bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Paracoccin Gene Silencing on
Paracoccidioides brasiliensis
Virulence
Authors: Fernandes Fabrício F. , Oliveira Aline F. , Landgraf Taise N. , Cunha Cristina , Carvalho Agostinho , Vendruscolo Patrícia E. , Gonçales Relber A. , Almeida Fausto , da Silva Thiago A. , Rodrigues Fernando , Roque-Barreira Maria Cristina
Published: July 2017

Among the endemic deep mycoses in Latin America, paracoccidioidomycosis (PCM), caused by thermodimorphic fungi of the
Paracoccidioides
genus, is a major cause of morbidity. Disease development and its manifestations are associated with both host and fungal factors. Concerning the latter, several recent studies have employed the methodology of gene modulation in
P. brasiliensis
using antisense RNA (AsRNA) and
Agrobacterium tumefaciens
-mediated transformation (ATMT) to identify proteins that influence fungus virulence. Our previous observations suggested that paracoccin (PCN), a multidomain fungal protein with both lectin and enzymatic activities, may be a potential
P. brasiliensis
virulence factor. To explore this, we used AsRNA and ATMT methodology to obtain three independent PCN-silenced
P. brasiliensis
yeast strains (As
PCN1
, As
PCN2
, and As
PCN3
) and characterized them with regard to
P. brasiliensis
biology and pathogenicity. As
PCN1
, As
PCN2
, and As
PCN3
showed relative PCN expression levels that were 60%, 40%, and 60% of that of the wild-type (WT) strain, respectively. PCN silencing led to the aggregation of fungal cells, blocked the morphological yeast-to-mycelium transition, and rendered the yeast less resistant to macrophage fungicidal activity. In addition, mice infected with As
PCN1
, As
PCN2
, and As
PCN3
showed a reduction in fungal burden of approximately 96% compared with those inoculated with the WT strain, which displayed a more extensive destruction of lung tissue. Finally, mice infected with the PCN-silenced yeast strains had lower mortality than those infected with the WT strain. These data demonstrate that PCN acts as a
P. brasiliensis
contributory virulence factor directly affecting fungal pathogenesis.

IMPORTANCE
The nonexistence of efficient genetic transformation systems has hampered studies in the dimorphic fungus
Paracoccidioides brasiliensis
, the etiological agent of the most frequent systemic mycosis in Latin America. The recent development of a method for gene expression knockdown by antisense RNA technology, associated with an
Agrobacterium tumefaciens
-mediated transformation system, provides new strategies for studying
P. brasiliensis
. Through this technology, we generated yeasts that were silenced for paracoccin (PCN), a
P. brasiliensis
component that has lectin and enzymatic properties. By comparing the phenotypes of PCN-silenced and wild-type strains of
P. brasiliensis
, we identified PCN as a virulence factor whose absence renders the yeasts unable to undergo the transition to mycelium and causes a milder pulmonary disease in mice, with a lower mortality rate. Our report highlights the importance of the technology used for
P. brasiliensis
transformation and demonstrates that paracoccin is a virulence factor acting on fungal biology and pathogenesis.
A Nonredundant Phosphopantetheinyl Transferase, PptA, Is a Novel Antifungal Target That Directs Secondary Metabolite, Siderophore, and Lysine Biosynthesis in
Aspergillus fumigatus
and Is Critical for Pathogenicity
Authors: Johns Anna , Scharf Daniel H. , Gsaller Fabio , Schmidt Hella , Heinekamp Thorsten , Straßburger Maria , Oliver Jason D. , Birch Mike , Beckmann Nicola , Dobb Katharine S. , Gilsenan Jane , Rash Bharatkumar , Bignell Elaine , Brakhage Axel A. , Bromley Michael J.
Published: July 2017

Secondary metabolites are key mediators of virulence for many pathogens.
Aspergillus fumigatus
produces a vast array of these bioactive molecules, the biosynthesis of which is catalyzed by nonribosomal peptide synthetases (NRPSs) or polyketide synthases (PKSs). Both NRPSs and PKSs harbor carrier domains that are primed for acceptance of secondary metabolic building blocks by a phosphopantetheinyl transferase (P-pant). The
A. fumigatus
P-pant PptA has been shown to prime the putative NRPS Pes1
in vitro
and has an independent role in lysine biosynthesis; however, its role in global secondary metabolism and its impact on virulence has not been described. Here, we demonstrate that PptA has a nonredundant role in the generation of the vast majority of detectable secondary metabolites in
A. fumigatus
, including the immunomodulator gliotoxin, the siderophores triacetylfusarinine C (TAFC) and ferricrocin (FC), and dihydroxy naphthalene (DHN)-melanin. We show that both the lysine and iron requirements of a
pptA
null strain exceed those freely available in mammalian tissues and that loss of PptA renders
A. fumigatus
avirulent in both insect and murine infection models. Since PptA lacks similarity to its mammalian orthologue, we assert that the combined role of this enzyme in both primary and secondary metabolism, encompassing multiple virulence determinants makes it a very promising antifungal drug target candidate. We further exemplify this point with a high-throughput fluorescence polarization assay that we developed to identify chemical inhibitors of PptA function that have antifungal activity.

