bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploiting the Annexin A1 pathway for the development of novel anti‐inflammatory therapeutics
Authors: Perretti Mauro , Dalli Jesmond
Published: October 2009

The appreciation that the inflammatory reaction does not ‘spontaneously’ finish, but rather that inflammatory resolution is an active phenomenon brought about by endogenous anti‐inflammatory agonists opens multiple opportunities for a reassessment of the complexity of inflammation and its main mediators. This review dwells on one of these pathways, the one centred around the glucocorticoid‐regulated protein Annexin A1 and its G protein‐coupled receptor. In recent years, much of the knowledge detailing the processes by which Annexin A1 expresses its anti‐inflammatory role on innate immunity has been produced. Moreover, the generation of the Annexin A1 null mouse colony has provided important proof‐of‐concept experiments demonstrating the inhibitory properties of this mediator in the context of inflammatory and/or tissue‐injury models. Therefore, Annexin A1 acts as a pivotal homeostatic mediator, where if absent, inflammation would overshoot and be prolonged. This new understanding scientific information could guide us onto the exploitation of the biological properties of Annexin A1 and its receptor to instigate novel drug discovery programmes for anti‐inflammatory therapeutics. This line of research relies on the assumption that anti‐inflammatory drugs designed upon endogenous anti‐inflammatory mediators would be burdened by a lower degree of secondary effects as these agonists would be mimicking specific pathways activated in our body for safe disposal of inflammation. We believe that the next few years will produce examples of such new drugs and the validity of this speculation could then be assessed.

This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Effectiveness of Marine Protected Areas in the Philippines for Biodiversity Conservation
Authors: WEEKS REBECCA , RUSS GARRY R. , ALCALA ANGEL C. , WHITE ALAN T.
Published: October 2009

Abstract:  Quantifying the extent to which existing reserves meet conservation objectives and identifying gaps in coverage are vital to developing systematic protected‐area networks. Despite widespread recognition of the Philippines as a global priority for marine conservation, limited work has been undertaken to evaluate the conservation effectiveness of existing marine protected areas (MPAs). Targets for MPA coverage in the Philippines have been specified in the 1998 Fisheries Code legislation, which calls for 15% of coastal municipal waters (within 15 km of the coastline) to be protected within no‐take MPAs, and the Philippine Marine Sanctuary Strategy (2004), which aims to protect 10% of coral reef area in no‐take MPAs by 2020. We used a newly compiled database of nearly 1000 MPAs to measure progress toward these targets. We evaluated conservation effectiveness of MPAs in two ways. First, we determined the degree to which marine bioregions and conservation priority areas are represented within existing MPAs. Second, we assessed the size and spacing patterns of reserves in terms of best‐practice recommendations. We found that the current extent and distribution of MPAs does not adequately represent biodiversity. At present just 0.5% of municipal waters and 2.7–3.4% of coral reef area in the Philippines are protected in no‐take MPAs. Moreover, 85% of no‐take area is in just two sites; 90% of MPAs are <1 km2. Nevertheless, distances between existing MPAs should ensure larval connectivity between them, providing opportunities to develop regional‐scale MPA networks. Despite the considerable success of community‐based approaches to MPA implementation in the Philippines, this strategy will not be sufficient to meet conservation targets, even under a best‐case scenario for future MPA establishment. We recommend that implementation of community‐based MPAs be supplemented by designation of additional large no‐take areas specifically located to address conservation targets.
Devising Appropriate Policies and Instruments in Support of Private Conservation Areas: Lessons Learned from the Klein Karoo, South Africa
Authors: PASQUINI LORENA , COWLING RICHARD M. , TWYMAN CHASCA , WAINWRIGHT JOHN
Published: October 2009

Abstract:  The amount of privately conserved land is increasing worldwide. The potential of these areas to contribute to the global conservation of biodiversity is significant, given that statutory protected areas alone will not suffice. Nevertheless, there is still inadequate support for private conservation areas, and further research on appropriate, flexible, and generally applicable incentive measures is necessary. We conducted 25 semistructured interviews with the owners of private conservation areas in the Little Karoo, South Africa, to examine landowner opinions of existing conservation policies and their relationships with the local conservation authority. We also assessed landowner preferences regarding conservation incentive measures. Landowners doubted the conservation authority's capacity to implement its stewardship program and were also discouraged by the bureaucracy of the program. The conservation authority was often viewed negatively, except where landowners had experienced personal contact from conservation staff or where strong social capital had formed among landowners. Landowners did not desire financial rewards for their conservation efforts, but sought recognition of their stewardship role and greater involvement from the conservation authority through personal contact. We conclude that conservation policies for private lands could benefit from the provision of extension services to landowners, promotion of formation of groups of landowners and other stakeholders, and public acknowledgment of the contributions private conservation areas make.
Effects of Harvest of Nontimber Forest Products and Ecological Differences between Sites on the Demography of African Mahogany
Authors: GAOUE OROU G. , TICKTIN TAMARA
Published: October 2009

