P. brasiliensis virulence is affected by SconC, the negative regulator of inorganic sulfur assimilation

Conidia/mycelium-to-yeast transition of Paracoccidioidesbrasiliensis is a critical step for the establishment of paracoccidioidomycosis, a systemic mycosis endemic in Latin America. Thus, knowledge of the factors that mediate this transition is of major importance for the design of intervention strategies. So far, the only known pre-requisites for the accomplishment of the morphological transition are the temperature shift to 37°C and the availability of organic sulfur compounds. In this study, we investigated the auxotrophic nature to organic sulfur of the yeast phase of Paracoccidioides, with special attention to P. brasiliensis species. For this, we addressed the role of SconCp, the negative regulator of the inorganic sulfur assimilation pathway, in the dimorphism and virulence of this pathogen. We show that down-regulation of SCONC allows initial steps of mycelium-to-yeast transition in the absence of organic sulfur compounds, contrarily to the wild-type fungus that cannot undergo mycelium-to-yeast transition under such conditions. However, SCONC down-regulated transformants were unable to sustain yeast growth using inorganic sulfur compounds only. Moreover, pulses with inorganic sulfur in SCONC down-regulated transformants triggered an increase of the inorganic sulfur metabolism, which culminated in a drastic reduction of the ATP and NADPH cellular levels and in higher oxidative stress. Importantly, the down-regulation of SCONC resulted in a decreased virulence of P. brasiliensis, as validated in an in vivo model of infection. Overall, our findings shed light on the inability of P. brasiliensis yeast to rely on inorganic sulfur compounds, correlating its metabolism with cellular energy and redox imbalances. Furthermore, the data herein presented reveal SconCp as a novel virulence determinant of P. brasiliensis.J.F.M. and J.G.R. were supported by a PhD grant from Fundacao para a Ciencia e Tecnologia (FCT). This work was supported by a grant from FCT (PTDC/BIA-MIC/108309/2008). M. Sturme. and M. Saraiva are Ciencia 2008 fellows. The authors would also like to thank FAPESP (Fundacao para Amparo a Pesquisa do Estado de Sao Paulo) and CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Replicating viral vector platform exploits alarmin signals for potent CD8⁺ T cell-mediated tumour immunotherapy.

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTL <sup>eff</sup> ) responses. Conversely, the induction of protective tumour-specific CTL <sup>eff</sup> and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTL <sup>eff</sup> responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTL <sup>eff</sup> influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy

Global comparison of warring groups in 2002–2007: fatalities from targeting civilians vs. fighting battles

Background Warring groups that compete to dominate a civilian population confront contending behavioral options: target civilians or battle the enemy. We aimed to describe degrees to which combatant groups concentrated lethal behavior into intentionally targeting civilians as opposed to engaging in battle with opponents in contemporary armed conflict. Methodology/Principal Findings We identified all 226 formally organized state and non-state groups (i.e. actors) that engaged in lethal armed conflict during 2002–2007: 43 state and 183 non-state. We summed civilians killed by an actor's intentional targeting with civilians and combatants killed in battles in which the actor was involved for total fatalities associated with each actor, indicating overall scale of armed conflict. We used a Civilian Targeting Index (CTI), defined as the proportion of total fatalities caused by intentional targeting of civilians, to measure the concentration of lethal behavior into civilian targeting. We report actor-specific findings and four significant trends: 1.) 61% of all 226 actors (95% CI 55% to 67%) refrained from targeting civilians. 2.) Logistic regression showed actors were more likely to have targeted civilians if conflict duration was three or more years rather than one year. 3.) In the 88 actors that targeted civilians, multiple regressions showed an inverse correlation between CTI values and the total number of fatalities. Conflict duration of three or more years was associated with lower CTI values than conflict duration of one year. 4.) When conflict scale and duration were accounted for, state and non-state actors did not differ. We describe civilian targeting by actors in prolonged conflict. We discuss comparable patterns found in nature and interdisciplinary research. Conclusions/Significance Most warring groups in 2002–2007 did not target civilians. Warring groups that targeted civilians in small-scale, brief conflict concentrated more lethal behavior into targeting civilians, and less into battles, than groups in larger-scale, longer conflict

Does urbanization explain differences in interactions between an insect herbivore and its natural enemies and mutualists?

