazunari , El-Nahas Ahmed M.
Published: March 2019

Oxygenated organic compounds derived from biomass (biofuel) are a promising alternative renewable energy resource. Alcohols are widely used as biofuels, but studies on bifunctional alcohols are still limited. This work investigates the unimolecular thermal degradation of 2-methoxyethanol (2ME) using DFT/BMK and ab initio (CBS-QB3 and G3) methods. Enthalpies of the formation of 2ME and its decomposition species have been calculated. Conventional transition state theory has been used to estimate the rate constant of the pyrolysis of 2ME over a temperature range of 298–2000 K. Production of methoxyethene via 1,3-H atom transfer represents the most kinetically favored path in the course of 2ME pyrolysis at room temperature and requires less energy than the weakest Cα − Cβ simple bond fission. Thermodynamically, the most preferred channel is methane and glycoladhyde formation. A ninefold frequency factor gives a superiority of the Cα − Cβ bond breaking over the Cγ − Oβ bond fission despite comparable activation energies of these two processes.
Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations
Authors: Becker Yann , Loignon Renée-Claude , Julien Anne-Sophie , Marcoux Geneviève , Allaeys Isabelle , Lévesque Tania , Rollet-Labelle Emmanuelle , Benk-Fortin Hadrien , Cloutier Nathalie , Melki Imène , Eder Lihi , Wagner Éric , Pelletier Martin , Hajj Hassan El , Tremblay Marie-Ève , Belleannée Clémence , Hébert Marie-Josée , Dieudé Mélanie , Rauch Joyce , Fortin Paul R. , Boilard Eric
Published: March 2019

Mitochondria are organelles that govern energy supply and control cell death. Mitochondria also express bacterial features, such as the presence of inner membrane cardiolipin and a circular genome rich in hypomethylated CpG motifs. While mitochondrial extrusion by damaged organs or activated cells is thought to trigger innate immunity, it is unclear whether extracellular mitochondria also stimulate an adaptive immune response. We describe the development of novel assays to detect autoantibodies specific to two distinct components of the mitochondrion: the mitochondrial outer membrane and mitochondrial DNA. Antibodies to these two mitochondrial constituents were increased in both human and murine systemic lupus erythematosus (SLE), compared to controls, and were present at higher levels than in patients with antiphospholipid syndrome or primary biliary cirrhosis. In both bi- and multi-variate regression models, antibodies to mitochondrial DNA, but not whole mitochondria, were associated with increased anti-dsDNA antibodies and lupus nephritis. This study describes new and optimized methods for the assessment of anti-mitochondrial antibodies, and demonstrates their presence in both human and murine SLE. These findings suggest that different mitochondrial components are immunogenic in SLE, and support the concept that extracellular mitochondria may provide an important source of circulating autoantigens in SLE.
Extended insight into the Mycobacterium chelonae-abscessus complex through whole genome sequencing of Mycobacterium salmoniphilum outbreak and Mycobacterium salmoniphilum-like strains
Authors: Behra Phani Rama Krishna , Das Sarbashis , Pettersson B. M. Fredrik , Shirreff Lisa , DuCote Tanner , Jacobsson Karl-Gustav , Ennis Don G. , Kirsebom Leif A.
Published: March 2019

Members of the Mycobacterium chelonae-abscessus complex (MCAC) are close to the mycobacterial ancestor and includes both human, animal and fish pathogens. We present the genomes of 14 members of this complex: the complete genomes of Mycobacterium salmoniphilum and Mycobacterium chelonae type strains, seven M. salmoniphilum isolates, and five M. salmoniphilum-like strains including strains isolated during an outbreak in an animal facility at Uppsala University. Average nucleotide identity (ANI) analysis and core gene phylogeny revealed that the M. salmoniphilum-like strains are variants of the human pathogen Mycobacterium franklinii and phylogenetically close to Mycobacterium abscessus. Our data further suggested that M. salmoniphilum separates into three branches named group I, II and III with the M. salmoniphilum type strain belonging to group II. Among predicted virulence factors, the presence of phospholipase C (plcC), which is a major virulence factor that makes M. abscessus highly cytotoxic to mouse macrophages, and that M. franklinii originally was isolated from infected humans make it plausible that the outbreak in the animal facility was caused by a M. salmoniphilum-like strain. Interestingly, M. salmoniphilum-like was isolated from tap water suggesting that it can be present in the environment. Moreover, we predicted the presence of mutational hotspots in the M. salmoniphilum isolates and 26% of these hotspots overlap with genes categorized as having roles in virulence, disease and defense. We also provide data about key genes involved in transcription and translation such as sigma factor, ribosomal protein and tRNA genes.
Dark-exciton valley dynamics in transition metal dichalcogenide alloy monolayers
Authors: Bragança Helena , Riche Flávio , Qu Fanyao , Lopez-Richard Victor , Marques Gilmar Eugenio
Published: March 2019

