The prominent role of neutrophils during the initial phase of infection by Leishmania parasites.

Neutrophils are rapidly and massively recruited to the site of Leishmania inoculation, where they phagocytose the parasites, some of which are able to survive within these first host cells. Neutrophils can thus provide a transient safe shelter for the parasites, prior to their entry into macrophages where they will replicate. In addition, neutrophils release and synthesize rapidly several factors including cytokines and chemokines. The mechanism involved in their rapid recruitment to the site of parasite inoculation, as well as the putative consequences of their massive presence on the microenvironment of the focus of infection will be discussed in the context of the development of the Leishmania-specific immune response

Angular momentum transport modeling: achievements of a gyrokinetic quasi-linear approach

QuaLiKiz, a model based on a local gyrokinetic eigenvalue solver is expanded to include momentum flux modeling in addition to heat and particle fluxes. Essential for accurate momentum flux predictions, the parallel asymmetrization of the eigenfunctions is successfully recovered by an analytical fluid model. This is tested against self-consistent gyrokinetic calculations and allows for a correct prediction of the ExB shear impact on the saturated potential amplitude by means of a mixing length rule. Hence, the effect of the ExB shear is recovered on all the transport channels including the induced residual stress. Including these additions, QuaLiKiz remains ~10 000 faster than non-linear gyrokinetic codes allowing for comparisons with experiments without resorting to high performance computing. The example is given of momentum pinch calculations in NBI modulation experiments

Survival Mechanisms Used by Some Leishmania Species to Escape Neutrophil Killing

Neutrophils are the most abundant leukocytes in human blood. Upon microbial infection, they are massively and rapidly recruited from the circulation to sites of infection where they efficiently kill pathogens. To this end, neutrophils possess a variety of weapons that can be mobilized and become effective within hours following infection. However, several microbes including some Leishmania spp. have evolved a variety of mechanisms to escape neutrophil killing using these cells as a basis to better invade the host. In addition, neutrophils are also present in unhealing cutaneous lesions where their role remains to be defined. Here, we will review recent progress in the field and discuss the different strategies applied by some Leishmania parasites to escape from being killed by neutrophils and as recently described for Leishmania mexicana, even replicate within these cells. Subversion of neutrophil killing functions by Leishmania is a strategy that allows parasite spreading in the host with a consequent deleterious impact, transforming the primary protective role of neutrophils into a deleterious one

Calving rates at tidewater glaciers vary strongly with ocean temperature

TerraSAR-X data were provided by DLR (project OCE1503), and funded by the Conoco Phillips-Lundin Northern Area Program through the CRIOS project (Calving Rates and Impact on Sea level). A.L. and S.B. are affiliated to the Climate Change Consortium of Wales (C3W). Mooring work is supported by the UK Natural Environment Research Council (Oceans 2025 and Northern Sea Program) and the Research Council of Norway (projects Cleopatra: 178766, Cleopatra II: 216537, and Circa: 214271/F20). Contribution by F.C. was undertaken through the Scottish Alliance for Geoscience Environment and Society (SAGES).Rates of ice mass loss at the calving margins of tidewater glaciers (frontal ablation rates) are a key uncertainty in sea level rise projections. Measurements are difficult because mass lost is replaced by ice flow at variable rates, and frontal ablation incorporates sub-aerial calving, and submarine melt and calving. Here we derive frontal ablation rates for three dynamically contrasting glaciers in Svalbard from an unusually dense series of satellite images. We combine ocean data, ice-front position and terminus velocity to investigate controls on frontal ablation. We find that frontal ablation is not dependent on ice dynamics, nor reduced by glacier surface freeze-up, but varies strongly with sub-surface water temperature. We conclude that calving proceeds by melt undercutting and ice-front collapse, a process that may dominate frontal ablation where submarine melt can outpace ice flow. Our findings illustrate the potential for deriving simple models of tidewater glacier response to oceanographic forcing.Publisher PDFPeer reviewe

