bluuebunny/crossref_metadata_2025 huggingface dataset:
Ecoepidemiology and Complete Genome Comparison of Different Strains of Severe Acute Respiratory Syndrome-Related
Rhinolophus
Bat Coronavirus in China Reveal Bats as a Reservoir for Acute, Self-Limiting Infection That Allows Recombination Events
Authors: Lau Susanna K. P. , Li Kenneth S. M. , Huang Yi , Shek Chung-Tong , Tse Herman , Wang Ming , Choi Garnet K. Y. , Xu Huifang , Lam Carol S. F. , Guo Rongtong , Chan Kwok-Hung , Zheng Bo-Jian , Woo Patrick C. Y. , Yuen Kwok-Yung
Published: January 2010

Despite the identification of severe acute respiratory syndrome-related coronavirus (SARSr-CoV) in
Rhinolophus
Chinese horseshoe bats (SARSr-Rh-BatCoV) in China, the evolutionary and possible recombination origin of SARSr-CoV remains undetermined. We carried out the first study to investigate the migration pattern and SARSr-Rh-BatCoV genome epidemiology in Chinese horseshoe bats during a 4-year period. Of 1,401 Chinese horseshoe bats from Hong Kong and Guangdong, China, that were sampled, SARSr-Rh-BatCoV was detected in alimentary specimens from 130 (9.3%) bats, with peak activity during spring. A tagging exercise of 511 bats showed migration distances from 1.86 to 17 km. Bats carrying SARSr-Rh-BatCoV appeared healthy, with viral clearance occurring between 2 weeks and 4 months. However, lower body weights were observed in bats positive for SARSr-Rh-BatCoV, but not Rh-BatCoV HKU2. Complete genome sequencing of 10 SARSr-Rh-BatCoV strains showed frequent recombination between different strains. Moreover, recombination was detected between SARSr-Rh-BatCoV Rp3 from Guangxi, China, and Rf1 from Hubei, China, in the possible generation of civet SARSr-CoV SZ3, with a breakpoint at the nsp16/spike region. Molecular clock analysis showed that SARSr-CoVs were newly emerged viruses with the time of the most recent common ancestor (tMRCA) at 1972, which diverged between civet and bat strains in 1995. The present data suggest that SARSr-Rh-BatCoV causes acute, self-limiting infection in horseshoe bats, which serve as a reservoir for recombination between strains from different geographical locations within reachable foraging range. Civet SARSr-CoV is likely a recombinant virus arising from SARSr-CoV strains closely related to SARSr-Rh-BatCoV Rp3 and Rf1. Such frequent recombination, coupled with rapid evolution especially in ORF7b/ORF8 region, in these animals may have accounted for the cross-species transmission and emergence of SARS.
Sustainability of Virulence in a Phage-Bacterial Ecosystem
Authors: Heilmann Silja , Sneppen Kim , Krishna Sandeep
Published: January 2010

Virulent phages and their bacterial hosts represent an unusual sort of predator-prey system where each time a prey is eaten, hundreds of new predators are born. It is puzzling how, despite the apparent effectiveness of the phage predators, they manage to avoid driving their bacterial prey to extinction. Here we consider a phage-bacterial ecosystem on a two-dimensional (2-d) surface and show that homogeneous space in itself enhances coexistence. We analyze different behavioral mechanisms that can facilitate coexistence in a spatial environment. For example, we find that when the latent times of the phage are allowed to evolve, selection favors “mediocre killers,” since voracious phage rapidly deplete local resources and go extinct. Our model system thus emphasizes the differences between short-term proliferation and long-term ecosystem sustainability.
Evolutionary Dynamics of Multiple Sublineages of H5N1 Influenza Viruses in Nigeria from 2006 to 2008
Authors: Fusaro Alice , Nelson Martha I. , Joannis Tony , Bertolotti Luigi , Monne Isabella , Salviato Annalisa , Olaleye Olufemi , Shittu Ismaila , Sulaiman Lanre , Lombin Lami H. , Capua Ilaria , Holmes Edward C. , Cattoli Giovanni
Published: January 2010

Highly pathogenic A/H5N1 avian influenza (HPAI H5N1) viruses have seriously affected the Nigerian poultry industry since early 2006. Previous studies have identified multiple introductions of the virus into Nigeria and several reassortment events between cocirculating lineages. To determine the spatial, evolutionary, and population dynamics of the multiple H5N1 lineages cocirculating in Nigeria, we conducted a phylogenetic analysis of whole-genome sequences from 106 HPAI H5N1 viruses isolated between 2006 and 2008 and representing all 25 Nigerian states and the Federal Capital Territory (FCT) reporting outbreaks. We identified a major new subclade in Nigeria that is phylogenetically distinguishable from all previously identified sublineages, as well as two novel reassortment events. A detailed analysis of viral phylogeography identified two major source populations for the HPAI H5N1 virus in Nigeria, one in a major commercial poultry area (southwest region) and one in northern Nigeria, where contact between wild birds and backyard poultry is frequent. These findings suggested that migratory birds from Eastern Europe or Russia may serve an important role in the introduction of HPAI H5N1 viruses into Nigeria, although virus spread through the movement of poultry and poultry products cannot be excluded. Our study provides new insight into the genesis and evolution of H5N1 influenza viruses in Nigeria and has important implications for targeting surveillance efforts to rapidly identify the spread of the virus into and within Nigeria.
Mutations Abrogating VP35 Interaction with Double-Stranded RNA Render Ebola Virus Avirulent in Guinea Pigs
Authors: Prins Kathleen C. , Delpeut Sebastien , Leung Daisy W. , Reynard Olivier , Volchkova Valentina A. , Reid St. Patrick , Ramanan Parameshwaran , Cárdenas Washington B. , Amarasinghe Gaya K. , Volchkov Viktor E. , Basler Christopher F.
Published: January 2010

