Prolonged Occupation Research Articles

A 3000-Year Record of Ground-Rupturing Earthquakes along the Central North Anatolian Fault near Lake Ladik, Turkey

The North Anatolian fault (NAF) is a similar to 1500 km long, arcuate, dextral strike-slip fault zone in northern Turkey that extends from the Karliova triple junction to the Aegean Sea. East of Bolu, the fault zone exhibits evidence of a sequence of large (M(w) > 7) earthquakes that occurred during the twentieth century that displayed a migrating earthquake sequence from east to west. Prolonged human occupation in this region provides an extensive, but not exhaustive, historical record of large earthquakes prior to the twentieth century that covers much of the last 2000 yr. In this study, we extend our knowledge of rupture events in the region by evaluating the stratigraphy and chronology of sediments exposed in a paleoseismic trench across a splay of the NAF at Destek, similar to 6: 5 km east of Lake Ladik (40.868 degrees N, 36.121 degrees E). The trenched fault strand forms an uphill-facing scarp and associated sediment trap below a small catchment area. The trench exposed a narrow fault zone that has juxtaposed a sequence of weakly defined paleosols interbedded with colluvium against highly fractured bedrock. We mapped magnetic susceptibility variations on the trench walls and found evidence for multiple visually unrecognized colluvial wedges. This technique was also used to constrain a predominantly dip-slip style of displacement on this fault splay. Sediments exposed in the trench were dated using both charcoal and terrestrial gastropod shells to constrain the timing of the earthquake events. While the gastropod shells consistently yielded (14)C ages that were too old (by similar to 900 yr), we obtained highly reliable (14)C ages from the charcoal by dating multiple components of the sample material. Our radiocarbon chronology constrains the timing of seven large earthquakes over the past 3000 yr prior to the 1943 Tosya earthquake, including event ages of (2 sigma error): A. D. 1437-1788, A. D. 1034-1321, A. D. 549-719, A. D. 17-585 (1-3 events), 35 B. C.-A. D. 28, 700-392 B. C., 912-596 B. C. Our results indicate an average interevent time of 385 +/- 166 degrees yr (1 sigma).

Mineralocorticoid Receptor Overexpression in Basolateral Amygdala Reduces Corticosterone Secretion and Anxiety

The amygdala plays a critical role in the development of anxiety and the regulation of stress hormone secretion. Reciprocally, stress and stress hormones can induce amygdala hypertrophy, a phenomenon related to enhanced anxiety. As such, modulating amygdaloid function can potentially reduce maladaptive features of the stress response. The amygdala contains two kind of receptor for corticosteroids, the adrenal steroid hormone released during stress: glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). Although high-affinity MRs are heavily occupied during basal conditions, low-affinity GRs are heavily occupied only by stress levels of glucocorticoids. Prolonged and heavy occupancy of GRs tends to mediate the deleterious effects of glucocorticoids on neurons, whereas MR occupancy tends to mediate beneficial effects. In this report, we overexpress MR in neurons of adult rat basolateral amygdala, with a herpes simplex viral vector coding for two copies of MR. Such overexpression reduced anxiety, as measured on an elevated plus-maze, and reduced the magnitude of glucocorticoid secretion after an acute stressor. Thus, increasing MR signaling in basolateral amygdala could be valuable in management of stress disorders.

