Comparative genomics provides insights into molecular adaptation to hypermetamorphosis and cantharidin metabolism in blister beetles (Coleoptera: Meloidae).

Blister beetles (Coleoptera: Meloidae) are currently subdivided into three subfamilies: Eleticinae (a basal group), Nemognathinae, and Meloinae. These are all characterized by the endogenous production of the defensive terpene cantharidin (CA), whereas the two most derived subfamilies show a hypermetamorphic larval development. Here, we provide novel draft genome assemblies of five species sampled across the three blister beetle subfamilies (Iselma pallidipennis, Stenodera caucasica, Zonitis immaculata, Lydus trimaculatus, and Mylabris variabilis) and performed a comparative analysis with other available Meloidae genomes and the closely-related canthariphilous species (Pyrochroa serraticornis) to disclose adaptations at a molecular level. Our results highlighted the expansion and selection of genes potentially responsible for CA production and metabolism, as well as its mobilization and vesicular compartmentalization. Furthermore, we observed adaptive selection patterns and gain of genes devoted to epigenetic regulation, development, and morphogenesis, possibly related to hypermetamorphosis. We hypothesize that most genetic adaptations occurred to support both CA biosynthesis and hypermetamorphosis, two crucial aspects of Meloidae biology that likely contributed to their evolutionary success.

The cranial apparatus glands of the canthariphilous Pyrochroa coccinea (Coleoptera: Pyrochroidae: Pyrochroinae), and their implications in sexual behaviour.

Some Pyrochroidae species are known as "canthariphilous" for their attraction to cantharidin (CTD), a toxic terpene with anti-predatory effects, produced in nature by only two beetle families (Meloidae and Oedemeridae). It has been demonstrated that males of Neopyrochroa flabellata ingesting CTD are positively selected by females. Indeed, the compound is re-emitted from a glandular cranial apparatus as secretions that are licked up by females during courtship behaviour, inducing copulation. Herein, we provide the first description of the glands associated to the cranial apparatus of male Pyrochroinae using the European species Pyrochroa coccinea as a model. Morphological analyses show that the cranial apparatus consists of a concave pit lined with short setae retaining secretions emitted through numerous glandular pores. Ultrastructural investigations reveal the presence of two different class 3 glands (Gl.A and Gl.B), intermixed at the level of the pit but exhibiting distinct features. Gl.A are mainly characterised by short conducting canals, rounded nuclei and electrondense vesicles while Gl.B are characterised by long conducting canals, irregular nuclei, vesicles containing a particulate substance and a multifolded plasma membrane. Observations of sexual behaviour are also reported for P. coccinea and compared to N. flabellata, confirming the involvement of cranial apparatus secretions in courtship behaviour.

A multiscale hybrid model for exploring the effect of Resolvin D1 on macrophage polarization during acute inflammation.

Dysregulated inflammation underlies various diseases. Specialized pro-resolving mediators (SPMs) like Resolvin D1 (RvD1) have been shown to resolve inflammation and halt disease progression. Macrophages, key immune cells that drive inflammation, respond to the presence of RvD1 by polarizing to an anti-inflammatory type (M2). However, RvD1's mechanisms, roles, and utility are not fully understood. This paper introduces a gene-regulatory network (GRN) model that contains pathways for RvD1 and other SPMs and proinflammatory molecules like lipopolysaccharides. We couple this GRN model to a partial differential equation-agent-based hybrid model using a multiscale framework to simulate an acute inflammatory response with and without the presence of RvD1. We calibrate and validate the model using experimental data from two animal models. The model reproduces the dynamics of key immune components and the effects of RvD1 during acute inflammation. Our results suggest RvD1 can drive macrophage polarization through the G protein-coupled receptor 32 (GRP32) pathway. The presence of RvD1 leads to an earlier and increased M2 polarization, reduced neutrophil recruitment, and faster apoptotic neutrophil clearance. These results support a body of literature that suggests that RvD1 is a promising candidate for promoting the resolution of acute inflammation. We conclude that once calibrated and validated on human data, the model can identify critical sources of uncertainty, which could be further elucidated in biological experiments and assessed for clinical use.

