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Biomedical subjects

Eric Miller

Publications and source records attributed to Eric Miller.

18 recordsLinked to original sources
PubMed2006

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria.

A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone-usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by approximately 90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone-subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.

Anti-Bacterial Agents↗
PubMed2006

Molecular mechanism of P pilus termination in uropathogenic Escherichia coli.

P pili are important adhesive fibres that are assembled by the conserved chaperone-usher pathway. During pilus assembly, the subunits are incorporated into the growing fibre by the donor-strand exchange mechanism, whereby the beta-strand of the chaperone, which complements the incomplete immunoglobulin fold of each subunit, is displaced by the amino-terminal extension of an incoming subunit in a zip-in-zip-out exchange process that is initiated at the P5 pocket, an exposed hydrophobic pocket in the groove of the subunit. In vivo, termination of P pilus growth requires a specialized subunit, PapH. Here, we show that PapH is incorporated at the base of the growing pilus, where it is unable to undergo donor-strand exchange. This inability is not due to a stronger PapD-PapH interaction, but to a lack of a P5 initiator pocket in the PapH structure, suggesting that PapH terminates pilus growth because it is lacking the initiation point by which donor-strand exchange proceeds.

Bacterial Adhesion↗
PubMed2006

The mechanical properties of E. coli type 1 pili measured by atomic force microscopy techniques.

The first step in the encounter between a host and a pathogen is attachment to the host epithelium. For uropathogenic Escherichia coli, these interactions are mediated by type 1 and P adhesive pili, which are long (approximately 1 microm) rods composed of more than 1000 protein subunits arranged in a helical structure. Here we used single-molecule atomic force microscopy to study the mechanical properties of type 1 pili. We found that type 1 pili readily extend under an applied force and that this extensibility is the result of unwinding the pilus rod's helical quaternary structure. The forced unraveling is also reversible, with helical rewinding taking place under considerable forces (approximately 60 pN). These data are similar to those obtained on P pili using optical tweezers, indicating that these are conserved properties of uropathogenic E. coli pili. We also show that our data can readily be reproduced using Monte Carlo simulation techniques based on a two-state kinetic model. This model provides a simple way to extrapolate the mechanical behavior of pili under a wide range of forces. We propose that type 1 pilus unraveling is an essential mechanism for absorbing physiological shear forces encountered during urinary tract infections and probably essential for adhesion and colonization of the bladder epithelium.

Biomechanical Phenomena↗
PubMed2006

Minor proteins and enzymes of the Drosophila eggshell matrix.

The Drosophila eggshell provides an in vivo model system for extracellular matrix assembly, in which programmed gene expression, cell migrations, extracellular protein trafficking, proteolytic processing, and cross-linking are all required to generate a multi-layered and regionally complex architecture. While abundant structural components of the eggshell are known and are being characterized, less is known about non-abundant structural, regulatory, and enzymatic components that are likely to play critical roles in eggshell assembly. We have used sensitive mass spectrometry-based analyses of fractionated eggshell matrices to validate six previously predicted eggshell proteins and to identify eleven novel components, and have characterized the expression patterns of many of their mRNAs. Among these are several putative structural or regulatory (non-enzymatic) proteins, most larger in mass than the major eggshell proteins and often showing preferential expression in follicle cells overlying specific structural features of the eggshell. Of particular note are the putative enzymes, some likely to be involved in matrix cross-linking (two yellow family members previously implicated in eggshell integrity, a heme peroxidase, and a small-molecule oxidoreductase) and others possibly involved in matrix proteolysis or adhesion (proteins related to cathepsins B and D). This work provides a framework for future molecular studies of eggshell assembly.

Animals↗
PubMed2006

Evaluation of the Texas Birth Defects Registry: an active surveillance system.

BACKGROUND: Evaluations of surveillance systems are necessary to determine if the goals of the system are being met, how efficiently the surveillance is being implemented, and if resources are being used appropriately. An evaluation of the Texas Birth Defects Registry was conducted to assess the overall quality of data collection and to examine variations across regions of the state. METHODS: The registry was evaluated by using published guidelines for evaluating public health surveillance systems; the evaluation included staff interviews, process observation, and secondary data analysis. RESULTS: The registry monitors >370,000 births/year through active surveillance, with considerable disparities in workload across regions of the state. Because of the geographic size and substantial population of Texas, data collection is complex. However, the estimated sensitivity of the system appears sufficient, and rates for selected defects are highly comparable with other U.S. active birth-defect surveillance systems. Registry staff continually monitor the quality of data collection and provide additional training. Amid unstable funding, the registry staff have demonstrated optimal foresight and flexibility to adapt and continue quality data collection. Timeliness needs to be improved and more consistent quality assurance is needed across regions of the state. Retaining staff and increasing visibility are essential to providing more stability. CONCLUSIONS: Active surveillance for birth defects is labor-intensive but provides invaluable data for its stakeholders. The Texas Birth Defects Registry has proven to be a quality surveillance system and a beneficial resource for Texas.