Private Military Contractors and International Law: An Introduction

A recent survey of young Europeans ’ opinions of national institutions has revealed, quite surprisingly, that armed forces enjoy the highest level of trust and prestige in a number of major European countries, well above parliaments, the judiciary, the church, political parties and business enterprises. 1 The profound motivations underlying this assessment remain unknown – one can only conjecture that they are related to the increasing sense of insecurity among young generations and perhaps with the politics of fear – fear of terrorism, of immigrants, environmental disasters, of fi nancial doom, and of the unknown – that have become widespread at the beginning of the 21st century. What is clear, however, is that in the perception of young generations, the armed forces still embody the core function of the state as guarantor of the security of citizens within the national territory. In contrast with this opinion, the trend in recent years has been progressively to privatize important sectors of governmental functions through the outsourcing of security and military services to private actors. Private military and security companies or ‘ contractors ’ thus replace soldiers and members of the armed forces in a variety of situations that include armed confl ict, prolonged military occupation, peacekeeping, and territorial administration in post-confl ict institutional building and intelligence gathering. This phenomenon, of course, has not led to the total privatization of armed forces. It remains rather limited in scope as compared to the operations of national militaries around the globe. Nevertheless, it has intensifi ed with the wars that have inaugurated the 21st century – Afghanistan and Iraq, led by the United States in particular – and it is being further fed by the increased activism of the European Union in international administration of critical territorial situations and peacekeeping operations, from

Generalized Darcy's Law by Control Volume Analysis Including Capillary and Orifice Effects

Abstract The equation of motion for single-phase fluid flow through porous media is derived by rigorous analysis of forces acting upon fluid based on a control volume momentum balance approach. Resistive forces associated with pore surface and pore throat are characterized by the capillary-orifice model of porous media. This analysis reveals deficiencies of previous efforts in deriving the generalized momentum equation. The present approach provides resolution to several issues, including porous media averaging of the pressure and shear-stress terms, effect of porous media heterogeneity and anisotropy, and threshold pressure gradient that must be overcome for fluid to flow through porous media. Introduction Derivation of generalized equation of momentum for fluids flowing through porous media has occupied many researchers and is not by any means a trivial task. Since its inception, the fundamental law of flow through porous media given by Darcy(1) has been scrutinized greatly and been the subject for many modifications to take into account the effect of other factors which are not considered by this law. In spite of an exhausting amount of effort, and prolonged occupation and obsession with derivation of an improved formulation, a satisfactory generalized equation of fluid motion in porous media still does not exist. In an effort to shed some light into the adequate treatment of the control volume balance approach, this paper attempts to revisit, modify and improve the generalized formulation presented by Das(2). Many researchers attempted to improve Darcy's law by various approaches to take into account other conditions of practical importance. The outstanding approaches have been developed primarily on the bases of dimensional analysis(3), control volume balance(1, 2) and porous media averaging(4–12). There are some discrepancies, however, between the results presented by various researchers. As pointed out by Civan(13), porous media averaging does not only require extremely complicated and intricate algebraic manipulation procedures, but also has been implemented inadequately in many studies. Consequently, debate about proper handling of various issues dealing with porous media averaging is still continuing, judging by the high number of papers being published. The results presented by various studies do not agree whether the porous media averaged pressure gradient term should include the porosity. The same concern can be raised about shear-stress. Liu and Masliyah(12) emphasize that averaging of pressure and viscosity terms in the microscopic equation of motion should be treated differently than the other terms. Also, the mathematical definition of partial derivatives assumes a limit as control volume approaches zero, i.e., collapses to a point of zero volume. By and large, discussion of differences introduced by the application of such a condition in deriving porous media equations of mass, momentum and energy conservation have been omitted, whereas, representative elementary bulk volume is a finite quantity in definition of volume averaged quantities used for deriving the porous media (macroscopic) equation of motion.

