bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress increases descending inhibition in mouse and human colon
Authors: Reed D. E. , Zhang Y. , Beyak M. J. , Lourenssen S. , Blennerhassett M. G. , Paterson W. G. , Vanner S. J.
Published: January 2016

Background

A relationship between stress and the symptoms of irritable bowel syndrome (IBS) has been well established but the cellular mechanisms are poorly understood. Therefore, we investigated effects of stress and stress hormones on colonic descending inhibition and transit in mouse models and human tissues.

Methods

Stress was applied using water avoidance stress (WAS) in the animal model or mimicked using stress hormones, adrenaline (5 nM), and corticosterone (1 μM). Intracellular recordings were obtained from colonic circular smooth muscle cells in isolated smooth muscle/myenteric plexus preparations and the inhibitory junction potential (IJP) was elicited by nerve stimulation or balloon distension oral to the site of recording.

Key Results

Water avoidance stress increased the number of fecal pellets compared to control (p < 0.05). WAS also caused a significant increase in IJP amplitude following balloon distension. Stress hormones also increased the IJP amplitude following nerve stimulation and balloon distension (p < 0.05) in control mice but had no effect in colons from stressed mice. No differences were observed with application of ATP between stress and control tissues, suggesting the actions of stress hormones were presynaptic. Stress hormones had a large effect in the nerve stimulated IJP in human colon (increased >50%). Immunohistochemical studies identified alpha and beta adrenergic receptor immunoreactivity on myenteric neurons in human colon.

Conclusions & Inferences

These studies suggest that WAS and stress hormones can signal via myenteric neurons to increase inhibitory neuromuscular transmission. This could lead to greater descending relaxation, decreased transit time, and subsequent diarrhea.
Flicker‐defined form stimuli are minimally affected by centre‐surround lateral contrast interactions
Authors: Denniss Jonathan , McKendrick Allison M.
Published: January 2016

Purpose

Flicker‐defined form (FDF) stimuli have recently been adopted for visual field testing. A key difference between FDF and traditional perimetric stimuli is that the entire display background contains flickering dots. The purpose of this study was to determine whether the perception of FDF stimuli is influenced by lateral interactions involving regions beyond the stimulus border in young healthy observers.

Methods

Experiment 1 measured the effect of surround size and retinal eccentricity on the detection of the FDF contour. Psychometric functions were collected for surround diameters of 20°, 30° and 40°, and with stimuli centred at eccentricities of 0°, 10° and 20°. Experiment 2 measured the effect of target‐surround temporal phase difference on apparent temporal contrast (flicker strength) of the target for both the FDF stimulus and a solid‐field stimulus. Psychometric functions were collected for target‐surround phase differences of 0°, 45°, 90°, 135° and 180°.

Results

Our results show a mild surround‐suppression effect for FDF stimuli that is independent of surround size. Magnitudes of FDF surround suppression were consistent with the reduced temporal contrast energy of the stimulus compared to solid‐field stimuli.

Conclusion

FDF stimuli necessarily have both flickering target and background. Our results suggest that visual field defects outside the target are unlikely to markedly influence the detection and perception of the FDF stimulus. Nevertheless, mild surround suppression of contrast arises for FDF stimuli, hence interactions between the background and the target area may influence FDF results in conditions that alter centre‐surround perceptual effects.
Public Perceptions of Regulatory Costs, Their Uncertainty and Interindividual Distribution
Authors: Johnson Branden B. , Finkel Adam M.
Published: January 2016

Public perceptions of both risks and regulatory costs shape rational regulatory choices. Despite decades of risk perception studies, this article is the first on regulatory cost perceptions. A survey of 744 U.S. residents probed: (1) How knowledgeable are laypeople about regulatory costs incurred to reduce risks? (2) Do laypeople see official estimates of cost and benefit (lives saved) as accurate? (3) (How) do preferences for hypothetical regulations change when mean‐preserving spreads of uncertainty replace certain cost or benefit? and (4) (How) do preferences change when unequal interindividual distributions of hypothetical regulatory costs replace equal distributions? Respondents overestimated costs of regulatory compliance, while assuming agencies underestimate costs. Most assumed agency estimates of benefits are accurate; a third believed both cost and benefit estimates are accurate. Cost and benefit estimates presented without uncertainty were slightly preferred to those surrounded by “narrow uncertainty” (a range of costs or lives entirely within a personally‐calibrated zone without clear acceptance or rejection of tradeoffs). Certain estimates were more preferred than “wide uncertainty” (a range of agency estimates extending beyond these personal bounds, thus posing a gamble between favored and unacceptable tradeoffs), particularly for costs as opposed to benefits (but even for costs a quarter of respondents preferred wide uncertainty to certainty). Agency‐acknowledged uncertainty in general elicited mixed judgments of honesty and trustworthiness. People preferred egalitarian distributions of regulatory costs, despite skewed actual cost distributions, and preferred progressive cost distributions (the rich pay a greater than proportional share) to regressive ones. Efficient and socially responsive regulations require disclosure of much more information about regulatory costs and risks.
The 3.8 Å structure of the U4/U6.U5 tri-snRNP: Insights into spliceosome assembly and catalysis
Authors: Wan Ruixue , Yan Chuangye , Bai Rui , Wang Lin , Huang Min , Wong Catherine C. L. , Shi Yigong
Published: January 2016

Structure of a key spliceosomal complex

In eukaryotes, when DNA is transcribed into RNA, the primary transcript has protein-coding sequences interrupted by noncoding sequences called introns. Introns are removed by a complex molecular machine, the spliceosome. Wan
et al.
determined the structure of a key subcomplex, the tri-SNP, that comprises three small nuclear RNAs and more than 30 proteins. The structure, determined by electron microscopy at 3.8 Å resolution, unexpectedly shows a primary RNA transcript bound in the tri-SNP. Further analysis revealed how the spliceosome assembles to achieve its complex functions.

