Enniatin and Beauvericin Biosynthesis in Fusarium Species: Production Profiles and Structural Determinant Prediction

Citation: Liuzzi, V. C., Mirabelli, V., Cimmarusti, M. T., Haidukowski, M., Leslie, J. F., Logrieco, A. F., . . . Mule, G. (2017). Enniatin and Beauvericin Biosynthesis in Fusarium Species: Production Profiles and Structural Determinant Prediction. Toxins, 9(2), 17. doi:10.3390/toxins9020045Members of the fungal genus Fusarium can produce numerous secondary metabolites, including the nonribosomal mycotoxins beauvericin (BEA) and enniatins (ENNs). Both mycotoxins are synthesized by the multifunctional enzyme enniatin synthetase (ESYN1) that contains both peptide synthetase and S-adenosyl-L-methionine-dependent N-methyltransferase activities. Several Fusarium species can produce ENNs, BEA or both, but the mechanism(s) enabling these differential metabolic profiles is unknown. In this study, we analyzed the primary structure of ESYN1 by sequencing esyn1 transcripts from different Fusarium species. We measured ENNs and BEA production by ultra-performance liquid chromatography coupled with photodiode array and Acquity QDa mass detector (UPLC-PDA-QDa) analyses. We predicted protein structures, compared the predictions by multivariate analysis methods and found a striking correlation between BEA/ENN-producing profiles and ESYN1 three-dimensional structures. Structural differences in the beta strand's Asn789-Ala793 and His797-Asp802 portions of the amino acid adenylation domain can be used to distinguish BEA/ENN-producing Fusarium isolates from those that produce only ENN

Gut mobilization improves behavioral symptoms and modulates urinary p-cresol in chronically constipated autistic children: A prospective study

Chronic constipation is common among children with ASD and is associated with more severe hyperactivity, anxiety, irritability, and repetitive behaviors. Young autistic children with chronic constipation display higher urinary, and foecal concentrations of p-cresol, an aromatic compound produced by gut bacteria, known to negatively affect brain function. Acute p-cresol administration to BTBR mice enhances anxiety, hyperactivity and stereotypic behaviors, while blunting social interaction. This study was undertaken to prospectively assess the behavioral effects of gut mobilization in young autistic children with chronic constipation, and to verify their possible correlation with urinary p-cresol. To this aim, 21 chronically constipated autistic children 2–8 years old were evaluated before (T0), 1 month (T1), and 6 months (T2) after intestinal mobilization, recording Bristol stool scale scores, urinary p-cresol concentrations, and behavioral scores for social interaction deficits, stereotypic behaviors, anxiety, and hyperactivity. Gut mobilization yielded a progressive and highly significant decrease in all behavioral symptoms over the 6-month study period. Urinary p-cresol levels displayed variable trends not significantly correlated with changes in behavioral parameters, mainly increasing at T1 and decreasing at T2. These results support gut mobilization as a simple strategy to ameliorate ASD symptoms, as well as comorbid anxiety and hyperactivity, in chronically constipated children. Variation in p-cresol absorption seemingly provides limited contributions, if any, to these behavioral changes. Further research will be needed to address the relative role of reduced abdominal discomfort following mobilization, as compared to specific modifications in microbiome composition and in gut bacteria-derived neuroactive compounds

Photons, neutrinos and large compact space dimensions

We compute the contribution of Kaluza-Klein graviton exchange to the cross section for photon-neutrino scattering. Unlike the usual situation where the virtual graviton exchange represents a small correction to a leading order electroweak or strong amplitude, in this case the graviton contribution is of the same order as the electroweak amplitude, or somewhat larger. Inclusion of the graviton contribution is not sufficient to allow high energy neutrinos to scatter from relic neutrinos in processes such as $\nu\bar{\nu}\to\gamma\gamma$, but the photon-neutrino decoupling temperature is substantially reduced.Comment: 8 pages, 3 figures LaTeX. Typos correcte

