Smith RM et al. (1954) Antibiot Chemother (Northfield) "Oligomycin, a new antifungal antibiotic."

McCoy E, Peterson WH, Smith RM

[Antibiot Chemother (Northfield), 1954]

Although the majority of antibiotics are of interest because of their activity against bacteria, a vigorous search is underway for antifungal agents. This effort stems from the resistance of many animal and plant pathogens to the known antibiotics. As a result of this effort, there are already about 50 well-defined antibiotics that are more or less active against the filamentous fungi, and because of the active search now in progress, many more such agents will undoubtedly be uncovered in the near future. These antibiotics can be classified into three groups based on the microorganisms that produce them. Among bacteria, the genus Bacillus has so far proved the most fruitful source of antibiotics. Examples of such antibiotics are bacillomycin, fungistatin, mycosubtilin, and toximycin. Those that have been sufficiently purified to judge are of polypeptide nature. Antifungal antibiotics derived from fungi are produced by a number of genera. Examples of such antibiotics are alternaric acid, aspergillic acid, gladiolic acid, glutinosin, griseofulvin, patulin, tricothecin, and viridin. The actinomycetes have yielded the largest number of antifungal agents, among them actinomycin, Actidione, antimycin, ascosin, candicidin, endomycin, fradicin, helixin, Rimocidin, and thiolutin. The antifungal antibiotics have not found widespread use because of inherent toxicity or other unfavorable properties. A few have been tried with some success against the agents of plant disease, and it may be in this and other nonmedical fields that they will have their greatest use. The purpose of this paper is to report a presumably new antifungal antibiotic, oligomycin.

Ma C et al. (2015) Molecules "Potent Activities of Roemerine against Candida albicans and the Underlying Mechanisms."

Yan L, Xu G, Wang C, He G, Du F, Jiang Y, Ma C, Rao G, He J

[Molecules, 2015]

Roemerine (RM) is an aporphine alkaloid isolated from the fresh rattan stem of Fibraurea recisa, and it has been demonstrated to have certain antifungal activity. This study aimed to investigate the antifungal activity of RM and the underlying mechanisms in Candida albicans (C. albicans). The in vitro antifungal activity of RM was evaluated by a series of experiments, including the XTT reduction assay, confocal laser scanning microscopy assay, scanning electron microscope assay. Results showed that 1 g/mL RM inhibited biofilm formation significantly (p < 0.01) both in Spider medium and Lee's medium. In addition, RM could inhibit yeast-to-hyphae transition of C. albicans in a dose-dependent manner. The biofilm-specific and hypha-specific genes such as YWP1, SAP5, SAP6, HWP1, ECE1 were up-regulated and EFG1 was down-regulated after 8 g/mL RM treatment. Furthermore, the toxicity of RM was investigated using C. elegans worms, three cancer cells and one normal cell. The date showed that RM had no significant toxicity. In conclusion, RM could inhibited the formation of C. albicans biofilm in vitro, but it had no fungicidal effect on planktonic C. albicans cells, and the anti-biofilm mechanism may be related to the cAMP pathway.

Gouveia GJ et al. (2021) Anal Chem "Long-Term Metabolomics Reference Material."

Andersen EC, Morse AM, Garcia BM, Edison AS, Shaver AO, Gouveia GJ, McIntyre LM

[Anal Chem, 2021]

The use of quality control samples in metabolomics ensures data quality, reproducibility, and comparability between studies, analytical platforms, and laboratories. Long-term, stable, and sustainable reference materials (RMs) are a critical component of the quality assurance/quality control (QA/QC) system; however, the limited selection of currently available matrix-matched RMs reduces their applicability for widespread use. To produce an RM in any context, for any matrix that is robust to changes over the course of time, we developed iterative batch averaging method (IBAT). To illustrate this method, we generated 11 independently grown <i>Escherichia coli</i> batches and made an RM over the course of 10 IBAT iterations. We measured the variance of these materials by nuclear magnetic resonance (NMR) and showed that IBAT produces a stable and sustainable RM over time. This <i>E. coli</i> RM was then used as a food source to produce a <i>Caenorhabditis elegans</i> RM for a metabolomics experiment. The metabolite extraction of this material, alongside 41 independently grown individual <i>C. elegans</i> samples of the same genotype, allowed us to estimate the proportion of sample variation in preanalytical steps. From the NMR data, we found that 40% of the metabolite variance is due to the metabolite extraction process and analysis and 60% is due to sample-to-sample variance. The availability of RMs in untargeted metabolomics is one of the predominant needs of the metabolomics community that reach beyond quality control practices. IBAT addresses this need by facilitating the production of biologically relevant RMs and increasing their widespread use.

