Transcriptomic analysis of synergy between antifungal drugs and iron chelators for alternative antifungal therapies

There is an urgent need to improve the efficacy and range of antifungal drugs due to a global increase in invasive fungal infections, which are difficult to treat and are associated with high rates of mortality. Developing new drugs is expensive and time consuming and synergistic therapies that enhance the efficacy of current drugs are an alternative approach. Iron chelators have been used as antifungal synergents in salvage therapy, however, how these cause synergy are unknown. This thesis aims to use a transcriptomic approach to understand the mechanistic detail of antifungal-chelator synergy in the pathogen Cryptococcus to find potential antifungal targets. It focuses on amphotericin B (AMB) and lactoferrin (LF) synergy and voriconazole (VRC) and EDTA antagonism upon screening the interactions of various antifungal - chelator combinations in Cryptococcus. LF was found to enhance the antifungal effect of AMB in two ways: via the dysregulation of stress responses and metal homeostasis that disrupted the cell’s ability to mount an appropriate stress response, and by overwhelming the cell’s stress response via the cumulative strain from ER stress, disruption of transmembrane transport processes and increased metal dysregulation. Metal homeostasis was vital to both processes and the direct disruption of metal homeostasis, via deletion of iron (Aft1, Cir1 and HapX) and zinc (Zap1 and Zap104) regulating transcription factors, resulted in increased AMB susceptibility. Analysis of drug-binding domains in Zap1 and Zap104 found these to contain druggable sites and be potential antifungal drug targets. EDTA in the presence of VRC was found to disrupt mitochondrial functions along with an up-regulation of drug efflux genes, suggesting a potential mechanism of antagonism by mediating the efflux of intracellular VRC. Overall, metal regulation is important for resisting antifungal stress and is a potential antifungal strategy, where Zap1 is a potential antifungal drug target

Decomposition of Lagrangian classes on K3 surfaces

We study the decomposability of a Lagrangian homology class on a K3 surface into a sum of classes represented by special Lagrangian submanifolds, and develop criteria for it in terms of lattice theory. As a result, we prove the decomposability on an arbitrary K3 surface with respect to the Kähler classes in dense subsets of the Kähler cone. Using the same technique, we show that the Kähler classes on a K3 surface which admit a special Lagrangian fibration form a dense subset also. This implies that there are infinitely many special Lagrangian 3-tori in any log Calabi-Yau 3-fold.https://arxiv.org/abs/2001.00202Othe

Boundary complexity and surface entropy of 2-multiplicative integer systems on Nd\mathbb{N}^d

In this article, we introduce the concept of the boundary complexity and prove that for a 2-multiplicative integer system (2-MIS) $X^{p}_{\Omega}$ on $\mathbb{N}$ (or $X^{\bf p}_{\Omega}$ on $\mathbb{N}^d,d\geq 2$), every point in $[h(X^p_\Omega), \log r]$ can be realized as a boundary complexity of a 2-MIS with a specific speed, where r stands for the number of the alphabets. The result is new and quite different from $\mathbb{N}^d$ subshifts of finite type (SFT) for $d\geq 1$. Furthermore, the rigorous formula of surface entropy for a $\mathbb{N}^d$ 2-MIS is also presented. This provides an efficient method to calculate the topological entropy for $\mathbb{N}^d$ 2-MIS and also provides an intrinsic differences between $\mathbb{N}^d$ $k$-MIS and SFTs for $d\geq 1$ and $k\geq 2$