IMPORTANCE
Fungal diseases are estimated to kill between 1.5 and 2 million people each year, which exceeds the global mortality estimates for either tuberculosis or malaria. Only four classes of antifungal agents are available to treat invasive fungal infections, and all suffer pharmacological shortcomings, including toxicity, drug-drug interactions, and poor bioavailability. There is an urgent need to develop a new class of drugs that operate via a novel mechanism of action. We have identified a potential drug target, PptA, in the fungal pathogen
Aspergillus fumigatus
. PptA is required to synthesize the immunotoxic compound gliotoxin, DHN-melanin, which
A. fumigatus
employs to evade detection by host cells, the amino acid lysine, and the siderophores TAFC and FC, which
A. fumigatus
uses to scavenge iron. We show that strains lacking the PptA enzyme are unable to establish an infection, and we present a method which we use to identify novel antifungal drugs that inactivate PptA.
Distinct features distinguishing IgG4-related disease from multicentric Castleman's disease
Authors: Sasaki Takanori , Akiyama Mitsuhiro , Kaneko Yuko , Mori Takehiko , Yasuoka Hidekata , Suzuki Katsuya , Yamaoka Kunihiro , Okamoto Shinichiro , Takeuchi Tsutomu
Published: July 2017

Objectives

Differentiating IgG4-related disease (IgG4-RD) from multicentric Castleman’s disease (MCD) is challenging because both diseases present high serum IgG4. The objective of this study is to clarify the differences in characteristics and identify a clinically useful approach to differentiate these two diseases.

Methods

Forty-five consecutive patients with untreated active IgG4-RD and 33 patients with MCD were included in this study, who visited our institution from January 2000 to August 2016. The clinical and laboratory findings for the patients of the two diseases were compared. Various combinations of the distinctive findings were evaluated to identify the most efficient differentiating features between IgG4-RD and MCD.

Results

The levels of serum IgG4 were not different between the two diseases. Orbits, lacrimal glands, salivary glands or pancreas were involved in 88.9% of IgG4-RD cases and only in 3.0% of MCD cases. All MCD cases involved lymph nodes. Atopic history was characteristic for IgG4-RD. The levels of C reactive protein (CRP) with a cut-off of 0.80 mg/dL and IgA with a cut-off of 330 mg/dL were the most distinctive. The combination of ‘Orbits, lacrimal glands, salivary glands or pancreas involvement, atopic history, or non-involvement of lymph node’ and ‘CRP ≤ 0.8 mg/dL or IgA ≤ 330 mg/dL’ yielded the probability of 97.8% in IgG4-RD, while that of 3.0 % in patients with MCD.

Conclusions

Our study revealed distinct features between IgG4-RD and MCD. Differentiating between the diseases based on those distinct features, including distribution of organ involvement, atopic history, levels of IgA and CRP, was a useful approach.
Remarks on BEC on graphs
Authors: Kanda Tomohiro
Published: July 2017

We consider Bose–Einstein condensation (BEC) on graphs with transient adjacency matrix. We prove the equivalence of BEC and non-factoriality of the quasi-free state. Moreover, quasi-free states exhibiting BEC decompose into generalized coherent states. We review necessary and sufficient conditions that a quasi-free state is faithful, factor, and pure and quasi-free states are quasi-equivalent, including the papers of Araki and Shiraishi [1], Araki [2], and Araki and Yamagami [3]. Using their formats and results, we prove necessary and sufficient conditions that a generalized coherent state is faithful, factor, and pure and generalized coherent states are quasi-equivalent as well.
Link prediction via layer relevance of multiplex networks
Authors: Yao Yabing , Zhang Ruisheng , Yang Fan , Yuan Yongna , Sun Qingshuang , Qiu Yu , Hu Rongjing
Published: July 2017

In complex networks, the existing link prediction methods primarily focus on the internal structural information derived from single-layer networks. However, the role of interlayer information is hardly recognized in multiplex networks, which provide more diverse structural features than single-layer networks. Actually, the structural properties and functions of one layer can affect that of other layers in multiplex networks. In this paper, the effect of interlayer structural properties on the link prediction performance is investigated in multiplex networks. By utilizing the intralayer and interlayer information, we propose a novel “Node Similarity Index” based on “Layer Relevance” (NSILR) of multiplex network for link prediction. The performance of NSILR index is validated on each layer of seven multiplex networks in real-world systems. Experimental results show that the NSILR index can significantly improve the prediction performance compared with the traditional methods, which only consider the intralayer information. Furthermore, the more relevant the layers are, the higher the performance is enhanced.
Deep Multi-Instance Multi-Label Learning for Image Annotation
Authors: Guo Hai-Feng , Han Lixin , Su Shoubao , Sun Zhou-Bao
Published: July 2017

Multi-Instance Multi-Label learning (MIML) is a popular framework for supervised classification where an example is described by multiple instances and associated with multiple labels. Previous MIML approaches have focused on predicting labels for instances. The idea of tackling the problem is to identify its equivalence in the traditional supervised learning framework. Motivated by the recent advancement in deep learning, in this paper, we still consider the problem of predicting labels and attempt to model deep learning in MIML learning framework. The proposed approach enables us to train deep convolutional neural network with images from social networks where images are well labeled, even labeled with several labels or uncorrelated labels. Experiments on real-world datasets demonstrate the effectiveness of our proposed approach.
Leibniz algebras whose subideals are ideals
Authors: Kurdachenko Leonid A. , Subbotin Igor Ya. , Yashchuk Viktoriia S.
Published: July 2017