Science
, this issue p.
466
In Vivo
-Expressed Proteins of Virulent Leptospira interrogans Serovar Autumnalis N2 Elicit Strong IgM Responses of Value in Conclusive Diagnosis
Authors: Raja Veerapandian , Shanmughapriya Santhanam , Kanagavel Murugesan , Artiushin Sergey C. , Velineni Sridhar , Timoney John F. , Natarajaseenivasan Kalimuthusamy
Published: January 2016

Leptospirosis is a serious zoonosis that is underdiagnosed because of limited access to laboratory facilities in Southeast Asia, Central and South America, and Oceania. Timely diagnosis of locally distributed serovars of high virulence is crucial for successful care and outbreak management. Using pooled patient sera, an expression gene library of a virulent
Leptospira interrogans
serovar Autumnalis strain N2 isolated in South India was screened. The identified genes were characterized, and the purified recombinant proteins were used as antigens in IgM enzyme-linked immunosorbent assay (ELISA) either singly or in combination. Sera (
n
= 118) from cases of acute leptospirosis along with sera (
n
= 58) from healthy subjects were tested for reactivity with the identified proteins in an ELISA designed to detect specific IgM responses. We have identified nine immunoreactive proteins, ArgC, RecA, GlpF, FliD, TrmD, RplS, RnhB, Lp28.6, and Lrr44.9, which were found to be highly conserved among pathogenic leptospires. Apparently, the proteins ArgC, RecA, GlpF, FliD, TrmD, and Lrr44.9 are expressed during natural infection of the host and undetectable in
in vitro
cultures. Among all the recombinant proteins used as antigens in IgM ELISA, ArgC had the highest sensitivity and specificity, 89.8% and 95.5%, respectively, for the conclusive diagnosis of leptospirosis. The use of ArgC and RecA in combination for IgM ELISA increased the sensitivity and specificity to 95.7% and 94.9%, respectively. ArgC and RecA thus elicited specific IgM responses and were therefore effective in laboratory confirmation of
Leptospira
infection.
Complete Genome Sequence of a Novel Clinical Isolate, Mycobacterium abscessus Strain NOV0213
Authors: Dymova M. A. , Alkhovik O. I. , Evdokimova L. S. , Cherednichenko A. G. , Petrenko T. I.
Published: January 2016

Mycobacterium abscessus
is a rapid-growing species of nontuberculous mycobacteria that is frequently associated with opportunistic infections in humans. We determined the complete genome sequence of the
M. abscessus
strain NOV0213, which was isolated from a patient with tuberculosis-like disease and with various antibiotic resistances.
Is congenital melanocytic naevus a link between Hirayama disease and moyamoya pattern: a new syndrome or a co-incidence?
Authors: Puri Inder , Vibha Deepti , Prasad Kameshwar , Bhatia Rohit
Published: January 2016

A 22-year-old man presented with a history of progressive weakness and wasting of the right hand and forearm for 12 months followed by similar symptoms in the left upper limb for the past 5 months. He also gave a history of episodes of loss of consciousness for the past 5 years with a frequency of one per 3 months. On examination, there were melanocytic naevi—one large lesion in the nape of the neck and multiple satellite lesions. On investigation, the cervical cord MRI was normal. The brain MRI and angiography showed a moyamoya pattern. Thus, this patient had congenital melanocytic naevi with Hirayama disease and moyamoya pattern. He was treated with extracranial–intracranial bypass for moyamoya disease. During 6-month follow-up, he has been stable. Although moyamoya syndrome has been associated with several systemic diseases and conditions, the coexistence of a moyamoya pattern with Hirayama disease and melanocytic naevi has not been described so far.
Recurrent pancreatitis after unremarkable colonoscopy, temporalised by CT imaging: an unusual case
Authors: Limb Christopher , Ibrahim Ibrahim A K , Fitzsimmons Sophie , Harper Ashton J
Published: January 2016

Acute pancreatitis is a common surgical presentation, frequently caused by gallstones and alcohol. Here we present an unusual case of a recurrent episode of pancreatitis after an unremarkable colonoscopy, in a patient with several pre-existing risk factors for pancreatitis. Before and after abdominal CT scans clearly demonstrate the acute inflammatory process affecting the pancreas and temporalise its development. Early resuscitation and appropriate involvement of high dependency care is advocated by all current guidelines to improve patient outcome. We consider possible aetiology and how early diagnosis and recognition of possible high-risk situations can expedite its investigation and management, helping to provide the best possible care.
A large, benign prostatic cyst presented with an extremely high serum prostate-specific antigen level
Authors: Chen Han-Kuang , Pemberton Richard
Published: January 2016

We report a case of a patient who presented with an extremely high serum prostate specific antigen (PSA) level and underwent radical prostatectomy for presumed prostate cancer. Surprisingly, the whole mount prostatectomy specimen showed only small volume, organ-confined prostate adenocarcinoma and a large, benign intraprostatic cyst, which was thought to be responsible for the PSA elevation.
Impact of childhood experience and adult well-being on eating preferences and behaviours
Authors: Russell Simon J , Hughes Karen , Bellis Mark A
Published: January 2016

Objectives

To examine the relative contribution of childhood experience, measured by childhood violence and childhood happiness, and adult well-being on adult eating preferences and behaviours, independent of proximal factors such as current deprivation.