Lawal TA et al. (2020) Orphanet J Rare Dis "Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990-2019."

Dowling JJ, Terry NL, Todd JJ, Wires ES, Lawal TA

[Orphanet J Rare Dis, 2020]

BACKGROUND: Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a life-threatening hypermetabolic condition and RYR1-related myopathies (RYR1-RM), a spectrum of rare neuromuscular disorders. In RYR1-RM, intracellular calcium dysregulation, post-translational modifications, and decreased protein expression lead to a heterogenous clinical presentation including proximal muscle weakness, contractures, scoliosis, respiratory insufficiency, and ophthalmoplegia. Preclinical model systems of RYR1-RM and MH have been developed to better understand underlying pathomechanisms and test potential therapeutics. METHODS: We conducted a comprehensive scoping review of scientific literature pertaining to RYR1-RM and MH preclinical model systems in accordance with the PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O'Malley. Two major electronic databases (PubMed and EMBASE) were searched without language restriction for articles and abstracts published between January 1, 1990 and July 3, 2019. RESULTS: Our search yielded 5049 publications from which 262 were included in this review. A majority of variants tested in RYR1 preclinical models were localized to established MH/central core disease (MH/CCD) hot spots. A total of 250 unique RYR1 variations were reported in human/rodent/porcine models with 95% being missense substitutions. The most frequently reported RYR1 variant was R614C/R615C (human/porcine total n=39), followed by Y523S/Y524S (rabbit/mouse total n=30), I4898T/I4897T/I4895T (human/rabbit/mouse total n=20), and R163C/R165C (human/mouse total n=18). The dyspedic mouse was utilized by 47% of publications in the rodent category and its RyR1-null (1B5) myotubes were transfected in 23% of publications in the cellular model category. In studies of transfected HEK-293 cells, 57% of RYR1 variations affected the RyR1 channel and activation core domain. A total of 15 RYR1 mutant mouse strains were identified of which ten were heterozygous, three were compound heterozygous, and a further two were knockout. Porcine, avian, zebrafish, C. elegans, canine, equine, and drosophila model systems were also reported. CONCLUSIONS: Over the past 30years, there were 262 publications on MH and RYR1-RM preclinical model systems featuring more than 200 unique RYR1 variations tested in a broad range of species. Findings from these studies have set the foundation for therapeutic development for MH and RYR1-RM.

Volpatti JR et al. (2020) Elife "Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline."

Groom L, Endo Y, Volpatti JR, Zuercher WJ, Brennan S, Roy P, Dirksen RT, Dowling JJ, Knox J, Noche R

[Elife, 2020]

Ryanodine receptor type I-related myopathies (RYR1-RMs) are a common group of childhood muscle diseases associated with severe disabilities and early mortality for which there are no available treatments. The goal of this study is to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a discovery pipeline using nematode, zebrafish, and mammalian cell models. We first performed large-scale drug screens in <i>C. elegans</i> which uncovered 74 hits. Targeted testing in zebrafish yielded positive results for two p38 inhibitors. Using mouse myotubes, we found that either pharmacological inhibition or siRNA silencing of p38 impaired caffeine-induced Ca²⁺ release from wild type cells while promoting intracellular Ca²⁺ release in <i>Ryr1</i> knockout cells. Lastly, we demonstrated that p38 inhibition blunts the aberrant temperature-dependent increase in resting Ca²⁺ in myotubes from an RYR1-RM mouse model. This unique platform for RYR1-RM therapy development is potentially applicable to a broad range of neuromuscular disorders.

Rosenberg R (1978) Worm Breeder's Gazette

Rosenberg R

[Worm Breeder's Gazette, 1978]

All eyes are on the newest fashion trend, the Dumpy Look . Pace setting designer I.M. Worm s androgynous wardrobe is all the rage in Paris. Bianca Jagger quips, Tres, tres - Women s Wear Daily writes, Elegans personified - Patti Smith thinks, The punks won t buy it and Craig Russell says, It fits right in with my act . A product of Mutant Isolation, Inc.

Kravtsov, V. et al. (2013) International Worm Meeting "The effects of aging on dendritic plasticity and PVD-FLP branch coexistence."

Podbilewicz, B., Oren-Suissa, M., Kravtsov, V.

