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Biomedical subjects

James L Smith

Publications and source records attributed to James L Smith.

At least 19 recordsLinked to original sources
PubMed2006

An alternative bactericidal mechanism of action for lantibiotic peptides that target lipid II.

Lantibiotics are polycyclic peptides containing unusual amino acids, which have binding specificity for bacterial cells, targeting the bacterial cell wall component lipid II to form pores and thereby lyse the cells. Yet several members of these lipid II-targeted lantibiotics are too short to be able to span the lipid bilayer and cannot form pores, but somehow they maintain their antibacterial efficacy. We describe an alternative mechanism by which members of the lantibiotic family kill Gram-positive bacteria by removing lipid II from the cell division site (or septum) and thus block cell wall synthesis.

Anti-Bacterial Agents↗
PubMed2006

Retinoic acid-induced CD38 expression in HL-60 myeloblastic leukemia cells regulates cell differentiation or viability depending on expression levels.

Retinoic acid-induced expression of the CD38 ectoenzyme receptor in HL-60 human myeloblastic leukemia cells is regulated by RARalpha and RXR, and enhanced or prevented cell differentiation depending on the level of expression per cell. RARalpha activation caused CD38 expression, as did RXR activation but not as effectively. Inhibition of MAPK signaling through MEK inhibition diminished the induced expression by both RARs and RXRs. Expression of CD38 enhanced retinoic acid-induced myeloid differentiation and G0 cell cycle arrest, but at higher expression levels, induced differentiation was blocked and retinoic acid induced a loss of cell viability instead. In the case of 1,25-dihydroxyvitamin D3, induced monocytic differentiation was also enhanced by CD38 and not enhanced by higher expression levels, but without induced loss of viability. Expression levels of CD38 thus regulated the cellular response to retinoic acid, either propelling cell differentiation or loss of viability. The cellular effects of CD38 thus depend on its expression level.

ADP-ribosyl Cyclase 1↗
PubMed2005

Retinoic acid induces expression of SLP-76: expression with c-FMS enhances ERK activation and retinoic acid-induced differentiation/G0 arrest of HL-60 cells.

Retinoic acid (RA) is known to cause MAPK signaling which propels G0 arrest and myeloid differentiation of HL-60 human myeloblastic leukemia cells. The present studies show that RA up-regulated expression of SLP-76 (Src-homology 2 domain-containing leukocyte-specific phospho-protein of 76 kDa), which became a prominent tyrosine-phosphorylated protein in RA-treated cells. SLP-76 is a known adaptor molecule associated with T-cell receptor and MAPK signaling. To characterize functional effects of SLP-76 expression in RA-induced differentiation and G0 arrest, HL-60 cells were stably transfected with SLP-76. Expression of SLP-76 had no discernable effect on RA-induced ERK activation, subsequent functional differentiation, or the rate of RA-induced G0 arrest. To determine the effects of SLP-76 in the presence of a RA-regulated receptor, SLP-76 was stably transfected into HL-60 cells already overexpressing the colony stimulating factor-1 (CSF-1) receptor, c-FMS, from a previous stable transfection. SLP-76 now enhanced RA-induced ERK activation, compared to parental c-FMS transfectants. It also enhanced RA-induced differentiation, evidenced by enhanced paxillin expression, inducible oxidative metabolism and superoxide production. RA-induced RB tumor suppressor protein hypophosphorylation was also enhanced, as was RA-induced G0 cell cycle arrest. A triple Y to F mutant SLP-76 known to be a dominant negative in T-cell receptor signaling failed to enhance RA-induced paxillin expression, but enhanced RA-induced ERK activation, differentiation and G0 arrest essentially as well as wild-type SLP-76. Thus, SLP-76 overexpression in the presence of c-FMS, a RA-induced receptor, had the effect of enhancing RA-induced cell differentiation. This is the first indication to our knowledge that RA induces the expression of an adapter molecule to facilitate induced differentiation via co-operation between c-FMS and SLP-76.

Adaptor Proteins, Signal Transducing↗
PubMed2005

UV-crosslinking of E1 small nucleolar RNA to proteins in frog oocytes.