Design

A cross-sectional, stratified, randomised sample survey using retrospective measures of childhood violence and happiness and self-reported measures of current well-being.

Setting

The North West Region of England between September 2012 and March 2013.

Participants

Individuals aged 18–95-year-olds from randomly selected households (participation was successful for 90% of eligible households and 78% of the total visited addresses; n=11 243).

Outcomes

Dichotomised measures for preference of healthy foods or ‘feel good’ foods and low or high daily fruit and vegetable consumption.

Results

After correcting for demographics, combined categories for childhood experience and dichotomised measures of adult well-being were found to be significantly related to adult food preferences and eating behaviours. Participants with unhappy and violent childhoods compared to those with happy and non-violent childhoods had adjusted ORs (95% CI, significance) of 2.67 (2.15 to 3.06, p<0.001) of having low daily fruit and vegetable intake (two or less portions) and 1.53 (1.29 to 1.81, p<0.001) of choosing ‘feel good’ foods over foods which were good for their long term health.

Conclusions

Daily intake of fruit and vegetables, linked to non-communicable diseases, and preference for ‘feel good’ foods, linked to obesity, are affected by childhood experience and adult well-being independent of demographic factors. Preventative interventions which support parent–child relationships and improve childhood experience are likely to reduce the development of poor dietary and other health-risk behaviours.
Assessment of adult body composition using bioelectrical impedance: comparison of researcher calculated to machine outputted values
Authors: Franco-Villoria Maria , Wright Charlotte M , McColl John H , Sherriff Andrea , Pearce Mark S ,   and the Gateshead Millennium Study core team
Published: January 2016

Objectives

To explore the usefulness of Bioelectrical Impedance Analysis (BIA) for general use by identifying best-evidenced formulae to calculate lean and fat mass, comparing these to historical gold standard data and comparing these results with machine-generated output. In addition, we explored how to best to adjust lean and fat estimates for height and how these overlapped with body mass index (BMI).

Design

Cross-sectional observational study within population representative cohort study.

Setting

Urban community, North East England

Participants

Sample of 506 mothers of children aged 7–8 years, mean age 36.3 years.

Methods

Participants were measured at a home visit using a portable height measure and leg-to-leg BIA machine (Tanita TBF-300MA).

Measures

Height, weight, bioelectrical impedance (BIA).

Outcome measures

Lean and fat mass calculated using best-evidenced published formulae as well as machine-calculated lean and fat mass data.

Results

Estimates of lean mass were similar to historical results using gold standard methods. When compared with the machine-generated values, there were wide limits of agreement for fat mass and a large relative bias for lean that varied with size. Lean and fat residuals adjusted for height differed little from indices of lean (or fat)/height2. Of 112 women with BMI >30 kg/m2, 100 (91%) also had high fat, but of the 16 with low BMI (<19 kg/m2) only 5 (31%) also had low fat.

Conclusions

Lean and fat mass calculated from BIA using published formulae produces plausible values and demonstrate good concordance between high BMI and high fat, but these differ substantially from the machine-generated values. Bioelectrical impedance can supply a robust and useful field measure of body composition, so long as the machine-generated output is not used.
Residual strength of underground structures in service
Authors: Kamel Taous , Limam Ali , Silvani Claire
Published: January 2016

Old tunnels suffer from deterioration and it is necessary to assess their residual strength to properly organize their repair and strengthen them. The stress state of underground structures evolves over time, firstly because of the advancement of the working face during construction, then due to gradual changes in soil properties and mechanical properties of materials composing the infrastructures, such as reduction of cohesion, loss of strength and (or) stiffness, etc. These changes are caused by combined actions such as creep and (or) weathering processes as well as the appearance of cracks that induce redistribution of stresses and therefore strains. This study investigates tunnels and galleries of the Paris underground. Macromodeling based on the finite element method allows consideration of different scenarios of tunnel-lining deterioration, specifically at the extrados of the galleries or tunnels. To understand changes in the stress state, and also damage occurrence and associated redistributions (stress and strain), it is necessary to model the delayed deformations. To model the infrastructure behavior, a time-dependency approach has been chosen. This approach can quantify the damage and predict the residual strength of this type of underground structure. An elastic–viscoplastic constitutive model with strain-softening is used to reproduce the appearance of the degraded zones and their behavior. The results obtained with the numerical approach reproduce Paris metro tunnel behavior, corroborate geoendoscopy results, clarify their interpretation, and improve the management of infrastructure repairs.
Leaf mass per area predicts palisade structural properties linked to mesophyll conductance in balsam poplar (Populus balsamifera L.)
Authors: Milla-Moreno Estefania A. , McKown Athena D. , Guy Robert D. , Soolanayakanahally Raju Y.
Published: January 2016