Supersymmetric Brane World Scenarios from Off-Shell Supergravity

Using N=2 off-shell supergravity in five dimensions, we supersymmetrize the brane world scenario of Randall and Sundrum. We extend their construction to include supersymmetric matter at the fixpoints.Comment: 15 pages, no figures, late

Mediation of supersymmetry breaking in extra dimensions

We review the mechanisms of supersymmetry breaking mediation that occur in sequestered models, where the visible and the hidden sectors are separated by an extra dimension and communicate only via gravitational interactions. By locality, soft breaking terms are forbidden at the classical level and reliably computable within an effective field theory approach at the quantum level. We present a self-contained discussion of these radiative gravitational effects and the resulting pattern of soft masses, and give an overview of realistic model building based on this set-up. We consider both flat and warped extra dimensions, as well as the possibility that there be localized kinetic terms for the gravitational fields.Comment: LaTex, 15 pages; brief review prepared for MPLA. v2: minor correction

Towards 5D Grand Unification without SUSY Flavor Problem

We consider the renormalization group approach to the SUSY flavor problem in the supersymmetric SU(5) model with one extra dimension. In higher dimensional SUSY gauge theories, it has been recently shown that power corrections due to the Kaluza-Klein states of gauge fields run the soft masses generated at the orbifold fixed point to flavor conserving values in the infra-red limit. In models with GUT breaking at the brane where the GUT scale can be larger than the compactification scale, we show that the addition of a bulk Higgs multiplet, which is necessary for the successful unification, is compatible with the flavor universality achieved at the compactification scale.Comment: JHEP style file of 35 pages with 3 figures, Version to appear in JHE

Whole-Exome and Transcriptome Sequencing Expands the Genotype of Majewski Osteodysplastic Primordial Dwarfism Type II

Microcephalic Osteodysplastic Primordial Dwarfism type II (MOPDII) represents the most common form of primordial dwarfism. MOPD clinical features include severe prenatal and postnatal growth retardation, postnatal severe microcephaly, hypotonia, and an increased risk for cerebrovascular disease and insulin resistance. Autosomal recessive biallelic loss-of-function genomic variants in the centrosomal pericentrin (PCNT) gene on chromosome 21q22 cause MOPDII. Over the past decade, exome sequencing (ES) and massive RNA sequencing have been effectively employed for both the discovery of novel disease genes and to expand the genotypes of well-known diseases. In this paper we report the results both the RNA sequencing and ES of three patients affected by MOPDII with the aim of exploring whether differentially expressed genes and previously uncharacterized gene variants, in addition to PCNT pathogenic variants, could be associated with the complex phenotype of this disease. We discovered a downregulation of key factors involved in growth, such as IGF1R, IGF2R, and RAF1, in all three investigated patients. Moreover, ES identified a shortlist of genes associated with deleterious, rare variants in MOPDII patients. Our results suggest that Next Generation Sequencing (NGS) technologies can be successfully applied for the molecular characterization of the complex genotypic background of MOPDII

Supergravity loop contributions to brane world supersymmetry breaking

We compute the supergravity loop contributions to the visible sector scalar masses in the simplest 5D `brane-world' model. Supersymmetry is assumed to be broken away from the visible brane and the contributions are UV finite due to 5D locality. We perform the calculation with N = 1 supergraphs, using a formulation of 5D supergravity in terms of N = 1 superfields. We compute contributions to the 4D effective action that determine the visible scalar masses, and we find that the mass-squared terms are negative.Comment: 12 pages, LaTeX 2

Fermion Mass Hierarchies and Small Mixing Angles from Extra Dimensions

In this paper we study renormalization-group evolutions of Yukawa matrices enhanced by Kaluza-Klein excited modes and analyze their infrared fixed-point structure. We derive necessary conditions to obtain hierarchies between generations on the fixed point. These conditions restrict how the fields in the models can extend to higher dimension. Several specific mechanisms to realize the conditions are presented. We also take account of generation mixing effects and find a scenario where the mixing angles become small at low energy even with large initial values at high-energy scale. A toy model is shown to lead realistic quark mass matrices.Comment: 23 pages, 7 figures, LaTeX, a supplementary explanation and references adde