E1/U17 small nucleolar RNA (snoRNA) is a box H/ACA snoRNA. To detect protein bands that UV-crosslink to E1 RNA primarily at uridines, frog oocytes were injected with [alpha-32P]UTP-labeled E1 RNA and incubated, isolated nuclei were UV irradiated, and nuclear contents were digested with RNase A. Wild-type E1 RNA specifically UV-crosslinked to several protein bands. To identify E1 RNA sites involved in these interactions, we tested 21 E1 RNA mutants, each consisting of substitutions in a conserved sequence or structure. UV-crosslinking of different protein bands to E1 RNA depended on one of the following sets of conserved E1 RNA segments: two 5' end RNA sites; five 5' half RNA sites; two 3' half RNA sites; or 14 sites located throughout E1 RNA. Of these conserved E1 RNA sites, UV-crosslinking apparently depended on sequences at 11 sites, and structures at 2 sites. Gel electrophoresis with and without RNA competition detected protein bands that are not common to all of the box H/ACA snoRNAs.

Animals↗
PubMed2005

Effects of aging on the biomechanics of slips and falls.

Although much has been learned in recent decades about the deterioration of muscular strength, gait adaptations, and sensory degradation among older adults, little is known about how these intrinsic changes affect biomechanical parameters associated with slip-induced fall accidents. In general, the objective of this laboratory study was to investigate the process of initiation, detection, and recovery of inadvertent slips and falls. We examined the initiation of and recovery from foot slips among three age groups utilizing biomechanical parameters, muscle strength, and sensory measurements. Forty-two young, middle-age, and older participants walked around a walking track at a comfortable pace. Slippery floor surfaces were placed on the track over force platforms at random intervals without the participants' awareness. Results indicated that younger participants slipped as often as the older participants, suggesting that the likelihood of slip initiation is similar across all age groups; however, older individuals' recovery process was much slower and less effective. The ability to successfully recover from a slip (thus preventing a fall) is believed to be affected by lower extremity muscle strength and sensory degradation among older individuals. Results from this research can help pinpoint possible intervention strategies for improving dynamic equilibrium among older adults.

Accidental Falls↗
PubMed2005

Colonic spirochetosis in animals and humans.

Colonic spirochetosis is a disease caused by the gram-negative bacteria Brachyspira aalborgi and Brachyspira pilosicoli. B. pilosicoli induces disease in both humans and animals, whereas B. aalborgi affects only humans and higher primates. Symptoms in humans include diarrhea, rectal bleeding, and abdominal cramps. Colonic spirochetosis is common in third world countries; however, in developed countries, the disease is observed mainly in homosexual males. Terminally ill patients infected with Brachyspira are particularly at risk for developing spirochetemia. Diarrhea, poor growth performance, and decreased feed-to-gain efficiency is seen in pigs with colonic spirochetosis. The disease in chickens is characterized by delayed and/or reduced egg production, diarrhea, poor feed conversion, and retarded growth. Thus, colonic spirochetosis can represent a serious economic loss in the swine and poultry industries. The organisms are transmitted by the fecal-oral route, and several studies have demonstrated that human, primate, pig, dog, or bird strains of B. pilosicoli can be transmitted to pigs, chickens, and mice. B. pilosicoli may be a zoonotic pathogen, and although it has not been demonstrated, there is a possibility that both B. pilosicoli and B. aalborgi can be transferred to humans via contact with the feces of infected animals, meat from infected animals, or food contaminated by food handlers. Neither B. pilosicoli nor B. aalborgi has been well characterized in terms of basic cellular functions, pathogenicity, or genetics. Studies are needed to more thoroughly understand these Brachyspira species and their disease mechanisms.

Animals↗
PubMed2005

Accumulation of explosives in hair.

The sorption of explosives (TNT, RDX, PETN, TATP, EGDN) to hair during exposure to their vapors is examined. Three colors of hair were simultaneously exposed to explosive vapor. Following exposure of hair, the sorbed explosive was removed by extraction with acetonitrile and quantified. Results show that sorption of explosives, via vapor diffusion, to black hair is significantly greater than to blond, brown or bleached hair. Furthermore, the rate of sorption is directly related to the vapor density of the explosive: EGDN > TATP >>>TNT >> PETN > RDX. In some cases, the explosive-containing hair was subject to repeated washings with sodium dodecylsulfate or simply left out in an open area to determine the persistence of the explosive contamination. While explosive is removed from hair with time or washing, some persists. These results indicate that hair can be a useful indicator of explosive exposure/handling.

