Multi-scale mechanistic modelling of the host defence in invasive aspergillosis reveals leucocyte activation and iron acquisition as drivers of infection outcome

Aspergillus species are ubiquitous environmental moulds, with spores inhaled daily by most humans. Immunocompromised hosts can develop an invasive infection resulting in high mortality. There is, therefore, a pressing need for host-centric therapeutics for this infection. To address it, we created a multi-scale computational model of the infection, focused on its interaction with the innate immune system and iron, a critical nutrient for the pathogen. The model, parameterized using published data, was found to recapitulate a wide range of biological features and was experimentally validated in vivo. Conidial swelling was identified as critical in fungal strains with high growth, whereas the siderophore secretion rate seems to be an essential prerequisite for the establishment of the infection in low-growth strains. In immunocompetent hosts, high growth, high swelling probability and impaired leucocyte activation lead to a high conidial germination rate. Similarly, in neutropenic hosts, high fungal growth was achieved through synergy between high growth rate, high swelling probability, slow leucocyte activation and high siderophore secretion. In summary, the model reveals a small set of parameters related to fungal growth, iron acquisition and leucocyte activation as critical determinants of the fate of the infection.     

Antibiotic susceptibility of Bifidobacterium thermophilum and Bifidobacterium pseudolongum isolates from animal sources

The widespread use of antimicrobial substances has led to resistant populations of microorganisms in several ecosystems. In animal husbandry, the application of antibiotics has contributed to resistance development in pathogenic and commensal bacteria. These strains or their resistance genes can be spread along several ecological routes, including the food chain. Antibiotic resistance is important in terms of the safety of industrial strains, such as probiotics for food and feed. Bifidobacterium thermophilum and Bifidobacterium pseudolongum are known to comprise the major part of the bifidobacterial microbiota in the gut and feces of cattle and pigs. In this study, the antimicrobial susceptibility in bifidobacterial isolates of these species was investigated. Isolates from the beef and pork production chain were identified and typed to strain level, and the antimicrobial susceptibility level was tested to a set of antibiotics. Isolates with low susceptibility levels were screened by PCR for already described resistance genes. Strains atypically resistant to clindamycin, erythromycin, and tetracycline were determined. The resistance genes tet(O), tet(W), and erm(X) were detected in the bifidobacterial species that were examined.     

Effect of chronic consumption of pistachios (Pistacia vera L.) on glucose metabolism in pre-diabetics and type 2 diabetics: A systematic review

Pistachio is a nut with high polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFA), polyphenols and carotenoids content, and the synergism between these compounds appears to affect glucose metabolism. In this systematic review we analyzed studies in which the effect of chronic consumption of pistachio on markers of glucose metabolism was evaluated in pre-diabetic and type 2 diabetics. We used the PubMed, Scopus, Cochrane and Lilacs databases. The research terms used were pistachio, pre-diabetes, type 2 diabetes mellitus, insulin resistance, blood glucose, hyperglycemia and glycated hemoglobin (HbA1c). Four articles were selected, of which three tested the intake of 50 to 57 g of pistachio/day and one 20% of the daily caloric intake, for a period of 1 to 4 months. Studies reported a decrease in fasting blood glucose, insulinemia, HOMA-IR, and fructosamine, but no change in HbA1c. Lower concentrations of miR-192 and miR-375 were also found, which correlated positively with HOMA-IR. The synergism between PUFA, MUFA, polyphenols and carotenoids present in pistachios can modulate specific miRNA, increasing insulin sensitivity through the PI3K-AKT signaling pathway. This modulation can be used as a tool to monitor the response to interventions, favoring the prevention and treatment of complications related to diabetes.     