Ebola virus (EBOV) protein VP35 is a double-stranded RNA (dsRNA) binding inhibitor of host interferon (IFN)-α/β responses that also functions as a viral polymerase cofactor. Recent structural studies identified key features, including a central basic patch, required for VP35 dsRNA binding activity. To address the functional significance of these VP35 structural features for EBOV replication and pathogenesis, two point mutations, K319A/R322A, that abrogate VP35 dsRNA binding activity and severely impair its suppression of IFN-α/β production were identified. Solution nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography reveal minimal structural perturbations in the K319A/R322A VP35 double mutant and suggest that loss of basic charge leads to altered function. Recombinant EBOVs encoding the mutant VP35 exhibit, relative to wild-type VP35 viruses, minimal growth attenuation in IFN-defective Vero cells but severe impairment in IFN-competent cells. In guinea pigs, the VP35 mutant virus revealed a complete loss of virulence. Strikingly, the VP35 mutant virus effectively immunized animals against subsequent wild-type EBOV challenge. These
in vivo
studies, using recombinant EBOV viruses, combined with the accompanying biochemical and structural analyses directly correlate VP35 dsRNA binding and IFN inhibition functions with viral pathogenesis. Moreover, these studies provide a framework for the development of antivirals targeting this critical EBOV virulence factor.
Acquisition of Complement Resistance through Incorporation of CD55/Decay-Accelerating Factor into Viral Particles Bearing Baculovirus GP64
Authors: Kaname Yuuki , Tani Hideki , Kataoka Chikako , Shiokawa Mai , Taguwa Shuhei , Abe Takayuki , Moriishi Kohji , Kinoshita Taroh , Matsuura Yoshiharu
Published: January 2010

A major obstacle to gene transduction by viral vectors is inactivation by human complementin vivo. One way to overcome this is to incorporate complement regulatory proteins, such as CD55/decay accelerating factor (DAF), into viral particles. Lentivirus vectors pseudotyped with the baculovirus envelope protein GP64 have been shown to acquire more potent resistance to serum inactivation and longer transgene expression than those pseudotyped with the vesicular stomatitis virus (VSV) envelope protein G. However, the molecular mechanisms underlying resistance to serum inactivation in pseudotype particles bearing the GP64 have not been precisely elucidated. In this study, we generated pseudotype and recombinant VSVs bearing the GP64. Recombinant VSVs generated in human cell lines exhibited the incorporation of human DAF in viral particles and were resistant to serum inactivation, whereas those generated in insect cells exhibited no incorporation of human DAF and were sensitive to complement inactivation. The GP64 and human DAF were detected on the detergent-resistant membrane and were coprecipitated by immunoprecipitation analysis. A pseudotype VSV bearing GP64 produced in human DAF knockdown cells reduced resistance to serum inactivation. In contrast, recombinant baculoviruses generated in insect cells expressing human DAF or carrying the human DAF gene exhibited resistance to complement inactivation. These results suggest that the incorporation of human DAF into viral particles by interacting with baculovirus GP64 is involved in the acquisition of resistance to serum inactivation.
Rapid Escape from Preserved Cross-Reactive Neutralizing Humoral Immunity without Loss of Viral Fitness in HIV-1-Infected Progressors and Long-Term Nonprogressors
Authors: van Gils Marit J. , Bunnik Evelien M. , Burger Judith A. , Jacob Yodit , Schweighardt Becky , Wrin Terri , Schuitemaker Hanneke
Published: January 2010

A substantial proportion of human immunodeficiency virus type 1 (HIV-1)-infected individuals has cross-reactive neutralizing activity in serum, with a similar prevalence in progressors and long-term nonprogressors (LTNP). We studied whether disease progression in the face of cross-reactive neutralizing serum activity is due to fading neutralizing humoral immunity over time or to viral escape. In three LTNP and three progressors, high-titer cross-reactive HIV-1-specific neutralizing activity in serum against a multiclade pseudovirus panel was preserved during the entire clinical course of infection, even after AIDS diagnosis in progressors. However, while early HIV-1 variants from all six individuals could be neutralized by autologous serum, the autologous neutralizing activity declined during chronic infection. This could be attributed to viral escape and the apparent inability of the host to elicit neutralizing antibodies to the newly emerging viral escape variants. Escape from autologous neutralizing activity was not associated with a reduction in the viral replication rate
in vitro
. Escape from autologous serum with cross-reactive neutralizing activity coincided with an increase in the length of the variable loops and in the number of potential N-linked glycosylation sites in the viral envelope. Positive selection pressure was observed in the variable regions in envelope, suggesting that, at least in these individuals, these regions are targeted by humoral immunity with cross-reactive potential. Our results may imply that the ability of HIV-1 to rapidly escape cross-reactive autologous neutralizing antibody responses without the loss of viral fitness is the underlying explanation for the absent effect of potent cross-reactive neutralizing humoral immunity on the clinical course of infection.
Comparison of the history obtained by patient-completed questionnaires with doctors’ standard notes for patients with acute abdominal pain
Authors: Saravanan B , Muhammad R , Geach R , Jenkinson L R
Published: January 2010

Background

Studies have shown that proformas improve the information recorded by junior doctors when they clerk patients with acute abdominal pain. This increases their diagnostic accuracy, but doctors are reluctant to use them. Patient-completed questionnaires are being used in elective surgery, but can they be used for patients with acute abdominal pain?