In this paper, we obtain the description of hyperabelian Leibniz algebras, whose subideals are ideals.
Euler quotients and Wilson quotients for polynomials over finite local rings
Authors: Iamthong Kittitat , Meemark Yotsanan
Published: July 2017

In this work, we introduce the Euler quotients and the Euler quotients of degree [Formula: see text] in polynomial rings over finite local rings. We have some analogous congruences as in the case of polynomial rings over finite fields. Moreover, we relate the sum of Euler quotients to Wilson quotient and obtain some nice congruences which allow us to have Lerch quotients.
Cooperative Vision-Based Object Transportation by Two Humanoid Robots in a Cluttered Environment
Authors: Rioux Antoine , Esteves Claudia , Hayet Jean-Bernard , Suleiman Wael
Published: July 2017

Although in recent years, there have been quite a few studies aimed at the navigation of robots in cluttered environments, few of these have addressed the problem of robots navigating while moving a large or heavy object. Such a functionality is especially useful when transporting objects of different shapes and weights without having to modify the robot hardware. In this work, we tackle the problem of making two humanoid robots navigate in a cluttered environment while transporting a very large object that simply could not be moved by a single robot. We present a complete navigation scheme, from the incremental construction of a map of the environment and the computation of collision-free trajectories to the design of the control to execute those trajectories. We present experiments made on real NAO robots, equipped with RGB-D sensors mounted on their heads, moving an object around obstacles. Our experiments show that a significantly large object can be transported without modifying the robot main hardware, and therefore that our scheme enhances the humanoid robots capacities in real-life situations.

Our contributions are: (1) a low-dimension multi-robot motion planning algorithm that finds an obstacle-free trajectory, by using the constructed map of the environment as an input, (2) a framework that produces continuous and consistent odometry data, by fusing the visual and the robot odometry information, (3) a synchronization system that uses the projection of the robots based on their hands positions coupled with the visual feedback error computed from a frontal camera, (4) an efficient real-time whole-body control scheme that controls the motions of the closed-loop robot–object–robot system.
Comparison Approach of Intersection Distances for Advanced TOA Trilateration
Authors: Hwang Suk-Seung , Pradhan Sajina
Published: July 2017

The time of arrival trilateration method is one of the representative algorithms for the location detection technology, which estimates the location of mobile station (MS) at a unique intersection point of three circles with radiuses corresponding to distances between MS and base stations (BSs) and centers corresponding to coordinates of BSs. However, there may be serious estimation errors, when they do not meet at a point because the estimated radiuses of them are increased. The solutions for reducing the estimation position error in the main case of meeting three circles with the extended radius have been recently provided as the shortest distance algorithm and the line intersection algorithm. In general, they have good performance for the location estimation, but they may have serious errors in some cases. In this paper, we propose the efficient location estimation algorithm for the specific case of two large circles and one relatively small circle, which is located in the area of two large circles. In this case, there are six intersections in total based on the three extended circles and a small circle has four intersections with two large circles. The proposed approach compares four distances based on four neighboring intersections and selects the shortest one. Finally, it determines the averaged coordinate of two intersections corresponding to the shortest distance, as the location of MS. The location-estimating performance of the proposed algorithm is illustrated by the computer simulation example.
Interplay Among Constitutes of Ebola Virus: Nucleoprotein, Polymerase L, Viral Proteins
Authors: Zhang Minchuan , He Peiming , Su Jing , Singh Dadabhai T. , Su Hailei , Su Haibin
Published: July 2017

Ebola virus is a highly lethal filovirus, claimed thousands of people in its recent outbreak. Seven viral proteins constitute ebola viral structure, and four of them (nucleoprotein (NP), polymerase L, VP35 and VP30) participate majorly in viral replication and transcription. We have elucidated a conformation change of NP cleft by VP35 NP-binding protein domains through superimposing two experimental NP structure images and discussed the function of this conformation change in the replication and transcription with polymerase complex (L, VP35 and VP30). The important roles of VP30 in viral RNA synthesis have also been discussed. A “tapping” model has been proposed in this paper for a better understanding of the interplay among the four viral proteins (NP, polymerase L, VP35 and VP30). Moreover, we have pinpointed some key residue changes on NP (both NP N- and C-terminal) and L between Reston and Zaire by computational studies. Together, this paper provides a description of interactions among ebola viral proteins (NP, L, VP35, VP30 and VP40) in viral replication and transcription, and sheds light on the complex system of viral reproduction.
Property Rights and CDS Spreads: When Is There a Strong Transfer Risk from the Sovereigns to the Corporates?
Authors: Bai Jennie , Wei Shang-Jin
Published: July 2017

