bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Serum Concentrations of Interleukin‐18 and Monocyte Chemoattractant Protein‐1 as Prognostic Indicators in Primary Immune‐Mediated Hemolytic Anemia in Dogs
Authors: Kjelgaard‐Hansen M. , Goggs R. , Wiinberg B. , Chan D.L.
Published: November 2010

Background:The cytokine response in immune‐mediated hemolytic anemia (IMHA) is poorly characterized and correlation with outcome is unknown.

Hypothesis/Objectives:To determine if cytokine activity is correlated with outcome in dogs with IMHA.

Animals:Twenty dogs with primary IMHA and 6 control dogs.

Methods:Prospective study on dogs with IMHA with blood sampling at admission. Serum activity of interleukin‐2 (IL‐2), IL‐4, IL‐6, IL‐7, IL‐8, IL‐10, IL‐15, IL‐18, monocyte chemoattractant protein‐1 (MCP‐1), granulocyte‐macrophage colony stimulating factor (GM‐CSF), interferon‐inducible protein‐10, interferon‐gamma, and keratinocyte chemoattractant (KC) was assessed.

Results:Thirty‐day case fatality rate was 25% (5/20 dogs). Increased concentrations (median [range]) of IL‐2 (45.5 ng/L [0;830] versus 0 ng/L [0;46.8]), IL‐10 (8.2 ng/L [0;60.6] versus 0 ng/L [0;88.2]), KC (1.7 μg/L [0.3;4.7] versus 0.5 μg/L [0.2;1.1]), and MCP‐1 (162 ng/L [97.6;438] versus 124 ng/L [90.2;168]) were observed in dogs with IMHA compared with controls. The cytokine profile was indicative of a mixture of pro‐ and anti‐inflammatory cytokines of various cellular origins. Cytokines/chemokines strongly associated with macrophage/monocyte activation and recruitment were significantly increased in nonsurvivors compared with survivors; IL‐15 (179 ng/L [48.0;570] versus 21.3 ng/L [0;193]), IL‐18 (199 ng/L [58.7;915] versus 37.4 ng/L [0;128]), GM‐CSF (134 ng/L [70.0;863] versus 57.6 ng/L [0;164]), and MCP‐1 (219 ng/L [135;438] versus 159 ng/L [97.6;274]), respectively. Logistic regression suggested increased IL‐18 and MCP‐1 concentrations were independently associated with mortality in this population (P<.05, Wald's type 3).

Conclusions and Clinical Importance:A mixed cytokine response is present in dogs with IMHA and mediators of macrophage activation and recruitment might serve as prognostic indicators.
From the World's First Design Policy to the World's Best Design Policy
Authors: Scherfig Christian , Brunander Merete , Melander Christina
Published: November 2010

Denmark's first national design policy was created in 1997, and there have been two more iterations since then. Currently, user‐centered design is taking center stage in the country's business life, and the Danes—always conscious of national public welfare—have been putting design to work in the public sector.
Local, Diffuse, and Bottom‐Up: A New Design Policy for Italy?
Authors: Arquilla Venanzio , Bianchini Massimo , Maffei Stefano
Published: November 2010

Despite its strong cultural heritage and tradition, Italy has no real national design policy, these writers charge. Instead, it has a fragmented and uncoordinated system of local initiatives that are insufficiently funded. Here is an attempt to imagine a redesigned model.
Designing a National Design Policy for Mexico
Authors: Frías Julio
Published: November 2010

In Mexico, a group of designers and academics have been at the forefront of a movement to install a national design policy. Politicians and municipal leaders have taken notice, and now Mexico City (one of the largest cities in the world) is establishing its own design policy, with the idea of improving several social programs.
Estonia's Tiger Leap into the World of Design
Authors: Poslawski Georg , Sipelgas Kristiina
Published: November 2010

The chance to create something new was given to Estonia 20 years ago when it regained its independence from foreign rule. In that short span of time, information technology has helped transform the country, and design is part of plans to improve social welfare and business prospects.
Design Policy: An Introduction to What Matters
Authors: Raulik‐Murphy Gisele , Cawood Gavin , Lewis Alan
Published: November 2010

National design policies don't follow a predetermined format. They depend heavily on the economic and political realities of the countries in which they are born. Nevertheless, this article argues that such policies—national design systems—are more likely to be successful than isolated initiatives, which tend to duplicate efforts and tackle only one part of a problem.
National Support for Design: Developing Propositional Models
Authors: Choi Youngok , Cooper Rachel , Lim Sungwoo , Evans Martyn
Published: November 2010

National design policies can encourage businesses to use design to develop and implement new products and services. They can even help solve some of the wicked problems that so plague the public sector. Taking the UK and South Korea as starting points, this paper explores some alternative models for developing and implementing these policies.
Evaluating the Effectiveness of Asian Design Policies
Authors: Ahn Sang‐Gyeun , Song Jeong‐Man
Published: November 2010

With their solid economic growth, China, South Korea, and Japan are having a direct impact on the world economy. All three countries have national design policies operated by the central government. But a closer look reveals significant differences.
Multi‐level Governance and Security: The Security Sector Reform Process in the Central African Republic
Authors: Bagayoko Niagalé
Published: November 2010

This paper analyses how the security sector reform (SSR) process in the Central African Republic has been defined and then implemented, putting emphasis on the interactions between national and international actors. Therefore, it advocates an approach which consists of expanding the agenda of the traditional multi‐level governance approach and which seeks to seize both the top‐down and the bottom‐up dynamics of decision‐making processes. The first objective is to capture the sets of actors and procedures which drive the reform process, and to map out the various levels of government at which decisions are made. Secondly – and more fundamentally – is to capture the intermingling of domestic and international decision‐making processes which increasingly overlap and interfere with each other in Southern countries.
Security systems in Francophone Africa
Authors: Bagayoko Niagalé
Published: November 2010

This research report is a broad‐based study that seeks to understand the structural and developmental processes that characterise the security sector in Francophone Africa.