Modifications to leaf structural components that drive variation in leaf mass per area (LMA) may substantially impact leaf physiology by changing how easily CO2 diffuses through intercellular air space to carboxylation sites in mesophyll tissues. Mesophyll conductance (gm) is inversely proportional to the total pathway length for CO2, including the structural resistances encountered. In balsam poplar (Populus balsamifera L.), gm increases with latitude, paralleled by an increase in LMA. We investigated a family of P. balsamifera (K4×C) with high variation in LMA for different characteristics (tissues, nitrogen content, ultrastructural attributes). We interpreted trait variability using a developmental scale quantified by the leaf plastochron index (LPI). Developmental age significantly affected LMA, but those effects were lost at LPI ≥ 6. We outlined contributions of anatomical components to LMA and found palisade mesophyll properties were the primary drivers of variation in LMA within mature leaves (LPI ≥ 6). Using anatomical data, we derived components corresponding to structural resistances for gm. Perimeters of palisade cells and surface area of palisade exposed to intercellular air space, which may strongly influence CO2 diffusion, were correlated to LMA. Variation in LMA is positively related to differences in structural features expected to increase the conductance to CO2 diffusion within palisade mesophyll.
Inconsistency Management from the Standpoint of Possibilistic Logic
Authors: Dubois Didier , Prade Henri
Published: January 2016

Uncertainty and inconsistency pervade human knowledge. Possibilistic logic, where propositional logic formulas are associated with lower bounds of a necessity measure, handles uncertainty in the setting of possibility theory. Moreover, central in standard possibilistic logic is the notion of inconsistency level of a possibilistic logic base, closely related to the notion of consistency degree of two fuzzy sets introduced by L. A. Zadeh. Formulas whose weight is strictly above this inconsistency level constitute a sub-base free of any inconsistency. However, several extensions, allowing for a paraconsistent form of reasoning, or associating possibilistic logic formulas with information sources or subsets of agents, or extensions involving other possibility theory measures, provide other forms of inconsistency, while enlarging the representation capabilities of possibilistic logic. The paper offers a structured overview of the various forms of inconsistency that can be accommodated in possibilistic logic. This overview echoes the rich representation power of the possibility theory framework.
Equations in Type-2 Fuzzy Sets
Authors: Harding John , Walker Carol , Walker Elbert
Published: January 2016

The main concern of this paper is with the equations satisfied by the algebra of truth values of type-2 fuzzy sets. That algebra has elements all mappings from the unit interval into itself with operations given by certain convolutions of operations on the unit interval. There are a number of positive results. Among them is a decision procedure, similar to the method of truth tables, to determine when an equation holds in this algebra. One particular equation that holds in this algebra implies that every subalgebra of it that is a lattice is a distributive lattice. It is also shown that this algebra is locally finite. Many questions are left unanswered. For example, we do not know whether or not this algebra has a finite equational basis, that is, whether or not there is a finite set of equations from which all equations satisfied by this algebra follow. This and various other topics about the equations satisfied by this algebra will be discussed.
Characterization of a Class of Possibility Distributions
Authors: Ralescu Dan , Ralescu Anca
Published: January 2016

This note presents the characterization of a fuzzy variable whose possibility distribution is a convex fuzzy set.
Fuzzy Intervals Application for Software Metrological Certification in Measurement and Information Systems
Authors: Semenov K. K. , Reznik L. K. , Solopchenko G. N.
Published: January 2016

This paper analyzes the advantages and disadvantages of two types of self-validating software that may run on into measurements devices: programs, which realize interval computations, and programs, which process inaccurate initial data that are expressed in terms of fuzzy intervals. The proposed analysis is presented from the viewpoint of metrology requirements. It is demonstrated that expressing measurement uncertainties in the form of fuzzy intervals results in the software that is better suited for its application in measurement systems.
On the OWA Aggregation with Probabilistic Inputs
Authors: Yager Ronald R.
Published: January 2016

We discuss the use of the ordered weighted averaging (OWA) operator in multi-criteria decision problems as a means of aggregating the individual criteria satisfactions. We emphasize the need for ordering the arguments, the criteria satisfactions, when using the OWA operator. We consider the situation where the criteria satisfactions have some uncertainty, are finite probability distributions and note the requirement of having to order probability distributions. We introduce the idea of using pairwise stochastic dominance to provide the necessary ordering relationship over the probability distributions. We note that while this approach is appropriate, it is often not possible, since the presence of a stochastic dominance relationship between all pairs of probability distributions is not always the case, the relationship is not complete. To circumvent this problem we introduce an approach called the probabilistic exceedance method (PEM), which allows us to provide a surrogate for the OWA aggregation of probability distributions that doesn't require a linear ordering over the probability distributions. We look at this in both the cases in which the criteria have equal and unequal importances.
Blending Ad Hoc and Formal Workflow Models in Support of Different Stakeholders Needs
Authors: Silva Filho Roberto Silveira , McKenna Monica , McDevitt Kevin
Published: January 2016

Workflow management systems (WfMSs) also known as business process management systems (BPMSs) are increasingly popular in today’s large organizations. In spite of this popularity, many processes are still supported by ad hoc systems based, for example, on spreadsheets and homegrown databases. In particular, there is a lack of flexible process automation approaches that are able to bridge the gap between these ad hoc solutions and large-scale systems. This paper reports on a flexible WfMS and approach that blends formal and informal workflow modeling and execution, thus supporting different types of processes. We validate our work by discussing its design and implementation, and by analyzing its use in four different use cases within Siemens business units. We also discuss the role of action items as important flexibility mechanisms behind our model. Showing its ability to handle exceptions and ad hoc workflows.
Insights from Single-File Diffusion into Cooperativity in Higher Dimensions
Authors: Ooshida Takeshi , Goto Susumu , Matsumoto Takeshi , Otsuki Michio
Published: January 2016