Uncovering Active Bacterial Symbionts in Three Species of Pollen-feeding Beetles (Nitidulidae: Meligethinae).

Microbial symbionts enable many phytophagous insects to specialize on plant-based diets through a range of metabolic services. Pollen comprises one-plant tissue consumed by such herbivores. While rich in lipids and proteins, its nutrient content is often imbalanced and difficult-to-access due to a digestibly recalcitrant cell wall. Pollen quality can be further degraded by harmful allelochemicals. To identify microbes that may aid in palynivory, we performed cDNA-based 16S rRNA metabarcoding on three related pollen beetles (Nitidulidae: Meligethinae) exhibiting different dietary breadths: Brassicogethes aeneus, B. matronalis, and Meligethes atratus. Nine bacterial symbionts (i.e., 97% OTUs) exhibited high metabolic activity during active feeding. Subsequent PCR surveys revealed varying prevalence of those from three Rickettsialles genera-Lariskella, Rickettsia, and Wolbachia-within beetle populations. Our findings lay the groundwork for future studies on the influence of phylogeny and diet on palynivorous insect microbiomes, and roles of symbionts in the use of challenging diets.

New Approach to Privacy-Preserving Clinical Decision Support Systems for HIV Treatment.

BACKGROUND: HIV treatment prescription is a complex process. Clinical decision support systems (CDSS) are a category of health information technologies that can assist clinicians to choose optimal treatments based on clinical trials and expert knowledge. The usability of some CDSSs for HIV treatment would be significantly improved by using the knowledge obtained by treating other patients. This knowledge, however, is mainly contained in patient records, whose usage is restricted due to privacy and confidentiality constraints. METHODS: A treatment effectiveness measure, containing valuable information for HIV treatment prescription, was defined and a method to extract this measure from patient records was developed. This method uses an advanced cryptographic technology, known as secure Multiparty Computation (henceforth referred to as MPC), to preserve the privacy of the patient records and the confidentiality of the clinicians' decisions. FINDINGS: Our solution enables to compute an effectiveness measure of an HIV treatment, the average time-to-treatment-failure, while preserving privacy. Experimental results show that our solution, although at proof-of-concept stage, has good efficiency and provides a result to a query within 24 min for a dataset of realistic size. INTERPRETATION: This paper presents a novel and efficient approach HIV clinical decision support systems, that harnesses the potential and insights acquired from treatment data, while preserving the privacy of patient records and the confidentiality of clinician decisions.

Molecular Characterization of Kunitz-Type Protease Inhibitors from Blister Beetles (Coleoptera, Meloidae).

Protease inhibitors are widely studied since the unrestricted activity of proteases can cause extensive organ lesions. In particular, elastase activity is involved in the pathophysiology of acute lung injury, for example during SARS-CoV-2 infection, while serine proteases and thrombin-like proteases are involved in the development and/or pathology of the nervous system. Natural protease inhibitors have the advantage to be reversible and with few side effects and thus are increasingly considered as new drugs. Kunitz-type protease inhibitors (KTPIs), reported in the venom of various organisms, such as wasps, spiders, scorpions, and snakes, have been studied for their potent anticoagulant activity and widespread protease inhibitor activity. Putative KTPI anticoagulants have been identified in transcriptomic resources obtained for two blister beetle species, Lydus trimaculatus and Mylabris variabilis. The KTPIs of L. trimaculatus and M. variabilis were characterized by combined transcriptomic and bioinformatics methodologies. The full-length mRNA sequences were divided on the base of the sequence of the active sites of the putative proteins. In silico protein structure analyses of each group of translational products show the biochemical features of the active sites and the potential protease targets. Validation of these genes is the first step for considering these molecules as new drugs for use in medicine.

New Evidence of Canthariphily: Tilloidea transversalis (Coleoptera: Cleridae) Sequestering Cantharidin From Lydus trimaculatus (Coleoptera: Meloidae).