Abstract:  The demographic impacts of harvesting nontimber forest products (NTFP) have been increasingly studied because of reports of potentially unsustainable harvest. Nevertheless, our understanding of how plant demographic response to harvest is altered by variation in ecological conditions, which is critical for developing realistic sustainable‐use plans, is limited. We built matrix population models to test whether and how variation in ecological conditions affects population responses to harvest. In particular, we examined the effect of bark and foliage harvest on the demography of populations of African mahogany (Khaya senegalensis) in two contrasting ecological regions of Benin, West Africa. K. senegalensis bark and foliage harvest significantly reduced its stochastic population growth rates, but ecological differences between regions had a greater effect on population growth rates than did harvest. The effect of harvest on population growth rates (Δλ) was slightly stronger in the moist than in the drier region. Life‐table response experiments revealed that the mechanism by which harvesting reduced λ differed between ecological regions. Lowered stasis (persistence) of larger life stages lead to a reduction in λ in the drier region, whereas lowered growth of all life stages lowered λ in moist region. Potential strategies to increase population growth rates should include decreasing the proportion of individuals harvested, promoting harvester‐owned plantations of African mahogany, and increasing survival and growth by promoting no‐fire zones in gallery forests. Our results show how population responses to harvest of NTFP may be altered by ecological differences across sites and emphasize the importance of monitoring populations over the climatic range in which they occur to develop more realistic recommendations for conservation.
Numerical Comparative Study on the Hemodynamic Performance of a New Helical Graft With Noncircular Cross Section and SwirlGraft
Authors: Sun Anqiang , Fan Yubo , Deng Xiaoyan
Published: October 2009

The helically distributed ribbons of thrombus, formed in the commercially available SwirlGraft (Veryan Medical, London, UK), are the result of its wall shear stress distribution, which has zonary areas of low wall shear stress. In order to overcome the inherent deficiency of the SwirlGraft, a new helical graft with a noncircular cross section was proposed and compared numerically with the SwirlGraft in terms of wall shear stress distribution, helicity of the swirling flow created, and pressure drop over the grafts. The numerical results showed that due to the modification to the geometrical configuration of the SwirlGraft, wall shear stress in the new helical graft model was enhanced, and the zones of low wall shear stress existing in the SwirlGraft were completely eliminated. The present numerical study also predicted a slightly steeper pressure drop and reduction in helicity in the new helical graft model in comparison with the SwirlGraft model. Based on the study, we believe that the new helical graft with a noncircular cross section may reduce the possibility of acute thrombus formation in the graft because the enhanced wall shear stress can impede the stay and adherence of platelets and leukocytes to the surface of the graft.
VERTICAL MIGRATION OF A MIXED‐SPECIES EUGLENA (EUGLENOPHYTA) ASSEMBLAGE INHABITING THE HIGH‐INTERTIDAL SANDS OF NYE BEACH, OREGON1
Authors: Kingston Michael B. , Gough Jennifer S.
Published: October 2009

Comparatively little is known about the vertical migration of the microphytobenthic community forming visible patches on high‐energy beaches. We collected surface and cored samples to evaluate the timing and extent of downward migration of a multispecies Euglena assemblage inhabiting Nye Beach, Oregon. Euglena density at the surface was highly variable and was not correlated with the time of low tide or instantaneous irradiance measurements; however, triplicate cores collected at low and high tides revealed a tidal rhythm in mean depth. On average, 95% of the assemblage occurred within 1 cm of the surface during low tide, but 54% of the assemblage was collected between 1 and 8 cm below the surface during high tide. A midday shading experiment revealed that short‐term changes in irradiance levels altered the Euglena density at the sediment surface by inducing vertical migration. This response to short‐term fluctuations in light may explain the weak correlation between cell density at the surface and time of day. The high‐intertidal location of these patches prevented the removal of nonmigrating cells by daily high tides, which increased the variability in surface samples and obscured the tidal migration rhythm detected in the core samples. Due in part to the semidiurnal nature of Oregon tides, this study provides in situ confirmation of past mesocosm research indicating that sediment disturbance during daily submersed periods is an important process in maintaining the quasi‐tidal rhythm in the appearance and disappearance of Euglena spp. from the surface of beaches and intertidal sandflats.
The Far-Reaching Influence of Hepatic Enzyme-Inducing Antiepileptic Drugs
Authors: Abou-Khalil Bassel W.
Published: October 2009

Effects of Antiepileptic Drugs on Lipids, Homocysteine, and C-Reactive Protein. Mintzer S, Skidmore CT, Abidin CJ, Morales MC, Chervoneva I, Capuzzi DM, Sperling MR. Ann Neurol 2009;65:448–456. OBJECTIVE: The widely prescribed anticonvulsants phenytoin and carbamazepine are potent inducers of cytochrome P450 enzymes, which are involved in cholesterol synthesis. We sought to determine whether these drugs have an effect on cholesterol and other serological markers of vascular risk. METHODS: We recruited 34 epilepsy patients taking carbamazepine or phenytoin in monotherapy whose physicians had elected to change treatment to one of the noninducing anticonvulsants lamotrigine or levetiracetam. Fasting blood samples were obtained both before and 6 weeks after the switch to measure serum lipid fractions, lipoprotein(a), C-reactive protein, and homocysteine. A comparator group of 16 healthy subjects underwent the same serial studies. RESULTS: In the epilepsy patients, switch from either phenytoin or carbamazepine produced significant declines in total cholesterol (-24.8 mg/dL), atherogenic (non-high-density lipoprotein) cholesterol (-19.9 mg/dL), triglycerides (-47.1 mg/dL) (all p < 0.0001), and C-reactive protein (-31.4%; p = 0.027). Patients who stopped taking carbamazepine also had a 31.2% decline in lipoprotein(a) level ( p = 0.0004), whereas those taken off phenytoin had a decrease in homocysteine level (-1.7 μmol/L; p = 0.005). All of these changes were significant when compared with those seen in healthy subjects ( p < 0.05). Results were similar whether patients were switched to lamotrigine or levetiracetam. INTERPRETATION: Switching epilepsy patients from the enzyme-inducers carbamazepine or phenytoin to the noninducing drugs levetiracetam or lamotrigine produces rapid and clinically significant amelioration in several serological markers of vascular risk. These findings suggest that phenytoin and carbamazepine may substantially increase the risk for cardiovascular and cerebrovascular disease.
Searching for the Lesion in “MRI-Normal” Neocortical Epilepsy—Plumb the Depths!
Authors: Miller John W.
Published: October 2009