Urbanization can alter the composition of arthropod communities. However, little is known about how urbanization affects ecological interactions. Using experimental colonies of the black bean aphid Aphis fabae Scopoli reared on Vicia faba L, we asked if patterns of predator-prey, host-parasitoid and ant-aphid mutualisms varied along an urbanization gradient across a large town in southern England. We recorded the presence of naturally occurring predators, parasitoid wasps and mutualistic ants together with aphid abundance. We examined how biotic (green areas and plant richness) and abiotic features (impervious surfaces and distance to town center) affected (1) aphid colony size, (2) the likelihood of finding predators, mutualistic ants and aphid mummies (indicating the presence of parasitoids), and (3) how the interplay among these factors affected patterns of parasitoid attack, predator abundance, mutualistic interactions and aphid abundance. The best model to predict aphid abundance was the number of mutualistic ants attending the colonies. Aphid predators responded negatively to both the proportion of impervious surfaces and to the number of mutualistic ants farming the colonies, and positively to aphid population size, whereas parasitized aphids were found in colonies with higher numbers of aphids and ants. The number of mutualistic ants attending was positively associated with aphid colony size and negatively with the number of aphid predators. Our findings suggest that for insect-natural enemy interactions, urbanization may affect some groups, while not influencing others, and that local effects (mutualists, host plant presence) will also be key determinants of how urban ecological communities are formed

Seasonal drought limits tree species across the Neotropics

AcceptedArticle in Press© 2016 Nordic Society Oikos.Within the tropics, the species richness of tree communities is strongly and positively associated with precipitation. Previous research has suggested that this macroecological pattern is driven by the negative effect of water-stress on the physiological processes of most tree species. This implies that the range limits of taxa are defined by their ability to occur under dry conditions, and thus in terms of species distributions predicts a nested pattern of taxa distribution from wet to dry areas. However, this 'dry-tolerance' hypothesis has yet to be adequately tested at large spatial and taxonomic scales. Here, using a dataset of 531 inventory plots of closed canopy forest distributed across the western Neotropics we investigated how precipitation, evaluated both as mean annual precipitation and as the maximum climatological water deficit, influences the distribution of tropical tree species, genera and families. We find that the distributions of tree taxa are indeed nested along precipitation gradients in the western Neotropics. Taxa tolerant to seasonal drought are disproportionally widespread across the precipitation gradient, with most reaching even the wettest climates sampled; however, most taxa analysed are restricted to wet areas. Our results suggest that the 'dry tolerance' hypothesis has broad applicability in the world's most species-rich forests. In addition, the large number of species restricted to wetter conditions strongly indicates that an increased frequency of drought could severely threaten biodiversity in this region. Overall, this study establishes a baseline for exploring how tropical forest tree composition may change in response to current and future environmental changes in this region.This paper is a product of the RAINFOR and ATDN networks and of ForestPlots.net researchers (http://www.forestplots.net). RAINFOR and ForestPlots have been supported by a Gordon and Betty Moore Foundation grant, the European Union’s Seventh Framework Programme (283080, ‘GEOCARBON’; 282664, ‘AMAZALERT’); European Research Council (ERC) grant ‘Tropical Forests in the Changing Earth System’ (T-FORCES), and Natural Environment Research Council (NERC) Urgency Grant and NERC Consortium Grants ‘AMAZONICA’ (NE/F005806/1) and ‘TROBIT’ (NE/D005590/1). Additional funding for fieldwork was provided by Tropical Ecology Assessment and Monitoring (TEAM) Network, a collaboration among Conservation International, the Missouri Botanical Garden, the Smithsonian Institution, and the Wildlife Conservation Society. A.E.M. receives a PhD scholarship from the T-FORCES ERC grant. O.L.P. is supported by an ERC Advanced Grant and a Royal Society Wolfson Research Merit Award. We thank Jon J. Lloyd, Chronis Tzedakis, David Galbraith, and two anonymous reviewers for helpful comments and Dylan Young for helping with the analyses. This study would not be possible without the extensive contributions of numerous field assistants and rural communities in the Neotropical forests. Alfredo Alarcón, Patricia Alvarez Loayza, Plínio Barbosa Camargo, Juan Carlos Licona, Alvaro Cogollo, Massiel Corrales Medina, Jose Daniel Soto, Gloria Gutierrez, Nestor Jaramillo Jarama, Laura Jessica Viscarra, Irina Mendoza Polo, Alexander Parada Gutierrez, Guido Pardo, Lourens Poorter, Adriana Prieto, Freddy Ramirez Arevalo, Agustín Rudas, Rebeca Sibler and Javier Silva Espejo additionally contributed data to this study though their RAINFOR participations. We further thank those colleagues no longer with us, Jean Pierre Veillon, Samuel Almeida, Sandra Patiño and Raimundo Saraiva. Many data come from Alwyn Gentry, whose example has inspired new generations to investigate the diversity of the Neotropics

