bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting Extensively Drug-Resistant Mycobacterium tuberculosis Phenotypes with Genetic Mutations
Authors: Rodwell Timothy C. , Valafar Faramarz , Douglas James , Qian Lishi , Garfein Richard S. , Chawla Ashu , Torres Jessica , Zadorozhny Victoria , Kim Min Soo , Hoshide Matt , Catanzaro Donald , Jackson Lynn , Lin Grace , Desmond Edward , Rodrigues Camilla , Eisenach Kathy , Victor Thomas C. , Ismail Nazir , Crudu Valeru , Gler Maria Tarcela , Catanzaro Antonino
Published: December 2013

Molecular diagnostic methods based on the detection of mutations conferring drug resistance are promising technologies for rapidly detecting multidrug-/extensively drug-resistant tuberculosis (M/XDR TB), but large studies of mutations as markers of resistance are rare. The Global Consortium for Drug-Resistant TB Diagnostics analyzed 417
Mycobacterium tuberculosis
isolates from multinational sites with a high prevalence of drug resistance to determine the sensitivities and specificities of mutations associated with M/XDR TB to inform the development of rapid diagnostic methods. We collected M/XDR TB isolates from regions of high TB burden in India, Moldova, the Philippines, and South Africa. The isolates underwent standardized phenotypic drug susceptibility testing (DST) to isoniazid (INH), rifampin (RIF), moxifloxacin (MOX), ofloxacin (OFX), amikacin (AMK), kanamycin (KAN), and capreomycin (CAP) using MGIT 960 and WHO-recommended critical concentrations. Eight genes (
katG
,
inhA
,
rpoB
,
gyrA
,
gyrB
,
rrs
,
eis
, and
tlyA
) were sequenced using Sanger sequencing. Three hundred seventy isolates were INH
r
, 356 were RIF
r
, 292 were MOX
r
/OFX
r
, 230 were AMK
r
, 219 were CAP
r
, and 286 were KAN
r
. Four single nucleotide polymorphisms (SNPs) in
katG
/
inhA
had a combined sensitivity of 96% and specificities of 97 to 100% for the detection of INH
r
. Eleven SNPs in
rpoB
had a combined sensitivity of 98% for RIF
r
. Eight SNPs in
gyrA
codons 88 to 94 had sensitivities of 90% for MOX
r
/OFX
r
. The
rrs
1401/1484 SNPs had 89 to 90% sensitivity for detecting AMK
r
/CAP
r
but 71% sensitivity for KAN
r
. Adding
eis
promoter SNPs increased the sensitivity to 93% for detecting AMK
r
and to 91% for detecting KAN
r
. Approximately 30 SNPs in six genes predicted clinically relevant XDR-TB phenotypes with 90 to 98% sensitivity and almost 100% specificity.
Differential Impact of PD-1 and/or Interleukin-10 Blockade on HIV-1-Specific CD4 T Cell and Antigen-Presenting Cell Functions
Authors: Porichis Filippos , Hart Meghan G. , Zupkosky Jennifer , Barblu Lucie , Kwon Douglas S. , McMullen Ashley , Brennan Thomas , Ahmed Rafi , Freeman Gordon J. , Kavanagh Daniel G. , Kaufmann Daniel E.
Published: December 2013

Antigen persistence in chronic infections and cancer upregulates inhibitory networks, such as the PD-1 and interleukin-10 (IL-10) pathways, that impair immunity and lead to disease progression. These pathways are attractive targets for immunotherapy, as demonstrated by recent clinical trials of PD-1/PD-L1 blockade in cancer patients. However, in HIV-1 infection not all subjects respond to inhibition of either pathway and the mechanistic interactions between these two networks remain to be better defined. Here we demonstrate that
in vitro
blockade of PD-L1 and/or IL-10Rα results in markedly different profiles of HIV-1-specific CD4 T cell restoration. Whereas PD-L1 blockade leads to balanced increase in gamma interferon (IFN-γ), IL-2, and IL-13 secretion, IL-10Rα blockade preferentially restores IFN-γ production. In viremic subjects, combined PD-L1/IL-10Rα blockade results in a striking 10-fold increase in IFN-γ secretion by HIV-1-specific CD4 T cells that is not observed in subjects with spontaneous (elite controllers) or therapy-induced control of viral replication. In contrast to the dramatic increase in IFN-γ production, concurrent blockade has a marginal additive effect on IL-2 production, IL-13 secretion, and HIV-1-specific CD4 T cell proliferation. IFN-γ produced by T
helper
cells upregulates PD-L1, HLA I/II, and IL-12 expression by monocytes. The effect of combined blockade on IFN-γ was dependent on reciprocal reinforcement through IL-12. These studies provide crucial information on the different immunoregulatory qualities of PD-1 and IL-10 in progressive disease and link exhausted virus-specific CD4 T cells and monocytes in the regulation of IFN-γ and IL-12 secretion.