Small Focal Cortical Dysplasia Lesions Are Located at the Bottom of a Deep Sulcus. Besson P, Andermann F, Dubeau F, Bernasconi A. Brain 2008;131(Pt 12):3246–3255. Focal cortical dysplasia (FCD) is often characterized by minor structural changes that may go unrecognized by standard radiological analysis. Visual assessment of morphological characteristics of FCD and sulci harboring them is difficult due to the complexity of brain convolutions. Our purpose was to elucidate and quantify the spatial relationship between FCD lesions and brain sulci using automated sulcal extraction and morphometry. We studied 43 consecutive FCD patients using high-resolution MRI. Lesions were classified into small and large using qualitative (detection on initial clinical assessment of conventional MRI) and quantitative (volume) criteria. Sulci were identified and labeled automatically using an algorithm based on a congregation of neural networks. Segmented FCD lesions and sulci were then simultaneously visualized in 3D. We measured mean and maximum depth of sulci related to each FCD and of the corresponding sulci in 21 healthy controls. In addition, we calculated sulcal depth within the FCD neighborhood. Twenty-one (21/43 = 49%) patients had small FCD lesions (volume range: 128–3093 mm ( 3 )). Among them, 17 (81%) had been overlooked during initial radiological evaluation and were subsequently identified using image processing. Eighteen (18/21 = 86%) small FCD lesions were located at the bottom of a sulcus. Two others were related to the walls of two sulci and one was located at the crown of a gyrus. Mean and maximum depth of sulci related to the FCD was higher than that of the corresponding sulci in controls ( p < 0.008). Sulcal depth within lesional neighborhood had larger mean depth than that of the entire sulcus ( p < 0.0002). Evidence that small FCD lesions are preferentially located at the bottom of an abnormally deep sulcus may be used to direct the search for developmental abnormalities, particularly in patients in whom large-scale MRI features are only mildly abnormal or absent.
First Do No Harm: Safety in the Epilepsy Monitoring Unit
Authors: Carlson Chad
Published: October 2009

Safety of Long-Term Video-Electroencephalographic Monitoring for Evaluation of Epilepsy. Noe KH, Drazkowski JF. Mayo Clin Proc 2009;84(6):495–500. OBJECTIVE: To determine the rate of medical complications from long-term video-electroencephalographic (EEG) monitoring for epilepsy. PATIENTS AND METHODS: We reviewed the medical records of 428 consecutive adult patients with epilepsy who were admitted for diagnostic scalp video-EEG monitoring at Mayo Clinic's site in Arizona from January 1, 2005 to December 31, 2006; 149 met inclusion criteria for the study. Seizure number and type as well as timing and the presence of seizure-related adverse outcomes were noted. RESULTS: Of the 149 adult patients included in the study, seizure clusters occurred in 35 (23%); 752 seizures were recorded. The mean time to first seizure was 2 days, with a mean length of stay of 5 days. Among these patients, there was one episode of status epilepticus, three potentially serious electrocardiographic abnormalities, two cases of postictal psychosis, and four vertebral compression fractures during a generalized convulsion, representing 11% of patients with a recorded generalized tonic–clonic seizure. No deaths, transfers to the intensive care unit, falls, dental injuries, or pulmonary complications were recorded. An adverse event requiring intervention or interfering with normal activity occurred in 21% of these patients. Length of stay was not affected by occurrence of adverse events. CONCLUSION: Prolonged video-EEG monitoring is an acceptably safe procedure. Adverse events occur but need not result in substantial morbidity or increase length of hospitalization. Appropriate precautions must be in place to prevent falls and promptly detect and treat seizure clusters, status epilepticus, serious electrocardiographic abnormalities, psychosis, and fractures.
Not All First Seizures Are Created Equally
Authors: Sirven Joseph I.
Published: October 2009

