The use of the ketogenic diet in the treatment of psychiatric disorders

Introduction: The ketogenic diet (KD) is a high-fat, low-carbohydrate, and moderate-protein diet that has shown benefit as a treatment in neurologic disorders and may serve as a therapeutic option in individuals with psychiatric disorders. Methods: A search was conducted using EBSCOhost and PubMed databases for studies relating to ketogenic or low-carbohydrate diets and psychiatric disorders. Results: A total of 32 experimental or observational studies were identified by initial search strategies, 14 of which met the criteria to be included in this analysis. Although specific diet formulations varied somewhat between studies, they all generally examined low-carbohydrate dietary intake with the goal of producing a ketotic state. The studies included in this review indicated the KD was beneficial in reducing symptoms associated with various psychiatric disorders. Discussion: This review summarizes the available evidence regarding the efficacy of the ketogenic diet in psychiatric disease states. Data from the studies analyzed demonstrated a positive response in individuals who were able to remain on the diet, regardless of the disease state. However, there is a need for more data to clearly define the specific benefits the KD may provide

Sequences and draft annotations of computationally predicted proteins from Balamuthia mandrillaris

This file contains the sequences and draft annotations of computationally predicted proteins from Balamuthia mandrillaris. The sequences are reconstructed from RNA sequencing of logarithmic phase trophozoites, the infective form of the amoeba. Reads were quality filtered with Trimmomatic and assembled de-novo with Trinity v2.8 (k-mer=25) and Spades v3.13 (k-mer=29 and 33) after clipping of the adaptor sequences. Further, quality-filtered reads were aligned to the published B. mandrillaris genome LFUI01 with STAR v2.6 and assembled with Trinity. The three assemblies thus obtained were combined with EvidentialGene v19jan01 (EviGene) with BUSCO homology scores as input for the classifier. This data set consists of the EviGene ‘main’ proteins. FASTA headers are derived from the annotations predicted with blast2go or PANNZER2 if blast2go failed.This dataset is a byproduct of the study described in: The transcriptome of Balamuthia mandrillaris trophozoites for structure-based drug design. https://doi.org/10.1038/s41598-021-99903-8Balamuthia mandrillaris, a pathogenic free-living amoeba (FLA), causes cutaneous skin lesions as well as the brain-eating disease: Balamuthia granulomatous amoebic encephalitis (GAE). These diseases, and diseases caused by other pathogenic FLA, Naegleria fowleri or Acanthamoeba species, are minimally studied. Chemotherapies for CNS disease caused by B. mandrillaris require vast improvement. Current therapeutics are limited to a small number of drugs that were previously discovered in the last century through in vitro testing or identified after use in the small pool of surviving reports.Using our recently published methodology to identify potentially useful therapeutics, we screened a collection of 85 compounds that have previously been reported to have antiparasitic activity. We identified 59 compounds that impacted growth at concentrations below 220 µM. Since there is no fully annotated genome or proteome, we used RNA-Seq to determine the gene products of the specific genes potentially targeted by the compounds in B. mandrillaris trophozoites. We identified the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing

Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba.

Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brain's frontal lobes. The amoeba thrives in warm, freshwater environments, with peak infection rates in the summer months and has a mortality rate of approximately 97%. A major contributor to the pathogen's high mortality is the lack of sensitivity of N. fowleri to current drug therapies, even in the face of combination-drug therapy. To enable rational drug discovery and design efforts we have pursued protein production and crystallography-based structure determination efforts for likely drug targets from N. fowleri. The genes were selected if they had homology to drug targets listed in Drug Bank or were nominated by primary investigators engaged in N. fowleri research. In 2017, 178 N. fowleri protein targets were queued to the Seattle Structural Genomics Center of Infectious Disease (SSGCID) pipeline, and to date 89 soluble recombinant proteins and 19 unique target structures have been produced. Many of the new protein structures are potential drug targets and contain structural differences compared to their human homologs, which could allow for the development of pathogen-specific inhibitors. Five of the structures were analyzed in more detail, and four of five show promise that selective inhibitors of the active site could be found. The 19 solved crystal structures build a foundation for future work in combating this devastating disease by encouraging further investigation to stimulate drug discovery for this neglected pathogen

Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases

Pathogenic free-living amoebae (pFLA) can cause life-threatening central nervous system (CNS) infections and warrant the investigation of new chemical agents to combat the rise of infection from these pathogens. Naegleria fowleri glucokinase (NfGlck), a key metabolic enzyme involved in generating glucose-6-phosphate, was previously identified as a potential target due to its limited sequence similarity with human Glck (HsGlck). Herein, we used our previously demonstrated multifragment kinetic target-guided synthesis (KTGS) screening strategy to identify inhibitors against pFLA glucokinases. Unlike the majority of previous KTGS reports, our current study implements a “shotgun” approach, where fragments were not biased by predetermined binding potentials. The study resulted in the identification of 12 inhibitors against 3 pFLA glucokinase enzymesNfGlck, Balamuthia mandrillaris Glck (BmGlck), and Acanthamoeba castellanii Glck (AcGlck). This work demonstrates the utility of KTGS to identify small-molecule binders for biological targets where resolved X-ray crystal structures are not readily accessible

Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases

Pathogenic free-living amoebae (pFLA) can cause life-threatening central nervous system (CNS) infections and warrant the investigation of new chemical agents to combat the rise of infection from these pathogens. Naegleria fowleri glucokinase (NfGlck), a key metabolic enzyme involved in generating glucose-6-phosphate, was previously identified as a potential target due to its limited sequence similarity with human Glck (HsGlck). Herein, we used our previously demonstrated multifragment kinetic target-guided synthesis (KTGS) screening strategy to identify inhibitors against pFLA glucokinases. Unlike the majority of previous KTGS reports, our current study implements a “shotgun” approach, where fragments were not biased by predetermined binding potentials. The study resulted in the identification of 12 inhibitors against 3 pFLA glucokinase enzymesNfGlck, Balamuthia mandrillaris Glck (BmGlck), and Acanthamoeba castellanii Glck (AcGlck). This work demonstrates the utility of KTGS to identify small-molecule binders for biological targets where resolved X-ray crystal structures are not readily accessible