Emerging Roles of Autophagy and Inflammasome in Ehrlichiosis

Human monocytic ehrlichiosis (HME) is a potentially life-threatening tick-borne rickettsial disease (TBRD) caused by the obligate intracellular Gram-negative bacteria, Ehrlichia. Fatal HME presents with acute ailments of sepsis and toxic shock-like symptoms that can evolve to multi-organ failure and death. Early clinical and laboratory diagnosis of HME are problematic due to non-specific flu-like symptoms and limitations in the current diagnostic testing. Several studies in murine models showed that cell-mediated immunity acts as a “double-edged sword” in fatal ehrlichiosis. Protective components are mainly formed by CD4 Th1 and NKT cells, in contrast to deleterious effects originated from neutrophils and TNF-α-producing CD8 T cells. Recent research has highlighted the central role of the inflammasome and autophagy as part of innate immune responses also leading to protective or pathogenic scenarios. Recognition of pathogen-associated molecular patterns (PAMPS) or damage-associated molecular patterns (DAMPS) triggers the assembly of the inflammasome complex that leads to multiple outcomes. Recognition of PAMPs or DAMPs by such complexes can result in activation of caspase-1 and -11, secretion of the pro-inflammatory cytokines IL-1β and IL-18 culminating into dysregulated inflammation, and inflammatory cell death known as pyroptosis. The precise functions of inflammasomes and autophagy remain unexplored in infections with obligate intracellular rickettsial pathogens, such as Ehrlichia. In this review, we discuss the intracellular innate immune surveillance in ehrlichiosis involving the regulation of inflammasome and autophagy, and how this response influences the innate and adaptive immune responses against Ehrlichia. Understanding such mechanisms would pave the way in research for novel diagnostic, preventative and therapeutic approaches against Ehrlichia and other rickettsial diseases

Contact metamorphism associated to the Penamacor - Monsanto granitic intrusion (Central Portugal): geochemical, isotopic and mineralogical features