Is a First Acute Symptomatic Seizure Epilepsy? Mortality and Risk for Recurrent Seizure. Hesdorffer DC, Benn EK, Cascino GD, Hauser WA. Epilepsia 2009;50(5):1102–1108. PURPOSE: To compare mortality and subsequent unprovoked seizure risk in a population-based study of acute symptomatic seizure and first unprovoked seizure due to static brain lesions. METHODS: We ascertained all first episodes of acute symptomatic seizure and unprovoked seizure due to central nervous system (CNS) infection, stroke, and traumatic brain injury (TBI). Subjects were residents of Rochester, Minnesota, identified through the Rochester Epidemiology Project's records-linkage system between January 1, 1955 and December 31, 1984. Information was collected on age, gender, seizure type, etiology, status epilepticus (SE), 30-day and 10-year mortality, and subsequent episodes of unprovoked seizure. RESULTS: Two hundred sixty-two individuals experienced a first acute symptomatic seizure and 148 individuals experienced a first unprovoked seizure, all due to static brain lesions. Individuals with a first acute symptomatic seizure were 8.9 times more likely to die within 30 days compared to those with a first unprovoked seizure [95% confidence intervals (CI) = 3.5–22.5] after adjustment for age, gender, and SE. Among 30-day survivors, the risk of 10-year mortality did not differ. Over the 10-year period, individuals with a first acute symptomatic seizure were 80% less likely to experience a subsequent unprovoked seizure compared with individuals with a first unprovoked seizure [adjusted rate ratio (RR) = 0.2, 95% CI = 0.2–0.4]. DISCUSSION: The prognosis of first acute symptomatic seizures differs from that of first unprovoked seizure when the etiology is stroke, TBI, and CNS infection. Acute symptomatic seizures have a higher early mortality and a lower risk for subsequent unprovoked seizure. These differences argue against the inclusion of acute symptomatic seizures as epilepsy.
How Ready Can a Synaptic Vesicle Be? SV2 May Have the Answer
Authors: Mathews Gregory C.
Published: October 2009

SV2 Renders Primed Synaptic Vesicles Competent for Ca2+-Induced Exocytosis. Chang WP, Südhof TC. J Neurosci 2009;29(4):883–897. Synaptic vesicle protein 2 (SV2), one of the first synaptic vesicle proteins identified, is characterized by multiple transmembrane regions that exhibit homology to sugar transporters, and by a highly glycosylated intravesicular sequence. Deletion of SV2 causes postnatal lethality in mice, primarily because of fulminant epilepsy. At the cellular level, deletion of SV2 impairs neurotransmitter release, but its function is unknown, and even the exact point at which release is affected in SV2-deleted synapses remains unclear. Using electrophysiological approaches, we now examine at what step in exocytosis the deletion of SV2 impairs release. Our data demonstrate that deletion of SV2 produces a decrease in evoked synaptic responses without causing changes in mini frequency, mini amplitude, the readily releasable pool of vesicles, or the apparent Ca2+ sensitivity of vesicle fusion. These findings indicate that a previously unidentified step may couple priming of synaptic vesicles to Ca2+ triggering of fusion, and that SV2 acts in this step to render primed synaptic vesicles fully Ca2+ responsive. To investigate the structural requirements for this function of SV2, we used rescue experiments. We demonstrate that conserved charged residues within the transmembrane regions and the intravesicular glycosylation of SV2 are required for its normal folding and trafficking. In contrast, the conserved putative synaptotagmin-binding sequence of SV2 is fully dispensable. Viewed together, these observations suggest that SV2 functions in a maturation step of primed vesicles that converts the vesicles into a Ca2+- and synaptotagmin-responsive state.
Epileptogenesis: A New Twist on the Balance of Excitation and Inhibition
Authors: Dudek F. Edward
Published: October 2009

Rapid Plasticity at Inhibitory and Excitatory Synapses in the Hippocampus Induced by Ictal Epileptiform Discharges. Lopantsev V, Both M, Draguhn A. Eur J Neurosci 2009;29(6):1153–1164. Epileptic seizures can induce pathological processes of plasticity in the brain that tend to promote the generation of further seizures. However, the immediate impact of epileptic seizures on cellular excitability remains poorly understood. In order to unravel such early mechanisms of epilepsy-induced plasticity, we studied synaptic transmission before and shortly after three ictal discharges induced by transient elevation of extracellular K+ in mouse hippocampal slices. Discharges were initiated in the CA3 region and propagated via the Schaffer collaterals into CA1 where they were associated with sustained membrane depolarization and bursts of action potentials in CA1 pyramidal cells. Subsequently, discharges were followed by long-term potentiation (LTP) of Schaffer collateral-evoked field excitatory postsynaptic potentials (EPSPs) in the CA1. The ability to generate epileptiform activity in response to repetitive stimulation was enhanced during LTP. Changes in both inhibitory and excitatory synaptic transmission contributed to LTP in CA1 pyramidal cells. Discharges reduced γ-aminobutyric acid-A receptor-mediated hyperpolarizing inhibitory postsynaptic potentials by shifting their reversal potentials in a positive direction. At the same time, the amplitudes of Schaffer collateral-evoked RS-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated EPSPs and action potential-independent miniature EPSPs were enhanced. However, N-methyl-d-aspartate receptor-mediated EPSPs remained unchanged. Paired-pulse stimulation revealed a reduced probability of glutamate release. Together, these changes in synaptic transmission produce a sustained increase in hippocampal excitability. We conclude that a few seizure-like ictal episodes are sufficient to cause fast and lasting changes in the excitation/inhibition balance in hippocampal networks, and therefore may contribute to early phases of progressive epileptogenesis.
FHL1 interacts with oestrogen receptors and regulates breast cancer cell growth
Authors: Ding Lihua , Niu Chang , Zheng Yiqiong , Xiong Zhihong , Liu Yufei , Lin Jing , Sun Huiwei , Huang Ke , Yang Wen , Li Xiru , Ye Qinong
Published: October 2009