Human Rights, Israel, and the Political Realities of Occupation

Various political realities influence the Israeli occupation of the West Bank and the Gaza Strip and, more generally, the vitality of the international law of occupation. The law of occupation—though ill-suited to modern international relations and ill-equipped for prolonged occupation—has been almost universally invoked as applicable to the Occupied Palestinian Territory (OPT). At the same time, international human rights law is increasingly viewed as applicable to occupation. This creates a dilemma for Israel because international humanitarian law and international human rights law contain conflicting prescriptions and policy goals with respect to the administration of occupied territory. In many instances, occupants seek United Nations Security Council action in order to reconcile this tension and to secure legal and political cover for their actions. By acting under Chapter VII of the United Nations Charter; the Security Council can create a select legal patchwork applicable to a particular occupation. This use of Chapter VII resolutions by the Security Council to create international law by fiat is an important trend in modern occupation. Yet geopolitics determines access to—and the content of—such resolutions, and the sensitive political context of the OPT currently makes this avenue unavailable to Israel. For the same reason, opponents of the Israeli occupation are unable to secure Security Council action to clarify and enforce Israeli legal obligations in the OPT. This Article considers these issues from the perspectives of both Israel and Palestinians in order to examine why the relative gain and loss in each case is not immediately clear. This Article also discusses how the legality of Israeli conduct in the OPT may be gauged in light of the conflicting international legal obligations imposed by human rights law and the law of occupation. A broader exploration of the impact of these phenomena reveals that these political realities serve to increase the influence of the Security Council while further undercutting the utility and relevance of the international law of occupation.

Israel's Settlement-Policy Stumbling-Block in the Middle East Peace Process

According to Israel's Guide to the Mideast Peace Process, charges regarding the illegality of Israeli settlements in the 1967 Occupied Palestinian Territory (OPT) have no foundation in international law. Peace efforts between Israel and Palestine will have no chance of success as long as Israel uses its prolonged military occupation to promote and protect its annexation-in-disguise of the West Bank and East Jerusalem. John Dugard has passed on this hard truth consistently as Special Rapporteur on the situation of human rights in the OPT. The international community should take the same hard line towards the Guide as it has done towards the Hamas Charter. If it wants to establish a just and lasting peace in the Middle East, it should not allow Israel to bend the truth any more in respect of the legality of the Israeli settlements in the OPT as Hamas has done in respect of the illegality of Israel.

Genetic variation and structure in native populations of the fire ant Solenopsis invicta: evolutionary and demographic implications

We studied population genetic variation and structure in the fire ant Solenopsis invicta using nuclear genotypic and mitochondrial DNA (mtDNA) sequence data obtained from samples collected throughout its native range. Geographic populations are strongly differentiated at both genomes, with such structure more pronounced in Brazil than in Argentina. Higher-level regional structure is evident from the occurrence of isolation-by-distance patterns among populations, the recognition of clusters of genetically similar, geographically adjacent populations by ordination analysis, and the detection of an mtDNA discontinuity between Argentina and Brazil coinciding with a previously identified landform of biogeographical relevance. Multiple lines of evidence from both genomes suggest that the ancestors of the ants we studied resembled extant northern Argentine S. invicta, and that existing Brazilian populations were established more recently by serial long-distance colonizations and/or range expansions. The most compelling evidence for this is the corresponding increase in FK (a measure of divergence from a hypothetical ancestor) and decrease in genetic diversity with distance from the Corrientes population in northern Argentina. Relatively deep sequence divergence among several mtDNA clades, coupled with geographical partitioning of many of them, suggests prolonged occupation of South America by S. invicta in more-or-less isolated regional populations. Such populations appear, in some cases, to have come into secondary contact without regaining the capacity to freely interbreed. We conclude that nominal S. invicta in its native range comprises multiple entities that are sufficiently genetically isolated and diverged to have embarked on independent evolutionary paths. © 2007 The Linnean Society of London, Biological Journal of the Linnean Society, 2007, 92, 541–560.

Rhetoric's Role in Context, Beginning with 9/11

This essay offers a dilemma-centered rhetorical history of the Iraq debacle, beginning with the president's melodramatic crisis narrative in the wake of the 9/11 attacks, continuing with the unraveling of that narrative in the run-up to war and during the prolonged occupation of Iraq, and culminating in situational entrapment, or quagmire, wherein the Bush administration's reputation for "staying on message" has lost its rhetorical glow.