When a sovereign faces the risk of debt default, it attempts to expropriate the private sector. But the likelihood of a transfer from the sovereign risk to corporate default risk can be mitigated by legal institutions that provide strong property rights protection. Using a novel credit default swaps (CDSs) dataset covering both government and corporate entities across 30 countries, this paper studies the strength of the transfer risk and the role of institutions in mitigating such risk. We find that sovereign risk on average has a statistically and economically significant influence on corporate credit risk. All else equal, a 100 basis points increase in the sovereign CDS spread leads to an increase in corporate CDS spreads by 74 basis points. The sovereign–corporate relation varies across corporations, with state-owned companies exhibiting a stronger relation. However, strong property rights institutions tend to weaken the connection. In contrast, contracting institutions (protection of creditor rights or minority shareholder rights) do not appear to matter in this context.
What Does Catastrophe Reveal for Whom? The Anthropology of Crises and Disasters at the Onset of the Anthropocene
Authors: Barrios Roberto E.
Published: July 2017

The modernist usage of the word crisis conveys the idea of an event that acts as a historical judgment, marks an epochal transition, and sometimes leads to a utopian era. Furthermore, current uses of crisis in the political sphere often figure catastrophic events as the result of errors and malfunctions, drawing attention away from the quotidian and normatively accepted practices and policies that produce them. Anthropological definitions of disaster, in contrast, understand catastrophes as the end result of historical processes by which human practices enhance the materially destructive and socially disruptive capacities of geophysical phenomena, technological malfunctions, and communicable diseases and inequitably distribute disaster risk according to lines of gender, race, class, and ethnicity. Despite this fundamental difference between customary and scholarly definitions of crises and disasters, the former term is commonly used to refer to the latter by political elites and academics alike. This article reviews the merits and limitations of the crisis concept in the analysis of disasters on the basis of anthropological research on catastrophes during the last 40 years and provides an overview of the analytical diversification of disaster anthropology since the 1970s.
Material Flow Accounting: Measuring Global Material Use for Sustainable Development
Authors: Krausmann Fridolin , Schandl Heinz , Eisenmenger Nina , Giljum Stefan , Jackson Tim
Published: July 2017

The growing extraction of natural resources and the waste and emissions resulting from their use are directly or indirectly responsible for humanity approaching or even surpassing critical planetary boundaries. A sound knowledge base of society's metabolism, i.e., the physical exchange processes between society and its natural environment and the production and consumption processes involved, is essential to develop strategies for more sustainable resource use. Economy-wide material flow accounting (MFA) is a framework that provides consistent compilations of the material inputs to national economies, changes in material stocks within the economic system, and material outputs to other economies and the environment. We present the conceptual foundations of MFA and derived indicators and review the current state of knowledge of global patterns and trends of extraction, trade, and use of materials. We discuss the relation of material use and economic development and the decoupling of material use from economic growth in the context of sustainable resource use policies.
Long-term effects of a renin inhibitor versus a thiazide diuretic on arterial stiffness and left ventricular diastolic function in elderly hypertensive patients
Authors: Okada Yoshiyuki , Shibata Shigeki , Fujimoto Naoki , Best Stuart A. , Levine Benjamin D. , Fu Qi
Published: July 2017

Arterial stiffness and cardiac function are important predictors of cardiovascular events in patients with hypertension, even with adequate blood pressure (BP) control. We evaluated whether a direct renin inhibitor, aliskiren, reduces arterial stiffness and modulates left ventricular function compared with a diuretic, hydrochlorothiazide, in elderly hypertensive patients. Twenty-one hypertensive patients [67 ± 14 (SD) yr] were randomly assigned to receive 6-mo aliskiren ( n = 11) or hydrochlorothiazide ( n = 10)-based therapy. We assessed β-stiffness of the local arteries, arterial elastance ( Ea), and echocardiographic variables, including early ( E) and late ( A) mitral inflow velocity, deceleration time of E, early ( E′) and late ( A′) diastolic mitral annular velocity, and left ventricular end-systolic elastance ( Ees) before and after treatment. BP decreased similarly ( P < 0.001) after both therapies. β-Stiffness of the carotid artery decreased after aliskiren but increased after hydrochlorothiazide treatment (aliskiren: 6.42 ± 2.34 pre vs. 5.07 ± 1.29 post; hydrochlorothiazide: 5.05 ± 1.78 vs. 7.25 ± 2.68, P = 0.001 for interaction). β-Stiffness of the femoral and radial arteries were not different after either treatment. Different from aliskiren, E decreased (73 ± 16 vs. 67 ± 14 cm/s, P = 0.026), and the deceleration time was prolonged (218 ± 40 vs. 236 ± 35 ms, P = 0.032) after hydrochlorothiazide therapy, whereas the E/ A, and E′ remained unchanged after both treatments. Ea and Ees decreased after aliskiren therapy (both P < 0.05), whereas the Ea/ Ees (ventricular-arterial coupling) was maintained after both treatments. Thus, aliskiren decreased the stiffness of carotid artery and left ventricular end-systolic elastance with maintenance of ventricular-arterial coupling without any effects on diastolic filling, while hydrochlorothiazide increased carotid arterial stiffness and slowed early diastolic filling in elderly hypertensive patients.
Orthodontic treatment-induced temporal alteration of jaw-opening reflex excitability
Authors: Sasaki Au , Hasegawa Naoya , Adachi Kazunori , Sakagami Hiroshi , Suda Naoto
Published: July 2017