Objective

To evaluate the history obtained by patient-completed questionnaires in patients with acute abdominal pain and compare this with the history recorded by the admitting junior doctors.

Design

Prospective observational study.

Subjects

116 adult patients aged 17–90 admitted as an emergency to the Department of Surgery at Ysbyty Gwynedd in North Wales.

Main outcome measures

Differences in the amount of information collected using patient-completed questionnaires and the history recorded by junior doctors. The questionnaires contained 17 points relating to general symptoms of the acute abdomen and five points related to gynaecological symptoms.

Results

Of the 116 patients studied, 100 (86.2%) completed the questionnaires. There were 60 female and 40 male patients and the median age was 49 years (range 17–90). Doctors recorded fewer than 50% of the general symptoms for acute abdominal pain and patients recorded 90% or more (p<0.0001). Doctors’ documentation of gynaecological symptoms was better, but still less detailed than patients’ (52–76% vs 92–100%).

Conclusion

Patient-completed questionnaires can be used to obtain a more accurate history than junior doctors for most patients admitted with acute abdominal pain.
Specialist practice in the community: chest medicine
Authors: O’Kelly N , Ghosh S , Smith J ,   Long-Term Conditions Team
Published: January 2010

The impact of long term conditions (LTCs) is an issue for all health care systems in the world today. With an aging population and the incidence of LTCs subsequently increasing, the impact on health economics is a challenging burden on all societies. Thus, delivering cost effective high quality care for all LTCs is a major challenge to both health payers and providers alike. This review discusses the various models of care adopted in health systems. It then focuses on community specialist services for respiratory disease in the context of this changing health environment and concentrates on the scope and evidence to support specialist respiratory community services. The review concludes with discussions surrounding the implementation of such services across two large primary care trusts in the UK, with particular focus on the arguments for their future development and incorporation with strategies that are cost effective, while helping older people with LTCs to maintain their health, functional ability and quality of care.
An overview of the management of morbid obesity
Authors: Monkhouse S J W , Morgan J D T , Bates S E , Norton S A
Published: January 2010

Obesity is a modern-day epidemic with serious physical, psychological and economic implications for the patients. Tackling obesity is now a priority for most healthcare providers. Managing such patients can be complex, emotional, time consuming and often frustrating. Obesity surgery, in its various forms, has revolutionised this struggle. With appropriate selection of patients, adequate resources and a multidisciplinary team involvement, obesity can now effectively be “cured”. It is vital that those who deal with obese patients know how to access these services and understand the processes involved in the journey from initial assessment to postoperative follow-up. Obesity surgery has a major impact in reducing obesity-related comorbidities such as diabetes and hypertension and contributes to society by returning patients to work. Prevention must be at the heart of any strategy to manage obesity, but, for established cases, surgery is taking centre stage and will continue to flourish as new techniques and procedures are developed.
ON TWO-DIMENSIONAL QUASITOPOLOGICAL FIELD THEORIES
Authors: TEOTONIO-SOBRINHO P. , MOLINA C. , YOKOMIZO N.
Published: January 2010

We study a class of lattice field theories in two dimensions that includes gauge theories. We show that in these theories it is possible to implement a broader notion of local symmetry, based on semisimple Hopf algebras. A character expansion is developed for the quasitopological field theories, and partition functions are calculated with this tool. Expected values of generalized Wilson loops are defined and studied with the character expansion.
CHAOS SYNCHRONIZATION VIA UNIDIRECTIONAL COUPLING AND ITS APPLICATION TO SECURE COMMUNICATION
Authors: WANG XINGYUAN , WANG MINGJUN
Published: January 2010

This paper studies chaos synchronization via unidirectional coupling. The self-synchronization of Lorenz systems, modified coupled dynamos systems and hyperchaotic Chen systems is studied by three methods: the Lyapunov function method, the global synchronization method and the numerical calculation of the largest Lyapunov exponent method. In regard to application to communication, we show that via transmitting single signal the synchronization of the drive system and the response system can be achieved. An example of applying self-synchronization of hyperchaotic Chen systems to chaotic masking secure communication is presented in this paper. Simulation results show the effectiveness of the method.
He's MAX–MIN METHOD FOR THE RELATIVISTIC OSCILLATOR AND HIGH ORDER DUFFING EQUATION
Authors: AZAMI R. , GANJI D. D. , BABAZADEH H. , DVAVODI A. G. , GANJI S. S.
Published: January 2010

This paper implements He's max–min method to solve accurately strong nonlinear oscillators. Maximal and minimal solution thresholds of a nonlinear problem can be easily found, and an approximate solution of the nonlinear equation can be easily deduced using He Chengtian's interpolation, which has a millennia history. Some typical examples are employed to illustrate its validity, effectiveness, and flexibility.
AN ALGORITHM FOR DIRECT SIMULATION OF LINEAR WAVE PROPAGATION IN IRREGULAR REGIONS
Authors: CHEN XUEMEI , ROGERS JOEL C. W. , MEANS STEVEN L. , SZYMCZAK WILLIAM G.
Published: January 2010