Terrestrial environments during MIS 11: evidence from the Palaeolithic site at West Stow, Suffolk, UK

Multidisciplinary investigations of the sequence at Beeches Pit, West Stow (Suffolk, UK), have a direct bearing the age of the Hoxnian Interglacial and its correlation with the continental Holsteinian and with the global marine record. At this site, glacial deposits (till and outwash gravels) referable to the Anglian Lowestoft Formation fill a subglacial channel cut in Chalk bedrock. Above these glacial deposits a series of interglacial sediments occurs, consisting of limnic, tufaceous and colluvial silts, lacking pollen but rich in shells, ostracods and vertebrates. Lower Palaeolithic flint artefacts of Acheulian character have also been recovered, including refitting examples. Charred material is abundant at certain horizons and many of the bones have been burned. Several discrete areas of burnt sediment are interpreted as hearths. The molluscan fauna comprises some 78 taxa and includes species of considerable zoogeographical and biostratigraphical importance. The land snail assemblage from the tufa consists of woodland taxa with no modern analogue, including species that are either extinct (e.g. Zonitoides sepultus) or which no longer live in Britain (e.g. Platyla polita, P. similis, Neniatlanta pauli). This is also the type locality of Retinella ( Lyrodiscus) skertchlyi, which belongs to a subgenus of zonitid land snail now living only on the Canary Islands. There are indications from this fauna (‘the Lyrodiscus biome’) that the climate was wetter and perhaps warmer than the present day. The vertebrate fauna is also noteworthy with species of open habitats, such as rabbit ( Oryctolagus cf . cuniculus), and of closed forest, such as squirrel ( Sciurus sp.) and garden dormouse ( Eliomys quercinus) present at different times. The occurrence of southern thermophiles, such as Aesculapian snake ( Zamenis longissimus), indicates temperatures warmer than those of eastern England today. The upper levels include much material reworked from the interglacial sediments, although there is clear faunal evidence for climatic deterioration. Both the molluscan and vertebrate faunas suggest correlation of the interglacial sediments with the Hoxnian. Uranium series dates from the tufa (∼455 ka BP), TL dates from burnt flints (414±30 ka BP) and a range of amino acid racemization data all support correlation of this interglacial with MIS 11. However, four OSL dates from sand beneath the interglacial sequence yield a mean age of 261±31 ka BP, far younger than all other age determinations and far younger than implied by the biostratigraphy. Archaeologically the site is unusual in showing prolonged human occupation within closed deciduous forest and evidence for controlled use of fire in a Lower Palaeolithic context. Biostratigraphical correlations with other Lower Palaeolithic sites support the suggestion that Acheulian and Clactonian industries both occurred in southern Britain during the same substage of the Hoxnian, although not necessarily at precisely the same time. The characteristics of the MIS 11 interglacial in Britain are discussed in the light of evidence from Beeches Pit and elsewhere.

543: Prolonged Androgen Receptor Occupancy at the PSA Promoter Occurs in Androgen-Independent Cells

543: Prolonged Androgen Receptor Occupancy at the PSA Promoter Occurs in Androgen-Independent Cells

Aromatase Inhibitors in Infertility Treatment: Risks and Benefits

Ovulatory disorders (such as polycystic ovary syndrome [PCOS]) are commonly treated with clomiphene citrate (CC), with rates of ovulation ranging between 50 and 90%. However, even though the majority of pregnancies occur within the first three cycles of treatment [1], the overall pregnancy rates are disappointingly low, ranging from 20–40% [2–4], and the likelihood of miscarriage is relatively high [5]. This discrepancy between high rates of ovulation and low rates of pregnancy is believed to be a consequence of the antiestrogenic effect of CC on peripheral targets, such as the endometrium (affecting its thickness and maturation) and the endocervix (affecting the production and quality of cervical mucus). The problem is compounded by the long half-life of CC and the persistence of an isomer, zuclomiphene, both of which lead to an accumulating antiestrogenic effect with consecutive cycles of treatment [6]. In addition, due to the prolonged occupation of estrogen receptors by CC in the hypothalamus, the circulating amount of estrogen may rise to high levels from ongoing stimulation of the follicles by endogenous follicle-stimulating hormone (FSH) production. Such supraphysiological levels of estrogen may be deleterious to the developing oocyte, sperm and embryo [7]. Consequently, better methods for inducing ovulation are desirable. Studies in animals suggest that aromatase, an enzyme necessary to convert androgens to estrogen, could be a potential target for the inhibition of estrogen production. Aromatase inhibitors (AIs) increased gonadotropin levels and ovarian weight in female rats [8], and have been found to produce multiple ovarian follicles in female primates [9]. The new generation of AIs (anastrozole, letrozole and vorozole) have more specific action, fewer side effects and lower