The impairment of orofacial motor function during orthodontic treatment needs to be addressed, because most orthodontic patients experience pain and motor excitability would be affected by pain. In the present study, the temporal alteration of the jaw-opening reflex excitability was investigated to determine if orthodontic treatment affects orofacial motor function. The excitability of jaw-opening reflex evoked by electrical stimulation on the gingiva and recorded bilaterally in the anterior digastric muscles was evaluated at 1 (D1), 3 (D3), and 7 days (D7) after orthodontic force application to the teeth of right side; morphological features (e.g., osteoclast genesis and tooth movement) were also evaluated. To clarify the underlying mechanism of orthodontic treatment-induced alteration of orofacial motor excitability, analgesics were administrated for 1 day. At D1 and D3, orthodontic treatment significantly decreased the threshold for inducing the jaw-opening reflex but significantly increased the threshold at D7. Other parameters of the jaw-opening reflex were also evaluated (e.g., latency, duration and area under the curve of anterior digastric muscles activity), and only the latency of the D1 group was significantly different from that of the other groups. Temporal alteration of the jaw-opening reflex excitability was significantly correlated with changes in morphological features. Aspirin (300 mg·kg−1·day−1) significantly increased the threshold for inducing the jaw-opening reflex, whereas a lower dose (75–150 mg·kg−1·day−1) of aspirin or acetaminophen (300 mg·kg−1·day−1) failed to alter the jaw-opening reflex excitability. These results suggest that an increase of the jaw-opening reflex excitability can be induced acutely by orthodontic treatment, possibly through the cyclooxygenase activation.

NEW & NOTEWORTHY It is well known that motor function is affected by pain, but the effect of orthodontic treatment-related pain on the trigeminal motor excitability has not been fully understood. We found that, during orthodontic treatment, trigeminal motor excitability is acutely increased and then decreased in a week. Because alteration of trigeminal motor function can be evaluated quantitatively by jaw-opening reflex excitability, the present animal model may be useful to search for alternative approaches to attenuate orthodontic pain.
Associations between Specific Redox Biomarkers and Age in a Large European Cohort: The MARK‐AGE Project
Authors: Weber Daniela , Stuetz Wolfgang , Toussaint Olivier , Debacq-Chainiaux Florence , Dollé Martijn E. T. , Jansen Eugène , Gonos Efstathios S. , Franceschi Claudio , Sikora Ewa , Hervonen Antti , Breusing Nicolle , Sindlinger Thilo , Moreno-Villanueva María , Bürkle Alexander , Grune Tilman
Published: July 2017

Oxidative stress and antioxidants play a role in age‐related diseases and in the aging process. We here present data on protein carbonyls, 3‐nitrotyrosine, malondialdehyde, and cellular and plasma antioxidants (glutathione, cysteine, ascorbic acid, uric acid, α‐tocopherol, and lycopene) and their relation with age in the European multicenter study MARK‐AGE. To avoid confounding, only data from countries which recruited subjects from all three study groups (five of eight centers) and only participants aged ≥55 years were selected resulting in data from 1559 participants. These included subjects from (1) the general population, (2) members from long‐living families, and (3) their spouses. In addition, 683 middle‐aged reference participants (35–54 years) served as a control. After adjustment for age, BMI, smoking status, gender, and country, there were differences in protein carbonyls, malondialdehyde, 3‐nitrotyrosine, α‐tocopherol, cysteine, and glutathione between the 3 study groups. Protein carbonyls and 3‐nitrotyrosine as well as cysteine, uric acid, and lycopene were identified as independent biomarkers with the highest correlation with age. Interestingly, from all antioxidants measured, only lycopene was lower in all aged groups and from the oxidative stress biomarkers, only 3‐nitrotyrosine was increased in the descendants from long‐living families compared to the middle‐aged control group. We conclude that both lifestyle and genetics may be important contributors to redox biomarkers in an aging population.
CD36 Gene Polymorphisms Are Associated with Intracerebral Hemorrhage Susceptibility in a Han Chinese Population
Authors: Gong Qiu-Wen , Liao Mao-Fan , Liu Liang , Xiong Xiao-Yi , Zhang Qin , Zhong Qi , Zhou Kai , Yang Yuan-Rui , Meng Zhao-You , Gong Chang-Xiong , Xu Rui , Yang Qing-Wu
Published: July 2017

The CD36 gene encodes a membrane glycoprotein (type B scavenger receptor, SR-B2) that plays a crucial role in lipid sensing, innate immunity, atherogenesis, and glycolipid metabolism. In this study, we aimed to investigate the association between CD36 gene polymorphisms and intracerebral hemorrhage (ICH) in a Han Chinese population. We performed genotype and allele analyses for eleven single nucleotide polymorphisms (SNPs) of CD36 in a case-controlled study involving 292 ICH patients and 298 control participants. Eleven SNPs were genotyped by the Improved Multiple Ligase Detection Reaction (iMLDR) method. The results indicated that the SNP rs1194182 values were significantly different between ICH group and control group in a dominant model after adjusting for confounding factors. The subgroup analysis conducted for rs1194182 showed that the allele G frequencies were significantly different between ICH patients and controls in hypertension group via a dominant model. We then analyzed the rs1194182 genotype distributions among different groups of the serum lipid groups, including BMI, TC, TG, HDL, and LDL. However, no significant differences were found in the analysis of other subgroups. Taken together, these findings indicate that rs1194182 polymorphism in the CD36 gene was associated with ICH, and genotype GG could be an independent predictor.
Impaired mRNA Expression of the Migration Related Chemokine Receptor CXCR4 in Mesenchymal Stem Cells of COPD Patients
Authors: Karagiannis K. , Proklou A. , Tsitoura E. , Lasithiotaki I. , Kalpadaki C. , Moraitaki D. , Sperelakis I. , Kontakis G. , Antoniou K. M. , Tzanakis N.
Published: July 2017