A numerical algorithm has been developed to simulate linear wave propagation in media containing irregular inhomogeneities, especially irregular voids in fluids. The computational domain is extended to include the regions occupied by the inhomogeneities through replacing the boundaries with properly chosen sources. The solution corresponding to Dirichlet boundary conditions on the inhomogeneities is presented. This algorithm can be used to calculate linear wave propagation in a fluid medium with multiple bubbles.
PORTRAITS OF RUSSIAN WOMEN ENTREPRENEURS: IDENTIFICATION AND WAYS OF LEADERSHIP
Authors: AALTIO IIRIS , PELTONEN HANNA
Published: January 2010

Entrepreneurship has developed in Russia during the past two decades, which is a short time to develop a firm business culture. Women are still a minority among entrepreneurs globally, also in Russia [Verhovskaya, O. and Dorokhina, M. (2008) GEM. Global Entrepreneurship Monitor, Executive Summary, Russia 2007, www.gemconsortium.org, 30.9.2008]. Our study focuses on Russian women entrepreneurship by means of an interview and photographs of 10 women entrepreneurs in the St. Petersburg area. We ask, how do they identify themselves in the current economic situation. Further, we ask if there is a specifically Russian type of women entrepreneurship and entrepreneurial identification. Finally, in the study it is also elaborated the interviewed women entrepreneurs' perceptions concerning the Russian market economy and its transition, as well as their views for the future.

This study results show that the women entrepreneurs make sense of their identity as leaders using expressions of autocracy and democracy. Moreover, they express a subjectively rich sense of their own entrepreneurship with no signs of marginality, and had an optimistic outlook on the future with wishes to expand and develop their businesses. Methodologically, the study contributes in combining the interview data and photograph analysis.
IMPACT OF SOCIAL CAPITAL DEVELOPMENT AND USE IN THE GROWTH PROCESS OF WOMEN-OWNED FIRMS
Authors: ROOMI MUHAMMAD AZAM
Published: January 2010

Drawing upon the Churchill and Lewis stage growth model of enterprises, this study explains the role of social capital possessed by women entrepreneurs in different stages of growth within their firms. Friends and family as well as women-only networks in the start-up stage; customers, staff, and suppliers in the survival stage; mixed networks as well as business and professional advisers in the success and take-off stages; and suppliers and/or distributors in the maturity stage have been found to be the main sources of women entrepreneurs' social capital. In particular, the study highlights industry differences as well as norms of behavior based on trust and obligation through which they successfully transform their contacts into useful resources. The availability of these resources as well as access to information, advice, and ideas act as a catalyst in developing and growing their businesses.
FEMALE ENTREPRENEURS' AUTHORITY: IS THE CREATIVE ASPECT OF AUTHORITY A MASCULINE FICTION IN MANAGERIAL AND ENTREPRENEURIAL PARADIGMS?
Authors: REDIEN-COLLOT RENAUD
Published: January 2010

Authority is the confirmation of the control an individual has over norms and codes (Sennet, 1981). It stimulates the development of social capital. Gender shapes authority. Bourdieu (1994) stresses that in traditional societies men can interpret and produce norms whereas women reproduce them and consequently may experience difficulties in constructing their authority. Butler (1990) confirms that this dichotomy is still effective in post-modern contexts.

In the literature on women entrepreneurs, scholars stress their lack of social capital as an impediment to growing the business and suggest that they should follow the male model (Aldrich et al., 1997; Ban et al., 1996). However, if one examines carefully the process of production of social capital, one would see that it is the result of a strict gender labor-division. In spite of their agentivity, female entrepreneurs fail to overcome this. Many of them may thus be tempted to adapt male patterns of authority.

The present study examines how women entrepreneurs and minority business owners assimilate authority that is encapsulated in the traditional male entrepreneurial discourse. Then it analyses the perception of women entrepreneurs on authority and its impact on their style of internal management and their strategies of networking. The results reveal that either female entrepreneurs adopt authority as a repressive tool of management that helps them to develop their social capital in restricted circles of influence or they scorn authority as the display of norms that may endanger the reputation of their firms and their social influence without proposing a clear alternative. Apparently, women entrepreneurs deny the creative aspects of authority that Sennet and his Foucaldian followers have detected in managers' behaviors in the context of organizational sociology.
GENDER LENSES IDENTIFY DIFFERENT WAVES AND WAYS OF UNDERSTANDING WOMEN ENTREPRENEURSHIP
Authors: KYRÖ PAULA
Published: January 2010

This article suggests that perhaps adopting gender lenses to study the interplay between gender theories and women entrepreneurship research might advance our understanding of women entrepreneurship and small business ownership. This interplay reveals three different waves in women entrepreneurship research: men-specific, stereotyping, and postmodern. To investigate this empirically, the article adopts the Finnish context and looks at how women experience being an entrepreneur and/or small business owner by employing the method of phenomenography. Finland as a country officially sets great store by equality, but at the same time still evinces a great deal of segregation. This paradox offers a fruitful ground for this study. The results provide new categories to women entrepreneurship and thus expand the third wave of research. These results indicate that we are far from understanding the dynamics between being a woman entrepreneur and the gendered structures and practices. Thus, further research is needed to deeper understand these dynamics.
WOMEN, GLASS CEILING, AND PROFESSIONALIZATION IN FAMILY SMEs: A MISSED LINK
Authors: SONGINI LUCREZIA , GNAN LUCA
Published: January 2010

Literature and practical evidence on the glass ceiling have showed that women's presence in ownership does not ensure that they can significantly influence firm decisional processes. Similarly women's presence in governance roles does not entail glass ceiling removal, even in family firms, which are expected to be a more favorable context.