IMPORTANCE
Infection with HIV results in most people in uncontrolled viral replication and progressive weakening of the body defenses. In the absence of antiviral therapy, this process results in clinical disease, or AIDS. An important reason why HIV continues to multiply is that a population of white blood cells called CD4 T cells that targets the virus fails to work properly. At least part of this impairment is under the control of inhibitory mechanisms that can be blocked to improve the function of these CD4 T cells. In this report, we show that blocking one or two of the molecules involved, called PD-1 and IL-10, has different effects on the individual functions of these cells and that one is strongly improved. We investigate how these effects are caused by interactions between CD4 T cells and antigen-presenting cells. These observations can have implications for new therapeutic approaches in HIV infection.
An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread
Authors: Stebbing Rachael E. , Irvin Susan C. , Rivera-Serrano Efraín E. , Boehme Karl W. , Ikizler Mine , Yoder Jeffrey A. , Dermody Terence S. , Sherry Barbara
Published: December 2013

Immunoreceptor tyrosine-based activation motifs (ITAMs) are signaling domains located within the cytoplasmic tails of many transmembrane receptors and associated adaptor proteins that mediate immune cell activation. ITAMs also have been identified in the cytoplasmic tails of some enveloped virus glycoproteins. Here, we identified ITAM sequences in three mammalian reovirus proteins: μ2, σ2, and λ2. We demonstrate for the first time that μ2 is phosphorylated, contains a functional ITAM, and activates NF-κB. Specifically, μ2 and μNS recruit the ITAM-signaling intermediate Syk to cytoplasmic viral factories and this recruitment requires the μ2 ITAM. Moreover, both the μ2 ITAM and Syk are required for maximal μ2 activation of NF-κB. A mutant virus lacking the μ2 ITAM activates NF-κB less efficiently and induces lower levels of the downstream antiviral cytokine beta interferon (IFN-β) than does wild-type virus despite similar replication. Notably, the consequences of these μ2 ITAM effects are cell type specific. In fibroblasts where NF-κB is required for reovirus-induced apoptosis, the μ2 ITAM is advantageous for viral spread and enhances viral fitness. Conversely, in cardiac myocytes where the IFN response is critical for antiviral protection and NF-κB is not required for apoptosis, the μ2 ITAM stimulates cellular defense mechanisms and diminishes viral fitness. Together, these results suggest that the cell type-specific effect of the μ2 ITAM on viral spread reflects the cell type-specific effects of NF-κB and IFN-β. This first demonstration of a functional ITAM in a nonenveloped virus presents a new mechanism for viral ITAM-mediated signaling with likely organ-specific consequences in the host.
Human T-Cell Leukemia Virus Type 1 Tax-Deregulated Autophagy Pathway and c-FLIP Expression Contribute to Resistance against Death Receptor-Mediated Apoptosis
Authors: Wang Weimin , Zhou Jiansuo , Shi Juan , Zhang Yaxi , Liu Shilian , Liu Yanxin , Zheng Dexian
Published: December 2013

The human T-cell leukemia virus type 1 (HTLV-1) Tax protein is considered to play a central role in the process that leads to adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax-expressing cells show resistance to apoptosis induced by Fas ligand (FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). The regulation of Tax on the autophagy pathway in HeLa cells and peripheral T cells was recently reported, but the function and underlying molecular mechanism of the Tax-regulated autophagy are not yet well defined. Here, we report that HTLV-1 Tax deregulates the autophagy pathway, which plays a protective role during the death receptor (DR)-mediated apoptosis of human U251 astroglioma cells. The cellular FLICE-inhibitory protein (c-FLIP), which is upregulated by Tax, also contributes to the resistance against DR-mediated apoptosis. Both Tax-induced autophagy and Tax-induced c-FLIP expression require Tax-induced activation of IκB kinases (IKK). Furthermore, Tax-induced c-FLIP expression is regulated through the Tax-IKK-NF-κB signaling pathway, whereas Tax-triggered autophagy depends on the activation of IKK but not the activation of NF-κB. In addition, DR-mediated apoptosis is correlated with the degradation of Tax, which can be facilitated by the inhibitors of autophagy.

IMPORTANCE
Our study reveals that Tax-deregulated autophagy is a protective mechanism for DR-mediated apoptosis. The molecular mechanism of Tax-induced autophagy is also illuminated, which is different from Tax-increased c-FLIP. Tax can be degraded via manipulation of autophagy and TRAIL-induced apoptosis. These results outline a complex regulatory network between and among apoptosis, autophagy, and Tax and also present evidence that autophagy represents a new possible target for therapeutic intervention for the HTVL-1 related diseases.
Phosphorylation of a Herpes Simplex Virus 1 dUTPase by a Viral Protein Kinase, Us3, Dictates Viral Pathogenicity in the Central Nervous System but Not at the Periphery
Authors: Kato Akihisa , Shindo Keiko , Maruzuru Yuhei , Kawaguchi Yasushi
Published: December 2013

Herpes simplex virus 1 (HSV-1) encodes Us3 protein kinase, which is critical for viral pathogenicity in both mouse peripheral sites (e.g., eyes and vaginas) and in the central nervous systems (CNS) of mice after intracranial and peripheral inoculations, respectively. Whereas some Us3 substrates involved in Us3 pathogenicity in peripheral sites have been reported, those involved in Us3 pathogenicity in the CNS remain to be identified. We recently reported that Us3 phosphorylated HSV-1 dUTPase (vdUTPase) at serine 187 (Ser-187) in infected cells, and this phosphorylation promoted viral replication by regulating optimal enzymatic activity of vdUTPase. In the present study, we show that the replacement of vdUTPase Ser-187 by alanine (S187A) significantly reduced viral replication and virulence in the CNS of mice following intracranial inoculation and that the phosphomimetic substitution at vdUTPase Ser-187 in part restored the wild-type viral replication and virulence. Interestingly, the S187A mutation in vdUTPase had no effect on viral replication and pathogenic effects in the eyes and vaginas of mice after ocular and vaginal inoculation, respectively. Similarly, the enzyme-dead mutation in vdUTPase significantly reduced viral replication and virulence in the CNS of mice after intracranial inoculation, whereas the mutation had no effect on viral replication and pathogenic effects in the eyes and vaginas of mice after ocular and vaginal inoculation, respectively. These observations suggested that vdUTPase was one of the Us3 substrates responsible for Us3 pathogenicity in the CNS and that the CNS-specific virulence of HSV-1 involved strict regulation of vdUTPase activity by Us3 phosphorylation.