Four and a half LIM protein 1 (FHL1) belongs to the Lin‐1, Isl‐1 and Mec‐3 (LIM)‐only protein family and plays important roles in muscle growth and carcinogenesis. However, the biological function of FHL1 remains largely unknown. Here, we show that FHL1 physically and functionally interacted with oestrogen receptors (ERs), which are involved in breast cancer development and progression. FHL1 bound specifically to the activation function‐1 domain of ER. Physical interaction of FHL1 and ER is required for FHL1 repression of oestrogen‐responsive gene transcription. FHL1 affected recruitment of ER to an oestrogen‐responsive promoter and ER binding to an oestrogen‐responsive element. Overexpression of FHL1 in breast cancer cells decreased expression of oestrogen‐responsive proteins, whereas knockdown of endogenous FHL1 with FHL1 small interfering RNA increased the expression of these proteins. Further analysis of 46 breast cancer samples showed that FHL1 expression negatively associated with oestrogen‐responsive gene expression in breast cancer cells. FHL1 inhibited anchorage‐dependent and ‐independent breast cancer cell growth. These results suggest that FHL1 may play an important role in ER signalling as well as breast cancer cell growth regulation.
Plasma gelsolin facilitates interaction between β2 glycoprotein I and α5β1 integrin
Authors: Bohgaki Miyuki , Matsumoto Masaki , Atsumi Tatsuya , Kondo Takeshi , Yasuda Shinsuke , Horita Tetsuya , Nakayama Keiichi I. , Okumura Fumihiko , Hatakeyama Shigetsugu , Koike Takao
Published: October 2009

Antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL) that directly recognizes plasma β2‐glycoprotein I (β2GPI). Tissue factor (TF), the major initiator of the extrinsic coagulation system, is induced on monocytes by aPL in vitro, explaining in part the pathophysiology in APS. We previously reported that the mitogen‐activated protein kinase (MAPK) pathway plays an important role in aPL‐induced TF expression on monocytes. In this study, we identified plasma gelsolin as a protein associated with β2GPI by using immunoaffinity chromatography and mass spectrometric analysis. An in vivo binding assay showed that endogenous β2GPI interacts with plasma gelsolin, which binds to integrin a5β1 through fibronectin. The tethering of β2GPI to monoclonal anti‐β2GPI autoantibody on the cell surface was enhanced in the presence of plasma gelsolin. Immunoblot analysis demonstrated that p38 MAPK protein was phosphorylated by monoclonal anti‐β2GPI antibody treatment, and its phosphorylation was attenuated in the presence of anti‐integrin a5β1 antibody. Furthermore, focal adhesion kinase, a downstream molecule of the fibronectin‐integrin signalling pathway, was phosphorylated by anti‐β2GPI antibody treatment. These results indicate that molecules including gelsolin and integrin are involved in the anti‐β2GPI antibody‐induced MAPK pathway on monocytes and that integrin is a possible therapeutic target to modify a prothrombotic state in patients with APS.
A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use
Authors: Wu Florence T. H. , Stefanini Marianne O. , Gabhann Feilim Mac , Kontos Christopher D. , Annex Brian H. , Popel Aleksander S.
Published: October 2009

Introduction

Molecular biology of sVEGFR1

Physiological and pathophysiological roles of sVEGFR1

Molecular mechanism of sVEGFR1’s anti‐angiogenic potential

sVEGFR1 as a clinical marker for disease

Plasma VEGF and sVEGFR1: non‐uniform predictors of angiogenic status across all diseases

Systems biology perspective: unifying interpretation of plasma angiogenic markers

Concluding remarks

Angiogenesis is the growth of new capillaries from pre‐existent microvasculature. A wide range of pathological conditions, from atherosclerosis to cancer, can be attributed to either excessive or deficient angiogenesis. Central to the physiological regulation of angiogenesis is the vascular endothelial growth factor (VEGF) system – its ligands and receptors (VEGFRs) are thus prime molecular targets of pro‐angiogenic and anti‐angiogenic therapies. Of growing interest as a prognostic marker and therapeutic target in angiogenesis‐dependent diseases is soluble VEGF receptor‐1 (sVEGFR1, also known as sFlt‐1) – a truncated version of the cell membrane‐spanning VEGFR1. For instance, it is known that sVEGFR1 is involved in the endothelial dysfunction characterizing the pregnancy disorder of pre‐eclampsia, and sVEGFR1’s therapeutic potential as an anti‐angiogenic agent is being evaluated in pre‐clinical models of cancer. This mini review begins with an examination of the protein domain structure and biomolecular interactions of sVEGFR1 in relation to the full‐length VEGFR1. A synopsis of known and inferred physiological and pathological roles of sVEGFR1 is then given, with emphasis on the utility of computational systems biology models in deciphering the molecular mechanisms by which sVEGFR1’s purported biological functions occur. Finally, we present the need for a systems biology perspective in interpreting circulating VEGF and sVEGFR1 concentrations as surrogate markers of angiogenic status in angiogenesis‐dependent diseases.
Ankyrin protein networks in membrane formation and stabilization
Authors: Cunha Shane R. , Mohler Peter J.
Published: October 2009

