The Immunomodulatory Action of Sialostatin L on Dendritic Cells Reveals Its Potential to Interfere with Autoimmunity

Sialostatin L (SialoL) is a secreted cysteine protease inhibitor identified in the salivary glands of the Lyme disease vector Ixodes scapularis. In this study, we reveal the mechanisms of SialoL immunomodulatory actions on the vertebrate host. LPS-induced maturation of dendritic cells from C57BL/6 mice was significantly reduced in the presence of SialoL. Although OVA degradation was not affected by the presence of SialoL in dendritic cell cultures, cathepsin S activity was partially inhibited, leading to an accumulation of a 10-kDa invariant chain intermediate in these cells. As a consequence, in vitro Ag-specific CD4(+) T cell proliferation was inhibited in a time-dependent manner by SialoL, and further studies engaging cathepsin S(-/-) or cathepsin L(-/-) dendritic cells confirmed that the immunomodulatory actions of SialoL are mediated by inhibition of cathepsin S. Moreover, mice treated with SialoL displayed decreased early T cell expansion and recall response upon antigenic stimulation. Finally, SialoL administration during the immunization phase of experimental autoimmune encephalomyelitis in mice significantly prevented disease symptoms, which was associated with impaired IFN-gamma and IL-17 production and specific T cell proliferation. These results illuminate the dual mechanism by which a human disease vector protein modulates vertebrate host immunity and reveals its potential in prevention of an autoimmune disease. The Journal of Immunology, 2009, 182: 7422-7429.

Prefrontal afferents to the dorsal raphe nucleus in the rat

The prefrontal cortex (PFC) receives strong inputs from monoaminergic cell groups in the brainstem and also sends projections to these nuclei. Recent evidence suggests that the PFC exerts a powerful top-down control over the dorsal raphe nucleus (DR) and that it may be involved in the actions of pharmaceutical drugs and drugs of abuse. In the light of these findings, the precise origin of prefrontal inputs to DR was presently investigated by using the cholera toxin subunit b (CTb) as retrograde tracer. All the injections placed in DR produced retrograde labeling in the medial, orbital, and lateral divisions of the PFC as well as in the medial part of the frontal polar cortex. The labeling was primarily located in layer V. Remarkably, labeling in the medial PFC was denser in its ventral part (infralimbic and ventral prelimbic cortices) than in its dorsal part (dorsal prelimbic, anterior cingulate and medial precentral cortices). After injections in the rostral or caudal DR, the largest number of labeled neurons was observed in the medial PFC, whereas after injections in the mid-rostrocaudal DR, the labeled neurons were more homogeneously distributed in the three main PFC divisions. A cluster of labeled neurons also was observed around the apex of the rostral pole of the accumbens, especially after rostral and mid-rostrocaudal DR injections. Overall, these results confirm the existence of robust preftontal projections to DR, mainly derived from the ventral part of the medial PFC, and underscore a substantial contribution of the frontal polar cortex. (C) 2008 Elsevier Inc. All rights reserved.

Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway

Giachini FR, Zemse SM, Carneiro FS, Lima VV, Carneiro ZN, Callera GE, Ergul A, Webb RC, Tostes RC. Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway. Am J Physiol Heart Circ Physiol 296: H489-H496, 2009. First published December 12, 2008; doi:10.1152/ajpheart.00251.2008.-Interleukin-10 (IL-10) is an anti-inflammatory cytokine with protective actions on the vasculature. On the other hand, endothelin ( ET)-1 has potent vasoconstrictor, mitogenic, and proinflammatory activities, which have been implicated in the pathophysiology of a number of cardiovascular diseases. We hypothesized that, in a condition where ET-1 expression is upregulated, i.e., on infusion of TNF-alpha, IL-10 confers vascular protection from ET-1-induced injury. Aortic rings and first-order mesenteric arteries from male C57BL/6 (WT) and IL-10-knockout (IL-10(-/-)) mice were treated with human recombinant TNF-alpha (220 ng.kg(-1).day(-1)) or vehicle (saline) for 14 days. TNF-alpha infusion significantly increased blood pressure in IL-10(-/-), but not WT, mice. TNF-alpha augmented vascular ET-1 mRNA expression in arteries from WT and IL-10(-/-) mice. ET type A (ETA) receptor expression was increased in arteries from IL-10(-/-) mice, and TNF-alpha infusion did not change vascular ETA receptor expression in control or IL-10(-/-) mice. Aorta and mesenteric arteries from TNF-alpha-infused IL-10(-/-) mice displayed increased contractile responses to ET-1, but not the ET type B receptor agonist IRL-1620. The ETA receptor antagonist atrasentan completely abolished responses to ET-1 in aorta and mesenteric vessels, whereas the ERK1/2 inhibitor PD-98059 abrogated increased contractions to ET-1 in arteries from TNF-alpha-infused IL-10(-/-) mice. Infusion of TNF-alpha, as well as knockdown of IL-10 (IL-10(-/-)), induced an increase in total and phosphorylated ERK1/2. These data demonstrate that IL-10 counteracts ET(A)-mediated vascular responses to ET-1, as well as activation of the ERK1/2 pathway.