IMPORTANCE
Herpes simplex virus 1 (HSV-1) encodes a viral protein kinase Us3 which is critical for pathogenicity both in peripheral sites and in the central nervous systems (CNS) of mice following peripheral and intracranial inoculations, respectively. Whereas some Us3 substrates involved in Us3 pathogenicity in peripheral sites have been reported, those involved in Us3 pathogenicity in the CNS remain to be identified. Here, we report that Us3 phosphorylation of viral dUTPase (vdUTPase) at serine 187 (Ser-187), which has been shown to promote the vdUTPase activity, appears to be critical for viral virulence in the CNS but not for pathogenic effects in peripheral sites. Since HSV proteins critical for viral virulence in the CNS are, in almost all cases, also involved in viral pathogenicity at peripheral sites, this phosphorylation event is a unique report of a specific mechanism involved in HSV-1 virulence in the CNS.
Sequences Related to SUMO Interaction Motifs in Herpes Simplex Virus 1 Protein ICP0 Act Cooperatively To Stimulate Virus Infection
Authors: Everett Roger D. , Boutell Chris , Pheasant Kathleen , Cuchet-Lourenço Delphine , Orr Anne
Published: December 2013

Herpes simplex virus type 1 immediate-early protein ICP0 is an E3 ubiquitin ligase of the RING finger class that degrades several cellular proteins during infection. This activity is essential for its functions in stimulating efficient lytic infection and productive reactivation from latency. ICP0 targets a number of proteins that are modified by the small ubiquitin-like SUMO family of proteins, and it includes a number of short sequences that are related to SUMO interaction motifs (SIMs). Therefore, ICP0 has characteristics that are related to those of cellular SUMO-targeted ubiquitin ligase enzymes. Here, we analyze the impact of mutation of a number of SIM-like sequences (SLSs) within ICP0 on HSV-1 replication and gene expression and their requirement for ICP0-mediated degradation of both sumoylated and unmodified promyelocytic leukemia (PML) and other sumoylated cellular proteins. One SLS in the central portion of the ICP0 sequence (SLS4) was found to be absolutely required for targeting cellular sumoylated species in general and sumoylated forms of PML other than those of PML isoform I. Mutation of a group of SLSs in the C-terminal quarter of ICP0 also reduced ICP0-mediated degradation of sumoylated PML in a cooperative manner. Although mutation of individual SLSs caused only modest decreases in viral replication, combined mutation of SLS4 with SLS sequences in the C-terminal quarter of the protein reduced plaque formation efficiency by up to two orders of magnitude. These results provide further evidence that the biological activities of ICP0 are connected with host cell sumoylation events.

IMPORTANCE
Herpes simplex virus type 1 protein ICP0 plays important roles in regulating the initial stages of lytic infection and productive reactivation from latency. ICP0 mediates its effects through inducing the degradation of cellular proteins that have repressive effects on viral gene expression. An increasing number of cellular proteins are known to be sensitive to ICP0-mediated degradation; therefore, it is important to understand how ICP0 selects its substrates for degradation. This study identifies sequence motifs within ICP0 that are involved in targeting cellular proteins that are modified by the SUMO family of ubiquitin-like proteins and describes how mutation of combinations of these motifs causes a 100-fold defect in viral infectivity.
Urine C-peptide creatinine ratio can be used to assess insulin resistance and insulin production in people without diabetes: an observational study
Authors: Oram Richard A , Rawlingson Andrew , Shields Beverley M , Bingham Coralie , Besser Rachel E J , McDonald Tim J , Knight Bridget A , Hattersley Andrew T
Published: December 2013

Objectives

The current assessment of insulin resistance (IR) in epidemiology studies relies on the blood measurement of C-peptide or insulin. A urine C-peptide creatinine ratio (UCPCR) can be posted from home unaided. It is validated against serum measures of the insulin in people with diabetes. We tested whether UCPCR could be a surrogate measure of IR by examining the correlation of UCPCR with serum insulin, C-peptide and HOMA2 (Homeostasis Model Assessment 2)-IR in participants without diabetes and with chronic kidney disease (CKD).

Design

Observational study.

Setting

Single-centre clinical research facility.

Participants

37 healthy volunteers and 30 patients with CKD (glomerular filtration rate 15–60) were recruited.

Primary and secondary endpoints

Serum insulin, C-peptide and glucose at fasting (0), 30, 60, 90 and 120 min were measured during an oral glucose tolerance test (OGTT). Second-void fasting UCPCR and 120 min post-OGTT UCPCR were collected. HOMA2-IR was calculated using fasting insulin and glucose. The associations between UCPCR and serum measures were assessed using Spearman's correlations.

Results

In healthy volunteers, fasting second-void UCPCR strongly correlated with serum insulin (rs=0.69, p<0.0001), C-peptide (rs=0.73, p<0.0001) and HOMA2-IR (rs=−0.69, p<0.0001). 120 min post-OGTT UCPCR correlated strongly with C-peptide and insulin area under the curve. In patients with CKD, UCPCR did not correlate with serum C-peptide, insulin or HOMA2-IR.