Introduction

Mechanisms that target and stabilize ankyrin

Ankyrins and disease

Conclusion

In eukaryotic cells, ankyrins serve as adaptor proteins that link membrane proteins to the underlying cytoskeleton. These adaptor proteins form protein complexes consisting of integral membrane proteins, signalling molecules and cytoskeletal components. With their modular architecture and ability to interact with many proteins, ankyrins organize and stabilize these protein networks, thereby establishing the infrastructure of membrane domains with specialized functions. To this end, ankyrin collaborates with a number of proteins including cytoskeletal proteins, cell adhesion molecules and large structural proteins. This review addresses the targeting and stabilization of protein networks related to ankyrin interactions with the cytoskeletal protein β‐spectrin, L1‐cell adhesion molecules and the large myofibrillar protein obscurin. The significance of these interactions for differential targeting of cardiac proteins and neuronal membrane formation is also presented. Finally, this review concludes with a discussion about ankyrin dysfunction in human diseases such as haemolytic anaemia, cardiac arrhythmia and neurological disorders.
Vaccination with SIVmac239Δnef activates CD4+ T cells in the absence of CD4+ T‐cell loss
Authors: Reeves R.K. , Gillis J. , Wong F.E. , Johnson R.P.
Published: October 2009

Background  Pathogenic HIV and SIV infections characteristically deplete central memory CD4+ T cells and induce chronic immune activation, but it is controversial whether this also occurs after vaccination with attenuated SIVs and whether depletion or activation of CD4+ T‐cell play roles in protection against wild‐type virus challenge.

Methods  Rhesus macaques were vaccinated with SIVmac239Δnef and quantitative and phenotypic polychromatic flow cytometry analyses were performed on mononuclear cells from blood, lymph nodes and rectal biopsies.

Results  Animals vaccinated with SIVmac239Δnef demonstrated no loss of CD4+ T cells in any tissue, and in fact CCR5+ and CD28+CD95+ central memory CD4+ T cells were significantly increased. In contrast, CD4+ T‐cell numbers and CCR5 expression significantly declined in unvaccinated controls challenged with SIVmac239. Also, intracellular Ki67 increased acutely as much as 3‐fold over baseline in all tissues after SIVmac239Δnef vaccination then declined following primary infection.

Conclusion  We demonstrated in this study that SIVmac239Δnef vaccination did not deplete CD4+ T cells but transiently activated and expanded the memory cell population. However, increases in numbers and activation of memory CD4+ T cells did not appear to influence protective immunity.
CD4 T cell subsets in the mucosa are CD28+Ki‐67−HLA‐DR−CD69+ but show differential infection based on α4β7 receptor expression during acute SIV infection
Authors: Kader M. , Bixler S. , Roederer M. , Veazey R. , Mattapallil J.J.
Published: October 2009

Background  CD4 T cell depletion in the mucosa has been well documented during acute HIV and SIV infections. The demonstration the HIV/SIVcan use the α4β7 receptor for viral entry suggests that these viruses selectively target CD4 T cells in the mucosa that express high levels of α4β7 receptor.

Methods  Mucosal samples obtained from SIV infected rhesus macaques during the early phase of infection were used for immunophenotypic analysis. CD4 T cell subsets were sorted based on the expression of β7 and CD95 to quantify the level of SIV infection in different subsets of CD4 T cells. Changes in IL‐17, IL‐21, IL‐23 and TGFβ mRNA expression was determined using Taqman PCR.

Results  CD4 T cells in the mucosa were found to harbor two major population of cells; ‐25% of CD4 T cells expressed the α4+β7hi phenotype, whereas the rest of the 75% expressed an α4+β7int phenotype. Both the subsets were predominantly CD28+Ki‐67‐HLA‐DR‐ but CD69+, and expressed detectable levels of CCR5 on their surface. Interestingly, however, α4+β7hiCD4 T cells were found to harbor more SIV than the α4+β7int subsets at day 10 pi. Early infection was associated with a dramatic increase in the expression of IL‐17, and IL‐17 promoting cytokines IL‐21, IL‐23, and TGFβ that stayed high even after the loss of mucosal CD4 T cells.

Conclusions  Our results suggest that the differential expression of the α4β7 receptor contributes to the differences in the extent of infection in CD4 T cell subsets in the mucosa. Early infection is associated dysregulation of the IL‐17 network in mucosal tissues involves other non‐Th‐17 cells that likely contributes to the pro‐inflammatory environment in the mucosa during acute stages of SIV infection.
Anti‐retroviral therapy fails to restore the severe Th‐17: Tc‐17 imbalance observed in peripheral blood during simian immunodeficiency virus infection
Authors: Kader M. , Bixler S. , Piatak M. , Lifson J. , Mattapallil J.J.
Published: October 2009

Background  Human immuno deficiency virus and simian immunodeficiency virus infections are characterized by a severe loss of Th‐17 cells (IL‐17+CD4+ T cells) that has been associated with disease progression and systemic dissemination of bacterial infections. Anti‐retroviral therapy (ART) has led to repopulation of CD4+ T cells in peripheral tissues with little sustainable repopulation in mucosal tissues. Given the central importance of Th‐17 cells in mucosal homeostasis, it is not known if the failure of ART to permanently repopulate mucosal tissues is associated with a failure to restore Th‐17 cells that are lost during infection.

Methods  Dynamics of α4+β7hi CD4+ T cells in peripheral blood of SIV infected rhesus macaques were evaluated and compared to animals that were treated with ART. The frequency of Th‐17 and Tc‐17 cells was determined following infection and after therapy. Relative expression of IL‐21, IL‐23, and TGFβ was determined using Taqman PCR.

