Smith RJ et al. (1988) Trop Med Parasitol "Vascular perfusion of Onchocerca volvulus nodules."

Williams JF, Smith RJ, Guderian RH, Cotter TP

[Trop Med Parasitol, 1988]

Perfusion of the vascular bed was achieved in 24 freshly excised nodules of Onchocerca volvulus varying from 0.5 to 2 cm in diameter. India Ink, Microfil polymer, or acrylate perfusates were passed through the vascular supply via cannulation of superficial capsular vessels. After clearing in glycerol or methyl salicylate, or KOH corrosion in the case of the acrylate, nodules were examined microscopically. Small nodules had an extensive blood supply, diffusely distributed throughout the nodule matrix, and in close association with the coils of the worms. In bigger nodules the central area appeared more dense, and intense vascularization appeared to be more peripheral; in the largest nodules the central core was not well vascularized, but a band of heavy vascularization was seen at the margin of the core, fed by superficial vessels and in close contact with worm coils. Very fine branches of the vascular tree were perfused by all three contrast media, but histologically there was evidence of incomplete filling of the smallest vessels. However, there was no extravasation of per-fusates around parasites, even where the approximation between between vessels and parasite surfaces was close. The possibility is considered that O. volvulus may control blood vessel proliferation by release of angiogenesis factors, analogous to rapidly growing solid tumors.

Smith RL et al. (2012) Front Genet "Premature and accelerated aging: HIV or HAART?"

Brul S, Smith RL, Budovskaya Y, de Boer R, van der Spek H

[Front Genet, 2012]

Highly active antiretroviral therapy (HAART) has significantly increased life expectancy of the human immunodeficiency virus (HIV)-positive population. Nevertheless, the average lifespan of HIV-patients remains shorter compared to uninfected individuals. Immunosenescence, a current explanation for this difference invokes heavily on viral stimulus despite HAART efficiency in viral suppression. We propose here that the premature and accelerated aging of HIV-patients can also be caused by adverse effects of antiretroviral drugs, specifically those that affect the mitochondria. The nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral drug class for instance, is known to cause depletion of mitochondrial DNA via inhibition of the mitochondrial specific DNA polymerase-. Besides NRTIs, other antiretroviral drug classes such as protease inhibitors also cause severe mitochondrial damage by increasing oxidative stress and diminishing mitochondrial function. We also discuss important areas for future research and argue in favor of the use of Caenorhabditis elegans as a novel model system for studying these effects.

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.

Smith CJ et al. (2012) Nat Neurosci "Netrin (UNC-6) mediates dendritic self-avoidance."

Smith CJ, Colon-Ramos DA, Miller DM, Watson JD, VanHoven MK

[Nat Neurosci, 2012]

Dendrites from a single neuron may be highly branched but typically do not overlap. Self-avoidance behavior has been shown to depend on cell-specific membrane proteins that trigger mutual repulsion. Here we report the unexpected discovery that a diffusible cue, the axon guidance protein UNC-6 (Netrin), is required for self-avoidance of sister dendrites from the PVD nociceptive neuron in Caenorhabditis elegans. We used time-lapse imaging to show that dendrites fail to withdraw upon mutual contact in the absence of UNC-6 signaling. We propose a model in which the UNC-40 (Deleted in Colorectal Cancer; DCC) receptor captures UNC-6 at the tips of growing dendrites for interaction with UNC-5 on the apposing branch to induce mutual repulsion. UNC-40 also responds to dendritic contact through another pathway that is independent of UNC-6. Our findings offer a new model for how an evolutionarily conserved morphogenic cue and its cognate receptors can pattern a fundamental feature of dendritic architecture.

Smith ES et al. (2013) J Biol Chem "A chemoreceptor that detects molecular carbon dioxide."

Smith ES, Martinez-Velazquez LA, Ringstad N

[J Biol Chem, 2013]

Animals from diverse phyla possess neurons that are activated by the product of aerobic respiration, CO2. It has long been thought that such neurons primarily detect the CO2 metabolites protons and bicarbonate. We have determined the chemical tuning of isolated CO2 chemosensory BAG neurons of the nematode Caenorhabditis elegans. We show that BAG neurons are principally tuned to detect molecular CO2, although they can be activated by acid stimuli. One component of the BAG transduction pathway, the receptor-type guanylate cyclase GCY-9, suffices to confer cellular sensitivity to both molecular CO2 and acid, indicating that it is a bifunctional chemoreceptor. We speculate that in other animals, receptors similarly capable of detecting molecular CO2 might mediate effects of CO2 on neural circuits and behavior.

Smith HE et al. (2016) G3 (Bethesda) "Mapping Challenging Mutations by Whole-Genome Sequencing."