Cardiac evaluation of candidates for kidney transplantation: value of exercise radionuclide angiocardiography

In view of the high incidence and mortality of coronary artery disease (CAD) in patients with kidney transplantation, a systematic cardiac evaluation was prospectively performed in 103 uraemic patients eligible for transplantation. After clinical examination, 28 patients with symptoms of CAD or diabetes mellitus were referred directly for coronary angiography, whereas the remaining 75 patients had rest and exercise radionuclide angiocardiography for evaluation of possible asymptomatic CAD. Among them, left ventricular ejection fraction was below 40% at rest or fell during exercise by at least 5 EF% in 12 patients; coronary angiography in nine showed CAD in four and hypertensive heart disease in five. In the remaining 63 (of 75) patients without severe resting left ventricular dysfunction or exercise ischaemia, the follow-up of 28 ±7 months revealed no clinical manifestation of CAD. Overall incidence of CAD in symptomatic and asymptomatic patients during a follow-up of 27 months after cardiac evaluation was 20 and 25% in non-diabetic and diabetic candidates for kidney transplantation, respectively (P = n.s.). Thus, clinical examination combined with exercise radionuclide angiocardiography in patients without signs or symptoms of heart disease had a high predictive accuracy for presence or absence of late manifestations of CAD. Exercise radionuclide angiocardiography is therefore a useful method for screening kidney transplantation candidates for asymptomatic CA

The interperiosteodural concept applied to the jugular foramen and its compartmentalization

OBJECTIVE The dura mater is made of 2 layers: the endosteal layer (outer layer), which is firmly attached to the bone, and the meningeal layer (inner layer), which directly covers the brain and spinal cord. These 2 dural layers join together in most parts of the skull base and cranial convexity, and separate into the orbital and perisellar compartments or into the spinal epidural space to form the extradural neural axis compartment (EDNAC). The EDNAC contains fat and/or venous blood. The aim of this dissection study was to anatomically verify the concept of the EDNAC by focusing on the dural layers surrounding the jugular foramen area. METHODS The authors injected 10 cadaveric heads (20 jugular foramina) with colored latex and fixed them in formalin. The brainstem and cerebellum of 7 specimens were cautiously removed to allow a superior approach to the jugular foramen. Special attention was paid to the meningeal architecture of the jugular foramen, the petrosal inferior sinus and its venous confluence with the sigmoid sinus, and the glossopharyngeal, vagus, and accessory nerves. The 3 remaining heads were bleached with a 20% hydrogen peroxide solution. This procedure produced softening of the bone without modifying the fixed soft tissues, thus permitting coronal and axial dissections. RESULTS The EDNAC of the jugular foramen was limited by the endosteal and meningeal layers and contained venous blood. These 2 dural layers joined together at the level of the petrous and occipital bones and separated at the inferior petrosal sinus and the sigmoid sinus, and around the lower cranial nerves, to form the EDNAC. Study of the dural sheaths allowed the authors to describe an original compartmentalization of the jugular foramen in 3 parts: 2 neural compartments-glossopharyngeal and vagal-and the interperiosteodural compartment. CONCLUSIONS In this dissection study, the existence of the EDNAC concept in the jugular foramen was demonstrated, leading to the proposal of a novel 3-part compartmentalization, challenging the classical 2-part compartmentalization, of the jugular foramen

Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner.

Th17 cells play critical roles in host defense and autoimmunity. Emerging data support a role for Notch signaling in Th17 cell differentiation but whether it is a positive or negative regulator remains unclear. We report here that T cell-specific deletion of Notch receptors enhances Th17 cell differentiation in the gut, with a corresponding increase in IL-17 secretion. An increase in Th17 cell frequency was similarly observed following immunization of T cell specific Notch mutant mice with OVA/CFA. However, in this setting, Th17 cytokine secretion was impaired, and increased intracellular retention of IL-17 was observed. Intracellular IL-17 co-localized with the CD71 iron transporter in the draining lymph node of both control and Notch-deficient Th17 cells. Immunization induced CD71 surface expression in control, but not in Notch-deficient Th17 cells, revealing defective CD71 intracellular transport in absence of Notch signaling. Moreover, Notch receptor deficient Th17 cells had impaired mTORC2 activity. These data reveal a context-dependent impact of Notch on vesicular transport during high metabolic demand suggesting a role for Notch signaling in the bridging of T cell metabolic demands and effector functions. Collectively, our findings indicate a prominent regulatory role for Notch signaling in the fine-tuning of Th17 cell differentiation and effector function