Effect of interval between induction of ovulation and artificial insemination (AI) and supplemental progesterone for resynchronization on fertility of dairy cows subjected to a 5-d timed AI program

Objectives were to investigate 2 intervals from induction of ovulation to artificial insemination (AI) and the effect of supplemental progesterone for resynchronization on fertility of lactating dairy cows subjected to a 5-d timed AI program. In experiment 1, 1,227 Holstein cows had their estrous cycles presynchronized with 2 injections of PGF_2α at 46 and 60 d in milk (DIM). The timed AI protocols were initiated with GnRH at 72 DIM, followed by 2 injections of PGF_2α at 77 and 78 DIM and a second injection of GnRH at either 56 (OVS56) or 72 h (COS72) after the first PGF_2α of the timed AI protocols. All cows were time-inseminated at 72 h after the first PGF_2α injection. Pregnancy was diagnosed on d 32 and 60 after AI. In experiment 2, 675 nonpregnant Holstein cows had their estrous cycles resynchronized starting at 34 d after the first AI. Cows received the OVS56 with (RCIDR) or without (RCON) supplemental progesterone, as an intravaginal insert, from the first GnRH to the first PGF_2α. Pregnancy diagnoses were performed on d 32 and 60 after AI. During experiment 2, subsets of cows had their ovaries scanned by ultrasonography at the first GnRH, the first PGF_2α, and second GnRH injections of the protocol. Blood was sampled on the day of AI and 7 d later, and concentrations of progesterone were determined in plasma. Cows were considered to have a synchronized ovulation if they had progesterone <1 and >2.26 ng/mL on the day of AI and 7 d later, respectively, and if no ovulation was detected between the first PGF_2α and second GnRH injections during resynchronization. In experiment 1, the proportion of cows detected in estrus at AI was greater for COS72 than OVS56 (40.6 vs. 32.4%). Pregnancy per AI (P/AI) did not differ between OVS56 (46.4%) and COS72 (45.5%). In experiment 2, cows supplemented with progesterone had greater P/AI compared with unsupplemented cows (51.3 vs. 43.1%). Premature ovulation tended to be greater for RCON than RCIDR cows (7.5 vs. 3.6%), although synchronization of the estrous cycle after timed AI was similar between treatments. Timing of induction of ovulation with GnRH relative to insemination did not affect P/AI of dairy cows enrolled in a 5-d timed AI program. Furthermore, during resynchronization starting on d 34 after the first AI, supplementation with progesterone improved P/AI in cows subjected to the 5-d timed AI protocol.     

Use of Spreadsheets as an Introductory Tool for Solving Fluid-Structure Interaction Problem

A simple and intuitive manner for solving fluid-structure interaction problem has been developed using Microsoft Excel spreadsheets. By eliminating the need of previous knowledge of any programming language, the method appears as an interesting introduction to numerical solutions of partial differential equations, due to the direct and didactic way that it is developed. Proposed procedure enables the analysis of tridimensional geometries using the finite difference method and can be extended to other differential equations or boundary conditions. The author＇s objective in this paper is to develop a simple and reliable preliminary method for solving acoustic fluid-structure interaction problems with application to dam-reservoir interaction phenomena and also contribute in the educational growth for undergraduate students that are beginning research in such matter.     

Effect of APE1 T2197G (Asp148Glu) Polymorphism on APE1, XRCC1, PARP1 and OGG1 Expression in Patients with Colorectal Cancer

It has been hypothesized that genetic variation in base excision repair (BER) might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients with colorectal cancer. The results indicate a downregulation of OGG1 and an upregulation of XRCC1 expression in tumor tissue. Regarding the anatomical location of APE1, OGG1 and PARP-1, a decrease in gene expression was observed among patients with cancer in the rectum. In patients with or without some degree of tumor invasion, a significant downregulation in OGG1 was observed in tumor tissue. Interestingly, when taking into account the tumor stage, patients with more advanced grades (III and IV) showed a significant repression for APE1, OGG1 and PARP-1. XRCC1 expression levels were significantly enhanced in tumor samples and were correlated with all clinical and histopathological data. Concerning the polymorphism T2197G, GG genotype carriers exhibited a significantly reduced expression of genes of the BER repair system (APE1, XRCC1 and PARP1). In summary, our data show that patients with colorectal cancer present expression changes in several BER genes, suggesting a role for APE1, XRCC1, PARP1 and OGG1 and APE1 polymorphism in colorectal carcinogenesis.     