Defective tissue repair and remodeling are main aspects of Chronic Obstructive Pulmonary Disease (COPD) pathophysiology. Bone marrow mesenchymal stem cells (BM-MSCs) have been implicated in this direction, as their functional impairment and recruitment could possibly contribute to disease development and progression. The present study characterizes for the first time the expression of migration related chemokine receptors and their ligands in BM-MSCs from COPD patients. CXCR4/SDF1a and CCR7/CCL19-CCL21 mRNA levels were evaluated in BM-MSCs obtained from twelve COPD patients and seven healthy donors. SDF1a protein levels in sera and BM-MSCs’ conditioned media were also evaluated. CXCR4, SDF1a, CCL19, and CCL21 mRNA levels were significantly reduced in COPD BM-MSCs while CCR7 levels were undetectable. Notably, SDF1a protein levels were marginally elevated in both patient sera and BM-MSCs’ conditioned media while the increase in SDF1a serum levels significantly correlated with disease severity in COPD. Our findings show posttranscriptional regulation of SDF1a levels in BM-MSCs of COPD patients and significant downregulation of SDF1a and CXCR4 mRNA indicating an involvement of the SDF1a signaling pathway in the disease pathophysiology.
Integron-Mediated Antibiotic Resistance inAcinetobacter baumanniiIsolated from Intensive Care Unit Patients, Babol, North of Iran
Authors: Deylam Salehi Mitra , Ferdosi-Shahandashti Elaheh , Yahyapour Yosef , Khafri Soraya , Pournajaf Abazar , Rajabnia Ramazan
Published: July 2017

Background. We investigated the integron types and their relation with antibiotic resistance amongA. baumanniiisolates collected from intensive care unit patients, Babol, north of Iran.Methods. In this cross-sectional study, a total of 73 bronchoalveolar lavage samples were obtained from patients in ICU. Susceptibility testing was performed by disk diffusion method. Types of integrons were identified by an integrase gene PCR.Results. In total, 47.9%A. baumanniiisolates were recovered from the BAL samples. All isolates were resistant to ceftazidime. 91.4% and 58.3% of isolates were MDR and XDR, respectively. The rate of colistin resistance with theE-test was 5.7%. Molecular analysis of class I, II, and III integrons showed that 25.7%, 88.6%, and 28.6% of the isolates carried theintI,intII, andintIIIgenes, respectively.Discussion. Our results show that different classes of integrons are commonly spread amongA. baumanniistrains and these genomic segments can play an important role in the acquisition of MDR and XDR phenotypes. So monitoring drug resistance inA. baumanniiisolates with the use ofintgene PCR is very important to plan specific infection control measures to prevent the spread of MDR-AB and XDR-AB in Iran’s hospitals.
Evaluation of Induced Settlements of Piled Rafts in the Coupled Static-Dynamic Loads Using Neural Networks and Evolutionary Polynomial Regression
Authors: Ghorbani Ali , Firouzi Niavol Mostafa
Published: July 2017

Coupled Piled Raft Foundations (CPRFs) are broadly applied to share heavy loads of superstructures between piles and rafts and reduce total and differential settlements. Settlements induced by static/coupled static-dynamic loads are one of the main concerns of engineers in designing CPRFs. Evaluation of induced settlements of CPRFs has been commonly carried out using three-dimensional finite element/finite difference modeling or through expensive real-scale/prototype model tests. Since the analyses, especially in the case of coupled static-dynamic loads, are not simply conducted, this paper presents two practical methods to gain the values of settlement. First, different nonlinear finite difference models under different static and coupled static-dynamic loads are developed to calculate exerted settlements. Analyses are performed with respect to different axial loads and pile’s configurations, numbers, lengths, diameters, and spacing for both loading cases. Based on the results of well-validated three-dimensional finite difference modeling, artificial neural networks and evolutionary polynomial regressions are then applied and introduced as capable methods to accurately present both static and coupled static-dynamic settlements. Also, using a sensitivity analysis based on Cosine Amplitude Method, axial load is introduced as the most influential parameter, while the ratio l/d is reported as the least effective parameter on the settlements of CPRFs.
Frame-Based Random Access with Interference Cancellation across Frames for Massive Machine Type Communications
Authors: Rim Minjoong , Chae Seungyeob
Published: July 2017

One of the main requirements for next generation mobile or wireless communication systems is to effectively support a large number of machine type communication devices for Internet of things applications. In order to improve the random access capability in frame-based slotted Aloha environments, coded random access techniques have been proposed, in which multiple copies of a packet are transmitted per frame and the copies are cancelled out from the received signal if any single copy is successfully received. They, however, may increase the transmission power by sending multiple copies per frame. Above all, for systems with a small number of slots per frame, they may not be able to improve the performance by readily reaching a congested state. This paper proposes a new frame-based random access scheme, which sends at most one copy of a packet per frame but uses interference cancellation to improve the performance. If a successfully received packet is a retransmitted one, the previously transmitted signals for the packet can be cancelled out from the received signals for trying to decode other received packets. The proposed scheme has different characteristics than coded random access schemes and can be also combined with them to further improve the performance.
Meprin Metalloprotease Deficiency Associated with Higher Mortality Rates and More Severe Diabetic Kidney Injury in Mice with STZ-Induced Type 1 Diabetes
Authors: Bylander John E. , Ahmed Faihaa , Conley Sabena M. , Mwiza Jean-Marie , Ongeri Elimelda Moige
Published: July 2017