Contact metamorphism related to Variscan and late-Variscan granitic plutons in the Iberian Peninsula is superimposed on medium-grade regional metamorphism, making it often difficult to evaluate per se the thermal effects due to those intrusions and explaining the paucity of scientific literature on the subject. An exhaustive set of geochemical, isotopic and mineralogical data on the contact-zone metasediments hosting the Penamacor-Monsanto granite (Central Iberian Zone, Portugal) provides a significant contribution to the characterization of low- to intermediate-grade contact metamorphism in geological contexts formerly affected by regional metamorphism. The metasediments hosting the Penamacor-Monsanto pluton belong to the extensive detrital sequence of the ante-Ordovician Schist-Greywacke Complex. Bulk geochemistry, oxygen isotope data and crystal-chemistry of key minerals from those contact-zone and neighbouring metasediments have made it possible to infer metamorphic conditions on the contact zone of this granitic intrusion, and to distinguish them from late boron-metasomatism at the exocontact. Mineral paragenesis (muscovite + biotite + chlorite quartz plagioclase cordierite, in spotted-schists; biotite + chlorite quartz plagioclase ( cordierite), in hornfelses) and the composition of these coexisting mineral phases indicate that most of the contact rocks reached the biotite zone (or even the cordierite zone, in some cases), equivalent to upper greenschist – lower amphibolite metamorphic grade. The relatively narrow range of O-isotope temperatures estimated for the crystallization of the marginal granites (550-625ºC) explains the absence of significant effects of thermal flow anisotropy on the contact-zone rocks. Besides, textural, paragenetic, mineralogical, isotopic and geochemical nuances observed in hornfelses and spotted-schists seem mainly related to the local host-rock heterogeneities, rather than to thermal effects. The relatively low temperatures estimated for granitoid emplacement and their restricted isotopic and mineralogical impacts on the metasedimentary host-rocks account for the narrow metamorphic aureole associated with the Penamacor-Monsanto pluton, and suggest this massif may correspond to the outcropping tip of a larger granitic intrusion at depth.Las intrusions graníticas Varíscicas y tardivaríscicas de la Península Ibérica dieron lugar a un metamorfsmo de contacto que afecta a un encajante previamente sometido a un metamorfsmo regional de grado medio, lo que difculta separar los efectos térmicos de aquellos regionales, y explica la escasez de estudios sobre el mismo. El estudio detallado de la zona de contacto entre el Granito de Penamacor-Monsanto (Zona Centro-Ibérica; Portugal) y su encajante metasedimentario mediante técnicas geoquímicas, mineralógicas e isotópicas supone una notable contribución al conocimiento y caracterización del metamorfsmo de contacto de grados bajos a intermedios en contextos geológicos previamente afectados por metamorfsmo regional. El encajante metasedimentario del Plutón de Penamacor-Monsanto es parte de la amplia secuencia detrítica ante-Ordovícia conocida como Complejo Esquisto-Grawackico. Datos geoquímicos de roca total y cristaloquímicos de los minerales más característicos, y relaciones isotópicas de oxígeno en la zona de contacto y metasedimentos aledaños permiten inferir las condiciones metamórfcas en la zona de contacto de dicha intrusión, y diferenciarla de aquella afectada por metasomatismo tardío por B. La paragénesis mineral (muscovita + biotita + clorita ± cuarzo ± plagioclasa ± cordierita en los esquistos moteados; biotita + clorita ± cuarzo ± plagiclasa (± cordierita) en corneanas) y la composición de las fases minerales coexistentes indican que la mayoría de rocas del contacto alcanzaron la zona de la biotita (e incluso, en algunos casos, aquella de la cordierita), equivalente a la parte alta del grado metamórfco de los esquistos verdes, o a la parte baja de las anfbolitas. El rango relativamente pequeño de temperaturas de cristalización de los granitos marginales (550-625°C), calculado mediante isótopos de oxígeno, explica la carencia de anisotropías térmicas signifcativas en las rocas del contacto. Las sutiles diferencias texturales, paragenéticas, mineralógicas, isotópicas y geoquímicas en esquistos moteados y corneanas parecen relacionadas con heterogeneidades locales de los encajantes, y no con efectos térmicos diferenciados. Las temperaturas relativamente bajas estimadas durante la intrusión del granito de Penamacor-Monsanto, y el limitado efecto mineralógico e isotópico sobre el encajante metasedimentario, dan lugar a una aureola de contacto estrecha, y sugieren que este macizo puede corresponder al techo de una intrusión mayor en profundidad.Funding was provided by FCT—Fundação para a Ciên cia e Tecnologia, through project METMOB (PTDC/CTE-GIX/116204/2009

A highly efficacious pediculicide based on dimeticone: Randomized observer blinded comparative trial

BACKGROUND: Infestation with the human head louse (Pediculus humanus capitis) occurs worldwide. Existing treatment options are limited, and reports of resistance to commonly used pediculicides have been increasing. In this trial we assessed the efficacy of a product containing a high (92%) concentration of the silicone oil dimeticone (identical in composition to NYDA(R)), as compared to a 1% permethrin lotion. METHODS: Randomized, controlled, observer blinded clinical trial. Participants were recruited from a poor urban neighbourhood in Brazil where pediculosis capitis was highly prevalent. To minimize reinfestation during the trial, participants (145 children aged 5-15 years with head lice infestations) were transferred to a holiday resort outside the endemic area for a period of 9 days. Two applications of dimeticone or 1% permethrin were done, seven days apart. Outcome measures were defined as cure (absence of vital head lice) after first application and before and after second applications, degree of itching, cosmetic acceptability, and clinical pathology. RESULTS: Overall cure rates were: day 2 - dimeticone 94.5% (95% CI: 86.6% - 98.5%) and permethrin 66.7% (95% CI: 54.6% - 77.3%; p < 0.0001); day 7 - dimeticone 64.4% (95% CI: 53.3% - 75.3%) and permethrin 59.7% (95% CI: 47.5% - 71.1%; p = 0.5); day 9 - dimeticone 97.2% (95% CI: 90.3% - 99.7%) and permethrin 67.6% (95% CI: 55.4%-78.2%); p < 0.0001). Itching was reduced similarly in both groups. Cosmetic acceptability was significantly better in the dimeticone group as compared to the permethrin group (p = 0.01). Two mild product-related incidents occurred in the dimeticone group. CONCLUSION: The dimeticone product is a safe and highly efficacious pediculicide. Due to its physical mode of action (interruption of the lice's oxygen supply of the central nervous system), development of resistance is unlikely. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15117709