Ethylene Glycols↗
PubMed2004

Kinetic profiles of p300 occupancy in vivo predict common features of promoter structure and coactivator recruitment.

Understanding the language encrypted in the gene regulatory regions of the human genome is a challenging goal for the genomic era. Although customary extrapolations from steady-state mRNA levels have been effective, deciphering these regulatory codes will require additional empirical data sets that more closely reflect the dynamic progression of molecular events responsible for inducible transcription. We describe an approach using chromatin immunoprecipitation to profile the kinetic occupancy of the transcriptional coactivator and histone acetyltransferase p300 at numerous mitogen-induced genes in activated T cells. Comparison of these profiles reveals a class of promoters that share common patterns of inducible expression, p300 recruitment, dependence on selective p300 domains, and sensitivity to histone deacetylase inhibitors. Remarkably, this class also shares an evolutionarily conserved promoter composition and structure that accurately predicts additional human genes with similar functional attributes. This "reverse genomic" approach will have broad application for the genome-wide classification of promoter structure and function.

Acetyltransferases↗
PubMed2004

The physiological role of ferritin-like compounds in bacteria.

Iron, as the ferrous or ferric ion, is essential for the life processes of all eukaryotes and most prokaryotes; however, the element is toxic when in excess of that needed for cellular homeostasis. Ferrous ions can react with metabolically generated hydrogen peroxide to yield toxic hydroxyl radicals that in turn degrade lipids, DNA, and other cellular biomolecules. Mechanisms have evolved in living systems for iron detoxification and for the removal of excess ferrous ions from the cytosol. These detoxification mechanisms involve the oxidation of excess ferrous ions to the ferric state and storage of the ferric ions in ferritin-like proteins. There are at least three types of ferritin-like proteins in bacteria: bacterial ferritin, bacterioferritin, and dodecameric ferritin. These bacterial proteins are related to the ferritins found in eukaryotes. The structure and physical characteristics of the ferritin-like compounds have been elucidated in several bacteria. Unfortunately, the physiological roles of the bacterial ferritin-like compounds have been less thoroughly studied. A few studies conducted with mutants indicated that ferritin-like compounds can protect bacterial cells from iron overload, serve as an iron source when iron is limited, protect the bacterial cells against oxidative stress and/or protect DNA against enzymatic or oxidative attack. There is very little information available concerning the roles that ferritin-like compounds might play in the survival of bacteria in food, water, soil, or eukaryotic host environments.

Adaptation, Physiological↗
PubMed2004

Quorum sensing: a primer for food microbiologists.

Quorum sensing is a signaling mechanism through which bacteria modulate a number of cellular functions (genes), including sporulation, biofilm formation, bacteriocin production, virulence responses, as well as others. Quorum sensing is a mechanism of cell-to-cell communication and is mediated by extracellular chemical signals generated by the bacteria when specific cell densities are reached. When the concentration of the signal (and cell population) is sufficiently high, the target gene or genes are either activated or repressed. Quorum sensing increases the ability of the bacteria to have access to nutrients or to more favorable environmental niches and enhances bacterial defenses against eukaryotic hosts, competing bacteria, and environmental stresses. The physiological and clinical aspects of quorum sensing have received considerable attention and have been studied at the molecular level. Little is known, however, on the role of quorum sensing in food spoilage or in the growth and/or toxin production of pathogens present in food. A number of compounds have been isolated or synthesized that antagonize quorum sensors, and application of these antagonists may potentially be useful in inhibiting the growth or virulence mechanisms of bacteria in different environments, including food. It is important that food microbiologists have an awareness and an understanding of the mechanisms involved in bacterial quorum sensing, since strategies targeting quorum sensing may offer a means to control the growth of undesirable bacteria in foods.

Bacteria↗
PubMed2003

Effects of age-related gait changes on the biomechanics of slips and falls.