Although each country has a distinct political history and tradition, similarities in the security apparatus, rooted in its inheritance from the colonial and post‐colonial periods, can be found between Francophone countries in Africa. In the former French colonies, there are similarities to the French security system which are very strong on the normative side, such as the legal and institutional framework or the defence and security actors. However, even if these Francophone African countries borrow a lot from an originally French security system in terms of the institutional design of their security apparatus, they deviate considerably from it in terms of daily practice.

The issue at stake in this paper is to highlight the kind of institutional framework prevailing in this set of countries and the specific considerations that international assistance will have to take into account. The paper also analyses briefly the difference between Anglophone and Francophone security systems.

Finally, it makes some recommendations that might assist the security sector reform policy agenda and donor and recipient responses to the security challenges faced in Francophone Africa.
Dividend Yields and Stock Returns: Evidence from the Korean Stock Market*
Authors: Park Jinwoo , Kim Moojoon
Published: November 2010

This paper examines the relation between dividend yields and stock returns in the Korean market, and provides some valuable implications in light of certain institutional features of the Korean market that differ from those in the USA and other countries. For five portfolios ranked by the long‐term dividend yield we find that stocks with higher dividend yield earn higher risk‐adjusted returns. Because after‐dividend‐tax returns are used in the present paper, this evidence suggests that the tax‐effect hypothesis proposed by Brennan (1970) is not supported in the Korean stock market and non‐tax reasons for the yield effect exist. Interestingly, the positive relation between yields and returns is common in all months except January in the Korean market, and is observed in both large‐firm and small‐firm stocks. In contrast with Keim (1985), this evidence suggests that the dividend yield effect is not another manifestation of the size effect. In addition, we find that the yield effect is not affected by excess returns around the ex‐dividend day, which coincides with the year end.
Assessing Sovereign Debt Strategies Under Alternative Term Structure Models*
Authors: Choi Geon‐Ho , Kim Myung‐Jig , Lee Hangyong
Published: November 2010

This paper examines the theoretical restrictions on alternative term structure models in assessing sovereign borrowing strategies. Our approach draws upon Hahm & Kim’s (2003) cost–risk analytic model of sovereign debt management within a mean–variance framework. To explore the effects of different interest rate modeling strategies on government debt portfolio selection, two models are considered; namely, the time series‐based dynamic Nelson–Siegel (DNS) model proposed by Diebold & Li (2006) and the DNS model with arbitrage‐free restrictions proposed by Christensen et al. (2008a). Using monthly spot rates for 12 maturities of nominal Korea Treasury Bonds (KTB) from September 2000 to November 2008, the present paper finds that a more generic term structure model, such as the DNS model, performs better in terms of smaller out‐of‐sample root mean squared errors at different forecast horizons. However, looking at the goodness‐of‐fit, the size of pricing errors and the magnitude of the root mean squared errors suggests that both models are reasonable representations of KTB spot curves. For the actual KTB position as of December 2007, the present paper shows that the 95% cost‐at‐risk level might be able to trim as much as 5–6% by rebalancing the portfolio. Furthermore, DNS models, both with and without no‐arbitrage restrictions, produce a consistent assessment of different strategies. This paper also shows that introducing new short‐term domestic debt instruments, such as 1‐year zero coupon KTB, would benefit government in terms of lowering both the average debt‐service cost and the 95% cost‐at‐risk. However, it is found that such benefits might dissipate if the issuance weights for such instruments exceed a certain level, which is approximately 4% of the position in the case of Korea.
H
∞

Guaranteed Cost Filtering for Uncertain Discrete-Time Switched Systems With Multiple Time-Varying Delays
Authors: Sun Haibin , Zong Guangdeng , Hou Linlin
Published: November 2010

This paper deals with the problem of H∞ guaranteed cost filtering for uncertain discrete-time switched systems with multiple time-varying delays. The switched system under consideration is subject to time-varying norm-bounded parameter uncertainties in all the system matrices. The aim is to design a filter, which guarantees the asymptotical stability of the error system with prescribed disturbance attenuation for all admissible uncertainties and the cost function value is not more than a specified upper bound. By resorting to a switched Lyapunov function, some delay-dependent sufficient conditions are presented in terms of linear matrix inequalities. A numerical example is provided to demonstrate the effectiveness of the proposed algorithms.
An Investigation of Flat-Plate Oscillating Heat Pipes
Authors: Cheng Peng , Thompson Scott , Boswell Joe , Ma H. B.
Published: November 2010

The heat transfer performance of flat-plate oscillating heat pipes (FP-OHPs) was investigated experimentally and theoretically. Two layers of channels were created by machining grooves on both sides of a copper plate in order to increase the channel number per unit volume. The channels had rectangular cross-sections with hydraulic diameters ranging from 0.762 mm to 1.389 mm. Acetone, water, diamond/acetone, gold/water, and diamond/water nanofluids were tested as working fluids. It was found that the FP-OHP’s thermal resistance depended on the power input and operating temperature. The FP-OHP charged with 0.0003 vol % gold/water nanofluids achieved a thermal resistance of 0.078 K/W while removing 560 W with a heat flux of 86.8 W/cm2. The thermal resistance was further decreased when the nanofluid was used as the working fluid. A mathematical model predicting the heat transfer performance was developed to predict the thermal performance of the FP-OHP. Results presented here will assist in the optimization of the FP-OHP and provide a better understanding of heat transfer mechanisms occurring in OHPs.
MnSOD, Angiogenesis, and Wounds: Let the Healing Begin!
Authors: Bremer Andrew A.
Published: November 2010