We report a comprehensive theory to describe exciton and biexciton valley dynamics in monolayer Mo1−xWxSe2 alloys. To probe the impact of different excitonic channels, including bright and dark excitons, intravalley biexcitons, intervalley scattering between bright excitons, as well as bright biexcitons, we have performed a systematic study from the simplest system to the most complex one. In contrast to the binary WSe2 monolayer with weak photoluminescence (PL) and high valley polarization at low temperatures and the MoSe2, that presents high PL intensity, but low valley polarization, our results demonstrate that it is possible to set up a ternary alloy with intermediate W-concentration that holds simultaneously a considerably robust light emission and an efficient optical orientation of the valley pseudospin. We find the critical value of W-concentration, xc, that turns alloys from bright to darkish. The dependence of the PL intensity on temperature shows three regimes: while bright monolayer alloys display a usual temperature dependence in which the intensity decreases with rising temperature, the darkish alloys exhibit the opposite behavior, and the alloys with x around xc show a non-monotonic temperature response. Remarkably, we observe that the biexciton enhances significantly the stability of the exciton emission against fluctuations of W-concentration for bright alloys. Our findings pave the way for developing high-performance valleytronic and photo-emitting devices.
An Effective Neutralizing Antibody Against Influenza Virus H1N1 from Human B Cells
Authors: Lee Cheng-Chung , Yang Chih-Ya , Lin Li-Ling , Ko Tzu-Ping , Chang Alarng Hsun-Lang , Chang Stanley Shi-Chung , Wang Andrew H.-J.
Published: March 2019

Influenza is a contagious acute respiratory disease caused by the influenza virus infection. Hemagglutinin (HA) is an important target in the therapeutic treatment and diagnostic detection of the influenza virus. Influenza A virus encompasses several different HA subtypes with different strains, which are constantly changing. In this study, we identified a fully human H1N1 neutralizing antibody (32D6) via an Epstein-Barr virus-immortalized B cell-based technology. 32D6 specifically neutralizes the clinically isolated H1N1 strains after the 2009 pandemic but not the earlier strains. The epitope was identified through X-ray crystallographic analysis of the 32D6-Fab/HA1 complex structure, which revealed a unique loop conformation located on the top surface of HA. The major region is composed of two peptide segments (residues 172–177 and 206–213), which form an abreast loop conformation. The residue T262 between the two loops forms a conformational epitope for recognition by 32D6. Three water molecules were observed at the interface of HA and the heavy chain, and they may constitute a stabilizing element for the 32D6-HA association. In addition, each 32D6-Fab is likely capable of blocking one HA trimer. This study provides important information on the strain specificity of 32D6 for the therapeutic treatment and detection of viral infection.
Network Pharmacology-Based identification of pharmacological mechanism of SQFZ injection in combination with Docetaxel on lung cancer
Authors: Li Tan , Baochen Zhu , Yue Zhang , Cheng Wang , Yali Wu , Zongxi Sun , Wantong Zhang , Yang Lu , Shouying Du
Published: March 2019

Docetaxel is the widely-used first-line therapy to treat lung cancer around the world. However, tumor progression and severe side effect occurred in some patients with docetaxel treatment. Most of the side effects were caused by immunocompromise, which limits the long-term use of docetaxel. Shenqi Fuzheng (SQFZ) injection has been used as adjuvant therapy to treat lung cancer which may enhance immunity as well. Owing to the complexity of drug combination, the mechanism of SQFZ injection in combination with docetaxel on lung cancer remains unclear. Therefore, a network pharmacology-based strategy was proposed in this study to help solve this problem. Network pharmacology approach comprising multiple components, candidate targets of component and therapeutic targets, has been used in this study. Also, in vivo and in vitro experiment was applied to verify the predicted targets from network pharmacology We established mouse lung cancer model and inject with docetaxel and SQFZ injection. Tumour weight, spleen index, thymus index, immunohistochemical staining and ELISA were conducted to evaluate the effect and underlying mechanisms of docetaxel and SQFZ injection. Besides A549 cells were also administrated by docetaxel and SQFZ.The indexes BCL2, CASP3 and CASP9 were determined after administration. The results indicated that combination of SQFZ and docetaxel could reduce tumour weight, enhance the spleen index, thymus index. Meanwhile, it could improve the activity of caspase-3 and IL-2 in mice and caspase-3, caspase-9 in A549 cell and inhibit the activity of BCL-2 in A549 cell, which verified the potential protective targets predicted by network pharmacology. In conclusion, combination of SQFZ and docetaxel could increase the curative effect by inducing tumour to apoptosis and play a key role on immunoprotection to reduce side effects.