bluuebunny/crossref_metadata_2025 huggingface dataset:
Patients with psoriatic arthritis who are not eligible for randomised controlled trials for TNF inhibitors have treatment response and drug survival similar to those who are eligible
Authors: Palsson Olafur , Love Thorvardur Jon , Gunnarsdottir Anna Ingibjorg , Gunnarsson Petur Sigurdur , Runarsdottir Eydis Erla , Krogh Niels Steen , Gudbjornsson Bjorn
Published: July 2019

Objectives

To determine in a retrospective cohort whether patients with psoriatic arthritis (PsA) who would not have fulfilled the inclusion criteria for randomised controlled trials (RCTs) for the TNF inhibitor (TNFi) chosen for their treatment (excl) have similar benefits and drug survival as those patients who would have (incl).

Methods

All patients with rheumatic disorders who are treated with biological disease-modifying antirheumatic drugs in Iceland are registered in ICEBIO. On 1 February 2016, 329 individuals with PsA were registered in ICEBIO, of whom 231 had data available for their first start of TNFi and could be evaluated according to the inclusion criteria of the respective RCTs. Disease activity was collected at baseline using Visual Analogue Scale (pain, fatigue and global (patient and physician) assessments), swollen joint count (SJC) and tender joint count (TJC), Disease Activity Score 28-joint count C reactive protein (DAS28-CRP) and Health Assessment Questionnaire (HAQ). Treatment response was measured at 6 and 18 months according to American College of Rheumatology response criteria, DAS28-CRP and Disease Activity Score in Psoriatic Arthritis for 28 joints. Drug survival rate was also analysed.

Results

The demographics of these two groups were similar at baseline, although the incl group had higher SJC (5.5 vs 3.8) and subsequently higher DAS28-CRP (4.6 vs 4.2). While a larger change in disease activity was observed in the incl group with respect to HAQ and SJC, both groups had similar disease activity at follow-up. Drug survival was similar in both groups.

Conclusions

Patients with PsA who would not have fulfilled the inclusion criteria in RCTs reach similar disease activity scores at follow-up of 6 and 18 months and have similar drug survival as those patients who would have been included in RCTs.
Petrochemistry and U–Pb (zircon) age of porphyry dykes at the McKenzie Gulch porphyry–skarn Cu–Ag–Au deposit, north-central New Brunswick, Canada: implications for emplacement age, tectonic setting, and mineralization potential
Authors: Massawe Ronald Joseph , Lentz David R.
Published: July 2019

North- to northeast-trending intermediate to felsic porphyry dykes in the McKenzie Gulch (MG) area intrude Upper Ordovician through Silurian calcareous sedimentary rocks of the Matapédia Group. These dykes are spatially associated with numerous copper–silver skarn occurrences. In this area, two distinct suites of dykes are recognized: plagioclase–hornblende porphyry (P–H) and quartz–plagioclase porphyry (Q–P). These suites yielded U–Pb (zircon) ages of 386.2 ± 3.1 Ma and 386.4 ± 3.3 Ma, respectively, indicating a coeval relationship and similar genesis despite slight geochemical and petrographical differences. Geochemical data indicate that the dykes are granodioritic to granitic to slightly tonalitic in composition with I-type and slab failure signatures. When compared with other granitoids in the region, the Murdochville suite in Gaspésie, Québec, is the only intrusion that exhibits slab failure magmatic signatures similar to the MG dykes. Magmas with slab failure signatures are compositionally similar to tonalite–trondhjemite–granodiorite (TTG) suites and adakites. They exhibit low Y and Yb concentrations and subsequent high Sr/Y and La/Yb ratios, which are interpreted to be the result of melting of subducting slab and mantle during the waning stages of collision and consequent slab failure. These processes were followed by assimilation and fractional crystallization of minerals such as hornblende and clinopyroxene (± titanite), which preferentially partition Y and heavy rare earth elements (HREE) in the absence of significant plagioclase. Magmas with similar geochemical characteristics worldwide have been proposed to be an important source for metals in most porphyry Cu and skarn deposits and consequently are a target during mineral exploration.
Coordination Mechanism for Contract Farming Supply Chain with Government Option Premium Subsidies
Authors: Yu Xing , Zhang Wei-Guo , Liu Yong-Jun
Published: July 2019

In this paper, we propose a new coordination mechanism of contract farming supply chain (hereinafter refer to as “company + farmer + option premium subsidy” or “the new/proposed mechanism”). In the new mechanism, the farmer’s interests are fully guarded by the protection price. Options are adopted by the company to hedge the downside risk and the government provides the company with option premium subsidies aiming to avoid default risk. The superiorities of the proposed mechanism compared with the traditional mechanism are illustrated in the theory and practical application. The results demonstrate that the proposed innovative subsidy mechanism is superior to the traditional and direct subsidy mechanism in regard of enhancing profits and increasing the order quantity, further to reduce the corporate default rate of the company. We also provide suggestions to determine the order quantity for the company and put forward a policy proposal to design the subsidy rate for the government. We advocate that the contract price and the strike price should be decided by the government rather than the company. We deem that the contract price should be the expected primary product price. The coordination of the proposed mechanism is reflected in making the entire supply chain more stable by balancing the interests of both the farmer and the company. By illustrating the predictions of our model under the case of a sudden change in the underlying parameters, we find that the proposed mechanism is robust even when higher volatility happens.
Research on Data Mining Algorithm Based on Pattern Recognition
Authors: Zhang Xuelong
Published: July 2019