Endothelial progenitor cells treated with gene transfer for MnSOD gene may be a new therapy for wound healing in diabetes patients.
Recycling Reagents to Improve Antibody Therapy
Authors: Ng Kenneth W.
Published: November 2010

Engineering therapeutic antibodies to be recycled for repeated use in the body can extend the effectiveness of these biologics.
When a Clot Buster Doesn't Work So Well
Authors: Damani Samir
Published: November 2010

A cytochrome gene variant links a reduced response to a common anticlotting drug to poor clinical outcome in heart disease patients.
Model synthesis of six-membered carbocyclic spironucleosides
Authors: Nencka Radim , Hřebabecký Hubert , Dračínský Martin
Published: November 2010

Model study focusing on the synthesis of carbocyclic spironucleosides is presented. Hydantoin base was built on the easily accessible ketone precursors by Bucherer–Bergs reaction. On saturated substrates the reaction proceeded smoothly. On α,β-unsaturated ketones, however, the Bucherer–Bergs reaction competed with Michael addition of cyanide ion. We showed that the equilibrium of the reaction could be significantly shifted depending on the applied reaction conditions. Significant diastereoselectivity was observed for tandem Michael addition/Bucherer–Bergs reaction.
Relationships between occupational history and serum concentrations of organochlorine compounds in exocrine pancreatic cancer
Authors: Bosch de Basea Magda , Porta Miquel , Alguacil Joan , Puigdomènech Elisa , Gasull Magda , Garrido José A , López Tomàs ,   for the PANKRAS II Study Group
Published: November 2010

Background

Previous studies investigating associations between occupational history and risk of exocrine pancreatic cancer (EPC) did not use biomarkers of exposure. The only two studies that measured internal concentrations of organochlorine compounds (OCs) in EPC did not analyse their relationship with occupation.

Objective

To analyse the relationship between occupational history and blood concentrations of seven OCs in patients with EPC.

Methods

Incident cases of EPC were prospectively identified, and during hospital admission were interviewed face-to-face on occupational history and life-style factors (n=135). Occupations were coded according to the International Standard of Occupations 1988. Some occupational exposures were also assessed with the Finnish job-exposure matrix (Finjem). Serum concentrations of OCs were analysed by high-resolution gas chromatography with electron-capture detection.

Results

Craftsmen and related trades workers had significantly higher concentrations of polychlorinated biphenyl (PCB) congeners 138, 153 and 180. Years worked in agriculture did not influence concentrations of p,p'-DDT, p,p'-DDE, hexachlorobenzene or β-hexachlorocyclohexane. Subjects who ever worked in agriculture had lower concentrations of PCBs (all p<0.05). Occupational exposure to lead, nickel and low frequency magnetic fields was significantly associated with higher concentrations of PCBs.

Conclusions

Certain occupations were associated with higher concentrations of PCBs, suggesting that these compounds may account for some increased risks found in previous studies. The lack of association between work in agriculture and concentrations of OC pesticides is consistent with occupation playing a lesser role than diet in influencing OC concentrations. Occupational studies on the relationships among exposure to industrial agents and EPC risk may need to consider adjusting for exposure to PCBs.
Pelvic congestion syndrome: the role of interventional radiology in the treatment of chronic pelvic pain
Authors: Freedman J , Ganeshan A , Crowe P M
Published: November 2010

Chronic pelvic pain is a common problem for female patients and is defined as pain that has been present for 6 months or more. Chronic pelvic pain with associated ovarian vein varicosities is termed pelvic congestion syndrome (PCS) and is an important but under-diagnosed condition. The aetiology of pelvic varicosities is reflux of blood in the ovarian veins due to the absence of functioning valves, resulting in retrograde blood flow and eventual venous dilatation. The cardinal presenting symptom of PCS is pelvic pain, usually described as a dull ache, without evidence of inflammatory disease. Clinical signs may include vulval varicosities extending on to the medial thigh and long saphenous territory as well as tenderness on deep palpation at the ovarian point; however, such signs are not always present. Non-invasive imaging (ultrasound, CT and magnetic resonance venography) plays a central role in establishing the diagnosis, excluding alternative causes of pelvic pain and providing a road map for novel minimally invasive treatment options that are now available. Day-case percutaneous-directed venous embolisation is now accepted as a valuable treatment option for PCS with promising results from early clinical trials and is fast becoming the first-line treatment option for this condition. This paper aims to raise awareness of PCS among clinicians and reviews the pathogenesis, imaging assessment and minimally invasive treatment options that are now available.
The effect of São Paulo's smoke-free legislation on carbon monoxide concentration in hospitality venues and their workers
Authors: Issa Jaqueline S , Abe Tania M O , Pereira Alexandre C , Megid Maria Cristina , Shimabukuro Cristina E , Valentin Luis Sergio O , Ferreira Marizete M da C , Nobre Moacyr R C , Lancarotte Ines , Barretto Antonio Carlos Pereira
Published: November 2010

Background

Studies have shown that there is no safe level of secondhand smoke (SHS) exposure and there is a close link between SHS and the risk of coronary heart disease and stroke. Carbon monoxide (CO) is one of the most important components present in SHS.