Conclusions

In participants with normal renal function, UCPCR may be a simple, practical method for the assessment of IR in epidemiology studies.
Vibrocompaction properties of dry sand
Authors: Denies N. , Canou J. , Roux J.-N. , Holeyman A.
Published: December 2013

The fundamental understanding of the behaviour of dry sand as it is being vibrated is necessary to properly address a number of engineering issues, such as the vibrocompaction process. The present paper first summarizes experimental works focusing on the effects of vibrations on the volume change of dry cohesionless soils. Original experiments characterizing the behaviour of dry sand subjected to vertical vibration are then presented. The volume change and the motion pattern displayed by vertically vibrated sand particles are discussed. When cohesionless soil, placed in a cylindrical container, is vertically vibrated under the gravitational field (g), experiments performed on dry Fontainebleau sand allow the distinction between three types of dynamic behaviours depending on the acceleration amplitude (a): the densification behaviour (a/g < 1), the instability surface behaviour (a/g ≈ 1), and the vibrofluid behaviour (a/g > 1). In the densification range, the sand simply settles. When the acceleration amplitude is increased beyond 1g, granular convection is observed and there is an instability in the sand mass leading to the emergence of an inclined free surface. If the acceleration amplitude is further increased, the free surface progressively flattens. There is an impressive dilatation of the whole sample and grain saltation is observed. The sand becomes fully vibrofluidized. The efficiency of the vibrocompaction process is finally discussed especially with regard to these dynamic behaviours.
AN M/M/1 QUEUE IN RANDOM ENVIRONMENT WITH DISASTERS
Authors: PAZ NOAM , YECHIALI URI
Published: December 2013

We study a M/M/1 queue in a multi-phase random environment, where the system occasionally suffers a disastrous failure, causing all present jobs to be lost. The system then moves to a repair phase. As soon as the system is repaired, it moves to phase i with probability qi ≥ 0. We use two methods of analysis to study the probabilistic behavior of the system in steady state: (i) via probability generating functions, and (ii) via matrix geometric approach. Due to the special structure of the Markov process describing the disaster model, both methods lead to explicit results, which are related to each other. We derive various performance measures such as mean queue sizes, mean waiting times, and fraction of lost customers. Two special cases are further discussed.
EFFICIENT LARGE-SCALE SERVICE CLUSTERING VIA SPARSE FUNCTIONAL REPRESENTATION AND ACCELERATED OPTIMIZATION
Authors: YU QI
Published: December 2013

Clustering techniques offer a systematic approach to organize the diverse and fast increasing Web services by assigning relevant services into homogeneous service communities. However, the ever increasing number of Web services poses key challenges for building large-scale service communities. In this paper, we tackle the scalability issue in service clustering, aiming to accurately and efficiently discover service communities over very large-scale services. A key observation is that service descriptions are usually represented by long but very sparse term vectors as each service is only described by a limited number of terms. This inspires us to seek a new service representation that is economical to store, efficient to process, and intuitive to interpret. This new representation enables service clustering to scale to massive number of services. More specifically, a set of anchor services are identified that allows each service to represent as a linear combination of a small number of anchor services. In this way, the large number of services are encoded with a much more compact anchor service space. Despite service clustering can be performed much more efficiently in the compact anchor service space, discovery of anchor services from large-scale service descriptions may incur high computational cost. We develop principled optimization strategies for efficient anchor service discovery. Extensive experiments are conducted on real-world service data to assess both the effectiveness and efficiency of the proposed approach. Results on a dataset with over 3,700 Web services clearly demonstrate the good scalability of sparse functional representation and the efficiency of the optimization algorithms for anchor service discovery.
DENSITY MEASUREMENT OF ETHANOL BLENDED FUELS
Authors: MAN JOHN
Published: December 2013

Density measurements for petro-ethanol blended fuels of various mixture ratios were conducted at temperatures from 5°C to 40°C using an oscillatory densitometer at the National Measurement Institute, Australia (NMIA). The petrol and ethanol fuels used for the preparation of samples of ethanol blends were supplied directly from a local petroleum refinery. Results were within the lower end of 0.06% repeatability and 0.3% reproducibility of the ASTM D4052-2011 method. The volume correction factors (VCF) for petrol and ethanol obtained from the measurement results agreed to within 0.1% and 0.01% of the values calculated as per American Petroleum Institute Standard 2540 Chapter 11.1 and 11.3.3 respectively. Based on a simple volume-mixture model, an equation was derived to calculate the VCF for petrol-ethanol blends. The measured and calculated values of VCF were in agreement within 0.1%. This paper presents the measurement method, results and the development of an equation for calculation of VCF for petro-ethanol blends.

Note from Publisher: This article contains the abstract only.
FLOW VELOCIMETRY FOR WEAKLY CONDUCTING ELECTROLYTES BASED ON HIGH RESOLUTION LORENTZFORCE MEASUREMENT
Authors: EBERT R. , VASILYAN S. , WIEDERHOLD A.
Published: December 2013

We demonstrate that a flow velocity measurement can be transformed into a non-invasive force measurement by metering the dragforce acting on a system of magnets that is arranged around a flow channel. This method is called Lorentzforce velocimetry and has been developed in the last years in our institute. It is a highly feasible principle for materials with large conductivity like liquid metals.

To evolve this method for weakly conducting fluids like salt water or molten glass the dragforce measurement is the challenging bottleneck. Here forces of 10−8 and less of the weightforce of the magnet system have to be resolved in the rather noisy environment of the flow channel.

In this paper different force measurement techniques get tested and compared. In the first setup the drag-force is acting on the magnets that are hanging as a pendulum with 0.5 m long wires on a mounting. Here the displacement in the range of a few μm can be detected with a laser interferometer and another optical positioning sensor. For the second setup the magnet system is attached to a state of the art electromagnetic force compensation balance. The balance is used in an unusual orientation: It is turned by 90 degrees to measure the horizontally acting Lorentzforce. Different ways of getting the correct force signal out of the two measurement setups will be presented and discussed.

