Chemoproteomic Profiling of for Characterization of Anti-fungal Kinase Inhibitors.

is a growing health concern as the leading causal agent of systemic candidiasis, a life-threatening fungal infection with a mortality rate of ∼40% despite best available therapy. Yck2, a fungal casein kinase 1 (CK1) family member, is the cellular target of inhibitors YK-I-02 (YK) and MN-I-157 (MN). Here, multiplexed inhibitor beads paired with mass spectrometry (MIB/MS) employing ATP-competitive kinase inhibitors were used to define the selectivity of these Yck2 inhibitors across the global proteome.

Butyrolactol A is a phospholipid flippase inhibitor that potentiates the bioactivity of caspofungin against resistant fungi.

Fungal infections cause millions of deaths annually and are challenging to treat due to limited antifungal options and increasing drug resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while , a notorious global threat, is also increasingly resistant. We performed a natural product extract screen for rescue of the activity of the echinocandin caspofungin against H99, identifying butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including .

Model selection and model robustness for population size estimation in two-sample capture-recapture studies.

Two-sample capture-recapture studies are commonly used in the epidemiological and ecological literature. Most of these studies have been limited to analysis using the Lincoln-Petersen estimator, especially in epidemiological studies. We examine the use of the Lincoln-Petersen estimator and two alternative closed-population methods: Huggins' conditional likelihood method and Pledger's likelihood method with mixtures.

The Cryptococcus neoformans STRIPAK complex controls genome stability, sexual development, and virulence.

The eukaryotic serine/threonine protein phosphatase PP2A is a heterotrimeric enzyme composed of a scaffold A subunit, a regulatory B subunit, and a catalytic C subunit. Of the four known B subunits, the B"' subunit (known as striatin) interacts with the multi-protein striatin-interacting phosphatase and kinase (STRIPAK) complex. Orthologs of STRIPAK components were identified in Cryptococcus neoformans, namely PP2AA/Tpd3, PP2AC/Pph22, PP2AB/Far8, STRIP/Far11, SLMAP/Far9, and Mob3.

Decoding the Functional Interactome of Non-Model Organisms with PHILHARMONIC.

Protein-protein interaction (PPI) networks are a fundamental resource for modeling cellular and molecular function, and a large and sophisticated toolbox has been developed to leverage their structure and topological organization to predict the functional roles of under-studied genes, proteins, and pathways. However, the overwhelming majority of experimentally-determined interactions from which such networks are constructed come from a small number of well-studied model organisms. Indeed, most species lack even a single experimentally-determined interaction in these databases, much less a network to enable the analysis of cellular function, and methods for computational PPI prediction are too noisy to apply directly.

Approximate IsoRank for Scalable and Functionally Meaningful Cross-Species Alignments of Protein Interaction Networks.

The IsoRank algorithm of Singh, Xu, and Berger was a pioneering algorithmic advance that applied spectral methods to the problem of cross-species global alignment of biological networks. We develop a new IsoRank approximation that exploits the mathematical properties of IsoRank's linear system to solve the problem in quadratic time with respect to the maximum size of the two protein-protein interaction (PPI) networks. We further propose a refinement to this initial approximation so that the updated result is even closer to the original IsoRank formulation while remaining computationally inexpensive.

The STRIPAK complex controls genome stability, sexual development, and virulence.

The eukaryotic serine/threonine protein phosphatase PP2A is a heterotrimeric enzyme composed of a scaffold A subunit, a regulatory B subunit, and a catalytic C subunit. Of the four known B subunits, the B"' subunit (known as striatin) interacts with the multi-protein striatin-interacting phosphatase and kinase (STRIPAK) complex. Orthologs of STRIPAK components were identified in , namely PP2AA/Tpd3, PP2AC/Pph22, PP2AB/Far8, STRIP/Far11, SLMAP/Far9, and Mob3.

Protocol to evaluate translation inhibition in Candida species using fluorescence microscopy and flow cytometry.

Translation inhibitors have therapeutic potential against Candida species. Here, we present a protocol to measure translation inhibition in Candida spp. We describe steps for employing an alkynylated methionine analog, L-homopropargylglycine (HPG), that becomes incorporated into newly synthesized proteins.

The spliceosome impacts morphogenesis in the human fungal pathogen .

At human body temperature, the fungal pathogen can transition from yeast to filamentous morphologies in response to host-relevant cues. Additionally, elevated temperatures encountered during febrile episodes can independently induce filamentation. However, the underlying genetic pathways governing this developmental transition in response to elevated temperatures remain largely unexplored.

The putative prenyltransferase Nus1 is required for filamentation in the human fungal pathogen Candida albicans.

Candida albicans is a major fungal pathogen of humans that can cause serious systemic infections in vulnerable immunocompromised populations. One of its virulence attributes is its capacity to transition between yeast and filamentous morphologies, but our understanding of this process remains incomplete. Here, we analyzed data from a functional genomic screen performed with the C.

Interdisciplinary approaches for the discovery of novel antifungals.

Pathogenic fungi are an increasing public health concern. The emergence of antifungal resistance coupled with the scarce antifungal arsenal highlights the need for novel therapeutics. Fortunately, the past few years have witnessed breakthroughs in antifungal development.

Allosteric inhibition of tRNA synthetase Gln4 by N-pyrimidinyl-β-thiophenylacrylamides exerts highly selective antifungal activity.

Candida species are among the most prevalent causes of systemic fungal infections, which account for ∼1.5 million annual fatalities. Here, we build on a compound screen that identified the molecule N-pyrimidinyl-β-thiophenylacrylamide (NP-BTA), which strongly inhibits Candida albicans growth.

A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen .

, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandins. Alarmingly, the efficacy of these antifungals against is hindered both by basal tolerance toward the drugs and the development of resistance mechanisms such as alterations of the drug's target, modulation of stress responses, and overexpression of efflux pumps.

Characterizing transcriptomic responses to sediment stress across location and morphology in reef-building corals.

Anthropogenic activities increase sediment suspended in the water column and deposition on reefs can be largely dependent on colony morphology. Massive and plating corals have a high capacity to trap sediments, and active removal mechanisms can be energetically costly. Branching corals trap less sediment but are more susceptible to light limitation caused by suspended sediment.

Insulin signaling and pharmacology in humans and in corals.

Once thought to be a unique capability of the Langerhans islets in the pancreas of mammals, insulin (INS) signaling is now recognized as an evolutionarily ancient function going back to prokaryotes. INS is ubiquitously present not only in humans but also in unicellular eukaryotes, fungi, worms, and . Remote homologue identification also supports the presence of INS and INS receptor in corals where the availability of glucose is largely dependent on the photosynthetic activity of the symbiotic algae.

Advancements and challenges in antifungal therapeutic development.

Over recent decades, the global burden of fungal disease has expanded dramatically. It is estimated that fungal disease kills approximately 1.5 million individuals annually; however, the true worldwide burden of fungal infection is thought to be higher due to existing gaps in diagnostics and clinical understanding of mycotic disease.

Respiration supports intraphagosomal filamentation and escape of from macrophages.

is a leading human fungal pathogen that often causes life-threatening infections in immunocompromised individuals. The ability of to transition between yeast and filamentous forms is key to its virulence, and this occurs in response to many host-relevant cues, including engulfment by host macrophages. While previous efforts identified genes required for filamentation in other conditions, the genes important for this morphological transition upon internalization by macrophages remained largely enigmatic.