Objective

To evaluate the impact of the smoking ban law in the city of Sao Paulo, Brazil, on the CO concentration in restaurants, bars, night clubs and similar venues and in their workers.

Methods

In the present study we measured CO concentration in 585 hospitality venues. CO concentration was measured in different environments (indoor, semi-open and open areas) from visited venues, as well as, in the exhaled air from approximately 627 workers of such venues. Measurements were performed twice, before and 12 weeks after the law implementation. In addition, the quality of the air in the city during the same period of our study was verified.

Results

The CO concentration pre-ban and pot-ban in hospitality venues was indoor area 4.57 (3.70) ppm vs 1.35 (1.66) ppm (p<0.0001); semi-open 3.79 (2.49) ppm vs 1.16 (1.14) ppm (p<0.0001); open area 3.31(2.2) ppm vs 1.31 (1.39) ppm (p<0.0001); smoking employees 15.78 (9.76) ppm vs 11.50 (7.53) ppm (p<0.0001) and non-smoking employees 6.88 (5.32) ppm vs 3.50 (2.21) ppm (p<0.0001). The average CO concentration measured in the city was lower than 1 ppm during both pre-ban and post-ban periods.

Conclusion

São Paulo's smoking-free legislation reduced significantly the CO concentration in hospitality venues and in their workers, whether they smoke or not.
PTAS FOR k-TOUR COVER PROBLEM ON THE PLANE FOR MODERATELY LARGE VALUES OF k
Authors: ADAMASZEK ANNA , CZUMAJ ARTUR , LINGAS ANDRZEJ
Published: November 2010

Let P be a set of n points in the Euclidean plane and let O be the origin point in the plane. In the k-tour cover problem (called frequently the capacitated vehicle routing problem), the goal is to minimize the total length of tours that cover all points in P, such that each tour starts and ends in O and covers at most k points from P.

The k-tour cover problem is known to be [Formula: see text]-hard. It is also known to admit constant factor approximation algorithms for all values of k and even a polynomial-time approximation scheme (PTAS) for small values of k, k = Ø( log n/ log log n).

In this paper, we significantly enlarge the set of values of k for which a PTAS is provable. We present a new PTAS for all values of k ≤ 2 log δ n, where δ = δ(ε). The main technical result proved in the paper is a novel reduction of the k-tour cover problem with a set of n points to a small set of instances of the problem, each with Ø((k/ε)Ø(1)) points.
FINDING ALL APPROXIMATE GAPPED PALINDROMES
Authors: HSU PING-HUI , CHEN KUAN-YU , CHAO KUN-MAO
Published: November 2010

We study the problem of finding all maximal approximate gapped palindromes in a string. More specifically, given a string S of length n, a parameter q ≥ 0 and a threshold k > 0, the problem is to identify all substrings in S of the form uvw such that (1) the Levenshtein distance between ur and w is at most k, where ur is the reverse of u and (2) v is a string of length q. The best previous work requires O(k2n) time. In this paper, we propose an O(kn)-time algorithm for this problem by utilizing an incremental string comparison technique. It turns out that the core technique actually solves a more general incremental string comparison problem that allows the insertion, deletion, and substitution of multiple symbols.
THE ROLES OF ADVICE TO ONE-TAPE LINEAR-TIME TURING MACHINES AND FINITE AUTOMATA
Authors: YAMAKAMI TOMOYUKI
Published: November 2010

We discuss the power and limitation of various "advice," when it is given particularly to weak computational models of one-tape linear-time Turing machines and one-way finite (state) automata. Of various advice types, we consider deterministically-chosen advice (not necessarily algorithmically determined) and randomly-chosen advice (according to certain probability distributions). In particular, we show that certain weak machines can be significantly enhanced in computational power when randomized advice is provided in place of deterministic advice.
OPTIMAL EXTRACTION OF IRREDUNDANT MOTIF BASES
Authors: APOSTOLICO ALBERTO , TAGLIACOLLO CLAUDIA
Published: November 2010

The problem of extracting a basis of irredundant motifs from a sequence is considered. In previous work such bases were built incrementally for all suffixes of the input string s in O(n3), where n is the length of s. Faster, non-incremental algorithms have been based on the landmark approach to string searching due to Fischer and Paterson, and exhibit respective time bounds of O(n2log n log |Σ|) and O(|Σ|n2log2n log log n), with Σ denoting the alphabet. The algorithm by Fischer and Paterson makes crucial use of the FFT, which is impractical with long sequences.

The present paper describes an off-line algorithm for binary strings that takes O(n2) time. The algorithm does not need to resort to the FFT and yet its performance is optimal for finite Σ.
A NEW PROOF OF THE THREE-SQUARES LEMMA FOR PARTIAL WORDS WITH ONE HOLE
Authors: KÄRKI TOMI
Published: November 2010

In this paper we give a new proof and a small improvement for the three-squares lemma for partial words with one hole. This recent result by Blanchet-Sadri et al. gives a lower bound for the length of the longest square in the situation where three squares begin at the same position of a one-hole word and the shortest square satisfies a primitivity condition.
ON THE HARDNESS OF THE BORDER LENGTH MINIMIZATION PROBLEM ON A RECTANGULAR ARRAY
Authors: KUNDETI VAMSI , RAJASEKARAN SANGUTHEVAR
Published: November 2010

DNA microarray technology has proven to be an invaluable tool for molecular biologists. Microarrays are used extensively in SNP detection, genomic hybridization, alternative splicing and gene expression profiling. However the manufacturers of the microarrays are often stuck with the problem of minimizing the effects of unwanted illumination (border length minimization (BLM)) which is a hard combinatorial problem. In this paper we prove that the BLM problem on a rectangular grid is NP-hard – this however does not mean the BLM problem on a square grid is NP-hard.