For generalization of the measurement principle the Lorentzforce is determined for different fluid profiles. In addition to that we have developed new systematic noise reduction methods to increase the resolution of both force measurement techniques by a factor of ten or larger which we will present here.
Large-conductance voltage- and Ca2+-activated K+ channel regulation by protein kinase C in guinea pig urinary bladder smooth muscle
Authors: Hristov Kiril L. , Smith Amy C. , Parajuli Shankar P. , Malysz John , Petkov Georgi V.
Published: December 2013

Large-conductance voltage- and Ca2+-activated K+ (BK) channels are critical regulators of detrusor smooth muscle (DSM) excitability and contractility. PKC modulates the contraction of DSM and BK channel activity in non-DSM cells; however, the cellular mechanism regulating the PKC-BK channel interaction in DSM remains unknown. We provide a novel mechanistic insight into BK channel regulation by PKC in DSM. We used patch-clamp electrophysiology, live-cell Ca2+ imaging, and functional studies of DSM contractility to elucidate BK channel regulation by PKC at cellular and tissue levels. Voltage-clamp experiments showed that pharmacological activation of PKC with PMA inhibited the spontaneous transient BK currents in native freshly isolated guinea pig DSM cells. Current-clamp recordings revealed that PMA significantly depolarized DSM membrane potential and inhibited the spontaneous transient hyperpolarizations in DSM cells. The PMA inhibitory effects on DSM membrane potential were completely abolished by the selective BK channel inhibitor paxilline. Activation of PKC with PMA did not affect the amplitude of the voltage-step-induced whole cell steady-state BK current or the single BK channel open probability (recorded in cell-attached mode) upon inhibition of all major Ca2+ sources for BK channel activation with thapsigargin, ryanodine, and nifedipine. PKC activation with PMA elevated intracellular Ca2+ levels in DSM cells and increased spontaneous phasic and nerve-evoked contractions of DSM isolated strips. Our results support the concept that PKC activation leads to a reduction of BK channel activity in DSM via a Ca2+-dependent mechanism, thus increasing DSM contractility.
Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease
Authors: Ganji Shobha H. , Kukes Gary D. , Lambrecht Nils , Kashyap Moti L. , Kamanna Vaijinath S.
Published: December 2013

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis. Niacin decreases plasma triglycerides, but its effect on hepatic steatosis is elusive. To examine the effect of niacin on steatosis, rats were fed either a rodent normal chow, chow containing high fat (HF), or HF containing 0.5% or 1.0% niacin in the diet for 4 wk. For regression studies, rats were first fed the HF diet for 6 wk to induce hepatic steatosis and were then treated with niacin (0.5% in the diet) while on the HF diet for 6 wk. The findings indicated that inclusion of niacin at 0.5% and 1.0% doses in the HF diet significantly decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the HF diet significantly regressed steatosis. Niacin had no effect on the mRNA expression of fatty acid synthesis or oxidation genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase, and carnitine palmitoyltransferase 1) but significantly inhibited mRNA levels, protein expression, and activity of diacylglycerol acyltrasferase 2, a key enzyme in triglyceride synthesis. These novel findings suggest that niacin effectively prevents and causes the regression of experimental hepatic steatosis. Approved niacin formulation(s) for other indications or niacin analogs may offer a very cost-effective opportunity for the clinical development of niacin for treating NAFLD and fatty liver disease.
The physical basis of renal fibrosis: effects of altered hydrodynamic forces on kidney homeostasis
Authors: Grabias Bryan M. , Konstantopoulos Konstantinos
Published: December 2013

Healthy kidneys are continuously exposed to an array of physical forces as they filter the blood: shear stress along the inner lumen of the tubules, distension of the tubular walls in response to changing fluid pressures, and bending moments along both the cilia and microvilli of individual epithelial cells that comprise the tubules. Dysregulation of kidney homeostasis via underlying medical conditions such as hypertension, diabetes, or glomerulonephritis fundamentally elevates the magnitudes of each principle force in the kidney and leads to fibrotic scarring and eventual loss of organ function. The purpose of this review is to summarize the progress made characterizing the response of kidney cells to pathological levels of mechanical stimuli. In particular, we examine important, mechanically responsive signaling cascades and explore fundamental changes in renal cell homeostasis after cyclic strain or fluid shear stress exposure. Elucidating the effects of these disease-related mechanical imbalances on endogenous signaling events in kidney cells presents a unique opportunity to better understand the fibrotic process.
Hydrochlorothiazide attenuates lithium-induced nephrogenic diabetes insipidus independently of the sodium-chloride cotransporter
Authors: Sinke Anne P. , Kortenoeven Marleen L. A. , de Groot Theun , Baumgarten Ruben , Devuyst Olivier , Wetzels Jack F. M. , Loffing Johannes , Deen Peter M. T.
Published: December 2013

