The prebiotic landscape: history, health and physiological benefits, and regulatory challenges - an IPA perspective part 1.

Prebiotics are becoming increasingly recognized by consumers, health care professionals and regulators as important contributors to health. Nonetheless, the development, progress, and adoption of prebiotics is hindered by loose terminology, various misconceptions about sources and types of compounds that may be classified as prebiotics, and the lack of consensus on a definition that satisfies regulators. Evolving knowledge of the microbiome and its effects on host health has generated opportunities for modulation of the microbiota that can support host health.

Geldanamycin-Induced Morphological Changes Require Candida albicans Hyphal Growth Regulatory Machinery.

In Candida albicans, geldanamycin treatment inhibits the essential chaperone Hsp90 and induces a change from yeast to filamentous morphology, likely by impeding cell cycle progression and division. However, filaments formed by wild-type cells upon geldanamycin exposure are quite different in appearance from true hyphae. We have observed that effects on morphology caused by geldanamycin treatment appear to vary in strains with defects in different morphological regulators.

Global Transcriptomic Analysis of the Candida albicans Response to Treatment with a Novel Inhibitor of Filamentation.

The opportunistic pathogenic fungus can cause devastating infections in immunocompromised patients. Its ability to undergo a morphogenetic transition from yeast to filamentous forms allows it to penetrate tissues and damage tissues, and the expression of genes associated with a number of pathogenetic mechanisms is also coordinately regulated with the yeast-to-hypha conversion. Therefore, it is widely considered that filamentation represents one of the main virulence factors of We have previously identified -[3-(allyloxy)-phenyl]-4-methoxybenzamide (compound 9029936) as the lead compound in a series of small-molecule inhibitors of filamentation and characterized its activity both and This compound appears to be a promising candidate for the development of alternative antivirulence strategies for the treatment of infections.

Contributions of Candida albicans Dimorphism, Adhesive Interactions, and Extracellular Matrix to the Formation of Dual-Species Biofilms with Streptococcus gordonii.

Fungal and bacterial populations coexist in the oral cavity, frequently forming mixed-species biofilms that complicate treatment against polymicrobial infections. However, despite relevance to oral health, the bidirectional interactions between these microbial populations are poorly understood. In this study, we aimed to elucidate the mechanisms underlying the interactions between the fungal species and the bacterial species as they coexist in mixed-species biofilms.

Morphology-Dependent Host FGF-2 Response as a Potential Therapeutic Target.

Angiogenesis mediated by proteins such as Fibroblast Growth Factor-2 (FGF-2) is a vital component of normal physiological processes and has also been implicated in contributing to the disease state associated with various microbial infections. Previous studies by our group and others have shown that , a common agent of candidiasis, induces FGF-2 secretion in vitro and angiogenesis in brains and kidneys during systemic infections. However, the underlying mechanism(s) via which the fungus increases FGF-2 production and the role(s) that FGF-2/angiogenesis plays in disease remain unknown.

Role of the Fractalkine Receptor in CNS Autoimmune Inflammation: New Approach Utilizing a Mouse Model Expressing the Human CX3CR1 Variant.

Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS) is the leading cause of non-traumatic neurological disability in young adults. Immune mediated destruction of myelin and oligodendrocytes is considered the primary pathology of MS, but progressive axonal loss is the major cause of neurological disability. In an effort to understand microglia function during CNS inflammation, our laboratory focuses on the fractalkine/CX3CR1 signaling as a regulator of microglia neurotoxicity in various models of neurodegeneration.

Characterization of a Biaryl Amide Anti-virulence Compound Targeting Filamentation and Biofilm Formation.

We have previously identified a small molecule compound, N-[3-(allyloxy)-phenyl]-4-methoxybenzamide (9029936), that exerts potent inhibitory activity against filamentation and biofilm formation by the SC5314 strain and represents a lead candidate for the development of anti-virulence approaches against infections. Here we present data from a series of experiments to further characterize its activity and drug-like characteristics. We demonstrate the activity of this compound against a panel of clinical isolates, including several displaying resistance to current antifungals; as well as against a set of gain of function strains in key transcriptional regulators of antifungal drug resistance.

Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Filamentation.

remains the main etiologic agent of candidiasis, the most common fungal infection and now the third most frequent infection in U.S. hospitals.

Targeting Candida albicans filamentation for antifungal drug development.

Candida albicans remains the main etiological agent of candidiasis, as this otherwise normal commensal of humans is capable of causing active infection in immune- and medically-compromised patients. The high morbidity and mortality rates associated with candidiasis, coupled with the emergence of drug resistance demand the development of novel therapeutic strategies. However, there is a paucity of selective targets that can be exploited in the development of new antifungals.

Examination of the pathogenic potential of Candida albicans filamentous cells in an animal model of haematogenously disseminated candidiasis.

The opportunistic fungal pathogen Candida albicans is an increasingly common threat to human health. Candida albicans grows in several morphologies and mutant strains locked in yeast or filamentous forms have attenuated virulence in the murine model of disseminated candidiasis. Thus, the ability to change shape is important for virulence.

A Novel Small Molecule Inhibitor of Biofilm Formation, Filamentation and Virulence with Low Potential for the Development of Resistance.

Background/objectives: is the principal causative agent of candidiasis, the most common fungal infection in humans. Candidiasis represents the third-to-fourth most frequent nosocomial infection worldwide, as this normal commensal of humans causes opportunistic infections in an expanding population of immune- and medically-compromised patients. These infections are frequently associated with biofilm formation, which complicates treatment and contributes to unacceptably high mortality rates.