Meprins are membrane-bound and secreted metalloproteinases consisting ofαand/orβsubunits that are highly expressed in kidney epithelial cells and are differentially expressed in podocytes and leukocytes (macrophages and monocytes). Several studies have implicated meprins in the progression of diabetic nephropathy (DN) and fibrosis-associated kidney disease. However, the mechanisms by which meprins modulate DN are not understood. To delineate the role of meprins in DN, we subjected meprinαβknockout (αβKO) mice and their wild-type (WT) counterparts to streptozotocin-induced type 1 diabetes. The 18-week survival rates were significantly lower for diabetic meprinαβKO mice when compared to those for their WT counterparts. There were significant decreases in mRNA and protein levels for both meprinαandβin diabetic WT kidneys. Furthermore, the blood urea nitrogen levels and urine albumin/creatinine ratios increased in diabetic meprinαβKO but not in diabetic WT mice, indicating that meprins may be protective against diabetic kidney injury. The brush border membrane levels of villin, a meprin target, significantly decreased in diabetic WT but not in diabetic meprinαβKO kidneys. In contrast, isoform-specific increases in cytosolic levels of the catalytic subunit of PKA, another meprin target, were demonstrated for both WT and meprinαβKO kidneys.
MicroRNA Regulation of Glycolytic Metabolism in Glioblastoma
Authors: Alfardus Huda , McIntyre Alan , Smith Stuart
Published: July 2017

Glioblastoma (GBM) is the most aggressive and common malignant brain tumour in adults. A well-known hallmark of GMB and many other tumours is aerobic glycolysis. MicroRNAs (miRNAs) are a class of short nonprotein coding sequences that exert posttranscriptional controls on gene expression and represent critical regulators of aerobic glycolysis in GBM. In GBM, miRNAs regulate the expression of glycolytic genes directly and via the regulation of metabolism-associated tumour suppressors and oncogenic signalling pathways. This review aims to establish links between miRNAs expression levels, the expression of GBM glycolytic regulatory genes, and the malignant progression and prognosis of GBM. In this review, the involvement of 25 miRNAs in the regulation of glycolytic metabolism of GBM is discussed. Seven of these miRNAs have been shown to regulate glycolytic metabolism in other tumour types. Further eight miRNAs, which are differentially expressed in GBM, have also been reported to regulate glycolytic metabolism in other cancer types. Thus, these miRNAs could serve as potential glycolytic regulators in GBM but will require functional validation. As such, the characterisation of these molecular and metabolic signatures in GBM can facilitate a better understanding of the molecular pathogenesis of this disease.
Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity
Authors: Oizel Kristell , Chauvin Cynthia , Oliver Lisa , Gratas Catherine , Geraldo Fanny , Jarry Ulrich , Scotet Emmanuel , Rabe Marion , Alves-Guerra Marie-Clotilde , Teusan Raluca , Gautier Fabien , Loussouarn Delphine , Compan Vincent , Martinou Jean-Claude , Vallette François M. , Pecqueur Claire
Published: July 2017

Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM.

Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry.

Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLNHigh and GLNLow, mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLNHigh GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLNHigh cultures are CD133neg and display a mesenchymal signature in contrast to CD133pos GLNLow GBM cells.

Conclusions: Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting. Clin Cancer Res; 23(20); 6292–304. ©2017 AACR.
Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia
Authors: Shen Na , Yan Fei , Pang Jiuxia , Zhao Na , Gangat Naseema , Wu Laichu , Bode Ann M. , Al-Kali Aref , Litzow Mark R. , Liu Shujun
Published: July 2017

Purpose: Receptor tyrosine kinases (RTKs) are frequently deregulated in leukemia, yet the biological consequences of this deregulation remain elusive. The mechanisms underlying aberrant methylation, a hallmark of leukemia, are not fully understood. Here we investigated the role of RTKs in methylation abnormalities and characterized the hypomethylating activities of RTK inhibitors.

Experimental Design: Whether and how RTKs regulate expression of DNA methyltransferases (DNMTs), tumor suppressor genes (TSGs) as well as global and gene-specific DNA methylation were examined. The pharmacologic activities and mechanisms of actions of RTK inhibitors in vitro, ex vivo, in mice, and in nilotinib-treated leukemia patients were determined.

Results: Upregulation of RTKs paralleled DNMT overexpression in leukemia cell lines and patient blasts. Knockdown of RTKs disrupted, whereas enforced expression increased DNMT expression and DNA methylation. Treatment with the RTK inhibitor, nilotinib, resulted in a reduction of Sp1-dependent DNMT1 expression, the diminution of global DNA methylation, and the upregulation of the p15INK4B gene through promoter hypomethylation in AML cell lines and patient blasts. This led to disruption of AML cell clonogenicity and promotion of cellular apoptosis without obvious changes in cell cycle. Importantly, nilotinib administration in mice and human patients with AML impaired expression of DNMTs followed by DNA hypomethylation, TSG re-expression, and leukemia regression.