Lithium is the most common cause of nephrogenic diabetes insipidus (Li-NDI). Hydrochlorothiazide (HCTZ) combined with amiloride is the mainstay treatment in Li-NDI. The paradoxical antidiuretic action of HCTZ in Li-NDI is generally attributed to increased sodium and water uptake in proximal tubules as a compensation for increased volume loss due to HCTZ inhibition of the Na-Cl cotransporter (NCC), but alternative actions for HCTZ have been suggested. Here, we investigated whether HCTZ exerted an NCC-independent effect in Li-NDI. In polarized mouse cortical collecting duct (mpkCCD) cells, HCTZ treatment attenuated the Li-induced downregulation of aquaporin-2 (AQP2) water channel abundance. In these cells, amiloride reduces cellular Li influx through the epithelial sodium channel (ENaC). HCTZ also reduced Li influx, but to a lower extent. HCTZ increased AQP2 abundance on top of that of amiloride and did not affect the ENaC-mediated transcellular voltage. MpkCCD cells did not express NCC mRNA or protein. These data indicated that in mpkCCD cells, HCTZ attenuated lithium-induced downregulation of AQP2 independently of NCC and ENaC. Treatment of Li-NDI NCC knockout mice with HCTZ revealed a significantly reduced urine volume, unchanged urine osmolality, and increased cortical AQP2 abundance compared with Li-treated NCC knockout mice. HCTZ treatment further resulted in reduced blood Li levels, creatinine clearance, and alkalinized urinary pH. Our in vitro and in vivo data indicate that part of the antidiuretic effect of HCTZ in Li-NDI is NCC independent and may involve a tubuloglomerular feedback response-mediated reduction in glomerular filtration rate due to proximal tubular carbonic anhydrase inhibition.
Activity in early visual areas predicts interindividual differences in binocular rivalry dynamics
Authors: Yamashiro Hiroyuki , Yamamoto Hiroki , Mano Hiroaki , Umeda Masahiro , Higuchi Toshihiro , Saiki Jun
Published: December 2013

When dissimilar images are presented to the two eyes, binocular rivalry (BR) occurs, and perception alternates spontaneously between the images. Although neural correlates of the oscillating perception during BR have been found in multiple sites along the visual pathway, the source of BR dynamics is unclear. Psychophysical and modeling studies suggest that both low- and high-level cortical processes underlie BR dynamics. Previous neuroimaging studies have demonstrated the involvement of high-level regions by showing that frontal and parietal cortices responded time locked to spontaneous perceptual alternation in BR. However, a potential contribution of early visual areas to BR dynamics has been overlooked, because these areas also responded to the physical stimulus alternation mimicking BR. In the present study, instead of focusing on activity during perceptual switches, we highlighted brain activity during suppression periods to investigate a potential link between activity in human early visual areas and BR dynamics. We used a strong interocular suppression paradigm called continuous flash suppression to suppress and fluctuate the visibility of a probe stimulus and measured retinotopic responses to the onset of the invisible probe using functional MRI. There were ∼130-fold differences in the median suppression durations across 12 subjects. The individual differences in suppression durations could be predicted by the amplitudes of the retinotopic activity in extrastriate visual areas (V3 and V4v) evoked by the invisible probe. Weaker responses were associated with longer suppression durations. These results demonstrate that retinotopic representations in early visual areas play a role in the dynamics of perceptual alternations during BR.
Effects of short-latency afferent inhibition on short-interval intracortical inhibition
Authors: Udupa Kaviraja , Ni Zhen , Gunraj Carolyn , Chen Robert
Published: December 2013

Peripheral nerve stimulation inhibits the motor cortex, and the process has been termed short-latency afferent inhibition (SAI) at interstimulus intervals (ISIs) of ∼20 ms. The objective of the present study was to test how SAI interacts with short-interval intracortical inhibition (SICI) under different stimulation conditions. We studied 20 healthy volunteers. Surface electromyogram was recorded from the first dorsal interosseous muscle. Using paired- and triple-pulse paradigms, we investigated how SAI interacts with SICI under these different conditions. The effects of different conditioning stimulus (CS) intensities (0.6–0.9 active motor threshold), SAI latencies (23 and 25 ms), and ISIs (2 and 3 ms) for SICI were examined in rest and active conditions. SAI had inhibitory interactions with SICI at different CS intensities for rest or active SICI, at SAI latencies of 23 and 25 ms. This interaction occurred at weak CS intensities for SICI when there was no inhibition, and SICI became facilitatory in the presence of SAI. This can be explained by SICI inhibiting SAI and not by saturation of inhibition. The interaction between SAI and SICI was greater for SICI at ISI of 3 ms than for ISI of 2 ms, suggesting that different circuits may be activated at these ISIs. We conclude that SAI and SICI have inhibitory interactions that are influenced by factors such as ISI and muscle activities, which should be considered in design and interpretation of cortical interaction studies.
Cornel Iridoid Glycoside Attenuates Tau Hyperphosphorylation by Inhibition of PP2A Demethylation
Authors: Yang Cui-cui , Kuai Xue-xian , Li Ya-li , Zhang Li , Yu Jian-chun , Li Lin , Zhang Lan
Published: December 2013

Aim. The aim of the present study was to investigate the effect of cornel iridoid glycoside (CIG) on tau hyperphosphorylation induced by wortmannin (WT) and GF-109203X (GFX) and the underlying mechanisms.Methods. Human neuroblastoma SK-N-SH cells were preincubated with CIG (50, 100, and 200 µg/ml, resp.) for 24 h and then exposed to 10 µM WT and 10 µM GFX for 3 h after washing out CIG. Immunohistochemistry was used to observe the microtubular cytoskeleton of the cultured cells. Western blotting was used to measure the phosphorylation level of tau protein, glycogen synthase kinase 3β(GSK-3β), and protein phosphatase 2A (PP2A). The activity of PP2A was detected by a biochemical assay.Results. Preincubation of CIG significantly attenuated the WT/GFX-induced tau hyperphosphorylation at the sites of Thr205, Thr212, Ser214, Thr217, Ser396, and PHF-1 and improved the damage of morphology and microtubular cytoskeleton of the cells. CIG did not prevent the decrease in p-AKT-ser473 and p-GSK-3β-ser9 induced by WT/GFX. However, CIG significantly elevated the activity of PP2A by reducing the demethylation of PP2A catalytic subunit (PP2Ac) at Leu309 and the ratio of PME-1/LCMT in the WT/GFX-treated cells. The results suggest that CIG may be beneficial to the treatment of AD.
Abundant Explicit and Exact Solutions for the Variable Coefficient mKdV Equations
Authors: Zheng Xiaoxiao , Shang Yadong , Huang Yong
Published: December 2013