Bradykinin inducible receptor is essential to lipopolysaccharide-induced acute lung injury in mice

Lipopolysaccharides from gram-negative bacteria are amongst the most common causative agents of acute lung injury, which is characterized by an inflammatory response, with cellular infiltration and the release of mediators/cytokines. There is evidence that bradykinin plays a role in lung inflammation in asthma but in other types of lung inflammation its role is less clear. In the present study we evaluated the role of the bradykinin B(1) receptor in acute lung injury caused by lipopolysaccharide inhalation and the mechanisms behind bradykinin actions participating in the inflammatory response. We found that in C57BI/6 mice, the bradykinin B(1) receptor expression was up-regulated 24 h after lipopolysaccharide inhalation. At this time, the number of cells and protein concentration were significantly increased in the bronchoalveolar lavage fluid and the mice developed airway hyperreactivity to methacholine. In addition, there was an increased expression of tumor necrosis factor-alpha, interleukin-1 beta and interferon-gamma and chemokines (monocytes chemotactic protein-1 and KC) in the bronchoalveolar lavage fluid and in the lung tissue. We then treated the mice with a bradykinin B, receptor antagonist, R-954 (Ac-Orn-[Oic(2), alpha-MePhe(5), D-beta Nal(7), Ile(8)]desArg(9)-bradykinin), 30 min after lipopolysaccharide administration. We observed that this treatment prevented the airway hyperreactivity as well as the increased cellular infiltration and protein content in the bronchoalveolar lavage fluid. Moreover, R-954 inhibited the expression of cytokines/chemokines. These results implicate bradykinin, acting through B(1) receptor, in the development of acute lung injury caused by lipopolysaccharide inhalation. (C) 2010 Elsevier B.V. All rights reserved.

ON INTEGRABLE CODIMENSION ONE ANOSOV ACTIONS OF R(k)

In this paper, we consider codimension one Anosov actions of R(k), k >= 1, on closed connected orientable manifolds of dimension n vertical bar k with n >= 3. We show that the fundamental group of the ambient manifold is solvable if and only if the weak foliation of codimension one is transversely affine. We also study the situation where one 1-parameter subgroup of R(k) admits a cross-section, and compare this to the case where the whole action is transverse to a fibration over a manifold of dimension n. As a byproduct, generalizing a Theorem by Ghys in the case k = 1, we show that, under some assumptions about the smoothness of the sub-bundle E(ss) circle plus E(uu), and in the case where the action preserves the volume, it is topologically equivalent to a suspension of a linear Anosov action of Z(k) on T(n).

Transitivity of codimension-one Anosov actions of R(k) on closed manifolds

We consider Anosov actions of R(k), k >= 2, on a closed connected orientable manifold M, of codimension one, i.e. such that the unstable foliation associated to some element of R(k) has dimension one. We prove that if the ambient manifold has dimension greater than k + 2, then the action is topologically transitive. This generalizes a result of Verjovsky for codimension-one Anosov flows.