We also give the first integer linear programming (ILP) formulation to solve BLM problem optimally. Experimental results indicate that our ILP method produces superior results (both in runtime and cost) compared to the current state of the art algorithms to solve the BLM problem optimally.
GENERALIZED GAMMA FUNCTIONS WITH CHARACTERS
Authors: KATAYAMA KOJI
Published: November 2010

The main objective of this paper is to define Γ-functions Γ[χ](v) with characters χ and study their properties. To this end, we ought to introduce L-functions [Formula: see text] of Hurwitz type. We prove that [Formula: see text] holds, which combines the theory at "s = 0" and the theory at "s = 1".
Insulin-induced serine phosphorylation of IRS-2 via ERK1/2 and mTOR: studies on the function of Ser675and Ser907
Authors: Fritsche Louise , Neukamm Sabine S. , Lehmann Rainer , Kremmer Elisabeth , Hennige Anita M. , Hunder-Gugel Andrea , Schenk Martin , Häring Hans-Ulrich , Schleicher Erwin D. , Weigert Cora
Published: November 2010

The identity of specific serine phosphorylation residues of insulin receptor substrate (IRS)-2 and their impact on insulin signal transduction are largely unknown. Ser675and Ser907of mouse IRS-2 are adjacent to PI 3-kinase or Grb2 binding domains, respectively. Using monoclonal phosphosite-specific antibodies, we demonstrated the phosphorylation of both serines after stimulation of Fao hepatoma cells with insulin, anisomycin, or phorbol esters. Phosphorylation of both sites was a late and prolonged event during insulin treatment and was also detected in liver tissue of insulin-treated as well as refed mice. Inhibition and siRNA-mediated knockdown of ERK1/2 indicated that the insulin-induced phosphorylation of Ser907was ERK dependent. Phosphorylation of Ser907did not prevent the insulin-induced association of IRS-2 with Grb2, but phosphorylation of the adjacent Tyr911was proved to be crucial in HEK 293 cells expressing IRS-2 Ala mutants. The insulin-induced phosphorylation of Ser675was prevented by inhibition and siRNA-mediated knockdown of mTOR but not of p70S6K1. Mutation of Ser675to Ala did not affect downstream insulin signaling but increased the half-life of the protein, suggesting an involvement of phospho-Ser675in an accelerated degradation of IRS-2. Moreover, the insulin-induced degradation of IRS-2 was blocked by inhibition of mTOR. We conclude that the two novel insulin-dependent serine phosphorylation sites of IRS-2 were not involved in the regulation of the adjacent PI 3-kinase and Grb2 binding domains but might be implicated in the ERK- and mTOR-mediated negative feedback control.
Inactivation of Bardet-Biedl syndrome genes causes kidney defects
Authors: Guo Deng-Fu , Beyer Andreas M. , Yang Baoli , Nishimura Darryl Y. , Sheffield Val C. , Rahmouni Kamal
Published: November 2010

Bardet-Biedl syndrome (BBS) is a rare hereditary autosomal recessive disease associated with several features including obesity, hypertension, and renal abnormalities. The underlying mechanisms of renal defects associated with BBS remain poorly defined. We examined the histological, molecular, and functional renal changes in BBS mouse models that have features of the human disorder. Interestingly, obese hypertensive Bbs4 −/− mice exhibited inflammatory infiltration and renal cysts, whereas the obese normotensive Bbs2 −/− mice had only minor inflammatory infiltration. Accordingly, the expression level of inducible nitric oxide synthase was elevated in the kidney of both BBS mice with a more marked increase in Bbs4 −/− mice. In contrast, endothelial nitric oxide synthase expression was decreased in Bbs4 −/−, but not Bbs2 −/−, mice. Similarly, the expression levels of transient receptor potential vanilloid 1 and 4 channels as well as β- and γ-subunits of epithelial Na channel were significantly reduced only in the kidney of Bbs4 −/− mice. Metabolic studies revealed changes in urine output and urinary concentrations of creatinine, blood urea nitrogen, sodium, and potassium with a more pronounced effect in Bbs4 −/− mice. Finally, we found that calorie restriction which prevented obesity in BBS mice reversed the morphological and molecular changes found in Bbs2 −/− and Bbs4 −/− mice, indicating the kidney abnormalities associated with BBS are obesity related. These findings extend our understanding of the function of BBS proteins and emphasize the importance of these proteins in renal physiology.
Cyclophosphamide induces NR2B phosphorylation-dependent facilitation on spinal reflex potentiation
Authors: Chang Chao-Hsiang , Peng Hsien-Yu , Wu Hsi-Chin , Lai Cheng-Yuan , Hsieh Ming-Chun , Lin Tzer-Bin
Published: November 2010