Prolonged TCR/CD28 Engagement Drives IL-2-Independent T Cell Clonal Expansion through Signaling Mediated by the Mammalian Target of Rapamycin

Proliferation of Ag-specific T cells is central to the development of protective immunity. The concomitant stimulation of the TCR and CD28 programs resting T cells to IL-2-driven clonal expansion. We report that a prolonged occupancy of the TCR and CD28 bypasses the need for autocrine IL-2 secretion and sustains IL-2-independent lymphocyte proliferation. In contrast, a short engagement of the TCR and CD28 only drives the expansion of cells capable of IL-2 production. TCR/CD28- and IL-2-driven proliferation revealed a different requirement for PI3K and for the mammalian target of rapamycin (mTOR). Thus, both PI3K and mTOR activities were needed for T cells to proliferate to TCR/CD28-initiated stimuli and for optimal cyclin E expression. In contrast, either PI3K or mTOR were sufficient for IL-2-driven cell proliferation as they independently mediated cyclin E induction. Interestingly, rapamycin delayed cell cycle entry of IL-2-sufficient T cells, but did not prevent their expansion. Together, our findings indicate that the TCR, CD28, and IL-2 independently control T cell proliferation via distinct signaling pathways involving PI3K and mTOR. These data suggest that Ag persistence and the availability of costimulatory signals and of autocrine and paracrine growth factors individually shape T lymphocyte expansion in vivo.

CCR5 Antagonists: Host-Targeted Antivirals for the Treatment of HIV Infection

The human chemokine receptors, CCR5 and CXCR4, are potential host targets for exogenous, small-molecule antagonists for the inhibition of HIV-1 infection. HIV-1 strains can be categorised by co-receptor tropism - their ability to utilise CCR5 (CCR5-tropic), CXCR4 (CXCR4-tropic) or both (dual-tropic) as a co-receptor for entry into susceptible cells. CCR5 may be the more suitable co-receptor target for small-molecule antagonists because a natural deletion in the CCR5 gene preventing its expression on the cell surface is not associated with any obvious phenotype, but can confer resistance to infection by CCR5-tropic strains - the most frequently sexually-transmitted strains. The current leading CCR5 antagonists in clinical development include maraviroc (UK-427,857, Pfizer), aplaviroc (873140, GlaxoSmithKline) and vicriviroc (SCH-D, Schering-Plough), which have demonstrated efficacy and tolerability in HIV-infected patients. Pharmacodynamic data also suggest that these compounds have a long plasma half-life and/or prolonged CCR5 occupancy, which may explain the delay in viral rebound observed following compound withdrawal in short-term monotherapy studies. A switch from CCR5 to CXCR4 tropism occurs spontaneously in approximately 50% of HIV-infected patients and has been associated with, but is not required for, disease progression. The possibility of a co-receptor tropism switch occurring under selection pressure by CCR5 antagonists is discussed. The completion of ongoing Phase lib/Ill studies of maraviroc, aplaviroc and vicriviroc will provide further insight into co-receptor tropism, HIV pathogenesis and the suitability of CCR5 antagonists as a potent new class of antiyirals for the treatment of HIV infection.