Finite temperature effective actions

We present, from first principles, a direct method for evaluating the exact fermion propagator in the presence of a general background held at finite temperature, which can be used to determine the finite temperature effective action for the system. As applications, we determine the complete one loop finite temperature effective actions for (0 + 1)-dimensional QED as well as the Schwinger model. These effective actions, which are derived in the real time (closed time path) formalism, generate systematically all the Feynman amplitudes calculated in thermal perturbation theory and also show that the retarded (advanced) amplitudes vanish in these theories. (C) 2009 Elsevier B.V. All rights reserved.

Electrostatic Interactions Are Not Sufficient to Account for Chitosan Bioactivity

Recent studies involving chitosan interacting with phospholipid monolayers that mimic cell membranes have brought molecular-level evidence for some of the physiological actions of chitosan, as in removing a protein from the membrane. This interaction has been proven to be primarily of electrostatic origin because of the positive charge OF chitosan in low pH solutions, but indirect evidence has also appeared of the presence of hydrophobic interactions. In this study, we provide definitive proof that model membranes are not affected merely by the charges in the amine groups of chitosan. Such a proof was obtained by comparing surface pressure and surface potential isotherms of dipalmitoyl phosphatidyl choline (DPPC) and dipalmitoyl phosphatidyl glycerol (DPPG) monolayers incorporating either chitosan or poly(allylamine hydrochloride) (PAH). As the latter is also positively charged and With the same charged Functional group as chitosan, similar effects should be observed in case the electrical charge was the only relevant parameter. Instead, we observed a large expansion in the surface pressure isotherms upon interaction with chitosan, whereas PAH had much smaller effects. Of particular relevance for biological implications, chitosan considerably reduced the monolayer elasticity, whereas PAH had almost no effect. it is clear therefore that chitosan action depends strongly either on its functional uncharged groups and/or on its specific conformation in solution.

Crossed products by twisted partial actions and graded algebras

For a twisted partial action e of a group G on an (associative non-necessarily unital) algebra A over a commutative unital ring k, the crossed product A x(Theta) G is proved to be associative. Given a G-graded k-algebra B = circle plus(g is an element of G) B-g with the mild restriction of homogeneous non-degeneracy, a criteria is established for B to be isomorphic to the crossed product B-1 x(Theta) G for some twisted partial action of G on B-1. The equality BgBg-1 B-g = B-g (for all g is an element of G) is one of the ingredients of the criteria, and if it holds and, moreover, B has enough local units, then it is shown that B is stably isomorphic to a crossed product by a twisted partial action of G. (c) 2008 Elsevier Inc. All rights reserved.

Actions of octocoral and tobacco cembranoids on nicotinic receptors

Nicotinic acetylcholine receptors (AChRs) are pentameric proteins that form agonist-gated cation channels through the plasma membrane. AChR agonists and antagonists are potential candidates for the treatment of neurodegenerative diseases. Cembranoids are naturally occurring diterpenoids that contain a 14-carbon ring. These diterpenoids interact with AChRs in complex ways: as irreversible inhibitors at the agonist sites, as noncompetitive inhibitors, or as positive modulators, but no cembranoid was ever shown to have agonistic activity on AChRs. The cembranoid eupalmerin acetate displays positive modulation of agonist-induced currents in the muscle-type AChR and in the related gamma-aminobutyric acid (GABA) type A receptor. Moreover, cembranoids display important biological effects, many of them mediated by nicotinic receptors. Cembranoids from tobacco are neuroprotective through a nicotinic anti-apoptotic mechanism preventing excitotoxic neuronal death which in part could result from anti-inflammatory properties of cembranoids. Moreover, tobacco cembranoids also have anti-inflammatory properties which could enhance their neuroprotective properties. Cembranoids from tobacco affect nicotine-related behavior: they increase the transient initial ataxia caused by first nicotine injection into naive rats and inhibit the expression of locomotor sensitization to repeated injections of nicotine. In addition, cembranoids are known to act as anti-tumor compounds. In conclusion, cembranoids provide a promising source of lead drugs for many clinical areas, including neuroprotection, smoking-cessation, and anti-cancer therapies. (C) 2009 Elsevier Ltd. All rights reserved.