It is well-established that cyclophosphamide (CYP) can sensitize the pelvic afferent nerve arising from the urinary bladder and therefore induce suprapubic pain. To test the possibility that CYP might mediate the development of visceral hypereflexia/hyperalgesia by facilitating spinal activity-dependent neural plasticity, we compared the pelvic-urethra reflex activity and spinal N-methyl-d-aspartate receptor NR2B subunit (NR2B) phosphorylation in rats treated with vehicle solution and CYP. Compared with vehicle solution, when accompanied by upregulation of phosphorylated NR2B expression in the lumbosacral (L6–S2) dorsal horn, CYP increased the evoked spikes in spinal reflex potentiation induced by repetitive stimulation (1 stimulation/1 s). Moreover, intraperitoneal pretreatments with NG-nitro-l-arginine methyl ester and roscovitine, nitric oxide synthase and cyclin-dependent protein kinase 5 (Cdk5) antagonists, respectively, overwrote CYP-enhanced reflex potentiation and NR2B phosphorylation. When compared with the untreated group, the treatment with small-interfering RNA of NR2B, which decreased the expression of NR2B expression, abolished CYP-dependent reflex facilitation and spinal NR2B phosphorylation. These results suggested that CYP might facilitate spinal reflex potentiation mediated by N-methyl-d-aspartate receptors and participate in the development of visceral hypereflexia/hyperalgesia through nitric oxide- and Cdk5-dependent NR2B phosphorylation at the lumbosacral dorsal horn.
Human Ability to Discriminate Direction of Three-Dimensional Force Stimuli Applied to the Finger Pad
Authors: Panarese Alessandro , Edin Benoni B.
Published: November 2010

Sensory information from tactile mechanoreceptors located in the glabrous skin of the hand is crucial for skillful object exploration and manipulation. These mechanoreceptors reliably encode the direction of fingertip forces, and the brain certainly relies on this information in both sensorimotor and cognitive tasks. In this study, we examined human ability to discriminate the direction of force stimuli applied to the volar surface of the index fingertip on the basis of tactile information only. We show that humans can discriminate three-dimensional (3D) force stimuli whose directions differ by an angle as small as 7.1° in the plane tangential to the skin surface. Moreover, we found that the discrimination ability was mainly affected by the time-varying phases of the stimulus, because adding a static plateau phase to the stimulus improved the discrimination threshold only to a limited extent.
Statistical Comparison of Spike Responses to Natural Stimuli in Monkey Area V1 With Simulated Responses of a Detailed Laminar Network Model for a Patch of V1
Authors: Rasch Malte J. , Schuch Klaus , Logothetis Nikos K. , Maass Wolfgang
Published: November 2010

A major goal of computational neuroscience is the creation of computer models for cortical areas whose response to sensory stimuli resembles that of cortical areas in vivo in important aspects. It is seldom considered whether the simulated spiking activity is realistic (in a statistical sense) in response to natural stimuli. Because certain statistical properties of spike responses were suggested to facilitate computations in the cortex, acquiring a realistic firing regimen in cortical network models might be a prerequisite for analyzing their computational functions. We present a characterization and comparison of the statistical response properties of the primary visual cortex (V1) in vivo and in silico in response to natural stimuli. We recorded from multiple electrodes in area V1 of 4 macaque monkeys and developed a large state-of-the-art network model for a 5 × 5-mm patch of V1 composed of 35,000 neurons and 3.9 million synapses that integrates previously published anatomical and physiological details. By quantitative comparison of the model response to the “statistical fingerprint” of responses in vivo, we find that our model for a patch of V1 responds to the same movie in a way which matches the statistical structure of the recorded data surprisingly well. The deviation between the firing regimen of the model and the in vivo data are on the same level as deviations among monkeys and sessions. This suggests that, despite strong simplifications and abstractions of cortical network models, they are nevertheless capable of generating realistic spiking activity. To reach a realistic firing state, it was not only necessary to include both N -methyl-d-aspartate and GABAB synaptic conductances in our model, but also to markedly increase the strength of excitatory synapses onto inhibitory neurons (>2-fold) in comparison to literature values, hinting at the importance to carefully adjust the effect of inhibition for achieving realistic dynamics in current network models.
Transcription factor MIST1 in terminal differentiation of mouse and human plasma cells
Authors: Capoccia Benjamin J. , Lennerz Jochen K. M. , Bredemeyer Andrew J. , Klco Jeffery M. , Frater John L. , Mills Jason C.
Published: November 2010

Despite their divergent developmental ancestry, plasma cells and gastric zymogenic (chief) cells share a common function: high-capacity secretion of protein. Here we show that both cell lineages share increased expression of a cassette of 269 genes, most of which regulate endoplasmic reticulum (ER) and Golgi function, and they both induce expression of the transcription factors X-box binding protein 1 ( Xbp1) and Mist1 during terminal differentiation. XBP1 is known to augment plasma cell function by establishing rough ER, and MIST1 regulates secretory vesicle trafficking in zymogenic cells. We examined morphology and function of plasma cells in wild-type and Mist1−/−mice and found subtle differences in ER structure but no overall defect in plasma cell function, suggesting that Mist1 may function redundantly in plasma cells. We next reasoned that MIST1 might be useful as a novel and reliable marker of plasma cells. We found that MIST1 specifically labeled normal plasma cells in mouse and human tissues, and, moreover, its expression was also characteristic of plasma cell differentiation in a cohort of 12 human plasma cell neoplasms. Overall, our results show that MIST1 is enriched upon plasma cell differentiation as a part of a genetic program facilitating secretory cell function and also that MIST1 is a novel marker of normal and neoplastic plasma cells in mouse and human tissues.
Peroxisome Proliferator-Activated Receptor -β/δ, -γAgonists and Resveratrol Modulate Hypoxia Induced Changes in Nuclear Receptor Activators of Muscle Oxidative Metabolism
Authors: Regnault Timothy R. H. , Zhao Lin , Chiu Jacky S. S. , Gottheil Stephanie K. , Foran Allison , Yee Siu-Pok
Published: November 2010