Diffusion in colloidal suspensions can be very slow due to the cage effect, which confines each particle within a short radius on one hand, and involves large-scale cooperative motions on the other. In search of insight into this cooperativity, here the authors develop a formalism to calculate the displacement correlation in colloidal systems, mainly in the two-dimensional (2D) case. To clarify the idea for it, studies are reviewed on cooperativity among the particles in the one-dimensional (1D) case, i.e. the single-file diffusion (SFD). As an improvement over the celebrated formula by Alexander and Pincus on the mean-square displacement (MSD) in SFD, it is shown that the displacement correlation in SFD can be calculated from Lagrangian correlation of the particle interval in the one-dimensional case, and also that the formula can be extended to higher dimensions. The improved formula becomes exact for large systems. By combining the formula with a nonlinear theory for correlation, a correction to the asymptotic law for the MSD in SFD is obtained. In the 2D case, the linear theory gives description of vortical cooperative motion.
Automated monitoring of high-temperature volcanic features: from high-spatial to very-high-temporal resolution
Authors: Ferrucci Fabrizio , Hirn Barbara
Published: January 2016

Developments in spaceborne Earth Observation (EO) sensor technology over the last decade, combined with well-tested physical models and multispectral data-processing techniques developed from the early 1980s, have paved the way to the global monitoring of volcanoes by sensors of metric, decametric, kilometric and multi-kilometric spatial resolution. Such variable geometries provide for revisit intervals ranging from about monthly – at high-spatial resolution in Low-Earth Orbit – to less than 5 min – at low-spatial resolution, from geostationary platforms. There are currently about 20 spacecrafts available for carrying out 24/7 quantitative observations of volcanic unrest, at all resolutions and as close as possible to real-time. We show some successful examples of synergetic EO on volcanoes on three continents from 10 different payloads, automatically processed with three, end-to-end unsupervised procedures, on eight major eruptions and a lava lake between 2006 and 2014.
Involvement of myristoylated alanine-rich C kinase substrate phosphorylation and translocation in cholecystokinin-induced amylase release in rat pancreatic acini
Authors: Satoh Keitaro , Narita Takanori , Katsumata-Kato Osamu , Sugiya Hiroshi , Seo Yoshiteru
Published: January 2016

Cholecystokinin (CCK) is a gastrointestinal hormone that induces exocytotic amylase release in pancreatic acinar cells. The activation of protein kinase C (PKC) is involved in the CCK-induced pancreatic amylase release. Myristoylated alanine-rich C kinase substrate (MARCKS) is a ubiquitously expressed substrate of PKC. MARCKS has been implicated in membrane trafficking in several cell types. The phosphorylation of MARCKS by PKC results in the translocation of MARCKS from the membrane to the cytosol. Here, we studied the involvement of MARCKS in the CCK-induced amylase release in rat pancreatic acini. Employing Western blotting, we detected MARCKS protein in the rat pancreatic acini. CCK induced MARCKS phosphorylation. A PKC-δ inhibitor, rottlerin, inhibited the CCK-induced MARCKS phosphorylation and amylase release. In the translocation assay, we also observed CCK-induced PKC-δ activation. An immunohistochemistry study showed that CCK induced MARCKS translocation from the membrane to the cytosol. When acini were lysed by a detergent, Triton X-100, CCK partially induced displacement of the MARCKS from the GM1a-rich detergent-resistant membrane fractions (DRMs) in which Syntaxin2 is distributed. A MARCKS-related peptide inhibited the CCK-induced amylase release. These findings suggest that MARCKS phosphorylation by PKC-δ and then MARCKS translocation from the GM1a-rich DRMs to the cytosol are involved in the CCK-induced amylase release in pancreatic acinar cells.
MicroRNA-155 deletion promotes tumorigenesis in the azoxymethane-dextran sulfate sodium model of colon cancer
Authors: Velázquez Kandy T. , Enos Reilly T. , McClellan Jamie L. , Cranford Taryn L. , Chatzistamou Ioulia , Singh Udai P. , Nagarkatti Mitzi , Nagarkatti Prakash S. , Fan Daping , Murphy E. Angela
Published: January 2016

Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to poor prognosis. However, whether miR-155 upregulation is predictive of a pro- or antitumorigenic response is unclear, as the limited preclinical data available remain controversial. We examined miR-155 expression in tumor tissue from colon cancer patients. Furthermore, we investigated the role of this microRNA in proliferation and apoptosis, inflammatory processes, immune cell populations, and transforming growth factor-β/SMAD signaling in a chemically induced (azoxymethane-dextran sulfate sodium) mouse model of colitis-associated colon cancer. We found a higher expression of miR-155 in the tumor region than in nontumor colon tissue of patients with colon cancer. Deletion of miR-155 in mice resulted in a greater number of polyps/adenomas, an increased symptom severity score, a higher grade of epithelial dysplasia, and a decrease in survival. Surprisingly, these findings were associated with an increase in apoptosis in the normal mucosa, but there was no change in proliferation. The protumorigenic effects of miR-155 deletion do not appear to be driven solely by dysregulation of inflammation, as both genotypes had relatively similar levels of inflammatory mediators. The enhanced tumorigenic response in miR-155−/−mice was associated with alterations in macrophages and neutrophils, as markers for these populations were decreased and increased, respectively. Furthermore, we demonstrated a greater activation of the transforming growth factor-β/SMAD pathway in miR-155−/−mice, which was correlated with the increased tumorigenesis. Given the multiple targets of miR-155, careful evaluation of its role in tumorigenesis is necessary prior to any consideration of its potential as a biomarker and/or therapeutic target in colon cancer.
Oxidative stress contributes to the enhanced expression of Gqα/PLCβ1 proteins and hypertrophy of VSMC from SHR: role of growth factor receptor transactivation
Authors: Atef Mohammed Emehdi , Anand-Srivastava Madhu B.
Published: January 2016

We showed previously that vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHRs) exhibit overexpression of Gqα/PLCβ1 proteins, which contribute to increased protein synthesis through the activation of MAP kinase signaling. Because oxidative stress has been shown to be increased in hypertension, the present study was undertaken to examine the role of oxidative stress and underlying mechanisms in enhanced expression of Gqα/PLCβ1 proteins and VSMC hypertrophy. Protein expression was determined by Western blotting, whereas protein synthesis and cell volume, markers for VSMC hypertrophy, were determined by [3H]-leucine incorporation and three-dimensional confocal imaging, respectively. The increased expression of Gqα/PLCβ1 proteins, increased protein synthesis, and augmented cell volume exhibited by VSMCs from SHRs were significantly attenuated by antioxidants N-acetyl-cysteine (NAC), a scavenger of superoxide anion, DPI, an inhibitor of NAD(P)H oxidase. In addition, PP2, AG1024, AG1478, and AG1295, inhibitors of c-Src, insulin-like growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), respectively, also attenuated the enhanced expression of Gqα/PLCβ1 proteins and enhanced protein synthesis in VSMCs from SHRs toward control levels. Furthermore, the levels of IGF-1R and EGFR proteins and not of PDGFR were also enhanced in VSMCs from SHRs, which were attenuated significantly by NAC, DPI, and PP2. In addition, NAC, DPI, and PP2 also attenuated the enhanced phosphorylation of IGF-1R, PDGFR, EGFR, c-Src, and EKR1/2 in VSMCs from SHRs. These data suggest that enhanced oxidative stress in VSMCs from SHRs activates c-Src, which through the transactivation of growth factor receptors and MAPK signaling contributes to enhanced expression of Gqα/PLCβ1 proteins and resultant VSMC hypertrophy.
β-Adrenergic-mediated vasodilation in young men and women: cyclooxygenase restrains nitric oxide synthase
Authors: Limberg Jacqueline K. , Johansson Rebecca E. , Peltonen Garrett L. , Harrell John W. , Kellawan J. Mikhail , Eldridge Marlowe W. , Sebranek Joshua J. , Schrage William G.
Published: January 2016

We tested the hypothesis that women exhibit greater vasodilator responses to β-adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to β-adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men ( n = 29, 26 ± 1 yr) and women ( n = 33, 25 ± 1 yr) during intra-arterial infusion of isoproterenol (β-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [ NG-monomethyl-l-arginine (l-NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow ÷ mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion ( P < 0.01), and this effect was not different between men and women ( P = 0.41). l-NMMA infusion had no effect on isoproterenol-mediated dilation in men ( P > 0.99) or women ( P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men ( P < 0.01) and women ( P = 0.04) and this rise was lost with subsequent l-NMMA infusion (men, P < 0.01; women, P < 0.05). β-Adrenergic vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to β-mediated vasodilation are not present. However, these data are the first to demonstrate β-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease.
Endothelial dysfunction following prolonged sitting is mediated by a reduction in shear stress
Authors: Restaino Robert M. , Walsh Lauren K. , Morishima Takuma , Vranish Jennifer R. , Martinez-Lemus Luis A. , Fadel Paul J. , Padilla Jaume
Published: January 2016

We and others have recently reported that prolonged sitting impairs endothelial function in the leg vasculature; however, the mechanism(s) remain unknown. Herein, we tested the hypothesis that a sustained reduction in flow-induced shear stress is the underlying mechanism by which sitting induces leg endothelial dysfunction. Specifically, we examined whether preventing the reduction in shear stress during sitting would abolish the detrimental effects of sitting on popliteal artery endothelial function. In 10 young healthy men, bilateral measurements of popliteal artery flow-mediated dilation were performed before and after a 3-h sitting period during which one foot was submerged in 42°C water (i.e., heated) to increase blood flow and thus shear stress, whereas the contralateral leg remained dry and served as internal control (i.e., nonheated). During sitting, popliteal artery mean shear rate was reduced in the nonheated leg (pre-sit, 42.9 ± 4.5 s−1; and 3-h sit, 23.6 ± 3.3 s−1; P < 0.05) but not in the heated leg (pre-sit, 38.9 ± 3.4 s−1; and 3-h sit, 63.9 ± 16.9 s−1; P > 0.05). Popliteal artery flow-mediated dilation was impaired after 3 h of sitting in the nonheated leg (pre-sit, 7.1 ± 1.4% vs. post-sit, 2.8 ± 0.9%; P < 0.05) but not in the heated leg (pre-sit: 7.3 ± 1.5% vs. post-sit, 10.9 ± 1.8%; P > 0.05). Collectively, these data suggest that preventing the reduction of flow-induced shear stress during prolonged sitting with local heating abolishes the impairment in popliteal artery endothelial function. Thus these findings are consistent with the hypothesis that sitting-induced leg endothelial dysfunction is mediated by a reduction in shear stress.
Lipopolysaccharide induces ICAM-1 expression via a c-Src/NADPH oxidase/ROS-dependent NF-κB pathway in human pulmonary alveolar epithelial cells
Authors: Cho Rou-Ling , Yang Chien-Chung , Lee I-Ta , Lin Chih-Chung , Chi Pei-Ling , Hsiao Li-Der , Yang Chuen-Mao
Published: January 2016

Upregulation of intercellular adhesion molecule-1 (ICAM-1) is frequently implicated in lung inflammation. Lipopolysaccharide (LPS) has been shown to play a key role in inflammation via adhesion molecule induction and then causes lung injury. However, the mechanisms underlying LPS-induced ICAM-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unclear. We showed that LPS induced ICAM-1 expression in HPAEpiCs, revealed by Western blotting, RT-PCR, real-time PCR, and promoter assay. Pretreatment with the inhibitor of c-Src (protein phosphatase-1, PP1), reactive oxygen species (ROS) (Edaravone), NADPH oxidase (apocynin and diphenyleneiodonium chloride), EGFR (AG1478), PDGFR (AG1296), phosphatidylinositol-3-kinase (PI3K) (LY294002), MEK1/2 (U0126), or NF-κB (Bay11-7082) and transfection with siRNAs of c-Src, EGFR, PDGFR, Akt, p47 phox, Nox2, Nox4, p42, and p65 markedly reduced LPS-induced ICAM-1 expression and monocyte adherence to HPAEpiCs challenged with LPS. In addition, we established that LPS stimulated phosphorylation of c-Src, EGFR, PDGFR, Akt, or p65, which was inhibited by pretreatment with their respective inhibitors. LPS induced Toll-like receptor 4 (TLR4), MyD88, TNF receptor-associated factor 6 (TRAF6), c-Src, p47 phox, and Rac1 complex formation 2, which was attenuated by transfection with c-Src or TRAF6 siRNA. Furthermore, LPS markedly enhanced NADPH oxidase activation and intracellular ROS generation, which were inhibited by PP1. We established that LPS induced p42/p44 MAPK activation via a c-Src/NADPH oxidase/ROS/EGFR, PDGFR/PI3K/Akt-dependent pathway in these cells. Finally, we observed that LPS significantly enhanced NF-κB and IκBα phosphorylation, NF-κB translocation, and NF-κB promoter activity, which were inhibited by PP1, Edaravone, apocynin, diphenyleneiodonium chloride, AG1478, AG1296, LY294002 , or U0126. These results demonstrated that LPS induces p42/p44 MAPK activation mediated through the TLR4/MyD88/TRAF6/c-Src/NADPH oxidase/ROS/EGFR, PDGFR/PI3K/Akt pathway, which in turn initiates the activation of NF-κB and ultimately induces ICAM-1 expression in HPAEpiCs.
Alcohol abuse and smoking alter inflammatory mediator production by pulmonary and systemic immune cells
Authors: Gaydos Jeanette , McNally Alicia , Guo Ruixin , Vandivier R. William , Simonian Philip L. , Burnham Ellen L.
Published: January 2016

Alcohol use disorders (AUDs) and tobacco smoking are associated with an increased predisposition for community-acquired pneumonia and the acute respiratory distress syndrome. Mechanisms are incompletely established but may include alterations in response to pathogens by immune cells, including alveolar macrophages (AMs) and peripheral blood mononuclear cells (PBMCs). We sought to determine the relationship of AUDs and smoking to expression of IFNγ, IL-1β, IL-6, and TNFα by AMs and PBMCs from human subjects after stimulation with lipopolysaccharide (LPS) or lipoteichoic acid (LTA). AMs and PBMCs from healthy subjects with AUDs and controls, matched on smoking, were cultured with LPS (1 μg/ml) or LTA (5 μg/ml) in the presence and absence of the antioxidant precursor N-acetylcysteine (10 mM). Cytokines were measured in cell culture supernatants. Expression of IFNγ, IL-1β, IL-6, and TNFα in AMs and PBMCs was significantly increased in response to stimulation with LPS and LTA. AUDs were associated with augmented production of proinflammatory cytokines, particularly IFNγ and IL-1β, by AMs and PBMCs in response to LPS. Smoking diminished the impact of AUDs on AM cytokine expression. Expression of basal AM and PBMC Toll-like receptors-2 and -4 was not clearly related to differences in cytokine expression; however, addition of N-acetylcysteine with LPS or LTA led to diminished AM and PBMC cytokine secretion, especially among current smokers. Our findings suggest that AM and PBMC immune cell responses to LPS and LTA are influenced by AUDs and smoking through mechanisms that may include alterations in cellular oxidative stress.
p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: importance in pulmonary inflammation due to cigarette smoke exposure
Authors: Tiwari Nivedita , Marudamuthu Amarnath S. , Tsukasaki Yoshikazu , Ikebe Mitsuo , Fu Jian , Shetty Sreerama
Published: January 2016

We previously demonstrated that tumor suppressor protein p53 augments plasminogen activator inhibitor-1 (PAI-1) expression in alveolar epithelial cells (AECs) during chronic cigarette smoke (CS) exposure-induced lung injury. Chronic lung inflammation with elevated p53 and PAI-1 expression in AECs and increased susceptibility to and exacerbation of respiratory infections are all associated with chronic obstructive pulmonary disease (COPD). We recently demonstrated that preventing p53 from binding to the endogenous PAI-1 mRNA in AECs by either suppressing p53 expression or blockading p53 interactions with the PAI-1 mRNA mitigates apoptosis and lung injury. Within this context, we now show increased expression of the C-X-C chemokines (CXCL1 and CXCL2) and their receptor CXCR2, and the intercellular cellular adhesion molecule-1 (ICAM-1), in the lung tissues of patients with COPD. We also found a similar increase in lung tissues and AECs from wild-type (WT) mice exposed to passive CS for 20 wk and in primary AECs treated with CS extract in vitro. Interestingly, passive CS exposure of mice lacking either p53 or PAI-1 expression resisted an increase in CXCL1, CXCL2, CXCR2, and ICAM-1. Furthermore, inhibition of p53-mediated induction of PAI-1 expression by treatment of WT mice exposed to passive CS with caveolin-1 scaffolding domain peptide reduced CXCL1, CXCL2, and CXCR2 levels and lung inflammation. Our study reveals that p53-mediated induction of PAI-1 expression due to chronic CS exposure exacerbates lung inflammation through elaboration of CXCL1, CXCL2, and CXCR2. We further provide evidence that targeting this pathway mitigates lung injury associated with chronic CS exposure.
Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer
Authors: Choudhary Alka , Zachek Brittany , Lera Robert F. , Zasadil Lauren M. , Lasek Amber , Denu Ryan A. , Kim Hyunjung , Kanugh Craig , Laffin Jennifer J. , Harter Josephine M. , Wisinski Kari B. , Saha Sandeep , Weaver Beth A. , Burkard Mark E.
Published: January 2016

Increased ploidy is common in tumors but treatments for tumors with excess chromosome sets are not available. Here, we characterize high-ploidy breast cancers and identify potential anticancer compounds selective for the high-ploidy state. Among 354 human breast cancers, 10% have mean chromosome copy number exceeding 3, and this is most common in triple-negative and HER2-positive types. Women with high-ploidy breast cancers have higher risk of recurrence and death in two patient cohorts, demonstrating that it represents an important group for improved treatment. Because high-ploidy cancers are aneuploid, rather than triploid or tetraploid, we devised a two-step screen to identify selective compounds. The screen was designed to assure both external validity on diverse karyotypic backgrounds and specificity for high-ploidy cell types. This screen identified novel therapies specific to high-ploidy cells. First, we discovered 8-azaguanine, an antimetabolite that is activated by hypoxanthine phosphoribosyltransferase 1 (HPRT1), suggesting an elevated gene-dosage of HPRT1 in high-ploidy tumors can control sensitivity to this drug. Second, we discovered a novel compound, 2,3-diphenylbenzo[g]quinoxaline-5,10-dione (DPBQ). DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. Mechanistic analysis demonstrates that DPBQ elicits a hypoxia gene signature and its effect is replicated, in part, by enhancing oxidative stress. Structure–function analysis defines the core benzo[g]quinoxaline-5,10 dione as being necessary for the polyploid-specific effects of DPBQ. We conclude that polyploid breast cancers represent a high-risk subgroup and that DPBQ provides a functional core to develop polyploid-selective therapy. Mol Cancer Ther; 15(1); 48–59. ©2015 AACR.
Systemic Inflammatory Response Syndrome Following Percutaneous Nephrolithotomy: Assessment of Risk Factors and Their Impact on Patient Outcomes
Authors: Singh Prabhjot , Yadav Siddharth , Singh Animesh , Saini Ashish K. , Kumar Rajeev , Seth Amlesh , Dogra Prem N.
Published: January 2016

Objectives: To identify perioperative risk factors for postoperative systemic inflammatory response syndrome (SIRS) and suggest possible modifications to reduce morbidity. Material and Methods: We prospectively analysed perioperative data such as history of pervious stone surgery, number and configuration of stones, presence of stent or nephrostomy, any previous positive urine culture, intraoperative renal pelvic urine and stone culture, aspiration of turbid urine on initial puncture, number of tracts required and clearance of stones, operative time and intraoperative hypotension and tachycardia of all patients who underwent percutaneous nephrolithotomy over a period of 15 months. Results: A total of 182 patients were included, average stone size was 2.8 cm, 36.2% had staghorn stones and 15.9% had an indwelling stent or nephrostomy. Despite sterile preoperative urine culture, renal pelvic urine culture (RPUC) was positive in 14.8% (27 patients) and stone culture was positive in 21.9% (40 patients). SIRS developed in 17.5% (32 patients) and septic shock in 1.09% (2 patients). On analysis younger age, positive RPUC and stone culture, longer operative time and intraoperative tachycardia correlated significantly with the development of SIRS. Conclusion: Intra-operative cultures are only therapy-guiding cultures during SIRS, as preoperative urine cultures seldom accurately depict bacteriological status of upper tracts and thus should be obtained in all patients.