Resistance of Leishmania (Viannia) Panamensis to Meglumine Antimoniate or Miltefosine Modulates Neutrophil Effector Functions.

Leishmania (Viannia) panamensis (L. (V.) p.) is the main causative agent of cutaneous leishmaniasis in Colombia and is usually treated with either meglumine antimoniate (MA) or miltefosine (MIL). In recent years, there has been increasing evidence of the emergence of drug-resistance against these compounds. Neutrophils are known to play an important role in immunity against Leishmania. These cells are rapidly recruited upon infection and are also present in chronic lesions. However, their involvement in the outcome of infection with drug-resistant Leishmania has not been examined. In this study, human and murine neutrophils were infected in vitro with MA or MIL drug-resistant L. (V.) p. lines derived from a parental L. (V.) p. drug-susceptible strain. Neutrophil effector functions were assessed analyzing the production of reactive oxygen species (ROS), the formation of neutrophil extracellular trap (NET) and the expression of cell surface activation markers. Parasite killing by neutrophils was assessed using L. (V.) p. transfected with a luciferase reporter. We show here that MA and MIL-resistant L. (V.) p. lines elicited significantly increased NET formation and MA-resistant L. (V.) p. induced significantly increased ROS production in both murine and human neutrophils, compared to infections with the parental MIL and MA susceptible strain. Furthermore, neutrophils exposed to drug-resistant lines showed increased activation, as revealed by decreased expression of CD62L and increased expression of CD66b in human neutrophils yet presented higher survival within neutrophils than the drug-susceptible strain. These results provide evidence that parasite drug-susceptibility may influences neutrophil activation and function as well as parasite survival within neutrophils. Further investigaton of the inter-relationship of drug susceptibility and neutrophil effector function should contribute to better understanding of the factors involved in susceptibility to anti-Leishmania drugs

The quorum-sensing molecules farnesol/homoserine lactone and dodecanol operate via distinct modes of action in Candida albicans

Living as a commensal, Candida albicans must adapt and respond to environmental cues generated by the mammalian host and by microbes comprising the natural flora. These signals have opposing effects on C. albicans, with host cues promoting the yeast-to-hyphal transition and bacteria-derived quorum-sensing molecules inhibiting hyphal development. Hyphal development is regulated through modulation of the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and it has been postulated that quorum-sensing molecules can affect filamentation by inhibiting the cAMP pathway. Here, we show that both farnesol and 3-oxo-C12-homoserine lactone, a quorum-sensing molecule secreted by Pseudomonas aeruginosa, block hyphal development by affecting cAMP signaling; they both directly inhibited the activity of the Candida adenylyl cyclase, Cyr1p. In contrast, the 12-carbon alcohol dodecanol appeared to modulate hyphal development and the cAMP signaling pathway without directly affecting the activity of Cyr1p. Instead, we show that dodecanol exerted its effects through a mechanism involving the C. albicans hyphal repressor, Sfl1p. Deletion of SFL1 did not affect the response to farnesol but did interfere with the response to dodecanol. Therefore, quorum sensing in C. albicans is mediated via multiple mechanisms of action. Interestingly, our experiments raise the possibility that the Burkholderia cenocepacia diffusible signal factor, BDSF, also mediates its effects via Sfl1p, suggesting that dodecanol's mode of action, but not farnesol or 3-oxo-C12-homoserine lactone, may be used by other quorum-sensing molecules