Potential geographic distribution of Hantavirus reservoirs in Brazil

Hantavirus cardiopulmonary syndrome is an emerging zoonosis in Brazil. Human infections occur via inhalation of aerosolized viral particles from excreta of infected wild rodents. Necromys lasiurus and Oligoryzomys nigripes appear to be the main reservoirs of hantavirus in the Atlantic Forest and Cerrado biomes. We estimated and compared ecological niches of the two rodent species, and analyzed environmental factors influencing their occurrence, to understand the geography of hantavirus transmission. N. lasiurus showed a wide potential distribution in Brazil, in the Cerrado, Caatinga, and Atlantic Forest biomes. Highest climate suitability for O. nigripes was observed along the Brazilian Atlantic coast. Maximum temperature in the warmest months and annual precipitation were the variables that most influence the distributions of N. lasiurus and O. nigripes, respectively. Models based on occurrences of infected rodents estimated a broader area of risk for hantavirus transmission in southeastern and southern Brazil, coinciding with the distribution of human cases of hantavirus cardiopulmonary syndrome. We found no demonstrable environmental differences among occurrence sites for the rodents and for human cases of hantavirus. However, areas of northern and northeastern Brazil are also apparently suitable for the two species, without broad coincidence with human cases. Modeling of niches and distributions of rodent reservoirs indicates potential for transmission of hantavirus across virtually all of Brazil outside the Amazon Basin

Preliminarno ispitivanje antimikotskog i citotoksičnog djelovanja derivata cikloalkil[b]tiofena PLS-DA analizom

A series of 2-[(arylidene)amino]-cycloalkyl[b]thiophene-3-carbonitriles (2a-x) was synthesized by incorporation of substituted aromatic aldehydes in Gewald adducts (1a-c). The title compounds were screened for their antifungal activity against Candida krusei and Criptococcusneoformans and for their antiproliferative activity against a panel of 3 human cancer cell lines (HT29, NCI H-292 and HEP). Forantiproliferative activity, the partial least squares (PLS) methodology was applied. Some of the prepared compounds exhibited promising antifungal and proliferative properties. The most active compounds for antifungal activity were cyclohexyl[b]thiophene derivatives, and forantiproliferative activity cycloheptyl[b]thiophene derivatives, especially 2-[(1H-indol-2-yl-methylidene)amino]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile (2r), which inhibited more than 97 % growth of the three cell lines. The PLS discriminant analysis (PLS-DA)applied generated good exploratory and predictive results and showed that the descriptors having shape characteristics were strongly correlated with the biological data.Koristeći supstituirane aromatske aldehide u Gewaldovim aduktima 1a-c sintetizirani su derivati 2-[(ariliden)amino]-cikloalkil[b]tiofen-3-karbonitrila (2a-x). Ispitano je antimikotsko djelovanje tih spojeva na gljivice Candida krusei i Criptococcus neoformans te antiproliferativno djelovanje na tri humane tumorske stanične linije (HT29, NCI H-292 i HEP). Za antiproliferativno djelovanje primijenjena je metoda parcijalnih najmanjih kvadrata (PLS) koristeći softverski program Pentacle. Neki od ispitanih spojeva pokazuju obećavajuće antimikotsko i antiproliferativno djelovanje. Najjače antimikotsko djelovanje imaju cikloheksil[b]tiofen derivati, a najjače antiproliferativno djelovanje cikloheptil[b]tiofen derivati, posebice 2-[(1H-indol-2-il-metiliden)amino]-5,6,7,8-tetrahidro-4H-ciklohepta[b]tiofen-3-karbonitril (2r), koji inhibira više od 97 % rast svih triju ispitivanih staničnih linija. Primijenjena PLS diskriminirajuća analiza dala je dobre istraživačke i prognostičke rezultate i pokazala da deskriptori dobro koreliraju s biološkim rezultatima

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente