Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism

The exposure to adverse environmental conditions (e.g., poor nutrition) may lead to increased disease risk in an individual and their descendants. In some cases, the results may be sexually dimorphic. A range of phenotypes has been associated with deficiency in or defective metabolism of the vitamin folate. However, the molecular mechanism linking folate metabolism to development is still not well defined nor is it clear whether phenotypes are sex-specific. The enzyme methionine synthase reductase (MTRR) is required for the progression of folate metabolism and the utilization of methyl groups from the folate cycle. Previously, we showed that the hypomorphic Mtrrgt mutation in mice results in metabolic disruption, epigenetic instability, and a wide spectrum of developmental phenotypes (e.g., growth defects, congenital malformations) at midgestation that appear in subsequent wildtype generations. This transgenerational effect only occurs through the maternal lineage. Here, we explore whether the phenotypes that result from either intrinsic or ancestral Mtrr deficiency are sexually dimorphic. We found that no sexual dimorphism is apparent in either situation when the phenotypes were broadly or specifically defined. However, when we focused on the group of phenotypically normal conceptuses derived from maternal grandparental Mtrr deficiency, we observed an apparent increase in placental efficiency in each subsequent generation leading to F4 generation female embryos that weigh more than controls. These data suggest that ancestral abnormal folate metabolism may lead to male grandprogeny that are less able to adapt or female grandprogeny that are programmed to become more sensitive to folate availability in subsequent generations.The following support was given: a Centre for Trophoblast Research (CTR) studentship to N.P., a Royal Society Newton International Fellowship to J.R., a Newnham College (Cambridge) studentship to K.M, and a Wellcome Trust 4-year PhD studentship in Developmental Mechanisms to G.E.T.B. This work was funded by a CTR Next Generation Fellowship, a Lister Research Prize, and an Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge joint research grant (to E.D.W.)

Fusion Rules of the Lowest Weight Representations of osp_q(1|2) at Roots of Unity: Polynomial Realization and Degeneration at Roots of Unity

The degeneracy of the lowest weight representations of the quantum superalgebra $osp_q(1|2)$ and their tensor products at exceptional values of %when deformation parameter $q$ takes exceptional values is studied. The main features of the structures of the finite dimensional lowest weight representations and their fusion rules are illustrated using realization of group generators as finite-difference operators acting in the space of the polynomials. The complete fusion rules for the decompositions of the tensor products at roots of unity are presented. The appearance of indecomposable representations in the fusions is described using Clebsh-Gordan coefficients derived for general values of $q$ and at roots of unity.Comment: 28 pages, 3 figures; completed (section 5, section 6); version published in JP

Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane C-type Lectin Receptors

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes

3D modeling of transport of excavated material in the open pit mines in the FlexSim program - cyclical operation of dump trucks

Model symulacyjny został wykonany na podstawie istniejącej kopalni, będącej własnością prywatnej spółki. Utworzony model zawierał elementy grafiki 3D odpowiadające maszynom i elementom przestrzeni mającym wpływ na udział czasowy poszczególnych składowych w cyklu wydobywczo-produkcyjnym. Przy użyciu narzędzi programu FlexSim zaprogramowano parametry logiczne i awarie maszyn, które uwzględniały straty czasowe związane z losowością harmonogramu pracy oraz niezawodnością. Symulacje zostały przeprowadzone dla zaprojektowanego modelu o określonych parametrach pracy 8-godzinnej i prawdopodobieństwie zdarzeń opartym na losowości uzyskanej przy zastosowaniu rozkładu normalnego. Modele stochastyczne polegały na tworzeniu różnych scenariuszy niezawodności maszyn oraz czasów załadunku i rozładunku. Przeprowadzone eksperymenty polegały na kilkukrotnej replikacji scenariusza opartego na rozkładzie prawdopodobieństwa ich wystąpienia poprzez modyfikację odchylenia standardowego.The simulation model has been performed based on an existing mine, owned by a private company. The created model contained elements of 3D graphics corresponding to machines and space’s elements having an impact on the time share of individual components in the mining and production cycle. Using the FlexSim’s tools, logical parameters and machine failures has been programmed, which took into account the time losses related to the randomness of the work schedule and reliability. The simulations have been carried out for a designed model with specific 8-hour operation parameters and event probability based on randomness obtained using a normal distribution. Stochastic models consisted in creating various scenarios of machine reliability as well as loading and unloading times. The experiments carried out consisted in several replicating the scenario based on the probability distribution of their occurrence by modifying the standard deviation