PPAR-α, PPAR-β, and PPAR-γ, and RXR in conjunction with PGC-1α and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR), and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C2C12muscle myoblasts displayed a reduction of PGC-1α, PPAR-α, and RXR-α mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1α protein was reduced, and PPAR-γ protein increased. The addition of a PPAR-β agonist (L165,041) for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1α, RXR-α, PPAR-α, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-α, PPAR-α mRNA, and PPAR-γ and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.
Synthesis and Characterization of Nanometer Ce0.75Zr0.25O2Powders by Solid-State Chemical Reaction Method
Authors: Zheng Yuying , Hu Zhengfa , Huang Huimin , Ji Wenjin , Sun Ming , Chen Changshui
Published: November 2010

The nanostructure Ce0.75Zr0.25O2powders have been successfully synthesized by using the mechanically activated solid-state chemical reaction method for the first time, with Ce2(CO)3, ZrOCl2⋅8H2O, and H2C2O4⋅2H2O as raw materials. The structure and morphology of Ce0.75Zr0.25O2powders were characterized to be in the single cubic phase and spherical shape via X-ray powder diffraction, transmission electron microscopy, X-ray Photoelectron Spectrometer, and BET surface area testing technique. The average size of particles was measured to be less than 20 nm, and the specific surface area was 85.4 m2/g. The TG-DTA investigation was used to reveal the possibly chemical reaction mechanism during the synthesis process. The activity of Ce0.75Zr0.25O2oxide solution in three-way catalysts was also valued in this work.
Animal Models to Study the Role of Long‐Term Hypergastrinemia in Gastric Carcinogenesis
Authors: Fossmark Reidar , Qvigstad Gunnar , Martinsen Tom Chr. , Hauso ⌀yvind , Waldum Helge L.
Published: November 2010

Patients with chronic hypergastrinemia due to chronic atrophic gastritis or gastrinomas have an increased risk of developing gastric malignancy, and it has been questioned whether also patients with hypergastrinemia caused by long‐term use of acid inhibiting drugs are at risk. Gastric carcinogenesis in humans is affected by numerous factors and progresses slowly over years. When using animal models with the possibility of intervention, a complex process can be dissected by studying the role of hypergastrinemia in carcinogenesis within a relatively short period of time. We have reviewed findings from relevant models where gastric changes in animal models of long‐term hypergastrinemia have been investigated. In all species where long‐term hypergastrinemia has been induced, there is an increased risk of gastric malignancy. There is evidence that hypergastrinemia is a common causative factor in carcinogenesis in the oxyntic mucosa, while other cofactors may vary in the different models.
Multicenter Study of the Association between Betapapillomavirus Infection and Cutaneous Squamous Cell Carcinoma
Authors: Bavinck Jan Nico Bouwes , Neale Rachel E. , Abeni Damiano , Euvrard Sylvie , Green Adele C. , Harwood Catherine A. , de Koning Maurits N.C. , Naldi Luigi , Nindl Ingo , Pawlita Michael , Pfister Herbert , Proby Charlotte M. , Quint Wim G.V. , ter Schegget Jan , Waterboer Tim , Weissenborn Sönke , Feltkamp Mariet C.W.
Published: November 2010

Human papillomaviruses (betaPV) from the beta genus cannot be classified according to their oncogenicity due to a paucity of information. This study evaluates the association between betaPV infection and cutaneous squamous cell carcinoma in conjunction with measures of UV exposure and susceptibility. We performed case–control studies in the Netherlands, Italy, and Australia, countries with profoundly different UV exposures. The presence of 25 betaPV types in eyebrow hair follicles was determined using a highly sensitive HPV DNA genotyping assay, and antibodies for the 15 most prevalent betaPV types in a total of 689 squamous cell carcinoma cases and 845 controls were detected using multiplex serology. Multivariate logistic regression models were used for case–control comparisons and interaction analyses. BetaPV DNA was detected in eyebrow hairs of more than 90% of all participants. The presence of betaPV DNA was associated with an increased risk of squamous cell carcinoma in the Netherlands (OR = 2.8; 95% CI 1.3–5.8) and Italy (OR = 1.7; 95% CI 0.79–3.6), but not in Australia (OR = 0.91; 95% CI 0.53–1.6). Seropositivity for betaPV in controls ranged between 52% and 67%. A positive antibody response against 4 or more betaPV types was associated with squamous cell carcinoma in Australia (OR = 2.2; 95% CI 1.4–3.3), the Netherlands (OR = 2.0; 95% CI 1.2–3.4) and fair-skinned Italians (OR = 1.6, 95% CI 0.94– 2.7). The association between UV susceptibility and squamous cell carcinoma was stronger in betaPV-seropositive people. These combined data support the hypothesis that betaPV may play a role in the development of cutaneous squamous cell carcinoma. Cancer Res; 70(23); 9777–86. ©2010 AACR.
A Novel Signaling Axis of Matriptase/PDGF-D/β-PDGFR in Human Prostate Cancer
Authors: Ustach Carolyn V. , Huang Wei , Conley-LaComb M. Katie , Lin Chen-Yong , Che Mingxin , Abrams Judith , Kim Hyeong-Reh Choi
Published: November 2010