Results  Treatment of SIV infected rhesus macaques with anti‐retroviral therapy was associated with a substantial repopulation of mucosal homing α4+β7hiCD4+ T cells in peripheral blood. This repopulation, however, was not accompanied by a restoration of Th‐17 responses. Interestingly, SIV infection was associated with an increase in Tc‐17 responses (IL‐17+CD8+ T cells) suggesting to a skewing in the ratio of Th‐17: Tc‐17 cells from a predominantly Th‐17 phenotype to a predominantly Tc‐17 phenotype. Surprisingly, Tc‐17 responses remained high during the course of therapy suggesting that ART failed to correct the imbalance in Th‐17 : Tc‐17 responses induced following SIV infection.

Conclusions  ART was associated with substantial repopulation of α4+β7hi CD4+ T cells in peripheral blood with little or no rebound of Th‐17 cells. On the other hand, repopulation of α4+β7hi CD4+ T cells was accompanied by persistence of high levels of Tc‐17 cells in peripheral blood. The dysregulation of Th‐17 and Tc‐17 responses likely plays a role in disease progression.
Macaca fascicularis are highly susceptible to an RT‐SHIV following intravaginal inoculation: a new model for microbicide evaluation
Authors: Jiang Y. , Tian B. , Agy M.B. , Saifuddin M. , Tsai C.‐C.
Published: October 2009

Background  Human immunodeficiency virus type 1 (HIV‐1) reverse transcriptase (RT) is a major target for antiretroviral strategy to block or curtail HIV infection. A suitable RT‐SHIV/macaque model is urgently needed for the evaluation of HIV/AIDS therapies and microbicides specifically targeting HIV‐1 RT.

Methods  Fifteen cynomolgus macaques (Macaca fascicularis) were divided into three groups (n = 5) and intravaginally inoculated with 4800, 1200, or 300 TCID50 of RT‐SHIVtc. Systemic infections of RT‐SHIVtc exposed macaques were determined by both virological and immunologic parameters during 24 weeks post‐challenge.

Results  Within 2 weeks post‐inoculation, 13 of 15 macaques became infected as confirmed by virus isolation, plasma viral RNA, proviral DNA, declined CD4+T cell counts in peripheral blood and seroconversion.

Conclusions  Results serve to validate the infectivity and pathogenicity of RT‐SHIVtc following vaginal exposure in M. fascicularis. This RT‐SHIVtc/macaque model could be suitable for the pre‐clinical evaluation of non‐nucleoside RT inhibitor‐based anti‐HIV microbicides.
A footprint of tree‐genetics on the biota of the forest floor
Authors: Barbour Robert C. , Baker Susan C. , O'Reilly‐Wapstra Julianne M. , Harvest Tammy M. , Potts Bradley M.
Published: October 2009

Understanding how far the effects of genes extend beyond the phenotype of an individual or population, is fundamental to the developing field of community genetics. We therefore assessed two geographically and genetically distinct populations of the Australian forest tree, Eucalyptusglobulus, and the existence of genetic effects on a leaf litter invertebrate community and soil characteristics within a 15 year old common garden. Twenty trees per population were randomly selected for felling and placement of the apical branch next to the stump. This produced a leaf litter habitat of known genotype. Pitfall trap sampling for invertebrates, and linseed bioassay analyses of soil, were conducted within this habitat. Two key findings emerged. Firstly, assessment of 27 invertebrate orders (57 924 individuals) revealed significant population‐level variation in leaf litter biodiversity (i.e. in community richness, abundance, composition and beta diversity). Secondly, considerable population‐level differences in soil characteristics were evident based on linseed germination and growth responses. While recent findings in E. globulus have demonstrated consequences of genetic variation within forest trees for organisms that interact directly (i.e. proximally) with the living tree, these findings highlight the distal impacts that intraspecific genetic variation may have on communities and ecosystems. Such community genetic considerations have important implications for in situ community conservation, biodiversity management within restoration and plantation forestry, and our understanding of community‐level evolutionary interactions involving foundation species.
Stage, age and individual stochasticity in demography
Authors: Caswell Hal
Published: October 2009

Demography is the study of the population consequences of the fates of individuals. Individuals are differentiated on the basis of age or, in general, life cycle stages. The movement of an individual through its life cycle is a random process, and although the eventual destination (death) is certain, the pathways taken to that destination are stochastic and will differ even between identical individuals; this is individual stochasticity. A stage‐classified demographic model contains implicit age‐specific information, which can be analyzed using Markov chain methods. The living stages in the life cycles are transient states in an absorbing Markov chain; death is an absorbing state. This paper presents Markov chain methods for computing the mean and variance of the lifetime number of visits to any transient state, the mean and variance of longevity, the net reproductive rate R0, and the cohort generation time. It presents the matrix calculus methods needed to calculate the sensitivity and elasticity of all these indices to any life history parameters. These sensitivities have many uses, including calculation of selection gradients. It is shown that the use of R0as a measure of fitness or an invasion exponent gives erroneous results except when R0=λ=1. The Markov chain approach is then generalized to variable environments (deterministic environmental sequences, periodic environments, iid random environments, Markovian environments). Variable environments are analyzed using the vec‐permutation method to create a model that classifies individuals jointly by the stage and environmental condition. Throughout, examples are presented using the North Atlantic right whale (Eubaleana glacialis) and an endangered prairie plant (Lomatium bradshawii) in a stochastic fire environment.
Spatial distributions of multiple plant species affect herbivore foraging selectivity
Authors: Wang Ling , Wang Deli , Bai Yuguang , Jiang Guitong , Liu Jushan , Huang Yue , Li Yexing
Published: October 2009

Spatial distribution of food resources is an important factor determining herbivore foraging. Previous studies have demonstrated that clumped distribution of preferred species increases its consumption by herbivores in single‐ or two‐species systems. However, the potential impact of distribution pattern of less preferred species on foraging was ignored. In natural grasslands with high species diversity and complexity, the spatial distribution of preferred species impacts on herbivore foraging may be strongly correlated with the distribution of less preferred species.