Cantharidin (CTD) is a defensive compound autogenously and exclusively produced by two phylogenetically related beetle families: Meloidae and Oedemeridae. Although this molecule usually acts as a strong deterrent against potential predators and parasites, some arthropod species, collectively named 'canthariphilous species', are attracted to CTD. Some species can sequester CTD from the CTD-producing species, using it as a chemical defense against enemies. The present paper focuses on the first-ever description of canthariphilous interactions between a checkered beetle species (Coleoptera: Cleridae) and a CTD -producing species. Field observations revealed individuals of the phytophagous beetle Tilloidea transversalis (Charpentier, 1825) (Coleoptera: Cleridae) biting individuals of the blister beetle Lydus trimaculatus (Fabricius, 1775) (Coleoptera: Meloidae). Laboratory behavioral experiments followed to verify if this peculiar behavior of T. transversalis also occurs on other co-occurring species. Moreover, chemical analyses were performed to assess whether T. transversalis can sequester CTD. Our results show that T. transversalis only attacks CTD-producing species. However, while chemical analyses prove that T. transversalis can sequester CTD from the hemolymph of L. trimaculatus, some clues (based on a CTD-baited traps sampling) suggest that this beetle, contrarily to other canthariphilous species, does not appear to show a high attraction to pure synthetic CTD. Thus, other unknown signals, alone or in combination with CTD, could be implicated in triggering the canthariphilous behaviors of T. transversalis.

Male Accessory Glands of Blister Beetles and Cantharidin Release: A Comparative Ultrastructural Analysis.

Members of the family Meloidae are known to produce cantharidin, a highly toxic monoterpene found in their hemolymph and exuded as droplets capable of deterring many predators. As a nuptial gift, males transfer large amounts of cantharidin to females via a spermatophore, which is formed by specific accessory glands containing high concentrations of this terpene. Using light, electron and ion beam microscopy, the ultrastructural features of the three pairs of male accessory glands as well as the glandular part of the vasa deferentia were comparatively investigated in seven species of blister beetles belonging to five different tribes and two subfamilies. All gland pairs examined share common features such as mesodermal derivation, the presence of muscle sheath, a developed rough endoplasmic reticulum, abundant mitochondria, secretory vesicles, and microvillated apical membranes. Within the same species, glands exhibit distinctive features, suggesting that each pair is responsible for the formation of a specific substance. The vasa deferentia, while showing many similarities within the family, often exhibit features unique to each of the individual species investigated, whereas the accessory glands of the first and second pairs display the highest degree of ultrastructural variability. A comparison across the species shows an interesting constancy limited to ultrastructural features in the third pair of accessory glands. The similarities and differences among the species are discussed in the light of the available literature and in relation to the potential role that blister beetles' male accessory glands could play in the storage and management of cantharidin.

Unraveling the role of male reproductive tract and haemolymph in cantharidin-exuding Lydus trimaculatus and Mylabris variabilis (Coleoptera: Meloidae): a comparative transcriptomics approach.

BACKGROUND: Meloidae (blister beetles) are known to synthetize cantharidin (CA), a toxic and defensive terpene mainly stored in male accessory glands (MAG) and emitted outward through reflex-bleeding. Recent progresses in understanding CA biosynthesis and production organ(s) in Meloidae have been made, but the way in which self-protection is achieved from the hazardous accumulation and release of CA in blister beetles has been experimentally neglected. To provide hints on this pending question, a comparative de novo assembly transcriptomic approach was performed by targeting two tissues where CA is largely accumulated and regularly circulates in Meloidae: the male reproductive tract (MRT) and the haemolymph. Differential gene expression profiles in these tissues were examined in two blister beetle species, Lydus trimaculatus (Fabricius, 1775) (tribe Lyttini) and Mylabris variabilis (Pallas, 1781) (tribe Mylabrini). Upregulated transcripts were compared between the two species to identify conserved genes possibly involved in CA detoxification and transport. RESULTS: Based on our results, we hypothesize that, to avoid auto-intoxication, ABC, MFS or other solute transporters might sequester purported glycosylated CA precursors into MAG, and lipocalins could bind CA and mitigate its reactivity when released into the haemolymph during the autohaemorrhaging response. We also found an over-representation in haemolymph of protein-domains related to coagulation and integument repairing mechanisms that likely reflects the need to limit fluid loss during reflex-bleeding. CONCLUSIONS: The de novo assembled transcriptomes of L. trimaculatus and M. variabilis here provided represent valuable genetic resources to further explore the mechanisms employed to cope with toxicity of CA in blister beetle tissues. These, if revealed, might help conceiving safe and effective drug-delivery approaches to enhance the use of CA in medicine.