Increasing evidence indicates the significance of platelet-derived growth factor receptor-β (β-PDGFR) signaling in prostate cancer (PCa). Accordingly, preclinical studies suggest the potential of β-PDGFR as a therapeutic target in metastatic PCa. However, a ligand responsible for β-PDGFR activation in PCa was unknown, and recent clinical trials with imatinib mesylate showed limited success due to normal tissue toxicity. Similarly, in spite of mounting evidence indicating the significance of matriptase in PCa, little is known about its substrates or molecular actions during PCa progression. Here, we identified PDGF-D as a ligand for β-PDGFR in PCa and discovered matriptase as its regulator. Matriptase activates PDGF-D by proteolytic removal of the CUB domain in a 2-step process, creating a hemidimer, followed by growth factor domain dimer (GFD-D) generation. Matriptase can deactivate PDGF-D by further proteolytic cleavage within the GFD, revealing its biphasic regulation. Importantly, PDGF-D/matriptase colocalization is accompanied with β-PDGFR phosphorylation in human PCa tissues. This study unveiled a novel signaling axis of matriptase/PDGF-D/β-PDGFR in PCa, providing new insights into functional interplay between serine protease and growth factor signaling networks. Cancer Res; 70(23); 9631–40. ©2010 AACR.
Integration of Host-Related Signatures with Cancer Cell–Derived Predictors for the Optimal Management of Anticancer Chemotherapy
Authors: Zitvogel Laurence , Kepp Oliver , Aymeric Laetitia , Ma Yuting , Locher Clara , Delahaye Nicolas F. , André Fabrice , Kroemer Guido
Published: November 2010

Current cancer management aims to integrate molecular signatures into the design of personalized therapies. Recent advances in “omics” done on tumor specimens have led to the identification of factors that either recognize cancers of dismal prognosis or pinpoint “druggable” signaling pathways, which can be interrupted by targeted therapies. However, accumulating evidence underscores the biological and clinical significance of immune predictors in several compartments (blood, serum, tumor) in a variety of malignancies. An additional aspect that has been overlooked is the bidirectional, tumor-host interaction during therapeutic intervention, suggesting that dynamic molecular, biochemical, and metabolic signatures should be developed in the future. We review immune parameters of prognostic or predictive value during cancer therapy, and highlight existing “descriptive-prognostic” and “functional-therapeutic” molecular signatures, with the hindsight of designing appropriate compensatory therapies. Cancer Res; 70(23); 9538–43. ©2010 AACR.
Melanoma Cells Express ICOS Ligand to Promote the Activation and Expansion of T-Regulatory Cells
Authors: Martin-Orozco Natalia , Li Yufeng , Wang Yijun , Liu Shijuan , Hwu Patrick , Liu Yong-Jun , Dong Chen , Radvanyi Laszlo
Published: November 2010

CD4+CD25+Foxp3+ T-regulatory cells (Tregs) accumulate in tumors; however, little is known about how the tumor environment influences this process. Here we show that human melanomas express inducible T-cell costimulator ligand (ICOS-L/B7H) that can provide costimulation through ICOS for the expansion of activated Tregs maintaining high Foxp3 and CD25 expression as well as a suppressive function. Thus, ICOS-L expression by melanoma tumor cells may directly drive Treg activation and expansion in the tumor microenvironment as another mechanism of immune evasion. Cancer Res; 70(23); 9581–90. ©2010 AACR.
Cancer Exosomes Trigger Fibroblast to Myofibroblast Differentiation
Authors: Webber Jason , Steadman Robert , Mason Malcolm D. , Tabi Zsuzsanna , Clayton Aled
Published: November 2010

There is a growing interest in the cell–cell communication roles in cancer mediated by secreted vesicles termed exosomes. In this study, we examined whether exosomes produced by cancer cells could transmit information to normal stromal fibroblasts and trigger a cellular response. We found that some cancer-derived exosomes could trigger elevated α-smooth muscle actin expression and other changes consistent with the process of fibroblast differentiation into myofibroblasts. We show that TGF-β is expressed at the exosome surface in association with the transmembrane proteoglycan betaglycan. Although existing in a latent state, this complex was fully functional in eliciting SMAD-dependent signaling. Inhibiting either signaling or betaglycan expression attenuated differentiation. While the kinetics and overall magnitude of the response were similar to that achieved with soluble TGF-β, we identified important qualitative differences unique to the exosomal route of TGF-β delivery, as exemplified by a significant elevation in fibroblast FGF2 production. This hitherto unknown trigger for instigating cellular differentiation in a distinctive manner has major implications for mechanisms underlying cancer-recruited stroma, fibrotic diseases, and wound-healing responses. Cancer Res; 70(23); 9621–30. ©2010 AACR.
Negative Regulation of p53 by the Long Isoform of ErbB3 Binding Protein Ebp1 in Brain Tumors
Authors: Kim Chung Kwon , Nguyen Truong L.X. , Joo Kyeung Min , Nam Do-Hyun , Park Jihye , Lee Kyung-Hoon , Cho Sung-Woo , Ahn Jee-Yin
Published: November 2010

The ErbB3 binding protein Ebp1 has been implicated in a number of human cancers. Ebp1 includes 2 isoforms, p48 and p42, that exhibit different cellular activities. Here we show that the larger p48 isoform is transforming and that it promotes cell growth, clonogenicity, and invasion in human glioblastoma (GBM). P48 overexpression in GBM cells facilitated tumorigenesis and enhanced tumor growth in mouse xenograft models. Human GBM tissues displayed elevated levels of p48 compared with surrounding normal tissues or low-grade tumors. Notably, p48 levels were inversely correlated with poor prognosis in GBM patients. We determined that p48 binds to the p53 E3 ligase HDM2, enhancing HDM2-p53 association and thereby promoting p53 polyubiquitination and degradation to reduce steady-state p53 levels and activity. Together, our findings suggest that p48 functions as an oncogene by promoting glioma tumorigenicity via interactions with HDM2 that contribute to p53 downregulation. Cancer Res; 70(23); 9730–41. ©2010 AACR.