Understanding resistance vs. susceptibility in visceral leishmaniasis using mouse models of Leishmania infantum Infection

Every year, up to 90,000 new cases of Visceral Leishmaniasis and 30,000 resultant deaths are estimated to occur worldwide. Such numbers give relevance to the continuous study of this complex form of the disease: a zoonosis and an anthroponosis; two known etiological agents (Leishmania infantum and L. donovani, respectively); with an estimated average ratio of 1 symptomatic per 10 asymptomatic individuals; and sometimes associated with atypical clinical presentations. This complexity, which results from a long co-evolutionary process involving vector-host, host-pathogen, and pathogen-vector interactions, is still not completely understood. The determinants of visceralization are not fully defined and the dichotomy resistance vs. susceptibility remains unsolved, translating into obstacles that delay the progress of global disease control. Inbred mouse models, with different susceptibility patterns to Leishmania infection, have been very useful in exploring this dichotomy. BALB/c and C57BL/6 mice were described as susceptible strains to L. donovani visceral infection, while SV/129 was considered resistant. Here, we used these three mouse models, but in the context of L. infantum infection, the other Leishmania species that cause visceral disease in humans, and dynamically compared their local and systemic infection-induced immune responses in order to establish a parallel and to ultimately better understand susceptibility vs. resistance in visceral leishmaniasis. Overall, our results suggest that C57BL/6 mice develop an intermediate "infection-phenotype" in comparison to BALB/c and SV/129 mouse strains, considering both the splenic parasite burden and the determined target organs weights. However, the immune mechanisms associated with the control of infection seem to be different in each mouse strain. We observed that both BALB/c and SV/129, but not C57BL/6 mice, show an infection-induced increase of splenic T follicular helper cells. On the other hand, differences detected in terms of CD21 expression by B cells early after infection, together with the quantified anti-Leishmania specific antibodies, suggest that SV/129 are faster than BALB/c and C57BL/6 mice in the assembly of an efficient B-cell response. Additionally, we observed an infection-induced increase in polyfunctional CD4+ T cells in the resistant SV/129 model, opposing an infection-induced increase in CD4+IL-10+ cells in susceptible BALB/c mice. Our data aligns with the observations reported for L. donovani infection and suggest that not only a single mechanism, but an interaction of several could be necessary for the control of this parasitic disease.The research leading to these results has received funding from the project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). PC was supported by Foundation for Science and Technology (FCT), Portugal, through the individual grant SFRH/BD/121252/2016

Alkalizing Reactions Streamline Cellular Metabolism in Acidogenic Microorganisms

An understanding of the integrated relationships among the principal cellular functions that govern the bioenergetic reactions of an organism is necessary to determine how cells remain viable and optimise their fitness in the environment. Urease is a complex enzyme that catalyzes the hydrolysis of urea to ammonia and carbonic acid. While the induction of urease activity by several microorganisms has been predominantly considered a stress-response that is initiated to generate a nitrogen source in response to a low environmental pH, here we demonstrate a new role of urease in the optimisation of cellular bioenergetics. We show that urea hydrolysis increases the catabolic efficiency of Streptococcus thermophilus, a lactic acid bacterium that is widely used in the industrial manufacture of dairy products. By modulating the intracellular pH and thereby increasing the activity of β-galactosidase, glycolytic enzymes and lactate dehydrogenase, urease increases the overall change in enthalpy generated by the bioenergetic reactions. A cooperative altruistic behaviour of urease-positive microorganisms on the urease-negative microorganisms within the same environment was also observed. The physiological role of a single enzymatic activity demonstrates a novel and unexpected view of the non-transcriptional regulatory mechanisms that govern the bioenergetics of a bacterial cell, highlighting a new role for cytosol-alkalizing biochemical pathways in acidogenic microorganisms