Larval features illuminating adult taxonomy? Case study in the European cardinal beetle species of the genus Pyrochroa (Coleoptera: Pyrochroidae: Pyrochroinae).

Larvae of the two European species of the genus Pyrochroa (P. coccinea and P. serraticornis) are redescribed, for the first time based on Italian samples, and new relevant and distinctive characters have emerged from P. serraticornis. Particularly, the presence of a single urogomphal pit between urogomphi (representing a new condition for the entire family), and new characters of mandibles, open new questions about the current taxonomic status of the European species.

Rosaceae, Brassicaceae and pollen beetles: exploring relationships and evolution in an anthophilous beetle lineage (Nitidulidae, Meligethes-complex of genera) using an integrative approach.

BACKGROUND: Meligethes are pollen-beetles associated with flowers of Rosaceae as larvae. This genus currently consists of 63 known species in two subgenera, Meligethes and Odonthogethes, predominantly occurring in the eastern Palaearctic. We analyzed 74 morphological and ecological characters (169 states) of all species, as well as of 11 outgroup species from 7 Meligethinae genera (including Brassicogethes), to investigate their phylogeny. We also conducted a parallel molecular analysis on 9 Meligethes, 9 Odonthogethes, 3 Brassicogethes and 2 Meligethinus species based on DNA sequence data from mitochondrial (COI, 16S) and nuclear (CAD) genes. RESULTS: Morphological phylogenetic reconstructions supported the monophyly of the whole genus and clades corresponding to purported subgenera Meligethes s.str. and Odonthogethes. Main species-groups were mostly confirmed, however some unresolved polytomies remained. Molecular data placed members of Brassicogethes (including 42 mostly W Palearctic species associated with Brassicaceae) as sister to Odonthogethes, with this clade being sister to Meligethes s.str. This phylogenetic scenario suggests that monophyletic Meligethes s.str., Odonthogethes and Brassicogethes should be regarded alternatively as three subgenera of a monophyletic Meligethes, or three genera in a monophyletic genus-complex, with mutually monophyletic Brassicogethes and Odonthogethes. Molecular analyses estimated the origin of this lineage at ca. 14-15 Mya from a common stem including Meligethinus. CONCLUSIONS: We hypothesize that the ancestor of Meligethes specialized on Rosaceae in the Middle Miocene (likely in Langhian Age) and subsequently radiated during Late Miocene and Plio-Pleistocene maintaining a trophic niche on this plant family. This radiation was primarily due to geographic isolation in E Asiatic mountain systems. Combined evidence from morphology, ancestral state parsimony reconstruction of host-plant associations and molecular evidence suggested that Rosoideae (Rosa spp.) represented the ancestral hosts of Meligethes s.str., followed by an independent shift of ancestral Odonthogethes (ca. 9-15 Mya) on Rubus (Rosoideae) and members of Rosaceae Spiraeoideae. Other ancestral Odonthogethes probably shifted again on the unrelated plant family Brassicaceae (maybe 8-14 Mya in S China), allowing a rapid westward radiation of the Brassicogethes clade.

A Novel Allele Specific Polymerase Chain Reaction (AS-PCR) Assay to Detect the V1016G Knockdown Resistance Mutation Confirms Its Widespread Presence in Aedes albopictus Populations from Italy.