New Meanings to Old Rituals : The Emergence of Mourning Rituals in Shiʿite Islam

This paper will discuss the emergence of Shiʿite mourning rituals around the grave of Husayn b. ʿAli. After the killing of Husayn at Karbala’ in 61/680, a number of men in Kufa feel deep regret for their neglect to come to the help of the grand­son of the Prophet. They gather and discuss how they can best make penitence for this crime. Eventually, they decide to take to arms and go against the Umayyad army – to kill those that killed Husayn, or be killed them­selves in the attempt to find revenge for him. Thus, they are called the Penitents (Ar. Tawwābūn). On their way to the battlefield they stop at Husayn’s tomb at Karbala’, dedicat­ing themselves to remorseful prayer, crying and wailing over the fate of Husayn and their own sin. When the Penitents perform certain ritual acts, such as weeping and wailing over the death of Husayn, visiting his grave, asking for God’s mercy upon him on the Day of Judgment, demand blood revenge for him etc., they enter into already existing rituals in the pre-Islamic Arab and early Muslim context. That is, they enter into rituals that were traditionally performed at the death of a person. What is new is that the rituals that the Penitents perform have partially received a new content. As described, the rituals are performed out of loyalty towards Husayn and the family of the Prophet. The lack of loyalty in connection with the death of Husayn is conceived of as a sin that has to be atoned. Blood revenge thus be­comes not only a pure action of revenge to restore honor, but equally an expression for true religious conversion and penitence. Humphrey and Laidlaw argue that ritual actions in themselves are not bearers of meaning, but that they are filled with mean­ing by the performer. Accord­ing to them, ritual actions are apprehensible, i.e. they can be, and should be filled with meaning, and the people who perform them try to do so within the context where the ritual is performed. The story of the Penitents is a clear example of mourning rituals as actions that survive from earlier times, but that are now filled with new meaning when they are performed in a new and developing move­ment with a different ideology. In later Shiʿism, these rituals are elaborated and become a main tenet of this form of Islam.

Ways of knowing in ways of moving : A study of the meaning of capability to move

The overall aim of this thesis has been to investigate the meaning of the capability to move in order to identify and describe this capability from the perspective of the one who moves in relation to specific movements. It has been my ambition to develop ways to explicate, and thereby open up for discussion, what might form an educational goal in the context of movements and movement activities in the school subject of physical education and health (PEH). In this study I have used a practical epistemological perspective on capability to move, a perspective that challenges the traditional distinction between mental and physical skills as well as between theoretical and practical knowledge. Movement actions, or ways of moving, are seen as expressions of knowing. In order to explore an understanding of the knowing involved in specific ways of moving, observations of  actors’ ways of moving and their own experiences of moving were brought together. Informants from three different arenas took part: from PEH in upper secondary school, from athletics and from free-skiing. The results of the analyses suggest it is possible to describe practitioners’ developed knowing as a number of specific ways of knowing that are in turn related to specific ways of moving. Examples of such specific ways of moving may be discerning and modifying one’s own rotational velocity and navigating one’s (bodily) awareness. Additionally, exploring learners’ pre-knowing of a movement ‘as something’ may be fruitful when planning the teaching and learning of capability to move. I have suggested that these specific ways of knowing might be regarded as educational goals in PEH. In conducting this study, I have also had the ambition to contribute to the ongoing discussion of what ‘ability’ in the PEH context might mean. In considering specific ways of knowing in moving, the implicit and taken-for-granted meaning of ‘standards of excellence’ and ‘sports ability’can be discussed, and challenged.

Automating condition monitoring of vegetation on railway trackbeds and embankments

Vegetation growing on railway trackbeds and embankments present potential problems. The presence of vegetation threatens the safety of personnel inspecting the railway infrastructure. In addition vegetation growth clogs the ballast and results in inadequate track drainage which in turn could lead to the collapse of the railway embankment. Assessing vegetation within the realm of railway maintenance is mainly carried out manually by making visual inspections along the track. This is done either on-site or by watching videos recorded by maintenance vehicles mainly operated by the national railway administrative body. A need for the automated detection and characterisation of vegetation on railways (a subset of vegetation control/management) has been identified in collaboration with local railway maintenance subcontractors and Trafikverket, the Swedish Transport Administration (STA). The latter is responsible for long-term planning of the transport system for all types of traffic, as well as for the building, operation and maintenance of public roads and railways. The purpose of this research project was to investigate how vegetation can be measured and quantified by human raters and how machine vision can automate the same process. Data were acquired at railway trackbeds and embankments during field measurement experiments. All field data (such as images) in this thesis work was acquired on operational, lightly trafficked railway tracks, mostly trafficked by goods trains. Data were also generated by letting (human) raters conduct visual estimates of plant cover and/or count the number of plants, either on-site or in-house by making visual estimates of the images acquired from the field experiments. Later, the degree of reliability of(human) raters’ visual estimates were investigated and compared against machine vision algorithms. The overall results of the investigations involving human raters showed inconsistency in their estimates, and are therefore unreliable. As a result of the exploration of machine vision, computational methods and algorithms enabling automatic detection and characterisation of vegetation along railways were developed. The results achieved in the current work have shown that the use of image data for detecting vegetation is indeed possible and that such results could form the base for decisions regarding vegetation control. The performance of the machine vision algorithm which quantifies the vegetation cover was able to process 98% of the im-age data. Investigations of classifying plants from images were conducted in in order to recognise the specie. The classification rate accuracy was 95%.Objective measurements such as the ones proposed in thesis offers easy access to the measurements to all the involved parties and makes the subcontracting process easier i.e., both the subcontractors and the national railway administration are given the same reference framework concerning vegetation before signing a contract, which can then be crosschecked post maintenance.A very important issue which comes with an increasing ability to recognise species is the maintenance of biological diversity. Biological diversity along the trackbeds and embankments can be mapped, and maintained, through better and robust monitoring procedures. Continuously monitoring the state of vegetation along railways is highly recommended in order to identify a need for maintenance actions, and in addition to keep track of biodiversity. The computational methods or algorithms developed form the foundation of an automatic inspection system capable of objectively supporting manual inspections, or replacing manual inspections.

Process evaluation of a knowledge translation intervention using facilitation of local stakeholder groups to improve neonatal survival in the Quang Ninh province, Vietnam

BACKGROUND: Annually, 2.8 million neonatal deaths occur worldwide, despite the fact that three-quarters of them could be prevented if available evidence-based interventions were used. Facilitation of community groups has been recognized as a promising method to translate knowledge into practice. In northern Vietnam, the Neonatal Health - Knowledge Into Practice trial evaluated facilitation of community groups (2008-2011) and succeeded in reducing the neonatal mortality rate (adjusted odds ratio, 0.51; 95 % confidence interval 0.30-0.89). The aim of this paper is to report on the process (implementation and mechanism of impact) of this intervention. METHODS: Process data were excerpted from diary information from meetings with facilitators and intervention groups, and from supervisor records of monthly meetings with facilitators. Data were analyzed using descriptive statistics. An evaluation including attributes and skills of facilitators (e.g., group management, communication, and commitment) was performed at the end of the intervention using a six-item instrument. Odds ratios were analyzed, adjusted for cluster randomization using general linear mixed models. RESULTS: To ensure eight active facilitators over 3 years, 11 Women's Union representatives were recruited and trained. Of the 44 intervention groups, composed of health staff and commune stakeholders, 43 completed their activities until the end of the study. In total, 95 % (n = 1508) of the intended monthly meetings with an intervention group and a facilitator were conducted. The overall attendance of intervention group members was 86 %. The groups identified 32 unique problems and implemented 39 unique actions. The identified problems targeted health issues concerning both women and neonates. Actions implemented were mainly communication activities. Communes supported by a group with a facilitator who was rated high on attributes and skills (n = 27) had lower odds of neonatal mortality (odds ratio, 0.37; 95 % confidence interval, 0.19-0.73) than control communes (n = 46). CONCLUSIONS: This evaluation identified several factors that might have influenced the outcomes of the trial: continuity of intervention groups' work, adequate attributes and skills of facilitators, and targeting problems along a continuum of care. Such factors are important to consider in scaling-up efforts.