Moreover, literature on women's role in family firms has focused mostly on women's expectations, values, and objectives, on the decision-making processes led by women, on their leadership styles and so on. Very few studies have dealt with women's contribution in strategy formulation, organizational structure design, implementing and using managerial mechanisms.

This article focuses on two main topics: the role of women in family firms and the professionalization of the company. It aims at understanding both women's involvement in governance and managerial roles, and the relationship with the family firms' professionalization. The findings reveal, on one hand, that family SMEs are a more favorable context for the removal of the glass ceiling only with regard to the roles of member of board of directors and functional director. On the other hand, they show that some managerial mechanisms, such as incentives and managerial reporting systems, are more relevant when women are involved in governance and managerial roles.
The Valuation of Information Technology Investments by Real Options Analysis
Authors: Lee Kuo-Jung , Shyu David S. , Dai Miao-Ling
Published: January 2010

This study establishes a dynamic model under real options analysis to analyze the optimal timing decision of information technology (IT) investments when the output price for firms is stochastic and benefits of IT investments are arisen from the increasing output price, increasing sale, and cost savings. We derive the closed form expression of the timing of IT investments and furthermore prove that IT investments rise at an increasing rate in economic booms and fall in economic busts. This study finds that increasing (decreasing) price volatility will delay (advance) the timing of IT investments. Increasing IT investments, however, may not delay the timing of IT investments. In addition, the decreasing (increasing) efficiency and increasing (decreasing) depreciation of IT investments will delay (advance) the timing of IT investments.
The Intraday Performance of Contrarian Strategies: Evidence from the Taiwan Stock Exchange
Authors: Wang Kuei-Yuan , Peng Su-Chun , Huang Yen-Sheng
Published: January 2010

This paper examines the intraday performance of contrarian strategies using data from 438 listed stocks on the Taiwan Stock Exchange in 2004. The results indicate significantly positive abnormal returns for the contrarian strategies. For the whole trading day, the contrarian strategies earn an average abnormal return of at least 0.18% for all strategies, and above 0.3% in 24 out of the 36 contrarian strategies prior to transaction costs. Moreover, the contrarian profit increases from a formation period of five minutes to 10 minutes, and then declines toward a longer formation period of 60 minutes. This pattern suggests that price reversals occur around 10 minutes into the formation period. The intraday analysis also indicates that the abnormal returns earned by the contrarian strategies are higher in the opening and the closing intervals than in the middle of the trading day. Finally, the results indicate that price reversals occur for both prior losers and prior winners, with prior winners experiencing larger price reversals than prior losers when the holding period becomes longer. However, the above results of profitable abnormal returns are based on gross returns before transaction costs were deducted. When reasonable explicit trading costs are considered, none of the 36 contrarian strategies produce any "free lunches" for investors.
An Empirical Test of a Resources Deployment Portfolio (RDP) Approach to Business Group ROE Decomposition
Authors: Chen David M. , Yang Li-Ling
Published: January 2010

This study proposes a resources deployment portfolio (RDP) approach to decomposing return on equity (ROE) for business analysis. The five components are return on operating equity (RoOE), return on financial equity (RoFE), return on other equity (RoXE), return on influencing equity (RoIE), and R&D intensiveness (R&DI). Empirical results demonstrate that RDP decomposition offers substantial improvement over DuPont decomposition in explaining market valuation. Confirming the perceived sustainability, RoOE is the most consistently significant component for both long-term and short-term value creation. In line with prior research findings, R&DI is generally significant in contributing to long-term value creation but is not significant for short-term value creation.
Different activation forms of MMP-2 oppositely affect the fate of endothelial cells
Authors: Shapiro Sarah , Khodalev Olga , Bitterman Haim , Auslender Ron , Lahat Nitza
Published: January 2010

Detachment of endothelial cells (ECs) from the extracellular matrix (ECM) is required not only for angiogenesis, but also for EC apoptosis. Matrix metalloproteinase (MMP)-2 plays a major role in the degradation of the ECM, supporting an essential role for this enzyme in both survival (angiogenesis) and death of ECs. Our aim was to study these seemingly paradoxical effects of MMP-2. We rationalized that inhibiting apoptosis would drive MMP-2 toward a prosurvival activity, clarifying the mechanisms involved. By employing specific inhibitors to two major apoptotic pathways in ECs, caspases and p38 MAPK (p38), we demonstrated that they differently affected EC behavior as well as MMP-2 expression. The p38 pathway appears to enhance MMP-2 synthesis, its partial (“intermediate”) and its full activation, probably via membrane type (MT)1-MMP, while caspases enhance MMP-2 synthesis and full activation but reduce MT1-MMP and MMP-2 intermediate form. Evaluation of the reciprocal influences of MMP-2 on ECs showed that the intermediate form supported survival and migration, and the fully active form led to cell death. In addition, a pro- and intermediate form-rich environment, even in the presence of the fully active form, exerted protective effects. Thus the seemingly conflicting effects of MMP-2 on EC survival may be explained by the ratio between the MMP-2 activation forms. A regulatory loop between active MMP-2 and p38 but not between MMP-2 and caspases was also observed, suggesting that MMP-2 is downstream to caspases where it serves as an “exterminator” molecule. Altogether, modification of caspase and p38 pathways, via changes of local MMP-2, affect survival and angiogenic steps in ECs.
Combining short-term metformin treatment and one bout of exercise does not increase insulin action in insulin-resistant individuals
Authors: Sharoff Carrie G. , Hagobian Todd A. , Malin Steven K. , Chipkin Stuart R. , Yu Haiyan , Hirshman Michael F. , Goodyear Laurie J. , Braun Barry
Published: January 2010