Polymerase chain reaction (PCR)-based genotyping of mutations in the voltage-sensitive sodium channel (vssc) associated with resistance to pyrethroid insecticides is widely used and represents a potential early warning and monitoring system for insecticide resistance arising in mosquito populations, which are vectors of different human pathogens. In the secondary vector Aedes albopictus-an Asian species that has invaded and colonized the whole world, including temperate regions-sequencing of domain II of the vssc gene is still needed to detect the V1016G mutation associated with pyrethroid resistance. In this study we developed and tested a novel allele-specific PCR (AS-PCR) assay to genotype the V1016G mutation in this species and applied it to the analysis of wild populations from Italy. The results confirm the high accuracy of the novel AS-PCR and highlight frequencies of the V1016G allele as >5% in most sampling sites, with peaks of 20-45% in coastal touristic sites where pyrethroid treatments are extensively implemented, mostly for mosquito nuisance reduction. The high frequency of this mutation observed in Italian Ae. albopictus populations should serve as a warning bell, advocating for increased monitoring and management of a phenomenon which risks neutralizing the only weapon today available to counteract (risks of) arbovirus outbreaks.

Filling the gaps in the global prevalence map of clinical antimicrobial resistance.

Surveillance is critical in containing globally increasing antimicrobial resistance (AMR). Affordable methodologies to prioritize AMR surveillance efforts are urgently needed, especially in low- and middle-income countries (LMICs), where resources are limited. While socioeconomic characteristics correlate with clinical AMR prevalence, this correlation has not yet been used to estimate AMR prevalence in countries lacking surveillance. We captured the statistical relationship between AMR prevalence and socioeconomic characteristics in a suite of beta-binomial principal component regression models for nine pathogens resistant to 19 (classes of) antibiotics. Prevalence data from ResistanceMap were combined with socioeconomic profiles constructed from 5,595 World Bank indicators. Cross-validated models were used to estimate clinical AMR prevalence and temporal trends for countries lacking data. Our approach provides robust estimates of clinical AMR prevalence in LMICs for most priority pathogens (cross-validated q2 > 0.78 for six out of nine pathogens). By supplementing surveillance data, 87% of all countries worldwide, which represent 99% of the global population, are now informed. Depending on priority pathogen, our estimates benefit 2.1 to 4.9 billion people living in countries with currently insufficient diagnostic capacity. By estimating AMR prevalence worldwide, our approach allows for a data-driven prioritization of surveillance efforts. For carbapenem-resistant Acinetobacter baumannii and third-generation cephalosporin-resistant Escherichia coli, specific countries of interest are located in the Middle East, based on the magnitude of estimates; sub-Saharan Africa, based on the relative prevalence increase over 1998 to 2017; and the Pacific Islands, based on improving overall model coverage and performance.

The male reproductive accessory glands of the blister beetle Meloe proscarabaeus Linnaeus, 1758 (Coleoptera: Meloidae): Anatomy and ultrastructure of the cantharidin-storing organs.

Blister beetles owe their name to their ability to release cantharidin, a blistering terpene, the highest concentration of which is retained in male accessory glands. The anatomy and ultrastructure of the three pairs of male reproductive accessory glands and the glandular region of the two vasa deferentia of Meloe proscarabaeus were investigated using light, electron and ion beam microscopy. All of the mesodermal glands here analysed share a common structural organization with an outer muscular layer and an inner glandular epithelium facing a broad lumen in which the secretory products are released. Developed rough endoplasmic reticulum, Golgi systems, abundant mitochondria, numerous secretory vesicles and a microvillated apical membrane are commonly found in the cells of different glandular epithelia, suggesting that all accessory gland pairs as well as the vasa deferentia are involved in an active synthesis. Nevertheless, each pair of glands appears specialized in the production of a specific set of substances, as suggested by the peculiarities in cellular ultrastructure and by the different aspect of the secretions stored in their glandular lumen. The above cited features of male accessory glands of M. proscarabaeus are compared with those of other beetles and some hints on their potential role in producing and/or concentrating cantharidin are provided.

Convection and the Extracellular Matrix Dictate Inter- and Intra-Biofilm Quorum Sensing Communication in Environmental Systems.