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

Antimicrobial peptides as novel anti-tuberculosis therapeutics

"Available online 24 May 2016"Tuberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, has recently joined HIV/AIDS as the world's deadliest infectious disease, affecting around 9.6 million people worldwide in 2014. Of those, about 1.2 million died from the disease. Resistance acquisition to existing antibiotics, with the subsequent emergence of Multi-Drug Resistant mycobacteria strains, together with an increasing economic burden, has urged the development of new anti-TB drugs. In this scope, antimicrobial peptides (AMPs), which are small, cationic and amphipathic peptides that make part of the innate immune system, now arise as promising candidates for TB treatment. In this review, we analyze the potential of AMPs for this application. We address the mechanisms of action, advantages and disadvantages over conventional antibiotics and how problems associated with its use may be overcome to boost their therapeutic potential. Additionally, we address the challenges of translational development from benchside to bedside, evaluate the current development pipeline and analyze the expected global impact from a socio-economic standpoint. The quest for more efficient and more compliant anti-TB drugs, associated with the great therapeutic potential of emerging AMPs and the rising peptide market, provide an optimal environment for the emergence of AMPs as promising therapies. Still, their pharmacological properties need to be enhanced and manufacturing-associated issues need to be addressed.Portuguese Foundation for Science and Technology (FCT) - UID/ BIO/04469/2013 unit ; COMPETE 2020 (POCI-01-0145-FEDER- 006684) ; SFRH/BPD/64958/2010Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462

Measurement of Trilinear Gauge Couplings in e+e−e^+ e^- Collisions at 161 GeV and 172 GeV

Trilinear gauge boson couplings are measured using data taken by DELPHI at 161~GeV and 172~GeV. Values for $WWV$ couplings ($V=Z, \gamma$) are determined from a study of the reactions \eeWW\ and \eeWev, using differential distributions from the $WW$ final state in which one $W$ decays hadronically and the other leptonically, and total cross-section data from other channels. Limits are also derived on neutral $ZV\gamma$ couplings from an analysis of the reaction \eegi

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

BACKGROUND Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS Positive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation. CONCLUSION This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts

Search for neutral heavy leptons produced in ZZ decays

Weak isosinglet Neutral Heavy Leptons (νm) have been searched for using data collected by the DELPHI detector corresponding to 3.3 × 106 hadronic Z0 decays at LEP1. Four separate searches have been performed, for short-lived νm production giving monojet or acollinear jet topologies, and for long-lived νm giving detectable secondary vertices or calorimeter clusters. No indication of the existence of these particles has been found, leading to an upper limit for the branching ratio BR(Z0 → νmν̄) of about 1.3 × 10-6 at 95% confidence level for νm masses between 3.5 and 50 GeV/c2. Outside this range the limit weakens rapidly with the νm mass. The results are also interpreted in terms of limits for the single production of excited neutrinos. © Springer-Verlag 1997

Muon reconstruction and identification efficiency in ATLAS using the full Run 2 pp collision data set at \sqrt{s}=13 TeV

This article documents the muon reconstruction and identification efficiency obtained by the ATLAS experiment for 139 \hbox {fb}^{-1} of pp collision data at \sqrt{s}=13 TeV collected between 2015 and 2018 during Run 2 of the LHC. The increased instantaneous luminosity delivered by the LHC over this period required a reoptimisation of the criteria for the identification of prompt muons. Improved and newly developed algorithms were deployed to preserve high muon identification efficiency with a low misidentification rate and good momentum resolution. The availability of large samples of Z\rightarrow \mu \mu and J/\psi \rightarrow \mu \mu decays, and the minimisation of systematic uncertainties, allows the efficiencies of criteria for muon identification, primary vertex association, and isolation to be measured with an accuracy at the per-mille level in the bulk of the phase space, and up to the percent level in complex kinematic configurations. Excellent performance is achieved over a range of transverse momenta from 3 GeV to several hundred GeV, and across the full muon detector acceptance of |\eta |<2.7