Results from the Diabetes Prevention Program highlight the effectiveness of metformin or regular physical activity in the prevention of type 2 diabetes. Independently, metformin and exercise increase insulin sensitivity, but they have not been studied in combination. To assess the combined effects, insulin-resistant subjects ( n = 9) matched for weight, body fat, and aerobic fitness were studied before any treatment (B), after 2–3 wk of 2,000 mg/day metformin (MET), and after metformin plus 40 min of exercise at 65% V̇o2peak (MET + Ex). A second group ( n = 7) was studied at baseline and after an identical bout of exercise with no metformin (Ex). Biopsies of the vastus lateralis were taken at B, after MET, immediately after MET + Ex ( group 1), or immediately after Ex ( group 2). Insulin sensitivity was assessed 4 h postexercise with a euglycemic hyperinsulinemic (40 mU·m2·min−1) clamp enriched with [6,6-2H]glucose. Insulin sensitivity was 54% higher after Ex ( P < 0.01), but there was no change with Met + Ex. Skeletal muscle AMPKα2 activity was elevated threefold ( P < 0.01) after Ex, but there was no increase with MET + Ex. These findings suggest that the combination of short-term metformin treatment and an acute bout of exercise does not enhance insulin sensitivity, and the addition of metformin may attenuate the well-documented effects of exercise alone.
Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo
Authors: Nyman Lara R. , Ford Eric , Powers Alvin C. , Piston David W.
Published: January 2010

Pancreatic islets are highly vascularized and arranged so that regions containing β-cells are distinct from those containing other cell types. Although islet blood flow has been studied extensively, little is known about the dynamics of islet blood flow during hypoglycemia or hyperglycemia. To investigate changes in islet blood flow as a function of blood glucose level, we clamped blood glucose sequentially at hyperglycemic (∼300 mg/dl or 16.8 mM) and hypoglycemic (∼50 mg/dl or 2.8 mM) levels while simultaneously imaging intraislet blood flow in mouse models that express green fluorescent protein in the β-cells or yellow fluorescent protein in the α-cells. Using line scanning confocal microscopy, in vivo blood flow was assayed after intravenous injection of fluorescent dextran or sulforhodamine-labeled red blood cells. Regardless of the sequence of hypoglycemia and hyperglycemia, islet blood flow is faster during hyperglycemia, and apparent blood volume is greater during hyperglycemia than during hypoglycemia. However, there is no change in the order of perfusion of different islet endocrine cell types in hypoglycemia compared with hyperglycemia, with the islet core of β-cells usually perfused first. In contrast to the results in islets, there was no significant difference in flow rate in the exocrine pancreas during hyperglycemia compared with hypoglycemia. These results indicate that glucose differentially regulates blood flow in the pancreatic islet vasculature independently of blood flow in the rest of the pancreas.
Adenosine A1receptor mediated suppression of adrenal activity in near-term fetal sheep
Authors: Jensen E. C. , Bennet L. , Fraser M. , Power G. G. , Hunter C. J. , Gunn A. J.
Published: January 2010

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a critical response to perinatal hypoxia. Recent data show that adenosine appears to inhibit baseline levels of fetal cortisol and to restrict the increase in ACTH and cortisol during moderate hypoxia. Because adenosine increases substantially during profound asphyxia, it is possible, but untested, that counterintuitively it might restrict the HPA response to more severe insults. It is unclear which receptors mediate the effects of adenosine on the HPA axis; however, adenosine A1receptor activation is important for adaptation to hypoxia. We therefore investigated whether adenosine A1receptor blockade modulates ACTH and cortisol levels in fetal sheep at 118 to 126 days gestation, randomly allocated to receive an intravenous infusion of either vehicle (vehicle-occlusion, n = 7) or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A1receptor antagonist, DPCPX-occlusion, n = 7) infused 60 min before and during 10 min of umbilical cord occlusion, or infusion of DPCPX for 70 min without occlusion (DPCPX-sham, n = 6). Experiments were terminated after 72 h. Fetal ACTH levels increased significantly ( P < 0.01) during occlusion, but not sham occlusion, and returned to baseline values by 60 min after occlusion. In the vehicle-occlusion group, fetal cortisol and cortisone plasma levels increased significantly ( P < 0.05) 60 min after the occlusion and returned to baseline values by 24 h. In contrast, there was a marked increase in both fetal cortisol and cortisone during DPCPX infusion before occlusion to a level greater even than the maximum rise seen after occlusion alone. This increase was sustained after occlusion, with increased cortisol levels compared with occlusion alone up to 72 h. In conclusion, fetal cortisol concentrations are suppressed by adenosine A1receptor activity, largely though a direct adrenal mechanism. This suppression can be partially overcome by supraphysiological stimuli such as asphyxia.
Different mechanisms of adjustment to a change of the photoperiod in the suprachiasmatic and liver circadian clocks
Authors: Sosniyenko Serhiy , Parkanová Daniela , Illnerová Helena , Sládek Martin , Sumová Alena
Published: January 2010