The mechanisms and impact of bacterial quorum sensing (QS) for the coordination of population-level behaviors are well studied under laboratory conditions. However, it is unclear how, in otherwise open environmental systems, QS signals accumulate to sufficient concentration to induce QS phenotypes, especially when quorum quenching (QQ) organisms are also present. We explore the impact of QQ activity on QS signaling in spatially organized biofilms in scenarios that mimic open systems of natural and engineered environments. Using a functionally differentiated biofilm system, we show that the extracellular matrix, local flow, and QQ interact to modulate communication. In still aqueous environments, convection facilitates signal dispersal while the matrix absorbs and relays signals to the cells. This process facilitates inter-biofilm communication even at low extracellular signal concentrations. Within the biofilm, the matrix further regulates the transport of the competing QS and QQ molecules, leading to heterogenous QS behavior. Importantly, only extracellular QQ enzymes can effectively control QS signaling, suggesting that the intracellular QQ enzymes may not have evolved to degrade environmental QS signals for competition.

Phylogeny, biogeography and systematics of the hyper-diverse blister beetle genus Hycleus (Coleoptera: Meloidae).

Hycleus is a hyper-diverse genus of blister beetles including ~500 species widely distributed in the Old World, currently divided into three "sections" and into 45 "phenetic" species groups according to morphological characters. Recently the monophyly of Hycleus was questioned pointing out its paraphyly with respect to the genera Ceroctis and Paractenodia. In this study, we built a time-calibrated phylogenetic tree based on DNA sequence data from mitochondrial and nuclear genes obtained from 125 species, to understand the phylogenetic relationships among the species of this genus, to infer the biogeographic processes behind their diversification, and to assess their taxonomy and classification. Our results identified four main lineages one of which included the species belonging to Ceroctis and Paractenodia; therefore, both taxa are now referred to Hycleus as new synonyms. The three described sections of Hycleus resulted polyphyletic and are rejected, whereas several species groups represented well supported clades. Hycleus likely originated in Africa during the Early Miocene (~20 Mya), and subsequently spread in Europe and western Asia. Later, in the Late Miocene (~6 Mya) a Saharo-Sindian group branched off from the Palaearctic lineage, whereas the Oriental Region was colonized following a dispersal event through the Arabian Peninsula from the Afrotropical Region (~5 Mya).

Game of neutrophils: modeling the balance between apoptosis and necrosis.

BACKGROUND: Neutrophils are one of the key players in the human innate immune system (HIIS). In the event of an insult where the body is exposed to inflammation triggering moieties (ITMs), neutrophils are mobilized towards the site of insult and antagonize the inflammation. If the inflammation is cleared, neutrophils go into a programmed death called apoptosis. However, if the insult is intense or persistent, neutrophils take on a violent death pathway called necrosis, which involves the rupture of their cytoplasmic content into the surrounding tissue that causes local tissue damage, thus further aggravating inflammation. This seemingly paradoxical phenomenon fuels the inflammatory process by triggering the recruitment of additional neutrophils to the site of inflammation, aimed to contribute to the complete neutralization of severe inflammation. This delicate balance between the cost and benefit of the neutrophils' choice of death pathway has been optimized during the evolution of the innate immune system. The goal of our work is to understand how the tradeoff between the cost and benefit of the different death pathways of neutrophils, in response to various levels of insults, has been optimized over evolutionary time by using the concepts of evolutionary game theory. RESULTS: We show that by using evolutionary game theory, we are able to formulate a game that predicts the percentage of necrosis and apoptosis when exposed to various levels of insults. CONCLUSION: By adopting an evolutionary perspective, we identify the driving mechanisms leading to the delicate balance between apoptosis and necrosis in neutrophils' cell death in response to different insults. Using our simple model, we verify that indeed, the global cost of remaining ITMs is the driving mechanism that reproduces the percentage of necrosis and apoptosis observed in data and neutrophils need sufficient information of the overall inflammation to be able to pick a death pathway that presumably increases the survival of the organism.

Supplemented Alkaline Phosphatase Supports the Immune Response in Patients Undergoing Cardiac Surgery: Clinical and Computational Evidence.