With the advent of the era of big data, people are eager to extract valuable knowledge from the rapidly expanding data, so that they can more effectively use these massive storage data. The traditional data processing technology can only achieve basic functions such as data query and statistics, and cannot achieve the goal of extracting the knowledge existing in the data to predict the future trend. Therefore, along with the rapid development of database technology and the rapid improvement of computer’s computing power, data mining (DM) came into existence. Research on DM algorithms includes knowledge of various fields such as database, statistics, pattern recognition and artificial intelligence. Pattern recognition mainly extracts features of known data samples. The DM algorithm using pattern recognition technology is a better method to obtain effective information from massive data, thus providing decision support, and has a good application prospect. Support vector machine (SVM) is a new pattern recognition algorithm proposed in recent years, which avoids dimension disaster by dimensioning and linearization. Based on this, this paper studies the DM algorithm based on pattern recognition, and proposes a DM algorithm based on SVM. The algorithm divides the vector of the SV set into two different types and iterates through multiple iterations to obtain a classifier that converges to the final result. Finally, through the cross-validation simulation experiment, the results show that the DM algorithm based on pattern recognition can effectively reduce the training time and solve the mining problem of massive data. The results show that the algorithm has certain rationality and feasibility.
Combinational Counters: A Low Overhead Approach to Address DPA Attacks
Authors: Zarrinchian Ghobad , Zamani Morteza Saheb
Published: July 2019

Differential Power Analysis (DPA) attacks are known as viable and practical techniques to break the security of cryptographic algorithms. In this type of attack, an adversary extracts the encryption key based on the correlation of consumed power of the hardware running encryption algorithms to the processed data. To address DPA attacks in the hardware layer, various techniques have been proposed thus far. However, current techniques generally impose high performance overhead. Especially, the power overhead is a serious issue which may limit the applicability of current techniques in power-constrained applications. In this paper, combinational counters are explored as a way to address the DPA attacks. By randomizing the consumed power in each clock cycle of the circuit operation, these counters can enhance the resistance of the cryptographic cores against DPA attacks with low power overhead as well as zero timing overhead. Experimental results for an AES S-Box module in 45[Formula: see text]nm technology reveal that the proposed technique is capable of achieving higher level of security in comparison to two other approaches while preserving the power and performance overhead at a same or lower level.
Nonlinear Analysis for Bending, Buckling and Post-buckling of Nano-Beams with Nonlocal and Surface Energy Effects
Authors: Nguyen Thai Binh , Reddy J. N. , Rungamornrat Jaroon , Lawongkerd Jintara , Senjuntichai Teerapong , Luong Van Hai
Published: July 2019

The modeling and analysis for mechanical response of nano-scale beams undergoing large displacements and rotations are presented. The beam element is modeled as a composite consisting of the bulk material and the surface material layer. Both Eringen nonlocal elasticity theory and Gurtin–Murdoch surface elasticity theory are adopted to formulate the moment–curvature relationship of the beam. In the formulation, the pre-existing residual stress within the bulk material, induced by the residual surface tension in the material layer, is also taken into account. The resulting moment-curvature relationship is then utilized together with Euler–Bernoulli beam theory and the elliptic integral technique to establish a set of exact algebraic equations governing the displacements and rotations at the ends of the beam. The linearized version of those equations is also established and used in the derivation of a closed-form solution of the buckling load of nano-beams under various end conditions. A discretization-free solution procedure based mainly upon Newton iterative scheme and a selected numerical quadrature is developed to solve a system of fully coupled nonlinear equations. It is demonstrated that the proposed technique yields highly accurate results comparable to the benchmark analytical solutions. In addition, the nonlocal and surface energy effects play a significant role on the predicted buckling load, post-buckling and bending responses of the nano-beam. In particular, the presence of those effects remarkably alters the overall stiffness of the beam and predicted solutions exhibit strong size-dependence when the characteristic length of the beam is comparable to the intrinsic length scale of the material surface.
A CNN-BASED RETINAL IMAGE QUALITY ASSESSMENT SYSTEM FOR TELEOPHTHALMOLOGY
Authors: WANG XUEWEI , ZHANG SHULIN , LIANG XIAO , ZHENG CHUN , ZHENG JINJIN , Sun MINGZHAI
Published: July 2019

Oculopathy is a widespread disease among people of all ages around the world. Teleophthalmology can facilitate the ophthalmological diagnosis for less developed countries that lack medical resources. In teleophthalmology, the assessment of retinal image quality is of great importance. In this paper, we propose a no-reference retinal image assessment system based on DenseNet, a convolutional neural network architecture. This system classified fundus images into good and bad quality or five categories: adequate, just noticeable blur, inappropriate illumination, incomplete optic disc, and opacity. The proposed system was evaluated on different datasets and compared to the applications based on other two networks: VGG-16 and GoogLenet. For binary classification, the good-and-bad binary classifier achieves an AUC of 1.000, and the degradation-specified classifiers that distinguish one specified degradation versus the rest achieve AUC values of 0.972, 0.990, 0.982, 0.982 for four categories, respectively. The multi-classification based on DenseNet achieves an overall accuracy of 0.927, which is significantly higher than 0.549 and 0.757 obtained using VGG-16 and GoogLeNet, respectively. The experimental results indicate that the proposed approach produces outstanding performance in retinal image quality assessment and is worth applying in ophthalmological telemedicine applications. In addition, the proposed approach is robust to the image noise. This study fills the gap of multi-classification in retinal image quality assessment.
HEMODYNAMIC MECHANISM OF “BLOOD STOLEN” PHENOMENON IN CORONARY ARTERY ANEURYSM
Authors: ZHANG XIAOYAN , WU DANDAN , MAO BOYAN , LI BAO , YANG HAISHENG , LIU YOUJUN
Published: July 2019

Blood is lost in coronary artery aneurysm (CAA), leading to a decrease in downstream blood flow, called the “blood stolen” phenomenon. In the clinic, the “blood stolen” phenomenon may lead to dilated myocardial ischemia. The mechanism of dilated myocardial ischemia, which is different from that of stenotic myocardial ischemia, has not yet been studied. The purpose of this study is to reveal the mechanism of dilated myocardial ischemia induced by the “blood stolen” phenomenon. In this paper, a lumped parameter model of the cardiovascular system with a CAA was established, a parallel structure was used to represent CAA. Three different sized CAAs were simulated, and their upstream and downstream blood flows were observed. The results showed that small and medium CAAs lead to 5.21% and 9.57% reductions, respectively, in the downstream flow. Giant CAAs lead to a more than 14% reduction in the downstream flow, while the upstream blood flow showed diastolic backward flow. The results of this numerical simulation are consistent with the clinical description. When blood flows into CAAs, it cannot flow downstream normally, and due to the wall elasticity of the CAA, there is diastolic backward flow, eventually leading to dilated myocardial ischemia. With expansion of the CAA, the “blood stolen” phenomenon will be more severe.
EFFECT OF STENOSIS SEVERITY ON SHEAR-INDUCED DIFFUSION OF RED BLOOD CELLS IN CORONARY ARTERIES
Authors: BURADI ABDULRAJAK , MORAB SUMANT , MAHALINGAM ARUN
Published: July 2019

In large blood vessels, migration of red blood cells (RBCs) affects the concentration of platelets and the transport of oxygen to the arterial endothelial cells. In this work, we investigate the locations where hydrodynamic diffusion of RBCs occurs and the effects of stenosis severity on shear-induced diffusion (SID) of RBCs, concentration distribution and wall shear stress (WSS). For the first time, multiphase mixture theory approach with Phillips shear-induced diffusive flux model coupled with Quemada non-Newtonian viscosity model has been applied to numerically simulate the RBCs macroscopic behavior in four different degrees of stenosis (DOS) geometries, viz., 30%, 50%, 70% and 85%. Considering SID of RBCs, the calculated average WSS increased by 77.70% which emphasises the importance of SID in predicting hemodynamic parameters. At the stenosis throat, it was observed that 85% DOS model had the lowest concentration of RBCs near the wall and highest concentration at the center. For the stenosis models with 70% and 85% DOS, the RBC lumen wall concentration at the distal section of stenosis becomes inhomogeneous with the maximum fluctuation of 1.568%. Finally, the wall regions with low WSS and low RBC concentrations correlate well with the atherosclerosis sites observed clinically.
NUMERICAL SIMULATION OF APPARENT DENSITY EVOLUTION OF TRABECULAR BONE UNDER FATIGUE LOADING: EFFECT OF BONE INITIAL PROPERTIES
Authors: BARKAOUI ABDELWAHED , KAHLA RABEB BEN , MERZOUKI TAREK , HAMBLI RIDHA
Published: July 2019

Bone remodeling is a physiological phenomenon coupling resorption and formation processes that are mainly mediated by osteoclasts and osteoblasts, in response to mechanical stimuli transduced by osteocytes to biochemical signals activating the bone multicellular unit. Under normal loading conditions, bone resorption and formation are balanced by a homeostasis process. When bone is subjected to overstress, microdamaging occurs, which induces a modification of the structural integrity and microarchitecture. This has drawn significant attention to the mechanical properties of bone. In this context, the current study has been carried out with the aim of numerically investigating the impact of the mechanical properties on the remodeling process of the trabecular bone under cyclic loading, highlighting the effects of different values of the mineral density and the Young’s modulus. This was performed using a mechanobiological model, coupling mechanical and biological approaches, allowing to numerically simulate the effect of the selected parameters for a 20-year-period of cyclic loading for 2D and 3D models of a human femur head. The current work is an explorative numerical study, and the obtained results revealed the changes in the overall stiffness of the bone according to the mechanical properties.
Numerical Simulation of Cracking Process in Rock Mass Under the Coupled Thermo-Mechanical Condition
Authors: Liu Xuewei , Liu Quansheng , He Jun , Yu Fangzheng
Published: July 2019

To investigate crack initiation and propagation of rock mass under coupled thermo-mechanical (TM) condition, a two-dimensional coupled TM model based on the numerical manifold method (NMM) is proposed, considering the effect of thermal damage on the rock physical properties and stress on the heat conductivity. Then, the NMM, using empirical strength criteria as the crack propagation critical criterion and physical cover as the minimum failure element, was extended for cracking process simulation. Furthermore, a high-order cover function was used to improve the calculation accuracy of stress. Therefore, the proposed method consists of three parts and has a high accuracy for simulating the cracking process in the rock mass under the coupled TM condition. The ability of the proposed model for high accuracy stress, crack propagation, and thermally-induced cracking simulation was verified by three examples. Finally, the proposed method was applied to simulate the stability of a hypothetical nuclear waste repository. Based on the outcome of this study, the application of NMM can be extended to study rock failure induced by multi-field coupling effect in geo-materials.
A note on spinor form of Lovelock differential identity
Authors: Trishin Vladimir N.
Published: July 2019

The paper is devoted to 2-spinor calculus methods in general relativity. New spinor form of the Lovelock differential identity is suggested. This identity is second-order identity for the Riemann curvature tensor. We provide an example that our spinorial treatment of Lovelock identity is effective for the description of solutions of Einstein–Maxwell equations. It is shown that the covariant divergence of Lipkin’s zilch tensor for the free Maxwell field vanishes on the solutions of Einstein–Maxwell equations if and only if the energy–momentum tensor of the electromagnetic field is Weyl-compatible.
Geometry, Zitterbewegung, quantization
Authors: Fabbri Luca
Published: July 2019

In the most general geometric background, we study the Dirac spinor fields with particular emphasis given to the explicit form of their gauge momentum and the way in which this can be inverted so as to give the expression of the corresponding velocity; we study how Zitterbewegung affects the motion of particles, focusing on the internal dynamics involving the chiral parts; we discuss the connections to field quantization, sketching in what way anomalous terms may be gotten eventually.
Dynamic analysis and numerical simulation of Spider-Insect system with migration
Authors: Jiang Hongling , Wang Lijuan , Yuan Hailong
Published: July 2019

Taking the spider as a controller of the insects is a very important Green Agricultural Technology. We established a partial differential equation model by adding diffusion term into classical Spider-Insect Model. Using the fixed point index theory, the sufficient condition for the existence of positive solutions is given. Based on the method of parabolic equations, the persistence of positive solution is also studied. Finally, the theoretical results are verified by numerical simulations. Our work shows that intrinsic growth rate of an insect is an important factor that affects its existence and persistence under certain conditions.
Overexpression of Aurora-A bypasses cytokinesis through phosphorylation of suppressed in lung cancer
Authors: Chiu Shao-Chih , Chen Kun-Chieh , Hsia Jiun-Yi , Chuang Cheng-Yen , Wan Chang-Xin , Wei Tong-You Wade , Huang Yun-Ru Jaoying , Chen Jo-Mei Maureen , Liao Yu-Ting Amber , Yu Chang-Tze Ricky
Published: July 2019

Mitosis is a complicated process by which eukaryotic cells segregate duplicated genomes into two daughter cells. To achieve the goal, numerous regulators have been revealed to control mitosis. The oncogenic Aurora-A is a versatile kinase responsible for the regulation of mitosis including chromosome condensation, spindle assembly, and centrosome maturation through phosphorylating a range of substrates. However, overexpression of Aurora-A bypasses cytokinesis, thereby generating multiple nuclei by unknown the mechanisms. To explore the underlying mechanisms, we found that SLAN, a potential tumor suppressor, served as a substrate of Aurora-A and knockdown of SLAN induced immature cytokinesis. Aurora-A phosphorylates SLAN at T573 under the help of the scaffold protein 14-3-3η. The SLAN phosphorylation-mimicking mutants T573D or T573E, in contrast to the phosphorylation-deficiency mutant T573A, induced higher level of multinucleated cells, and the endogenous SLAN p573 resided at spindle midzone and midbody with the help of the microtubule motor MKLP1. The Aurora-A- or SLAN-induced multiple nuclei was prevented by the knockdown of 14-3-3η or Aurora-A respectively, thereby revealing a 14-3-3η/Aurora-A/SLAN cascade negatively controlling cytokinesis. Intriguingly, SLAN T573D or T573E inactivated and T573A activated the key cytokinesis regulator RhoA. RhoA interacted with SLAN np573, i.e., the nonphosphorylated form of SLAN at T573, which localized to the spindle midzone dictated by RhoA and ECT2. Therefore, we report here that SLAN mediates the Aurora-A-triggered cytokinesis bypass and SLAN plays dual roles in that process depending on its phosphorylation status.
The developmentally regulated fetal enterocyte gene, ZP4, mediates anti-inflammation by the symbiotic bacterial surface factor polysaccharide A on Bacteroides fragilis
Authors: Gorreja Frida , Rush Stephen TA , Kasper Dennis L. , Meng Di , Walker W. Allan
Published: July 2019

Initial colonizing bacteria play a critical role in completing the development of the immune system in the gastrointestinal tract of infants. Yet, the interaction of colonizing bacterial organisms with the developing human intestine favors inflammation over immune homeostasis. This characteristic of bacterial-intestinal interaction partially contributes to the pathogenesis of necrotizing enterocolitis (NEC), a devastating premature infant intestinal inflammatory disease. However, paradoxically some unique pioneer bacteria (initial colonizing species) have been shown to have a beneficial effect on the homeostasis of the immature intestine and the prevention of inflammation. We have reported that one such pioneer bacterium, Bacteroides fragilis ( B. fragilis), and its surface component polysaccharide A (PSA) inhibit IL-1β-induced inflammation in a human primary fetal small intestinal cell line (H4 cells). In this study, using transcription profiling of H4 cellular RNA after pretreatment with or without PSA before an inflammatory stimulation of IL-1β, we have begun to further determine the cellular mechanism for anti-inflammation. We show that a developmentally regulated gene, zona pellucida protein 4 ( ZP4), is uniquely elevated after IL-1β stimulation and reduced with PSA exposure. ZP4 was known as a sperm receptor-mediating species-specific binding protein in the initial life of mammals. However, its intestinal epithelial function is unclear. We found that ZP4 is a developmentally regulated gene involved with immune function and regulated by both Toll-like receptor 2 and 4. Knockdown of ZP4-affected PSA inhibited IL-8 mRNA expression in response to IL-1β. This represents an initial study of ZP4 innate immune function in immature enterocytes. This study may lead to new opportunity for efficient treatment of NEC.