The formation of linear aggregates in magnetic hyperthermia: implications on specific absorption rate and magnetic anisotropy.

The design and application of magnetic nanoparticles for use as magnetic hyperthermia agents has garnered increasing interest over the past several years. When designing these systems, the fundamentals of particle design play a key role in the observed specific absorption rate (SAR). This includes the particle's core size, polymer brush length, and colloidal arrangement.

High-content phenotypic screenings to identify inhibitors of Candida albicans biofilm formation and filamentation.

Candida species represent the main cause of opportunistic fungal infections worldwide, and Candida albicans remains the most common etiological agent of candidiasis, now the third to fourth most common nosocomial infection. These infections are typically associated with high morbidity and mortality, mainly due to the limited efficacy of current antifungal drugs. In C.

Discrete nanoparticles induce loss of Legionella pneumophila biofilms from surfaces.

Nanoparticles (NPs) have been shown to induce dispersal events in microbial biofilms but the mechanism of the dispersal is unknown. Biofilms contaminate many man-made aquatic systems such as cooling towers, spas and dental lines. Within these biofilms, Legionella pneumophila is a primary pathogen, leading to these environments serving as sources for disease outbreaks.

The effect of magnetically induced linear aggregates on proton transverse relaxation rates of aqueous suspensions of polymer coated magnetic nanoparticles.

It has been recently reported that for some suspensions of magnetic nanoparticles the transverse proton relaxation rate, R(2), is dependent on the time that the sample is exposed to an applied magnetic field. This time dependence has been linked to the formation of linear aggregates or chains in an applied magnetic field via numerical modeling. It is widely known that chain formation occurs in more concentrated ferrofluids systems and that this has an affect on the ferrofluid properties.

BRG1 and NRG1 form a novel feedback circuit regulating Candida albicans hypha formation and virulence.

In the opportunistic fungal pathogen Candida albicans both cellular morphology and the capacity to cause disease are regulated by the transcriptional repressor Nrg1p. One of the genes repressed by Nrg1p is BRG1, which encodes a putative GATA family transcription factor. Deletion of both copies of this gene prevents hypha formation.

Investigating the function of Ddr48p in Candida albicans.

Candidiasis now represents the fourth most frequent nosocomial infection both in the United States and worldwide. Candida albicans is an increasingly common threat to human health as a consequence of AIDS, steroid therapy, organ and tissue transplantation, cancer therapy, broad-spectrum antibiotics, and other immune defects. The pathogenic potential of C.

Validation of the tetracycline regulatable gene expression system for the study of the pathogenesis of infectious disease.

Understanding the pathogenesis of infectious disease requires the examination and successful integration of parameters related to both microbial virulence and host responses. As a practical and powerful method to control microbial gene expression, including in vivo, the tetracycline-regulatable system has recently gained the favor of many investigative groups. However, some immunomodulatory effects of the tetracyclines, including doxycycline, could potentially limit its use to evaluate host responses during infection.

Candida albicans adhesin Als3p is dispensable for virulence in the mouse model of disseminated candidiasis.

The presence of specific proteins, including Ece1p, Hwp1p and Als3p, distinguishes the Candida albicans hyphal cell wall from that of yeast-form cells. These proteins are thought to be important for the ability of C. albicans cells to adhere to living and non-living surfaces and for the cell-to-cell adhesion necessary for biofilm formation, and also to be pivotal in mediating C.

Evaluation of tissue engineered models of the oral mucosa to investigate oral candidiasis.

Candida albicans is a commensal organism that can be isolated from the majority of healthy individuals. However, in certain susceptible individuals C. albicans can become pathogenic leading to the mucocutaneous infection; oral candidiasis.

The transcriptional regulator Nrg1p controls Candida albicans biofilm formation and dispersion.

The ability of Candida albicans to reversibly switch morphologies is important for biofilm formation and dispersion. In this pathogen, Nrg1p functions as a key negative regulator of the yeast-to-hypha morphogenetic transition. We have previously described a genetically engineered C.

Pseudohyphal regulation by the transcription factor Rfg1p in Candida albicans.

The opportunistic human fungal pathogen Candida albicans is a major cause of nosocomial infections. One of the fundamental features of C. albicans pathogenesis is the yeast-to-hypha transition.

An analysis of the impact of NRG1 overexpression on the Candida albicans response to specific environmental stimuli.

The ability of the opportunistic fungal pathogen Candida albicans to form filaments has been strongly linked to its capacity to cause disease in humans. We previously described the construction of a strain in which filamentation can be modulated both in vitro and in vivo by placing one copy of the NRG1 gene under the control of a tetracycline-regulatable promoter. To further characterize the role of NRG1 in controlling filamentous growth, and in an attempt to determine whether NRG1 downregulation is a requirement for filamentation per se, or is only necessary under certain environmental conditions, we have conducted an analysis of the growth of the tet-NRG1 strain under a variety of in vitro conditions.

Adhesion of Candida albicans to endothelial cells under physiological conditions of flow.

Candida albicans is a commensal organism that under certain circumstances can become pathogenic. During systemic infection C. albicans is disseminated via the circulation to distant organs, where it causes multiple organ failure.

Efficacy of a genetically engineered Candida albicans tet-NRG1 strain as an experimental live attenuated vaccine against hematogenously disseminated candidiasis.

We report on the efficacy of the genetically engineered Candida albicans tet-NRG1 strain as an experimental live, attenuated vaccine against disseminated candidiasis in both immunocompetent and immunodeficient mice mostly dependent on T-cell immunity. This experimental vaccination model may represent an important tool to unravel the mechanisms of protective immunity during candidiasis.