A laboratory study was conducted to examine gait changes associated with aging and the effect of these changes on initiation of slips and frequency of falls utilizing newly defined biomechanical parameters of slips and falls. Twenty-eight participants from two age groups (young and old) walked around a circular track at a comfortable pace wearing a safety harness. A slippery floor surface was placed on the walking track over the force plate at random time intervals without the participants' awareness. Synchronized kinetic and kinematic measurements were obtained on both slippery and non-slippery walking surfaces. The results indicated that older participants' horizontal heel contact velocity was significantly faster, step length was significantly shorter, and transitional acceleration of the whole body centre-of-mass (COM) was significantly slower than younger participants. Older participants' initial friction demand, as measured by required coefficient of friction (RCOF), was not significantly different than their younger counterparts. Additionally, older participants slipped longer and faster, and fell more often than younger participants. A comparison of horizontal heel contact velocity for participants who fell with participants who did not fall indicated that, in general, fallers' horizontal heel contact velocity was faster than non-fallers. However, a comparison of RCOF for participants who fell with participants who did not fall suggested that RCOF was not a totally deterministic factor influencing actual fall events. These findings suggest that gait changes associated with aging (especially higher horizontal heel contact velocity and slower transition of the whole body COM) affect initiation of slip-induced falls.

Accidental Falls↗
PubMed2003

Targeting combinatorial transcriptional complex assembly at specific modules within the interleukin-2 promoter by the immunosuppressant SB203580.

The proximal promoter sequence of the interleukin-2 (IL-2) gene contains a series of composite sites or modules that controls much of its responsiveness to environmental stimuli. The integrated targeting of these modules is therefore a major mode of regulation. This report describes how multiple functional hierarchies, required for the recruitment of the p300 co-activator to the CD28RE/AP1 (TRE) module of the IL-2 promoter, are selectively disrupted in human T-cells by the immunosuppressive and anti-inflammatory actions of the p38 mitogen-activated protein kinase inhibitor (MAPK), SB203580. The molecular hierarchies targeted by SB203580 include the combinatorial interaction of NF-kappaB and CREB at the CD28RE/AP1 element coupled with the subsequent dynamic co-assembly and activation of p300. Several aspects of this targeting are linked to the ability of SB203580 to inhibit p38 MAPK-controlled pathways. Together, these results provide the molecular basis through which the combinatorial structure and context of the composite elements of the IL-2 promoter dictates mitogen responsiveness and drug susceptibility that are quantitatively and qualitatively distinct from the isolated action of single consensus sequences and/or transcriptional motifs.

Amino Acid Motifs↗
PubMed2003

The role of gastric acid in preventing foodborne disease and how bacteria overcome acid conditions.

The secretion of hydrochloric acid by the stomach plays an important role in protecting the body against pathogens ingested with food or water. A gastric fluid pH of 1 to 2 is deleterious to many microbial pathogens; however, the neutralization of gastric acid by antacids or the inhibition of acid secretion by various drugs may increase the risk of food- or waterborne illnesses. Peptic ulcer disease is often treated by decreasing or eliminating gastric acid secretion, and such treatment blocks the protective antibacterial action of gastric fluid. The majority of peptic ulcer disease cases originate from Helicobacter pylori infections. Treatment of H. pylori-induced peptic ulcers with antibiotics reduces the need for drugs that inhibit gastric acid secretion and thereby diminishes the risk of food- and waterborne illness for peptic ulcer disease patients. Many bacterial pathogens, such as Escherichia coli, Salmonella Typhimurium, and H. pylori, can circumvent the acid conditions of the stomach by developing adaptive mechanisms that allow these bacteria to survive in acid environments. As a consequence, these bacteria can survive acidic stomach conditions and pass into the intestinal tract, where they can induce gastroenteritis.

Antacids↗
PubMed2003

Trends in explosive contamination.

This study sought to assign a rough order of magnitude for the amount of explosive residue likely to be available in real-world searches for clandestine explosives. A variety of explosives (TNT, TATP, HMX, AN, RDX, PETN) in various forms (powder, flake, detonating cord, plastic) were carefully weighed or cut into containers, and the amount of residue inadvertently remaining on the work area, hands, or containers was quantified. This was used to evaluate the spillage potential of each explosive. The adhesion of each explosive to a glass surface was quantified from amount of explosive adhering to the inside of a glass vial into which the explosive had been placed and then removed by vigorous tapping. In powdered form, most of the explosives--TNT, PETN, RDX, HMX, and TATP--exhibited similar spillage and adhesion to glass. However, PETN as sheet explosive and plasticized RDX (C-4), showed very little potential to contaminate surfaces, either by spillage or adhesion to glass.