Update on Aplaviroc: An HIV Entry Inhibitor Targeting CCR5

Aplaviroc (873140) is a novel spirodiketopiperazine CCR5 antagonist that binds specifically to human CCR5 and allosterically inhibits HIV entry. Aplaviroc has exhibited potent in vivo antiviral activity (1.66 log decrease in viral load at nadir) following 10 days of monotherapy. In vitro studies of antiviral activity demonstrate that aplaviroc is active against HIV isolates from a variety of clades as well as those resistant to current HIV therapies targeting RT, PR, and gp41. In vitro studies suggest prolonged CCR5 receptor occupancy (RO) by aplaviroc with an offset halflife of >100 hours. In vivo studies following short term aplaviroc administration using CCR5-specific mAb demonstrate substantial and prolonged CCR5 RO (>50%) by aplaviroc, when plasma drug levels were undetectable, observed for approximately 5 days.

FARAWAY, SO CLOSE: THE LEGAL STATUS OF GAZA AFTER ISRAEL'S DISENGAGEMENT

On 12 September 2005, at around 7 a.m., the last group of Israeli soldiers left the Gaza Strip, thereby ending 38 years of continued Israeli military presence in the area. In a short ceremony at one of the exit gates, IDF Brigadier-General Aviv Kochavi, the departing Gaza Region Commander, stated: ‘the responsibility for whatever takes place inside befalls upon the [Palestinian] Authority.’ On that same night, the IDF Chief of Southern Command, Major-General Dan Harel, promulgated an official decree proclaiming the end of military rule in the Gaza Strip and formally nullifying the decree issued on 6 June 1967, which instituted military rule in the region. So came to end Israel's prolonged occupation of Gaza – or did it?

Prolonged Central μ-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing

The opioid antagonist nalmefene offers an alternative to traditional pharmacological treatments for alcoholism. The present study was designed to investigate the relationship between nalmefene plasma concentration and central mu-opioid receptor occupancy after a clinically effective dose (20 mg, orally). Pharmacokinetics and mu-opioid receptor occupancy of nalmefene after single and repeated dosing over 7 days was studied in 12 healthy subjects. Serial blood samples were obtained after both dosings, and pharmacokinetic parameters for nalmefene and main metabolites were determined. Central mu-opioid receptor occupancy of nalmefene was measured with positron emission tomography (PET) and [(11)C]carfentanil at four time points (3, 26, 50, 74 h) after both dosings. Nalmefene was rapidly absorbed in all subjects. The mean t(1/2) of nalmefene was 13.4 h after single and repeated dosing. The accumulation of nalmefene and its main metabolites in plasma during the repeated dosing period was as expected for a drug with linear pharmacokinetics, and steady-state was reached for all analytes. Both nalmefene dosings resulted in a very high occupancy at mu-opioid receptors (87-100%), and the decline in the occupancy was similar after both dosings but clearly slower than the decline in the plasma concentration of nalmefene or metabolites. High nalmefene occupancy (83-100%) persisted at 26 h after the dosings. The prolonged mu-opioid receptor occupancy by nalmefene indicates slow dissociation of the drug from mu-opioid receptors. These results support the rational of administering nalmefene when needed before alcohol drinking, and they additionally suggest that a high mu-opioid receptor occupancy can be maintained when nalmefene is taken once daily.

National Mobilization: An Option in Future Conflicts?