This paper is concerned with the variable coefficients mKdV (VC-mKdV) equation. First, through some transformation we convert VC-mKdV equation into the constant coefficient mKdV equation. Then, using the first integral method we obtain the exact solutions of VC-mKdV equation, such as rational function solutions, periodic wave solutions of triangle function, bell-shape solitary wave solution, kink-shape solitary wave solution, Jacobi elliptic function solutions, and Weierstrass elliptic function solution. Furthermore, with the aid of Mathematica, the extended hyperbolic functions method is used to establish abundant exact explicit solution of VC-mKdV equation. By the results of the equation, the first integral method and the extended hyperbolic function method are extended from the constant coefficient nonlinear evolution equations to the variable coefficients nonlinear partial differential equation.
Is All Human Hearing Cochlear?
Authors: Emami Seyede Faranak
Published: December 2013

The objective of this cross‐sectional study was to investigate the possibility that the saccule may contribute to human hearing. The forty participants included twenty healthy people and twenty other subjects selected from patients who presented with benign paroxysmal positional vertigo to Audiology Department of Hazrat Rasoul Akram hospital (Tehran, Iran). Assessments comprised of audiological evaluations, cervical vestibular evoked myogenic potentials (cVEMPs), recognition of spoken phonemes in white noise (Rsp in wn), and auditory brainstem response to 500 Hz tone burst (ABR500 HZ). Twenty affected ears with decreased vestibular excitability as detected by abnormal cVEMPs revealed decreased scores of Rsp in wn and abnormal findings of ABR500 HZ. Both unaffected and normal ears had normal results. Multiple comparisons of mean values of cVEMPs and ABR500 HZ between three groups were significant (P < 0.05, ANOVA). The correlation between RSP in wn and p13 latencies was significant. The peak‐to‐peak amplitudes showed significant correlation to RSP in wn. The correlation between RSP in wn and the latencies of n23 was significant. In high‐level of noisy competing situations, healthy human saccular sensation can mediate the detection of low frequencies and possibly help in cochlear hearing for frequency and intensity discrimination. So, all human hearing is not cochlear.
On a Nonsymmetric Keyfitz-Kranzer System of Conservation Laws with Generalized and Modified Chaplygin Gas Pressure Law
Authors: Cheng Hongjun , Yang Hanchun
Published: December 2013

This paper is devoted to the study of a nonsymmetric Keyfitz-Kranzer system of conservation laws with the generalized and modified Chaplygin gas pressure law, which may admit delta shock waves, a topic of interest. Firstly, we solve the Riemann problems with piecewise constant data having a single discontinuity. For the generalized Chaplygin gas pressure law, the solution consists of three different structures:R+J,S+J, andδ. Existence and uniqueness of delta shock solution are established under the generalized Rankine-Hugoniot relation and entropy condition. For the modified Chaplygin gas pressure law, the structures of solution areR+JandS+J. Secondly, we discuss the limits of Riemann solutions for the modified Chaplygin gas pressure law as the pressure law tends to the generalized Chaplygin gas one. In particular, for some cases, the solutionS+Jtends to a delta shock wave, and it is different from the delta shock wave for the generalized Chaplygin gas pressure law with the same initial data. Thirdly, we simulate the Riemann solutions and examine the formation process of delta shock wave by employing the Nessyahu-Tadmor scheme. The numerical results are coincident with the theoretical analysis.
Computable Throughput and Metastability in a Cellular Automaton Model for Traffic Flow
Authors: Gantner Ryan
Published: December 2013

A cellular automaton model for traffic flow is analyzed. For this model, it is shown that under ergodic initial configurations, the distribution of cars will converge in time to a mixture of free flow and solid blocks. Furthermore, the nature of the free flow and solid block distributions is fully described, thus allowing for a specific computation of throughput in terms of the parameters. The model is also shown to exhibit a hysteresis phenomenon, which is similar to what has been observed on actual highways.
Preparation and Enhancement of Thermal Conductivity of Heat Transfer Oil‐Based MoS2 Nanofluids
Authors: Zeng Yuan-Xian , Zhong Xiu-Wen , Liu Zhao-Qing , Chen Shuang , Li Nan
Published: December 2013

The lipophilic MoS2 nanoparticles are synthesized by surface modification with stearic acid (SA). The heat transfer oil‐based nanofluids, with the mass fraction of lipophilic nanoparticles varying from 0.25% up to 1.0%, are prepared and their thermal conductivity is determined at temperatures ranging from 40 to 200°C using an apparatus based on the laser flash method. It has been found that the nanofluids have higher thermal conductivity and the thermal conductivity enhancement increased not only with increasing mass fraction of nanoparticles, but also with increasing temperature in the range 40–180°C The results show a 38.7% enhancement of the thermal conductivity of MoS2 nanofluid with only 1.0% mass fraction at 180°C.
Modelling and Optimization Studies on a Novel Lipase Production by Staphylococcus arlettae through Submerged Fermentation
Authors: Chauhan Mamta , Chauhan Rajinder Singh , Garlapati Vijay Kumar
Published: December 2013