Differentiated Patterns of Legume Sensitisation in Peanut-Allergic Patients

Patients with peanut allergy are often serologically sensitised to other legumes. If primary peanut allergy was contracted, secondary allergies to other legume plants may develop. The cross-sensitisation implies an enhanced risk of food-related anaphylaxis for the patients even if its clinical relevance is under discussion. In the present study, 32 patients with anti-peanut immunoglobulin E-levels (IgE) of at least class 1 according to the ImmunoCap™ classification system were included. The patients had been referred to the Norwegian National Register and Reporting System for Severe Allergic Reactions to Food with histories of anaphylaxis by the consumption of legume-containing foods. The patient sera were analysed for IgE that reacted to peanut (Arachis hypogea), soybean (Glycine max), pea (Pisum sativum), lupin (Lupinus albus) and fenugreek (Trigonella foenum graecum). Immunoblot experiments were performed using extracts of in total eight different legume plants. IgE measurements and blot analyses revealed differentiated patterns of legume sensitisation. One third of the patients had anti-peanut IgE class 4 to 6. In contrast, just one patient had specific IgE higher than class 4 to respectively pea, soybean and fenugreek. However, ten patients had elevated anti-fenugreek IgE (≥class 3), significantly more than for the other legumes. The second highest levels were found for soybean, followed by pea and lupin. The immunoblots showed particularly strong IgE binding to proteins at 12, 22, 30, 36 and 50 kDa for all legumes, indicating that the major peanut allergens Ara h 1, Ara h 2 and Ara h 3 are strong candidates for causing cross-sensitivity.     

Conformational Stabilization of Gp41-Mimetic Miniproteins Opens Up New Ways of Inhibiting HIV-1 Fusion

Inhibition of the HIV-1 fusion process constitutes a promising strategy to neutralize the virus at an early stage before it enters the cell. In this process, the envelope glycoprotein (Env) plays a central role by promoting membrane fusion. We previously identified a vulnerability at the flexible C-terminal end of the gp41 C-terminal heptad repeat (CHR) region to inhibition by a single-chain miniprotein (named covNHR-N) that mimics the first half of the gp41 N-terminal heptad repeat (NHR). The miniprotein exhibited low stability, moderate binding to its complementary CHR region, both as an isolated peptide and in native trimeric Envs, and low inhibitory activity against a panel of pseudoviruses. The addition of a disulfide bond stabilizing the miniprotein increased its inhibitory activity, without altering the binding affinity. Here, to further study the effect of conformational stability on binding and inhibitory potency, we additionally stabilized these miniproteins by engineering a second disulfide bond stapling their N-terminal end, The new disulfide-bond strongly stabilizes the protein, increases binding affinity for the CHR target and strongly improves inhibitory activity against several HIV-1 strains. Moreover, high inhibitory activity could be achieved without targeting the preserved hydrophobic pocket motif of gp41. These results may have implications in the discovery of new strategies to inhibit HIV targeting the gp41 CHR region.     

Parallel discovery of network motifs

Many natural structures can be naturally represented by complex networks. Discovering network motifs, which are overrepresented patterns of inter-connections, is a computationally hard task related to graph isomorphism. Sequential methods are hindered by an exponential execution time growth when we increase the size of motifs and networks. In this article we study the opportunities for parallelism in existing methods and propose new parallel strategies that adapt and extend one of the most efficient serial methods known from the Fanmod tool. We propose both a master–worker strategy and one with distributed control, in which we employ a randomized receiver initiated methodology capable of providing dynamic load balancing during the whole computation process. Our strategies are capable of dealing both with exact and approximate network motif discovery. We implement and apply our algorithms to a set of representative networks and examine their scalability up to 128 processing cores. We obtain almost linear speedups, showcasing the efficiency of our proposed approach and are able to reach motif sizes that were not previously achievable using conventional serial algorithms.