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Pulmonary Abnormalities in Mice with Paracoccidioidomycosis: A Sequential Study Comparing High Resolution Computed Tomography and Pathologic Findings

Paracoccidioidomycosis (PCM) is a fungal infection caused by the dimorphic fungus Paracoccidioides brasiliensis. It occurs preferentially in rural workers in whom the disease is severe and may cause incapacitating pulmonary sequelae. Assessment of disease progression and treatment outcome normally includes chest x-rays or CT studies. Existing experimental PCM models have focused on several aspects, but none has done a radiologic or image follow-up evaluation of pulmonary lesions considered as the fungus primary target. In this study, the lungs of mice infected with fungal conidia were studied sequentially during the chronic stage of their experimental mycosis by noninvasive high resolution medical computed tomography, and at time of sacrifice, also by histopathology to characterize pulmonary abnormalities. Three basic lung lesion patterns were revealed by both techniques: nodular-diffuse, confluent and pseudo-tumoral which were located mainly around the hilus thus accurately reflecting the situation in human patients. The experimental design of this study decreases the need to sacrifice a large number of animals, and serves to monitor treatment efficacy by means of a more rational approach to the study of human pulmonary diseases. The findings we are reporting open new avenues for experimental research, increase our understanding of the mycosis pathogenesis and consequently have repercussions in patients' care

Renal vasculitis in Colombia

A retrospective review of publications about primary vasculitis cases was performed from the Colombian medical literature, the clinical and pathological features are described.The Renal vasculitis occurred in 33.9% of cases of primary vasculitis reviewed and was more frequent in women. The main clinical, hematological, immunological variables and nephropathology and immunosuppressive treatments used findings are described

Large-scale unit commitment under uncertainty: an updated literature survey

The Unit Commitment problem in energy management aims at finding the optimal production schedule of a set of generation units, while meeting various system-wide constraints. It has always been a large-scale, non-convex, difficult problem, especially in view of the fact that, due to operational requirements, it has to be solved in an unreasonably small time for its size. Recently, growing renewable energy shares have strongly increased the level of uncertainty in the system, making the (ideal) Unit Commitment model a large-scale, non-convex and uncertain (stochastic, robust, chance-constrained) program. We provide a survey of the literature on methods for the Uncertain Unit Commitment problem, in all its variants. We start with a review of the main contributions on solution methods for the deterministic versions of the problem, focussing on those based on mathematical programming techniques that are more relevant for the uncertain versions of the problem. We then present and categorize the approaches to the latter, while providing entry points to the relevant literature on optimization under uncertainty. This is an updated version of the paper "Large-scale Unit Commitment under uncertainty: a literature survey" that appeared in 4OR 13(2), 115--171 (2015); this version has over 170 more citations, most of which appeared in the last three years, proving how fast the literature on uncertain Unit Commitment evolves, and therefore the interest in this subject

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112