NEW & NOTEWORTHY This study extends previous observations to define the cellular mechanisms of polysaccharide A-induced anti-inflammation in immature enterocytes using transcription profiling of enterocyte genes after preexposure to polysaccharide A before an inflammatory stimulus with IL-1β.
Analysis of biological networks in the endothelium with biomimetic microsystem platform
Authors: Kruse Kevin , Klomp Jeff , Sun Mitchell , Chen Zhang , Santana Dianicha , Huang Fei , Kanabar Pinal , Maienschein-Cline Mark , Komarova Yulia A.
Published: July 2019

Here we describe a novel method for studying the protein “interactome” in primary human cells and apply this method to investigate the effect of posttranslational protein modifications (PTMs) on the protein’s functions. We created a novel “biomimetic microsystem platform” (Bio-MSP) to isolate the protein complexes in primary cells by covalently attaching purified His-tagged proteins to a solid microscale support. Using this Bio-MSP, we have analyzed the interactomes of unphosphorylated and phosphomimetic end-binding protein-3 (EB3) in endothelial cells. Pathway analysis of these interactomes demonstrated the novel role of EB3 phosphorylation at serine 162 in regulating the protein’s function. We showed that phosphorylation “switches” the EB3 biological network to modulate cellular processes such as cell-to-cell adhesion whereas dephosphorylation of this site promotes cell proliferation. This novel technique provides a useful tool to study the role of PTMs or single point mutations in activating distinct signal transduction networks and thereby the biological function of the protein in health and disease.
The relationship between DJ-1 and S100A8 in human primary alveolar type II cells in emphysema
Authors: Lin Chih-Ru , Bahmed Karim , Tomar Dhanendra , Marchetti Nathaniel , Criner Gerard J. , Bolla Sudhir , Wilson Mark A. , Madesh Muniswamy , Kosmider Beata
Published: July 2019

Pulmonary emphysema is characterized by alveolar type II (ATII) cell death, destruction of alveolar wall septa, and irreversible airflow limitation. Cigarette smoke induces oxidative stress and is the main risk factor for this disease development. ATII cells isolated from nonsmokers, smokers, and patients with emphysema were used for this study. ATII cell apoptosis in individuals with this disease was detected. DJ-1 and S100A8 have cytoprotective functions against oxidative stress-induced cell injury. Reduced DJ-1 and S100A8 interaction was found in ATII cells in patients with emphysema. The molecular function of S100A8 was determined by an analysis of the oxidation status of its cysteine residues using chemoselective probes. Decreased S100A8 sulfination was observed in emphysema patients. In addition, its lower levels correlated with higher cell apoptosis induced by cigarette smoke extract in vitro. Cysteine at position 106 within DJ-1 is a central redox-sensitive residue. DJ-1 C106A mutant construct abolished the cytoprotective activity of DJ-1 against cell injury induced by cigarette smoke extract. Furthermore, a molecular and complementary relationship between DJ-1 and S100A8 was detected using gain- and loss-of-function studies. DJ-1 knockdown sensitized cells to apoptosis induced by cigarette smoke extract, and S100A8 overexpression provided cytoprotection in the absence of DJ-1. DJ-1 knockout mice were more susceptible to ATII cell apoptosis induced by cigarette smoke compared with wild-type mice. Our results indicate that the impairment of DJ-1 and S100A8 function may contribute to cigarette smoke-induced ATII cell injury and emphysema pathogenesis.
The role of DJ-1 in human primary alveolar type II cell injury induced by e-cigarette aerosol
Authors: Bahmed Karim , Lin Chih-Ru , Simborio Hannah , Karim Loukmane , Aksoy Mark , Kelsen Steven , Tomar Dhanendra , Madesh Muniswamy , Elrod John , Messier Elise , Mason Robert , Unterwald Ellen M. , Eisenstein Toby K. , Criner Gerard J. , Kosmider Beata
Published: July 2019

The alveolus participates in gas exchange, which can be impaired by environmental factors and toxins. There is an increase in using electronic cigarettes (e-cigarettes); however, their effect on human primary alveolar epithelial cells is unknown. Human lungs were obtained from nonsmoker organ donors to isolate alveolar type II (ATII) cells. ATII cells produce and secrete pulmonary surfactant and restore the epithelium after damage, and mitochondrial function is important for their metabolism. Our data indicate that human ATII cell exposure to e-cigarette aerosol increased IL-8 levels and induced DNA damage and apoptosis. We also studied the cytoprotective effect of DJ-1 against ATII cell injury. DJ-1 knockdown in human primary ATII cells sensitized cells to mitochondrial dysfunction as detected by high mitochondrial superoxide production, decreased mitochondrial membrane potential, and calcium elevation. DJ-1 knockout (KO) mice were more susceptible to ATII cell apoptosis and lung injury induced by e-cigarette aerosol compared with wild-type mice. Regulation of the oxidative phosphorylation (OXPHOS) is important for mitochondrial function and protection against oxidative stress. Major subunits of the OXPHOS system are encoded by both nuclear and mitochondrial DNA. We found dysregulation of OXPHOS complexes in DJ-1 KO mice after exposure to e-cigarette aerosol, which could disrupt the nuclear/mitochondrial stoichiometry, resulting in mitochondrial dysfunction. Together, our results indicate that DJ-1 deficiency sensitizes ATII cells to damage induced by e-cigarette aerosol leading to lung injury.
Vascular α1-adrenergic sensitivity is enhanced in chronic kidney disease
Authors: Sprick Justin D. , Morison Doree L. , Stein C. Michael , Li Yunxiao , Paranjape Sachin , Fonkoue Ida T. , DaCosta Dana R. , Park Jeanie
Published: July 2019

Chronic kidney disease (CKD) is often complicated by difficult-to-control hypertension, in part due to chronic overactivation of the sympathetic nervous system (SNS). CKD patients also exhibit a greater increase in arterial blood pressure for a given increase in sympathetic nerve activation, suggesting an augmented vasoconstrictive response to SNS activation (i.e., neurovascular transduction). One potential mechanism of increased sympathetic neurovascular transduction is heightened sensitivity of the vascular α1-adrenergic receptors (α1ARs), the major effectors of vasoconstriction in response to norepinephrine release at the sympathetic nerve terminals. Therefore, we hypothesized that patients with CKD have increased vascular α1AR sensitivity. We studied 32 patients with CKD stages III and IV (age 59.9 ± 1.3 yr) and 19 age-matched controls (CON, age 63.2 ± 1.6 yr). Using a linear variable differential transformer (LVDT), we measured change in venoconstriction in response to exponentially increasing doses of the selective α1AR agonist phenylephrine (PE) administered sequentially into a dorsal hand vein. Individual semilogarithmic PE dose-response curves were constructed for each participant to determine the PE dose at which 50% of maximum venoconstriction occurred (ED50), reflecting α1AR sensitivity. In support of our hypothesis, CKD patients had a lower PE ED50 than CON (CKD = 2.23 ± 0.11 vs. CON = 2.63 ± 0.20, P = 0.023), demonstrating increased vascular α1AR sensitivity. Additionally, CKD patients had a greater venoconstrictive capacity to PE than CON ( P = 0.015). Augmented α1AR sensitivity may contribute mechanistically to enhanced neurovascular transduction in CKD and may explain, in part, the greater blood pressure reactivity exhibited in these patients.
Increased pyruvate dehydrogenase activity in skeletal muscle of growth-restricted ovine fetuses
Authors: Pendleton Alexander L. , Humphreys Laurel R. , Davis Melissa A. , Camacho Leticia E. , Anderson Miranda J. , Limesand Sean W.
Published: July 2019

Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower fractional rates of glucose oxidation and greater gluconeogenesis, indicating lactate shuttling between skeletal muscle and liver. Suppression of pyruvate dehydrogenase ( PDH) activity was proposed because of greater pyruvate dehydrogenase kinase (PDK) 4 and PDK1 mRNA concentrations in IUGR muscle. Although PDK1 and PDK4 inhibit PDH activity to reduce pyruvate metabolism, PDH protein concentrations and activity have not been examined in skeletal muscle from IUGR fetuses. Therefore, we evaluated the protein concentrations and activity of PDH and the kinases and phosphatases that regulate PDH phosphorylation status in the semitendinosus muscle from placenta insufficiency-induced IUGR sheep fetuses and control fetuses. Immunoblots were performed for PDH, phosphorylated PDH (E1α), PDK1, PDK4, and pyruvate dehydrogenase phosphatase 1 and 2 (PDP1 and PDP2, respectively). Additionally, the PDH, lactate dehydrogenase (LDH), and citrate synthase (CS) enzymatic activities were measured. Phosphorylated PDH concentrations were 28% lower (P < 0.01) and PDH activity was 67% greater (P < 0.01) in IUGR fetal muscle compared with control. PDK1, PDK4, PDP1, PDP2, and PDH concentrations were not different between groups. CS and LDH activities were also unaffected. Contrary to the previous speculation, PDH activity was greater in skeletal muscle from IUGR fetuses, which parallels lower phosphorylated PDH. Therefore, greater expression of PDK1 and PDK4 mRNA did not translate to greater PDK1 or PDK4 protein concentrations or inhibition of PDH as proposed. Instead, these findings show greater PDH activity in IUGR fetal muscle, which indicates that alternative regulatory mechanisms are responsible for lower pyruvate catabolism.
Unsilencing of native LepRs in hypothalamic SF1 neurons does not rescue obese phenotype in LepR-deficient mice
Authors: Senn Seraina S. , Le Foll Christelle , Whiting Lynda , Tarasco Erika , Duffy Sonya , Lutz Thomas A. , Boyle Christina Neuner
Published: July 2019

Leptin receptor (LepR) signaling in neurons of the ventromedial nucleus of the hypothalamus (VMH), specifically those expressing steroidogenic factor-1 (SF1), have been proposed to play a key role in controlling energy balance. By crossing LepR-silenced (LepRloxTB) mice with those expressing SF1-Cre, we unsilenced native LepR specifically in the VMH and tested whether SF1 neurons in the VMH are critical mediators of leptin’s effect on energy homeostasis. LepRloxTB × SF1-Cre [knockout (KO)/Tg+] mice were metabolically phenotyped and compared with littermate controls that either expressed or were deficient in LepRs. Leptin-induced phosphorylated STAT3 was present in the VMH of KO/Tg+ mice and absent in other hypothalamic nuclei. VMH leptin signaling did not ameliorate obesity resulting from LepR deficiency in chow-fed mice. There was no change in food intake or energy expenditure when comparing complete LepR-null mice with KO/Tg+ mice, nor did KO/Tg+ mice show improved glucose tolerance. The presence of functional LepRs in the VMH mildly enhanced sensitivity to the pancreatic hormone amylin. When maintained on a high-fat diet (HFD), there was no reduction in diet-induced obesity in KO/Tg+ mice, but KO/Tg+ mice had improved glucose tolerance after 7 wk on an HFD compared with LepR-null mice. We conclude that LepR signaling in the VMH alone is not sufficient to correct metabolic dysfunction observed in LepR-null mice.
6-Shogaol protects against ischemic acute kidney injury by modulating NF-κB and heme oxygenase-1 pathways
Authors: Han Sang Jun , Kim Mihwa , D’Agati Vivette D. , Lee H. Thomas
Published: July 2019

Acute kidney injury (AKI) due to renal ischemia-reperfusion (I/R) is a major clinical problem without effective therapy. Ginger is one of the most widely consumed spices in the world, and 6-shogaol, a major ginger metabolite, has anti-inflammatory effects in neuronal and epithelial cells. Here, we demonstrate our novel findings that 6-shogaol treatment protected against renal I/R injury with decreased plasma creatinine, blood urea nitrogen, and kidney neutrophil gelatinase-associated lipocalin mRNA synthesis compared with vehicle-treated mice subjected to renal I/R. Additionally, 6-shogaol treatment reduced kidney inflammation (decreased proinflammatory cytokine and chemokine synthesis as well as neutrophil infiltration) and apoptosis (decreased TUNEL-positive renal tubular cells) compared with vehicle-treated mice subjected to renal I/R. In cultured human and mouse kidney proximal tubule cells, 6-shogaol significantly attenuated TNF-α-induced inflammatory cytokine and chemokine mRNA synthesis. Mechanistically, 6-shogaol significantly attenuated TNF-α-induced NF-κB activation in human renal proximal tubule cells by reducing IKKαβ/IκBα phosphorylation. Furthermore, 6-shogaol induced a cytoprotective chaperone heme oxygenase (HO)-1 via p38 MAPK activation in vitro and in vivo. Consistent with these findings, pretreatment with the HO-1 inhibitor zinc protoporphyrin IX completely prevented 6-shogaol-mediated protection against ischemic AKI in mice. Taken together, our study showed that 6-shogaol protects against ischemic AKI by attenuating NF-κB activation and inducing HO-1 expression. 6-Shogaol may provide a potential therapy for ischemic AKI during the perioperative period.
Solute and water transport along an inner medullary collecting duct undergoing peristaltic contractions
Authors: Layton Anita T.
Published: July 2019

The mechanism by which solutes accumulate in the inner medulla of the mammalian kidney has remained incompletely understood. That persistent mystery has led to hypotheses based on the peristaltic contractions of the pelvic wall smooth muscles. It has been demonstrated the peristaltic contractions propel fluid down the collecting duct in boluses. In antidiuresis, boluses are sufficiently short that collecting ducts may be collapsed most of the time. In this study, we investigated the mechanism by which about half of the bolus volume is reabsorbed into the collecting duct cells despite the short contact time. To accomplish this, we developed a dynamic mathematical model of solute and water transport along a collecting duct of a rat papilla undergoing peristaltic contractions. The model predicts that, given preexisting axial concentration gradients along the loops of Henle, ∼40% of the bolus volume is reabsorbed as the bolus flows down the inner medullary collecting duct. Additionally, simulation results suggest that while the contraction-induced luminal hydrostatic pressure facilitates water extraction from the bolus, that pressure is not necessary to concentrate the bolus. Also, neither the negative interstitial pressure generated during the relaxation phase nor the concentrating effect of hyaluronic acid has a significant effect on bolus concentration. Taken together, these findings indicate that the high collecting duct apical water permeability allows a substantial amount of water to be extracted from the bolus, despite its short transit time. However, the potential role of the peristaltic waves in the urine-concentrating mechanism remains to be revealed.
Between-ear sound frequency disparity modulates a brain stem biomarker of binaural hearing
Authors: Brown Andrew D. , Anbuhl Kelsey L. , Gilmer Jesse I. , Tollin Daniel J.
Published: July 2019

The auditory brain stem response (ABR) is an evoked potential that indexes a cascade of neural events elicited by sound. In the present study we evaluated the influence of sound frequency on a derived component of the ABR known as the binaural interaction component (BIC). Specifically, we evaluated the effect of acoustic interaural (between-ear) frequency mismatch on BIC amplitude. Goals were to 1) increase basic understanding of sound features that influence this long-studied auditory potential and 2) gain insight about the persistence of the BIC with interaural electrode mismatch in human users of bilateral cochlear implants, presently a limitation on the prospective utility of the BIC in audiological settings. Data were collected in an animal model that is audiometrically similar to humans, the chinchilla ( Chinchilla lanigera; 6 females). Frequency disparities and amplitudes of acoustic stimuli were varied over broad ranges, and associated variation of BIC amplitude was quantified. Subsequently, responses were simulated with the use of established models of the brain stem pathway thought to underlie the BIC. Collectively, the data demonstrate that at high sound intensities (≥85 dB SPL), the acoustically elicited BIC persisted with interaurally disparate stimulation (click frequencies ≥1.5 octaves apart). However, sharper tuning emerged at moderate sound intensities (65 dB SPL), with the largest BIC occurring for stimulus frequencies within ~0.8 octaves, equivalent to ±1 mm in cochlear place. Such responses were consistent with simulated responses of the presumed brain stem generator of the BIC, the lateral superior olive. The data suggest that leveraging focused electrical stimulation strategies could improve BIC-based bilateral cochlear implant fitting outcomes.

NEW & NOTEWORTHY Traditional hearing tests evaluate each ear independently. Diagnosis and treatment of binaural hearing dysfunction remains a basic challenge for hearing clinicians. We demonstrate in an animal model that the prospective utility of a noninvasive electrophysiological signature of binaural function, the binaural interaction component (BIC), depends strongly on the intensity of auditory stimulation. Data suggest that more informative BIC measurements could be obtained with clinical protocols leveraging stimuli restricted in effective bandwidth.
Estradiol rapidly modulates excitatory synapse properties in a sex- and region-specific manner in rat nucleus accumbens core and caudate-putamen
Authors: Krentzel Amanda A. , Barrett Lily R. , Meitzen John
Published: July 2019

Estradiol acutely facilitates sex differences in striatum-dependent behaviors. However, little is understood regarding the underlying mechanism. In striatal regions in adult rodents, estrogen receptors feature exclusively extranuclear expression, suggesting that estradiol rapidly modulates striatal neurons. We tested the hypothesis that estradiol rapidly modulates excitatory synapse properties onto medium spiny neurons (MSNs) of two striatal regions, the nucleus accumbens core and caudate-putamen in adult female and male rats. We predicted there would be sex-specific differences in pre- and postsynaptic locus and sensitivity. We further analyzed whether MSN intrinsic properties are predictive of estrogen sensitivity. Estradiol exhibited sex-specific acute effects in the nucleus accumbens core: miniature excitatory postsynaptic current (mEPSC) frequency robustly decreased in response to estradiol in female MSNs, and mEPSC amplitude moderately increased in response to estradiol in both male and female MSNs. This increase in mEPSC amplitude is associated with MSNs featuring increased intrinsic excitability. No MSN intrinsic electrical property associated with changes in mEPSC frequency. Estradiol did not acutely modulate mEPSC properties in the caudate-putamen of either sex. This is the first demonstration of acute estradiol action on MSN excitatory synapse function. This demonstration of sex and striatal region-specific acute estradiol neuromodulation revises our understanding of sex hormone action on striatal physiology and resulting behaviors.

NEW & NOTEWORTHY This study is the first to demonstrate rapid estradiol neuromodulation of glutamatergic signaling on medium spiny neurons (MSNs), the major output neuron of the striatum. These findings emphasize that sex is a significant biological variable both in MSN sensitivity to estradiol and in pre- and postsynaptic mechanisms of glutamatergic signaling. MSNs in different regions exhibit diverse responses to estradiol. Sex- and region-specific estradiol-induced changes to excitatory signaling on MSNs explain sex differences partially underlying striatum-mediated behaviors and diseases.
Molecular determinants of afferent sensitization in a rat model of cystitis with urothelial barrier dysfunction
Authors: Montalbetti Nicolas , Rooney James G. , Rued Anna C. , Carattino Marcelo D.
Published: July 2019

The internal surface of the urinary bladder is covered by the urothelium, a stratified epithelium that forms an impermeable barrier to urinary solutes. Increased urothelial permeability is thought to contribute to symptom generation in several forms of cystitis by sensitizing bladder afferents. In this report we investigate the physiological mechanisms that mediate bladder afferent hyperexcitability in a rat model of cystitis induced by overexpression in the urothelium of claudin-2 (Cldn2), a tight junction-associated protein upregulated in bladder biopsies from patients with interstitial cystitis/bladder pain syndrome. Patch-clamp studies showed that overexpression of Cldn2 in the urothelium sensitizes a population of isolectin GS-IB4-negative [IB4(−)] bladder sensory neurons with tetrodotoxin-sensitive (TTX-S) action potentials. Gene expression analysis revealed a significant increase in mRNA levels of the delayed-rectifier voltage-gated K+channel (Kv)2.2 and the accessory subunit Kv9.1 in this population of bladder sensory neurons. Consistent with this finding, Kv2/Kv9.1 channel activity was greater in IB4(−) bladder sensory neurons from rats overexpressing Cldn2 in the urothelium than in control counterparts. Likewise, current density of TTX-S voltage-gated Na+(Nav) channels was greater in sensitized neurons than in control counterparts. Significantly, guangxitoxin-1E (GxTX-1E), a selective blocker of Kv2 channels, blunted the repetitive firing of sensitized IB4(−) sensory neurons. In summary, our studies indicate that an increase in the activity of TTX-S Navand Kv2/Kv9.1 channels mediates repetitive firing of sensitized bladder sensory neurons in rats with increased urothelial permeability.

NEW & NOTEWORTHY Hyperexcitability of sensitized bladder sensory neurons in a rat model of interstitial cystitis/bladder pain syndrome (IC/BPS) results from increased activity of tetrodotoxin-sensitive voltage-gated Na+and delayed-rectifier voltage-gated K+(Kv)2/Kv9.1 channels. Of major significance, our studies indicate that Kv2/Kv9.1 channels play a major role in symptom generation in this model of IC/BPS by maintaining the sustained firing of the sensitized bladder sensory neurons.