Following the terrorist attacks of 9/11, some commentators drew a parallel between al Qaeda's strike and Japan's bombing of Pearl Harbor, and between the ensuing struggle and the Second World War. There was sporadic talk of mobilization, which was easily enough dismissed as out of step with the realities of the War on Terror. Unconventional warfighters like terrorists are by definition immune to the massive concentrations of power that are the traditional object of a mobilization. At the same time, conventional war is generally regarded as oriented toward smaller, more professional, and high-tech forces fighting in demassified conflicts. (1) However, despite a great deal of hand-wringing on the part of social critics, the really difficult question was not asked: Would a World War II-scale mobilization even have been possible after 9/11 if it had been deemed an appropriate response? With a much reduced emphasis on military competition between the great powers and far less talk of American declinism today than there was 15 years ago, the ability of major economies to bear drastically enlarged military burdens has been discussed far less of late. Even Paul Kennedy, who popularized the declinist thesis in The Rise and Fall of the Great Powers in 1987, recently backed away from it. (2) Nonetheless, two major developments have set the stage for a new debate on rises in military expenditures. The first of these developments is a changed economic and fiscal outlook, specifically a return to the massive US budget deficits of the 1980s, and less exuberant economic expectations than was the case just a few years ago. The illusion of perfection at no cost has largely faded. The other development is the demands placed on US forces since 9/11, with talk of their being stretched too thin by commitments in Iraq and elsewhere becoming fairly widespread. While the possible emergence of a large peer competitor has never disappeared from consideration, other motivations for mobilization have emerged in recent years. One is the drive to terrorist-proof the United States, the final bill for which may run into the trillions. (3) Another is a more open embrace of an imperial position likely to involve more preventative and unilateral actions, as well as prolonged occupations and nation-building projects, and the extension of America's sphere of influence to new regions like sub-Saharan Africa and Central Asia. These factors already have led to the post-9/11 expansion of the defense budget and the institution of the Department of Homeland Security, hailed as the biggest reshuffling of the executive branch since 1947. They also have brought renewed discussion of conscription and the expansion of the armed forces, with bills pending in Congress to increase the US armed forces by tens of thousands of personnel over the next five years. American requirements, capacities, and investments aside, the question of military expansion also speaks to the capacities of other nations and the relationship of the United States with them, in terms of both the dangers of great power conflict and the international distribution of security responsibilities. The European Union and Japan, for instance, have been seeking to develop militaries capable of meeting enlarged international responsibilities since well before 9/11, efforts which have been extremely sluggish. Europe set for itself the relatively modest goal of being able to deploy a 60,000-strong force 3,000 miles away for one year by 2003. That target date has come and gone, and it seems unlikely that any such force will be made operational before 2012--if then. The Defense Capabilities Initiative, intended to close the growing technological gap between Europe and the United States, has been similarly disappointing. (4) Observers looking to explain that sluggishness, like Robert Kagan in his recent book On Paradise and Power, have commonly focused on the relatively pacifistic political cultures of the EU's member states. …

Subconductance states in OmpF gating

Discrepancies were noted in the published conductance of the Escherichia coli porin OmpF. Results from various papers are hard to compare because of the use of different channel preparations, salt types and concentrations, and electrophysiological techniques (black lipid membrane (BLM) vs. patch clamp). To reconcile these data, we present a side-by-side comparison of OmpF activity studied with the two techniques on the same preparation of pure protein, and in the same low salt concentrations (150 mM KCl). The novel aspect of OmpF porin behavior revealed by this comparison is the ubiquitous existence of states of smaller conductance than the monomeric conductance (subconductance states), regardless of the techniques or experimental conditions used, and the drastic enhancement of subconductance gating by polyamines. Transitions to subconductance states have received little attention in previous publications, in particular when BLM electrophysiology was used. Monomeric closures are rare in recordings at clamped potentials, at least at voltages lower than ∼100–120 mV. Most closing activity is in the form of subconductance gating, which becomes more dominant in the presence of spermine, with a more frequent and prolonged occupation of these substates. A discussion of the molecular basis for this hallmark behavior of porin is presented.