Journal Article↗
PubMed2003

Quantification and aging of the post-blast residue of TNT landmines.

Post-blast residues are potential interferents to chemical detection of landmines. To assess the potential problem related to 2,4,6-trinitrotoluene (TNT), its post-blast residue was identified and quantified. In the first part of this study laboratory-scale samples of TNT (2 g) were detonated in a small-scale explosivity device (SSED) to evaluate the explosive power and collect post-blast residue for chemical analysis. Initiator size was large relative to the TNT charge; thus, issues arose regarding choice of initiator, residue from the initiator, and afterburning of TNT. The second part of this study detonated 75 to 150 g of military-grade TNT (typical of antipersonnel mines) in 55-gal barrels containing various witness materials (metal plates, sand, barrel walls, the atmosphere). The witness materials were analyzed for explosive residue. In a third set of tests, 75-g samples of TNT were detonated over soil (from Fort Leonard Wood or Sandia National Laboratory) in an indoor firing chamber (100 by 4.6 by 2.7 m high). Targeted in these studies were TNT and four explosive-related compounds (ERC): 2,4-dinitrotoluene (DNT), 1,3-dinitrobenzene (DNB), 2- and 4-aminodinitrotoluene (2-ADNT and 4-ADNT). The latter two are microbial degradation products of TNT. Post-blast residue was allowed to age in the soils as a function of moisture contents (5 and 10%) in order to quantify the rate of degradation of the principal residues (TNT, DNT, and DNB) and formation of the TNT microbial degradation products (2-ADNT and 4-ADNT). The major distinction between landmine leakage and post-blast residue was not the identity of the species but relative ratios of amounts. In landmine leakage the DNT/TNT ratio was usually greater than 1. In post-blast residue it was on the order of 1 to 1/100th of a percent, and the total amount of pre-blast residue (landmine leakage) was a factor of 1/100 to 1/1000 less than post-blast. In addition, landmine leakage resulted in low DNT/ADNT ratios, usually less than 1, whereas pre-blast residues started with ratios above 20. Because with time DNT decreased and ADNT increased, over a month the ratio decreased by a factor of 2. The rate of TNT degradation in soil observed in this study was much slower than that reported when initial concentrations of TNT were lower. Degradation rates yielded half-lives of 40 and 100 days for 2,4-DNT and TNT, respectively.

Journal Article↗
PubMed2002

Cross-regulation of T cell growth factor expression by p53 and the Tax oncogene.

In this study, we demonstrate that p53 directly inhibits expression of the T cell growth factor (IL-2) in activated T cells. This repression is independent of the intrinsic transcriptional activity of p53 and is mediated by the Tax-responsive CD28RE-3'-12-O-tetradecanoylphorbol-13-acetate response element (AP1) element of the IL-2 promoter. Coexpression of the Tax oncogene causes full reversal of this repression through coordinate targeting of p300, CREB, and the NF-kappaB pathways. Paradoxically, IL-2 repression by p53 is not reversed by mdm2. Instead, mdm2 represses the IL-2 promoter by a mechanism that is synergistic with p53 and resistant to Tax reversal. The p300 structure-function studies show that these effects are linked to competitive associations among p53, Tax, and mdm2 with multiple domains of p300. The functional outcome of these antagonistic associations is revealed further by the observation that Tax and p53 induce apoptosis in activated T cells through separate and mutually exclusive pathways. Interestingly, both pathways are abrogated by mdm2. These results provide evidence that a dynamic interplay, between Tax and specific elements of the p53 network, mediates growth factor expression and programmed cell death in activated T cells.

Apoptosis↗
PubMed2002

Novel cell-specific and dominant negative anti-apoptotic roles of p73 in transformed leukemia cells.

Although extensive homology exists between related genes p53 and p73, recent data suggest that the family members have divergent roles. We demonstrate that the differential regulatory roles of p53 family member p73 are highly cell-context and promoter-specific. Full-length p73 expressed in the transformed leukemia cell line Jurkat behaves as a specific dominant negative transcriptional repressor of the cell cycle inhibitor gene p21 and blocks p53-mediated apoptosis. These findings provide evidence for a new mechanism in oncogenesis through which the functional properties of p73 can be altered in an inheritable and cell-specific fashion independent of transcriptional coding.

Apoptosis↗