Conclusions: Our findings demonstrate RTKs as novel regulators of DNMT-dependent DNA methylation and define DNA methylation status in AML cells as a pharmacodynamic marker for their response to RTK-based therapy, providing new therapeutic avenues for RTK inhibitors in overcoming epigenetic abnormalities in leukemia. Clin Cancer Res; 23(20); 6254–66. ©2017 AACR.
Population-Based Study on the Epidemiology of Ménière's Disease
Authors: Bruderer Saskia G. , Bodmer Daniel , Stohler Nadja A. , Jick Susan S. , Meier Christoph R.
Published: July 2017

Background and Objective: Ménière's disease (MD) is a disorder of the inner ear typically showing recurrent acute episodes of vertigo, hearing loss, and tinnitus. Epidemiologic studies on MD are scarce. We assessed the incidence rates (IRs) of MD and describe the characteristics of MD cases, comparing them to control patients without recorded evidence of MD. Study Design: We conducted a retrospective population-based follow-up study and a nested case-control analysis using data from the UK-based Clinical Practice Research Datalink. Methods: We identified patients between 18 and 79 years of age with an incident MD diagnosis between January 1993 and December 2014. We assessed the IRs of betahistine-treated MD. In the nested case-control analysis, we matched 4 controls to each MD case on sex, age, general practice, years of active history in the database, and calendar time. We conducted a χ2 test to present p values in order to compare the prevalence of demographics, comorbidities, and co-medication between cases and controls. Results: We identified 5,508 MD cases and 22,032 MD-free controls (65.4% females). The overall IR for MD in the UK was 13.1 per 100,000 person-years. More cases were female, and the mean age at diagnosis was 55.4 ± 13.7 years. Smoking and alcohol consumption were less prevalent among MD cases. Depression, other affective disorders, sleeping disorders, anxiety, and migraine were more prevalent among MD cases than among controls. Conclusions: MD is uncommon in primary care in the UK with a preponderance among females.
Exosomes: A Cancer Theranostics Road Map
Authors: Panagiotara Angeliki , Markou Athina , Lianidou Evi S. , Patrinos George P. , Katsila Theodora
Published: July 2017

Interindividual variability is yet to be fully characterized, and for this, optimum patient stratification and companion diagnostics are still lacking. Especially when complex disease phenotypes and/or polygenic diseases are considered, patient monitoring and disease management become rather challenging, while acquired resistance to therapy and/or toxicity events are among the unmet needs in the clinic. No doubt, biomarkers are of great importance to disease management and tailor-made theranostics. Microfluidics has gathered great attention lately, mostly due to its low-invasive nature compared to tissue biopsies. Low invasiveness becomes greatly advantageous for microfluidics practices as the latter mirror cell biology revolutionizing cancer diagnostics and management. Recent advances in microfluidics hold the promise of robust clinical diagnostics after they have demonstrated effective exosome separation. We feel that microfluidics-based exosome isolation techniques, if cost-effective, could be implemented in the clinic and/or resource-scarce settings. This article (a) discusses exosomes, (b) comments on the first microfluidic advances in the field of cancer theranostics, (c) presents such advances in exosomes as complementary to liquid biopsies with an emphasis on circulating tumor cells, and (d) proposes a road map for future developments.
Downregulation of Macrophage-Derived T-UCR uc.306 Associates with Poor Prognosis in Hepatocellular Carcinoma
Authors: Luo Hong-Lin , Chen Jie , Luo Tao , Wu Fei-Xiang , Liu Jun-Jie , Wang Hui-Feng , Chen Miao , Li Le-Qun , Li Hang
Published: July 2017

Background/Aims: Increasing evidence suggests that T-UCRs are involved in the development of cancer. In this study, we evaluated the role of a macrophage-derived T-UCR, uc.306, in the prognosis of hepatitis B (HBV)-related hepatocellular carcinoma (HCC). Methods: The uc.306 was obtained by screening microassay data obtained during the polarization of U937 cells from the M2 to M1 phenotype. Uc.306 and macrophage molecule markers were detected by qPCR. Immunohistochemical (IHC) assays were used to examine the M1/M2 status of 90 paired HCC tissues. Kaplan-Meier tests and multivariable Cox regression models were used to analyze predictive confidences, survival, and risk factors. Results: In total, 2,977 differentially expressed T-UCRs were obtained, of which 257 showed fold changes >1.5. The uc.306 was upregulated in M1 cells and was predicted to be involved in the Wnt pathway. The IHC results showed that M1 macrophages (CD68+) were present in the para-tumor tissues, while the M2 phenotype (CD163+) was mainly in the HCC tissues. Uc.306 had a lower expression in the HCC tissues than in that of the para-tumor tissues in 30 paired HCC training sets (P < 0.0001), and 252 paired HCC testing sets (P < 0.0001). Low expression of uc.306 was significantly associated with a shorter overall survival (P < 0.05). Conclusions: The uc.306 may be a promising biomarkerfor HBV-related HCC, providing a novel marker for the prognosis of HCC.