Jaramillo-Lambert A, Golden A, Fabritius AS, Smith HE

[G3 (Bethesda), 2016]

Whole-genome sequencing provides a rapid and powerful method for identifying mutations on a global scale, and has spurred a renewed enthusiasm for classical genetic screens in model organisms. The most commonly characterized category of mutation consists of monogenic, recessive traits, due to their genetic tractability. Therefore, most of the mapping methods for mutation identification by whole-genome sequencing are directed toward alleles that fulfill those criteria (i.e., single-gene, homozygous variants). However, such approaches are not entirely suitable for the characterization of a variety of more challenging mutations, such as dominant and semi-dominant alleles or multigenic traits. Therefore, we have developed strategies for the identification of those classes of mutations, using polymorphism mapping in Caenorhabditis elegans as our model for validation. We also report an alternative approach for mutation identification from traditional recombinant crosses, and a solution to the technical challenge of sequencing sterile or terminally arrested strains where population size is limiting. The methods described herein extend the applicability of whole-genome sequencing to a broader spectrum of mutations, including classes that are difficult to map by traditional means.

Smith SA et al. (2011) ILAR J "Culture and maintenance of selected invertebrates in the laboratory and classroom."

Smith SA, Scimeca JM, Mainous ME

[ILAR J, 2011]

Invertebrate species have been used for many years in the laboratory and teaching environment. We discuss some of the most commonly maintained invertebrates--the nematode (Caenorhabditis elegans), the California sea hare (Aplysia californica), the fruit fly (Drosophila melanogaster), terrestrial hermit crabs, the horseshoe crab (Limulus polyphemus), and cephalopods--and briefly describe general techniques for culturing them in captivity. The aim of this article is to give potential users an idea of the materials, methods, and effort required to maintain each type of organism in a laboratory or classroom setting.

Smith KR et al. (2011) Cytoskeleton (Hoboken) "A role for central spindle proteins in cilia structure and function."

Wang PI, Basten SG, Marcotte EM, Giles RH, Wallingford JB, Kieserman EK, Smith KR

[Cytoskeleton (Hoboken), 2011]

Cytokinesis and ciliogenesis are fundamental cellular processes that require strict coordination of microtubule organization and directed membrane trafficking. These processes have been intensely studied, but there has been little indication that regulatory machinery might be extensively shared between them. Here, we show that several central spindle/midbody proteins (PRC1, MKLP-1, INCENP, centriolin) also localize in specific patterns at the basal body complex in vertebrate ciliated epithelial cells. Moreover, bioinformatic comparisons of midbody and cilia proteomes reveal a highly significant degree of overlap. Finally, we used temperature-sensitive alleles of PRC1/spd-1 and MKLP-1/zen-4 in C. elegans to assess ciliary functions while bypassing these proteins' early role in cell division. These mutants displayed defects in both cilia function and cilia morphology. Together, these data suggest the conserved reuse of a surprisingly large number of proteins in the cytokinetic apparatus and in cilia.

Smith MG et al. (2004) Mol Cell Biol "Microbial synergy via an ethanol-triggered pathway."

Smith MG, Snyder M, Des Etages SG

[Mol Cell Biol, 2004]

We have discovered a microbial interaction between yeast, bacteria, and nematodes. Upon coculturing, Saccharomyces cerevisiae stimulated the growth of several species of Acinetobacter, including, A. baumannii, A. haemolyticus, A. johnsonii, and A. radioresistens, as well as several natural isolates of Acinetobacter. This enhanced growth was due to a diffusible factor that was shown to be ethanol by chemical assays and evaluation of strains lacking ADH1, ADH3, and ADH5, as all three genes are involved. in ethanol production by yeast. This effect is specific to ethanol: methanol, butanol, and dimethyl sulfoxide were unable to stimulate growth to any appreciable level. Low doses of ethanol not only stimulated growth to a higher cell density but also served as a signaling molecule: in the presence of ethanol, Acinetobacter species were able to withstand the toxic effects of salt, indicating that ethanol alters cell physiology. Furthermore, ethanol-fed A. baumannii displayed increased pathogenicity when confronted with a predator, Caenorhabditis elegans. Our results are consistent with the concept that ethanol can serve as a signaling molecule which can affect bacterial physiology and survival.

Smith RL et al. (2015) Methods Mol Biol "In vivo visualization and quantification of mitochondrial morphology in C. elegans."

Smith RL, De Vos WH, van der Spek H, Manders EM, de Boer R

[Methods Mol Biol, 2015]

Caenorhabditis elegans is a highly malleable model system, intensively used for functional, genetic, cytometric, and integrative studies. Due to its simplicity and large muscle cell number, C. elegans has frequently been used to study mitochondrial deficiencies caused by disease or drug toxicity. Here, we describe a robust and efficient method to visualize and quantify mitochondrial morphology in vivo. This method has many practical and technical advantages above traditional (manual) methods and provides a comprehensive analysis of mitochondrial morphology.