Changes in photoperiod modulate the circadian system, affecting the function of the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The aim of the present study was to elucidate the dynamics of adjustment to a change of a long photoperiod with 18 h of light to a short photoperiod with 6 h of light of clock gene expression rhythms in the mouse SCN and in the peripheral clock in the liver, as well as of the locomotor activity rhythm. Three, five, and thirteen days after the photoperiod change, daily profiles of Per1, Per2, and Rev-erbα expression in the rostral, middle, and caudal parts of the SCN and of Per2 and Rev-erbα in the liver were determined by in situ hybridization and real-time RT-PCR, respectively. The clock gene expression rhythms in the different SCN regions, desynchronized under the long photoperiod, attained synchrony gradually following the transition from long to short days, mostly via advancing the expression decline. The photoperiodic modulation of the SCN was due not only to the degree of synchrony among the SCN regions but also to different waveforms of the rhythms in the individual SCN parts. The locomotor activity rhythm adjusted gradually to short days by advancing the activity onset, and the liver rhythms adjusted by advancing the Rev-erbα expression rise and Per2 decline. These data indicate different mechanisms of adjustment to a change of the photoperiod in the central SCN clock and the peripheral liver clock.
Integrative mechanisms of blood pressure regulation in humans and rats: cross-species similarities
Authors: Charkoudian N. , Gusman E. , Joyner M. J. , Wallin B. G. , Osborn J.
Published: January 2010

As our understanding of the importance of individualized medicine continues to grow, the clinical relevance of interindividual variability in hemodynamic variables is receiving increasing attention. However, it is not known whether the rat, which is often used for studies of cardiovascular regulation, exhibits similar interindividual variability. In the present study, we evaluated whether the magnitude of interindividual variability in cardiac output (CO) and total peripheral resistance (TPR) was similar in humans and in rats. We assessed interindividual variability of mean arterial pressure (MAP), CO, and TPR during control conditions in normotensive humans ( n = 40) and during normotension and deoxycorticosterone acetate-salt hypertension in Sprague-Dawley rats ( n = 16). Humans and rats showed marked interindividual variability in CO and TPR but low variability in MAP. During deoxycorticosterone acetate-salt hypertension, CO was maintained, but TPR was elevated compared with the baseline period. We conclude that the magnitudes of interindividual variability of MAP, CO, and TPR are quantitatively similar in humans and rats, providing support for the relevance of this variability in both species and suggesting that studies in rats could be designed to address questions specific to individualized medicine in hypertension.
Endogenous activation of spinal 5-hydroxytryptamine (5-HT) receptors contributes to the thermoregulatory activation of brown adipose tissue
Authors: Madden Christopher J. , Morrison Shaun F.
Published: January 2010

Neurons in the rostral raphe pallidus (RPa) play an essential role in the regulation of sympathetically mediated metabolism and thermogenesis in brown adipose tissue (BAT). The presence of serotonergic neurons in the RPa that are retrogradely labeled following pseudorabies virus injections into BAT suggests that these neurons play a role in the regulation of BAT. In urethane/chloralose-anesthetized rats, whole body cooling decreased skin (−5.7 ± 2.3°C) and core (−1.3 ± 0.2°C) temperatures and resulted in an increase in BAT sympathetic nerve activity (SNA; +1,026 ± 344% of baseline activity). Serial microinjections of the 5-hydroxytryptamine (5-HT) receptor antagonist, methysergide (1.2 nmol/site), but not saline vehicle, into the intermediolateral cell column (IML) in spinal segments T2–T5 markedly attenuated the cooling-evoked increase in BAT SNA (remaining area under the curve, AUC: 36 ± 9% of naive cooling response). Microinjections of the 5-HT1A receptor antagonist, WAY-100635 (1.2 nmol/site), or the 5-HT7 receptor antagonist, SB-269970 (1.2 nmol/site), into the T2–T5 IML also attenuated the cold-evoked increase in BAT SNA (remaining activity at peak inhibition: 47 ± 8% and 39 ± 12% of the initial cold-evoked response, respectively). The increases in BAT SNA evoked by microinjection of N-methyl-d-aspartate (NMDA) (12 pmol) or bicuculline (30 pmol) into the RPa were attenuated following microinjections of methysergide, but not saline vehicle, into the T2–T5 IML (NMDA remaining AUC, 64 ± 13% of naive response; bicuculline remaining AUC, 52 ± 5% of naive response). These results are consistent with our earlier demonstration of a potentiating effect of 5-HT within the IML on BAT SNA and indicate that activation of 5-HT1A and 5-HT7 receptors in the spinal cord contributes to increases in BAT SNA and thermogenesis.
A rapidly occurring compensatory decrease in physical activity counteracts diet-induced weight loss in female monkeys
Authors: Sullivan Elinor L. , Cameron Judy L.
Published: January 2010