Habitat et mode de vie des chasseurs paléolithiques de la Caune de l'Arago (600 000–400 000 ans)

Several human occupations have been identified within the deposits of the Caune de l’Arago Cave site, dated from 700 000 years to 100 000 years old. The exceptional wealth of these archeological levels provides an opportunity for the study of different types of habitat and behavioral patterns of Paleolithic hunters between 600 000 and 400 000 years ago. Results from preliminary studies, carried out over the last 30 years on these archeological levels, allow for the proposition of a typology for cave habitats during the Middle Pleistocene in the south of France. In fact, four types of habitat were identified and defined. They have been described according to different characteristics such as, the thickness of the archeological accumulation, the animal species represented, the season during which the animals were hunted, the state of conservation of the fossils discovered, the morpho-technological and typological characteristics of the lithics, the categories of raw materials used and the territory exploited by the hominids inhabiting the cave, as defined by the raw materials represented. The four habitation types defined are: the long duration habitat, where the cave was used as a home base; the temporary seasonal habitat, in which case the cave served as a secondary campsite; the hunting stopover and the bivouac, during which the cave was used as a refuge for short term stays. Behavioral patterns appear to be directly related to the type of habitat and oriented towards a principal activity: hunting. The activities performed by the inhabitants of the cave seem to be more diversified during prolonged or seasonal occupations, whereas they appear to be reduced or very specialised during brief stays. Generally, The characteristics studied show that the Caune de l’Arago Cave site had multiple uses over time for Anteneandertalian family groups and hunters who left traces of their activities, allowing us to better understand their lifestyle.

Benefit-risk assessment of long-acting beta2-agonists in asthma.

The use of a regular long-acting beta2-adrenoceptor agonists (beta2-agonists; LABA) is now established in asthma guidelines as the preferred option for second-line controller therapy in addition to inhaled corticosteroids. This has been driven by data showing beneficial effects of LABAs on exacerbation rates, in turn suggesting a putative corticosteroid-sparing effect. As LABAs are devoid of any clinically meaningful anti-inflammatory activity in vivo, their effects on exacerbations are presumably due to a diurnal stabilising effect on airway smooth muscle. LABAs have marked effects on symptoms and lung function, and this may make it difficult to assess anti-inflammatory control with inhaled corticosteroids when used in a combination inhaler such as fluticasone propionate/salmeterol or budesonide/formoterol. The use of fixed-dose combination inhalers is in many respects counter-intuitive to conventional teaching regarding flexible dosage titration with inhaled corticosteroids. It would therefore seem prudent first to gain optimal control of inflammation with inhaled corticosteroids before considering adding a LABA. Increasing the dosage of inhaled corticosteroids will have a relatively greater effect on exacerbations than on symptoms and lung function, whereas the converse applies when adding a LABA. Another option is to add a leukotriene receptor antagonist, which confers additional anti-inflammatory activity and is as effective on exacerbations as adding a LABA. Despite in vitro and ex vivo data showing a ligand-independent effect of LABAs on glucocorticoid receptor activation, clinical data do not indicate any relevant synergy between LABAs and inhaled corticosteroids when used together in the same inhaler. In particular, there is no evidence of potentiation by LABAs of the in vivo anti-inflammatory activity of inhaled corticosteroids that would suggest any genuine corticosteroid-sparing activity. Nonetheless, the data support the additive effects of inhaled corticosteroids and LABAs when used together due to their separate effects on inflammation and smooth muscle, respectively. Tolerance with LABAs is a predictable pharmacological phenomenon that occurs despite concomitant therapy with inhaled corticosteroids. Moreover, cross-tolerance also develops to short-acting beta2-agonists used for protection against bronchoconstrictor stimuli as a result of LABA-induced down-regulation, desensitisation and prolonged occupancy of beta2-adrenoceptors. The exact role of beta2-adrenoceptor polymorphism in determining tolerance with LABAs requires further prospective clinical studies evaluating long-term effects on outcomes such as exacerbations in patients with relevant genotypes and haplotypes. The next decade will provide challenging issues for clinicians with respect to defining further the role of LABAs as add-on controller therapy, particularly in evaluating the long-term effects of combination inhalers on inflammatory outcomes and airway remodelling.