Our aims were to determine the effect of distribution of both preferred and other plant species on herbivore foraging under conditions close to a native, multi‐species foraging environment, and conceptualize the relationships between spatial distribution of food resources and herbivore consumption. We hypothesized that random distribution of non‐preferred species reduces herbivore consumption of preferred species because the dispersion of less preferred species likely disturbs herbivore foraging. We conducted an experiment using three species with five combinations of clumped and random distribution patterns. Three species Lathyrus quinquenervius, Phragmites australis and Leymus chinensis, were of high, intermediate and low preferences by sheep, respectively. Results showed that distribution of low preferred species, but not that of high preferred one, affected the consumption of preferred species. Sheep obtained higher consumption of high preferred species when low preferred species followed a clumped distribution than a random distribution. Distance between aggregations of high and low preferred species did not affect sheep foraging. It was concluded that the effects of spatial distribution of preferred species on its consumption are dependent on herbivore foraging strategy, and sheep can consume more preferred species when there is a consistent spatial pattern between preferred species and the entire food resource, and that the random dispersion of low preferred species in grassland may reduce herbivore consumption of high preferred species, thus minimizing selective grazing.
Genetics, intensity‐dependence, and host manipulation in the trematodeCurtuteria australis: following the strategies of others?
Authors: Leung Tommy L. F. , Keeney Devon B. , Poulin Robert
Published: October 2009

Manipulation of host phenotype by parasites can require a collective effort from many individuals. The cost of manipulation may only be paid by the individuals actually inducing the manipulation, while its benefits are reaped by all. Here, we determine if there is genetic variation in manipulative effort among different clonal lineages of the trematodeCurtuteria australis, and whether the decision to manipulate is context‐dependent.C. australisimpairs the burrowing efficiency of its second intermediate host, the cockleAustrovenus stutchburyi, by encysting at the tip of the cockle's foot, which facilitates the parasite's trophic transmission to shorebirds. However, manipulative individuals at the tip of the foot are vulnerable to non‐host predators (foot‐cropping fish); in contrast, those encysted at the base of the foot, although they do not contribute to manipulation, are safe from foot‐croppers and can benefit from altered host phenotype. In an experimental study, different clonal lineages showed no significant variation in their tendency to encyst in the tip versus the base of the foot, with only the former contributing to host manipulation. However, the decision to manipulate was intensity‐dependent: the greater the number of parasites already committed to manipulation (i.e. already encysted in the foot tip), the more likely newly arriving parasites were to join them. These findings indicate considerable intraspecific variation in the strategies adopted by ‘manipulator’ parasites, with external influences determining what a parasite actually does.
A trophic pathway from biogenic methane supports fish biomass in a temperate lake ecosystem
Authors: Ravinet Mark , Syväranta Jari , Jones Roger I. , Grey Jonathan
Published: October 2009

Although some primary consumers such as chironomid larvae are known to exploit methane‐derived carbon via microbial consortia within aquatic food webs, few studies have traced the onward transfer of such carbon to their predators. The ruffe Gymnocephalus cernuus is a widespread benthivorous fish which feeds predominantly on chironomid larvae and is well adapted for foraging at lower depths than other percids. Therefore, any transfer of methanogenic carbon to higher trophic levels might be particularly evident in ruffe. We sampled ruffe and chironomid larvae from the littoral, sub‐littoral and profundal areas of Jyväsjärvi, Finland, a lake which has previously been shown to contain chironomid larvae exhibiting the very low stable carbon isotope ratios indicative of methane exploitation. A combination of fish gut content examination and stable isotope analysis was used to determine trophic linkages between fish and their putative prey. Irrespective of the depth from which the ruffe were caught, their diet was dominated by chironomids and pupae although the proportions of taxa changed. Zooplankton made a negligible contribution to ruffe diet. A progressive decrease in δ13C and δ15N values with increasing water column depth was observed for both chironomid larvae and ruffe, but not for other species of benthivorous fish. Furthermore, ruffe feeding at greater depths were significantly larger than those feeding in the littoral, suggesting an ontogenetic shift in habitat use, rather than diet, as chironomids remained the predominant prey item. The outputs from isotope mixing models suggested that the incorporation of methane‐derived carbon to larval chironomid biomass through feeding on methanotrophic bacteria increased at greater depth, varying from 0% in the littoral to 28% in the profundal. Using these outputs and the proportions of littoral, sub‐littoral or profundal chironomids contributing to ruffe biomass, we estimated that 17% of ruffe biomass in this lake was ultimately derived from chemoautotrophic sources. Methanogenic carbon thus supports considerable production of higher trophic levels in lakes.