To study changes in energy balance occurring during the initial phases of dieting, 18 adult ovariectomized female monkeys were placed on a low-fat diet, and available calories were reduced by 30% compared with baseline consumption for 1 mo. Surprisingly, there was not significant weight loss; however, daily activity level (measured by accelerometry) decreased soon after diet initiation and reached statistical significance by the 4th wk of dieting (18 ± 5.6% decrease, P = 0.02). During a 2nd mo of dieting, available calories were reduced by 60% compared with baseline consumption, leading to 6.4 ± 1.7% weight loss and further suppression of activity. Metabolic rate decreased by 68 ± 12 kcal/day, with decreased activity accounting for 41 ± 9 kcal/day, and the metabolic activity of the weight lost accounting for 21 ± 5 kcal/day. A second group of three monkeys was trained to run on a treadmill for 1 h/day, 5 days/wk, at 80% maximal capacity, leading to increased calorie expenditure of 69.6 ± 10.7 kcal/day (equivalent to 49 kcal/day for 7 days). We conclude that a diet-induced decrease in physical activity is the primary mechanism the body uses to defend against diet-induced weight loss, and undertaking a level of exercise that is recommended to counteract weight gain and promote weight loss is able to prevent the compensatory decrease in physical activity-associated energy expenditure that slows diet-induced weight loss.
A potential role for hypothalamomedullary POMC projections in leptin-induced suppression of food intake
Authors: Zheng Huiyuan , Patterson Laurel M. , Rhodes Christopher J. , Louis Gwendolyn W. , Skibicka Karolina P. , Grill Harvey J. , Myers Martin G. , Berthoud Hans-Rudolf
Published: January 2010

Melanocortin-3/4 receptor ligands administered to the caudal brain stem potently modulate food intake by changing meal size. The origin of the endogenous ligands is unclear, because the arcuate nucleus of the hypothalamus and the nucleus of the solitary tract (NTS) harbor populations of proopiomelanocortin (POMC)-expressing neurons. Here we demonstrate that activation of hypothalamic POMC neurons leads to suppression of food intake and that this suppression is prevented by administration of a melanocortin-3/4 receptor antagonist to the NTS and its vicinity. Bilateral leptin injections into the rat arcuate nucleus produced long-lasting suppression of meal size and total chow intake. These effects were significantly blunted by injection of SHU-9119 into the fourth ventricle, although SHU-9119 increased meal size and food intake during the first, but not the second, 14-h observation period. Leptin effects on meal size and food intake were abolished throughout the 40-h observation period by injection of SHU-9119 into the NTS at a dose that by itself had no effect. Neuron-specific tracing from the arcuate nucleus with a Cre-inducible tract-tracing adenovirus in POMC-Cre mice showed the presence of labeled axons in the NTS. Furthermore, density of α-melanocyte-stimulating hormone-immunoreactive axon profiles throughout the NTS was decreased by ∼70% after complete surgical transection of connections with the forebrain in the chronic decerebrate rat model. The results further support the existence of POMC projections from the hypothalamus to the NTS and suggest that these projections have a functional role in the control of food intake.
ANG II receptor blockade enhances anti-inflammatory macrophages in anti-glomerular basement membrane glomerulonephritis
Authors: Aki Kaoru , Shimizu Akira , Masuda Yukinari , Kuwahara Naomi , Arai Takashi , Ishikawa Arimi , Fujita Emiko , Mii Akiko , Natori Yasuhiro , Fukunaga Yoshitaka , Fukuda Yuh
Published: January 2010

Macrophages are heterogeneous immune cell populations that include classically activated and alternatively activated (M2) macrophages. We examined the anti-inflammatory effect of ANG II type 1 receptor (AT1R) blocker (ARB) on glomerular inflammation in a rat model of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). The study focused on infiltrating CD8+and CD4+cells and macrophages, as well as the heterogeneity of intraglomerular macrophages. Wistar-Kyoto rats were treated with high-dose olmesartan (3 mg·kg−1·day−1), low-dose olmesartan (0.3 mg·kg−1·day−1), or vehicle (control) 7 days before induction of anti-GBM GN. Control rats showed mainly CD8+cells and ED1+macrophages, with a few CD4+cells infiltrating the glomeruli. Necrotizing and crescentic glomerular lesions developed by day 7 with the increase of proteinuria. AT1R was expressed on CD8+and CD4+cells and on ED1+macrophages. Low-dose ARB had no anti-inflammatory effects in anti-GBM GN. However, high-dose ARB reduced glomerular infiltration of CD8+cells and ED1+macrophages and suppressed necrotizing and crescentic lesions by days 5 to 7 ( P < 0.05). In addition, high-dose ARB reduced the numbers of ED3+-activated macrophages, suppressed glomerular TNF-α and IFN-γ production, and downregulated M1-related chemokine and cytokines (monocyte chemoattractant protein type 1, IL-6, and IL-12). High-dose ARB also enhanced ED2+M2 macrophages by day 7 with upregulation of glomerular IL-4 and IL-13 and augmented CCL17, IL-1 receptor antagonist, and IL-10. We concluded that high-dose ARB inhibits glomerular inflammation by increasing the numbers of M2 macrophages and upregulation of anti-inflammatory cytokines and by suppressing M1 macrophage development with downregulation of M1-related proinflammatory cytokines.