[International Worm Meeting, 2013]

Self-avoidance, tiling and coexistence are the main mechanisms that enable the best dendritic coverage. C. elegans undergoes aging-associated changes that ultimately lead to decreased functionality of the organism, including its neurological functions. Recent research has shown that the nervous system of C. elegans undergoes changes and alterations during aging including dendritic morphology (Tank et al., 2011). We study dendritic plasticity, aging and spatial dendritic organization of two highly arborized mechanoreceptors in C. elegans, PVD and FLP (Oren-Suissa et al., 2010). PVD dendrites of L4s and young adults show regenerative ability following dendrotomy (laser induced severing of dendrites). Our working hypothesis is that in older ages this ability to regenerate is compromised. Previous studies and our preliminary results indicate that PVD and FLP do not overlap in larval stages (Smith et al., 2010). In addition, dendrites within each bilateral PVD do not overlap through a self-avoidance mechanism (Smith et al., 2012). We found that (1) the coverage fields of the PVD and FLP overlap in adult worms, which indicates coexistence and not tiling. This overlap increases as the worm ages. (2) PVDs show aberrant arborization at the age of 9 days of adulthood. (3) Dramatic increase in self-avoidance defects as animals age. In humans many neurodegenerative diseases as well as generalized cognitive decline are associated with age, aberrant arborization or both (e.g. autism and Alzheimer's disease). However our understanding of how these disorders are triggered and aggravated is scarce. Our research provides an insight into the aging and regeneration process of individual neurons. Oren-Suissa, M., et al. (2010). Science 328, 1285-1288. Smith, C.J. et al. (2010). Developmental Biology 345, 18-33. Smith, C.J., et al. (2012). Nature Neuroscience 15, 731-737. Tank, E.M.H. et al. (2011). Journal of Neuroscience 31, 9279-9288.

Yu Z et al. (2011) J Environ Sci (China) "Behavior toxicity to Caenorhabditis elegans transferred to the progeny after exposure to sulfamethoxazole at environmentally relevant concentrations."

Yu Z, Jiang L, Yin D

[J Environ Sci (China), 2011]

Sulfamethoxazole (SMX) is one of the most common detected antibiotics in the environment. In order to study whether SMX can affect behavior and growth and whether these effects could be transferred to the progeny, Caenorhabditis elegans was exposed at environmentally relevant concentrations for 24, 48, 72 and 96 hr, respectively. After exposure, the exposed parent generation (P0) was measured for behavior and growth indicators, which were presented as percentage of controls (POC). Then their corresponding unexposed progeny (F1) was separated and measured for the same indicators. The lowest POC for P0 after 96 hr-exposure at 100 mg/L were 37.8%, 12.7%, 45.8% and 70.1% for body bending frequency (BBF), reversal movement (RM), Omega turns (OT) and body length (BL), respectively. And F1 suffered defects with the lowest POC as 55.8%, 24.1%, 48.5% and 60.7% for BBF, RM, OT and BL, respectively. Defects in both P0 and F1 showed a time- and concentration-dependent fashion and behavior indicators showed better sensitivity than growth indicator. The observed effects on F1 demonstrated the transferable properties of SMX. Defects of SMX at environmental concentrations suggested that it is necessary to perform further systematical studies on its ecological risk in actual conditions.

Cassada RC et al. (1980) Worm Breeder's Gazette "initial characterization of ts embryonic defective (emb) mutants (Goettingen set)."

Culotti MR, Cassada RC, Von Ehrenstein G, Isnenghi E

[Worm Breeder's Gazette, 1980]

[See Figure 1] Already published allelism: Wood et al., 1980: b117=b189; b246 = let- 2.Miwa et al., 1980: hc57 = hc62; hc61 = hc67. Our global complementation results: g1 = g4; g16 = g65 = hc61 = hc67; g36 = hc65; g23 = g34 = hc70 = b117 = b189; g37 = b246 = let-2; b84 = hc66; g14 = g43; g57 = b1O. From frequency of multiple alleles we estimate 200-400 genes essential for embryogenesis. Mapping is in progress. We are also doing tsp's, R + H Tests, and cellular defects ( Isnenghi, Cassada, Radnia, Schierenberg, K. Smith, v. Ehrenstein).

Zaridah MZ et al. (2001) J Ethnopharmacol "In vitro antifilarial effects of three plant species against adult worms of subperiodic Brugia malayi."

Omar AW, Idid SZ, Zaridah MZ, Khozirah S

[J Ethnopharmacol, 2001]

Five aqueous extracts from three plant species, i.e., dried husks (HX), dried seeds (SX) and dried leaves (LX) of Xylocarpus granatum (Meliaceae), dried stems (ST) of Tinospora crispa (Menispermaceae) and dried leaves (LA) of Andrographis paniculata (Acanthaceae) were tested in vitro against adult worms of subperiodic Brugia malayi. The relative movability (RM) value of the adult worms over the 24-h observation period was used as a measure of the antifilarial activity of the aqueous extracts. SX extract of X. granatum demonstrated the strongest activity, followed by the LA extract of A. paniculata, ST extract of T. crispa, HX extract and LX extract of X. granatum.