Microbial enzymes from extremophilic regions such as hot spring serve as an important source of various stable and valuable industrial enzymes. The present paper encompasses the modeling and optimization approach for production of halophilic, solvent, tolerant, and alkaline lipase from Staphylococcus arlettae through response surface methodology integrated nature inspired genetic algorithm. Response surface model based on central composite design has been developed by considering the individual and interaction effects of fermentation conditions on lipase production through submerged fermentation. The validated input space of response surface model (with R2 value of 96.6%) has been utilized for optimization through genetic algorithm. An optimum lipase yield of 6.5 U/mL has been obtained using binary coded genetic algorithm predicted conditions of 9.39% inoculum with the oil concentration of 10.285% in 2.99 hrs using pH of 7.32 at 38.8°C. This outcome could contribute to introducing this extremophilic lipase (halophilic, solvent, and tolerant) to industrial biotechnology sector and will be a probable choice for different food, detergent, chemical, and pharmaceutical industries. The present work also demonstrated the feasibility of statistical design tools integration with computational tools for optimization of fermentation conditions for maximum lipase production.
Determination of Ivermectin in Medicated Feeds by Liquid Chromatography with Fluorescence Detection
Authors: Pietruk Konrad , Jedziniak Piotr
Published: December 2013

A labour‐ and time‐effective analytical procedure for determination of ivermectin in medicated feed at recommended level of 2.0 mg kg−1 has been developed and validated. The analyte was extracted from grinded feed samples with acetonitrile and derivatisated with N‐methylimidazole and trifluoracetic anhydride. The fluorescent derivatives were analysed by liquid chromatography method using C8 column. The isocratic conditions using acetonitrile, methanol, water, and tetrahydrofuran were applied. Fluorescence detection was performed at 365 nm (excitation) and 475 nm (emission) wavelengths. The total analysis time was 10 min. The validation results of the method (within‐laboratory reproducibility 4.0% CV, mean recovery 100.1%) confirm the appropriate precision and accuracy of the developed method.
Phase‐Field Simulations at the Atomic Scale in Comparison to Molecular Dynamics
Authors: Berghoff Marco , Selzer Michael , Nestler Britta
Published: December 2013

Early solidification is investigated using two different simulation techniques: the molecular dynamics (MD) and the phase‐field (PF) methods. While the first describes the evolution of a system on the basis of motion equations of particles, the second grounds on the evolution of continuous local order parameter field. The aim of this study is to probe the ability of the mesoscopic phase‐field method to make predictions of growth velocity at the nanoscopic length scale. For this purpose the isothermal growth of a spherical crystalline cluster embedded in a melt is considered. The system in study is Ni modeled with the embedded atom method (EAM). The bulk and interfacial properties required in the PF method are obtained from MD simulations. Also the initial configuration obtained from MD data is used in the PF as input. Results for the evolution of the cluster volume at high and moderate undercooling are presented.
Fundal Height Growth Curve for Underweight and Overweight and Obese Pregnant Women in Thai Population
Authors: Deeluea Jirawan , Sirichotiyakul Supatra , Weerakiet Sawaek , Arora Rajin , Patumanond Jayanton
Published: December 2013

Objectives. To develop fundal height growth curves for underweight and overweight and obese pregnant women based on gestational age from last menstrual period and/or ultrasound. Methods. A retrospective study was conducted at four hospitals in the northern part of Thailand between January 2009 and March 2011. Fundal height, gestational age, height, and prepregnancy weight were extracted from antenatal care and delivery records. Fundal height growth curves were presented as smoothed function of the 10th, 50th, and 90th percentiles between 20 and 40 weeks of gestation, derived from multilevel models. Results. Fundal height growth curve of the underweight was derived from 1,486 measurements (208 women) and the overweight and obese curve was derived from 1,281 measurements (169 women). The 50th percentile line of the underweight was 0.1–0.4 cm below the normal weight at weeks 23–31 and 0.5–0.8 cm at weeks 32–40. The overweight and obese line was 0.1–0.4 cm above the normal weight at weeks 22–29 and 0.6–0.8 cm at weeks 30–40. Conclusions. Fundal height growth curves of the underweight and overweight and obese pregnant women were different from the normal weight. In monitoring or screening for abnormal intrauterine growth in these women, fundal height growth curves specifically developed for such women should be applied.
Chondroprotective Activity ofMurraya exoticathrough Inhibitingβ-Catenin Signaling Pathway
Authors: Wu Longhuo , Liu Haiqing , Zhang Rui , Li Linfu , Li Jialin , Hu Haibo , Huang Hao
Published: December 2013

Osteoarthritis (OA) is a degenerative joint disease that affects millions of people. Currently, there is no effective drug treatment for it. The purpose of this study is to investigate the chondroprotective effects ofMurraya exotica(L.) on OA. The rat OA models were duplicated to prepare for separating OA chondrocytes, synovial fluid (SF), and serum containingM. exotica(50 mg/kg, 100 mg/kg, and 200 mg/kg),M. exoticashowed the activity of decreasing the contents of TNF-αand IL-1βin SF and the chondrocyte apoptosis in a dose-dependent manner. To investigate the probable mechanism, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to determine gene expression and protein profiles, respectively. The results reveal thatM. exoticacan downregulate mRNA and protein expressions ofβ-catenin and COX-2 and reporter activity significantly. Conclusively,M. exoticaexhibits antiapoptotic chondroprotective activity probably through inhibitingβ-catenin signaling.