Alkaline phosphatase (AP) is an enzyme that exhibits anti-inflammatory effects by dephosphorylating inflammation triggering moieties (ITMs) like bacterial lipopolysaccharides and extracellular nucleotides. AP administration aims to prevent and treat peri- and post-surgical ischemia reperfusion injury in cardiothoracic surgery patients. Recent studies reported that intravenous bolus administration and continuous infusion of AP in patients undergoing coronary artery bypass grafting with cardiac valve surgery induce an increased release of liver-type "tissue non-specific alkaline phosphatase" (TNAP) into the bloodstream. The release of liver-type TNAP into circulation could be the body's way of strengthening its defense against a massive ischemic insult. However, the underlying mechanism behind the induction of TNAP is still unclear. To obtain a deeper insight into the role of AP during surgery, we developed a mathematical model of systemic inflammation that clarifies the relation between supplemented AP and TNAP and describes a plausible induction mechanism of TNAP in patients undergoing cardiothoracic surgery. The model was validated against clinical data from patients treated with bovine Intestinal AP (bIAP treatment) or without AP (placebo treatment), in addition to standard care procedures. We performed additional in-silico experiments adding a secondary source of ITMs after surgery, as observed in some patients with complications, and predicted the response to different AP treatment regimens. Our results show a strong protective effect of supplemented AP for patients with complications. The model provides evidence of the existence of an induction mechanism of liver-type tissue non-specific alkaline phosphatase, triggered by the supplementation of AP in patients undergoing cardiac surgery. To the best of our knowledge this is the first time that a quantitative and validated numerical model of systemic inflammation under clinical treatment conditions is presented.

Unexpectedly high Plasmodium sporozoite rate associated with low human blood index in Anopheles coluzzii from a LLIN-protected village in Burkina Faso.

Despite the effectiveness of mass distribution of long-lasting insecticidal nets (LLINs) in reducing malaria transmission in Africa, in hyperendemic areas such as Burkina Faso the burden of malaria remains high. We here report the results of a 4-month survey on the feeding habits and Plasmodium infection in malaria vectors from a village in Burkina Faso one year following a national LLIN distribution programme. Low values of human blood index (HBI) observed in the major malaria vectors in the area (Anopheles coluzzii: N = 263, 20.1%; An. arabiensis: 5.8%, N = 103) are consistent with the hypothesis that LLINs reduced the availability of human hosts to mosquitoes. A regression meta-analysis of data from a systematic review of published studies reporting HBI and sporozoite rates (SR) for An. gambiae complex revealed that the observed SR values (An. coluzzii: 7.6%, N = 503; An. arabiensis: 5.3%, N = 225) are out of the ranges expected based on the low HBI observed. We hypothesize that a small fraction of inhabitants unprotected by bednets acts as a "core group" repeatedly exposed to mosquito bites, representing the major Plasmodium reservoir for the vectors, able to maintain a high risk of transmission even in a village protected by LLINs.

A study on the dynamics of temporary HIV treatment to assess the controversial outcomes of clinical trials: An in-silico approach.

It is still unclear under which conditions temporary combined antiretroviral therapy (cART) results in a prolonged remission after interruption. Clinical trials have contradicting reposts about the effect of cART during primary HIV infection on the disease progression. Here we propose that the apparent contradiction is due the presence of a window of opportunity for cART treatment observed in the in silico studies. We study non-linear correlations in the HIV dynamics over time using information theory. This approach requires a large dataset of CD4+ T lymphocytes and viral load concentrations over time. Since it is unfeasible to collect the required amount of data in clinical trials we use C-ImmSim, a clinically validated in silico model of the HIV infection, to simulate the HIV infection and temporary cART in 500 virtual patients for a period of 6 years post infection in time steps of 8 hours. We validate the results of our model with two published clinical trials of temporary cART in acute infection and analyse the impact of cART on the immune response. Our quantitative analysis predicts a "window of opportunity" of about ten months after the acute phase during which a temporary cART has significantly longer-lasting beneficial effects on the immune system as compared to treatment during the chronic phase. This window may help to explain the controversial outcomes of clinical trials that differ by the starting time and duration of the short-term course cART and provides a critical insight to develop appropriate protocols for future clinical trials.