Congenital Abnormalities↗
PubMed2006

The effect of recent stimulant use on sustained attention in HIV-infected adults.

Evidence suggests that stimulant use may exacerbate the deleterious cognitive effects of HIV, and that it has similar neuropathological consequences. In the current study, we examined the effect of recent stimulant use on sustained attention in adults infected with HIV. The sample consisted of 23 non-drug users and 17 stimulant users (cocaine and/or methamphetamine), all who were HIV-positive. Drug use was determined via urine toxicology. Sustained attention was assessed with the Conners' Continuous Performance Task--second edition (CPT-II). Groups were compared on overall performance variables, as well as patterns of performance across time. Compared to the non-drug users, stimulant users showed a gradual increase in reaction time variability and omission errors. Stimulant users' scores indicated impaired vigilance relative to an age and gender-matched normative sample. The groups were equivalent on other measures of attention, global neuropsychological functioning, mood, and demographic variables. The results indicate that recent stimulant use among HIV-infected adults adversely affects sustained attention.

Adult↗
PubMed2006

Metal injection moulding for medical devices.

One moulding process is described here that offers speed and cost savings together with precision and robust material properties. New product designers are advised to design for it from the outset.

Biomedical Technology↗
PubMed2005

Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer.

The majority of ovarian cancer patients are treated with platinum-based chemotherapy, but the emergence of resistance to such chemotherapy severely limits its overall effectiveness. We have shown that development of resistance to this treatment can modify cell signaling responses in a model system wherein cisplatin treatment has altered cell responsiveness to ligands of the erbB receptor family. A cisplatin-resistant ovarian carcinoma cell line PE01CDDP was derived from the parent PE01 line by exposure to increasing concentrations of cisplatin, eventually obtaining a 20-fold level of resistance. Whereas PE01 cells were growth stimulated by the erbB receptor-activating ligands, such as transforming growth factor-alpha (TGFalpha), NRG1alpha, and NRG1beta, the PE01CDDP line was growth inhibited by TGFalpha and NRG1beta but unaffected by NRG1alpha. TGFalpha increased apoptosis in PE01CDDP cells but decreased apoptosis in PE01 cells. Differences in extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling were also found, which may be implicated in the altered cell response to ligands. Microarray analysis revealed 51 genes whose mRNA increased by at least 2-fold in PE01CDDP cells relative to PE01 (including FRA1, ETV4, MCM2, AXL, MT3, TRAP1, and FANCG), whereas 36 genes (including IGFBP3, TRAM1, and KRT4 and KRT19) decreased by a similar amount. Differential display reverse transcriptase-PCR identified altered mRNA expression for TCP1, SLP1, proliferating cell nuclear antigen, and ZXDA. Small interfering RNA inhibition of FRA1, TCP1, and MCM2 expression was associated with reduced growth and FRA1 inhibition with enhanced cisplatin sensitivity. Altered expression of these genes by cytotoxic exposure may provide survival advantages to cells including deregulation of signaling pathways, which may be critical in the development of drug resistance.

Adenocarcinoma↗
PubMed2005

Patterns of mercury deposition and concentration in northeastern North America (1996-2002).

Data from 13 National Atmospheric Deposition Program Mercury Monitor Network (NADP/ MDN) monitoring stations (1996-2002) and the Underhill (VT) event-based monitoring site (1993-2002) were evaluated for spatial and temporal trends. More precipitation and mercury deposition occurred in the southern and coastal MDN sites, except for the Underhill site, which received more mercury deposition than surrounding sites. Precipitation patterns varied. Regionally, higher concentrations of mercury were recorded during the late spring and summer months. Several sub-regional clusters of MDN sites were evident, based on mercury deposition patterns. In general, more mercury was deposited during the summer months. "Enhanced" weekly deposition (> 250 ng/m2) and distinct seasonal deposition patterns were evident at all MDN sites. Regionally, high depositional periods contributed significantly to annual loads (< 20%- approximately 60%). Southern and coastal sites measured more frequent periods of high deposition than inland sites. Spring and summer "enhanced" deposition may be important contributing factors to mercury bioaccumulation during the growing season. Recent regional reductions of mercury emissions were not reflected in the regional mercury concentration or deposition data. Few sites showed linear relations between the concentration of mercury in precipitation and acid rain co-contaminants (sulfates and nitrates).

Air Pollutants↗
PubMed2005

Sulphate, nitrogen and base cation budgets at 21 forested catchments in Canada, the United States and Europe.

To assess the concern over declining base cation levels in forest soils caused by acid deposition, input-output budgets (1990s average) for sulphate (SO(4)), inorganic nitrogen (NO(3)-N; NH(4)-N), calcium (Ca), magnesium (Mg) and potassium (K) were synthesised for 21 forested catchments from 17 regions in Canada, the United States and Europe. Trend analysis was conducted on monthly ion concentrations in deposition and runoff when more than 9 years of data were available (14 regions, 17 sites). Annual average SO(4) deposition during the 1990s ranged between 7.3 and 28.4 kg ha(-1) per year, and inorganic nitrogen (N) deposition was between 2.8 and 13.8 kg ha(-1) per year, of which 41-67% was nitrate (NO(3)-N). Over the period of record, SO(4) concentration in deposition decreased in 13/14 (13 out of 14 total) regions and SO(4) in runoff decreased at 14/17 catchments. In contrast, NO(3)-N concentrations in deposition decreased in only 1/14 regions, while NH(4)-N concentration patterns varied; increasing at 3/14 regions and decreasing at 2/14 regions. Nitrate concentrations in runoff decreased at 4/17 catchments and increased at only 1 site, whereas runoff levels of NH(4)-N increased at 5/17 catchments. Decreasing trends in deposition were also recorded for Ca, Mg, and K at many of the catchments and on an equivalent basis, accounted for up to 131% (median 22%) of the decrease in acid anion deposition. Base cation concentrations in streams generally declined over time, with significant decreases in Ca, Mg and K occurring at 8, 9 and 7 of 17 sites respectively, which accounted for up to 133% (median 48%) of the decrease in acid anion concentration. Sulphate export exceeded input at 18/21 catchments, likely due to dry deposition and/or internal sources. The majority of N in deposition (31-100%; median 94%) was retained in the catchments, although there was a tendency for greater NO(3)-N leaching at sites receiving higher (<7 kg ha(-1) per year) bulk inorganic N deposition. Mass balance calculations show that export of Ca and Mg in runoff exceeds input at all 21 catchments, but K export only exceeds input at 16/21 sites. Estimates of base cation weathering were available for 18 sites. When included in the mass balance calculation, Ca, Mg and K exports exceeded inputs at 14, 10 and 2 sites respectively. Annual Ca and Mg losses represent appreciable proportions of the current exchangeable soil Ca and Mg pools, although losses at some of the sites likely occur from weathering reactions beneath the rooting zone and there is considerable uncertainty associated with mineral weathering estimates. Critical loads for sulphur (S) and N, using a critical base cation to aluminium ratio of 10 in soil solution, are currently exceeded at 7 of the 18 sites with base cation weathering estimates. Despite reductions in SO(4) and H(+) deposition, mass balance estimates indicate that acid deposition continues to acidify soils in many regions with losses of Ca and Mg of primary concern.

Acid Rain↗
PubMed2005

Couple-focused group intervention for women with early stage breast cancer.

This study examined the efficacy of a couple-focused group intervention on psychological adaptation of women with early stage breast cancer and evaluated whether perceived partner unsupportive behavior or patient functional impairment moderated intervention effects. Two hundred thirty-eight women were randomly assigned to receive either 6 sessions of a couple-focused group intervention or usual care. Intent-to-treat growth curve analyses indicated that participants assigned to the couples' group reported lower depressive symptoms. Women rating their partners as more unsupportive benefited more from the intervention than did women with less unsupportive partners, and women with more physical impairment benefited more from the intervention group than did women with less impairment. Subgroup analyses comparing women attending the couple-focused group intervention with women not attending groups and with usual care participants indicated that women attending sessions reported significantly less distress than did women receiving usual care and women who dropped out of the intervention.

Adult↗
PubMed2004

Immune responses of breast cancer patients to mutated epidermal growth factor receptor (EGF-RvIII, Delta EGF-R, and de2-7 EGF-R).

Mutated epidermal growth factor receptor (EGF-RvIII, DeltaEGF-R, and de2-7 EGF-R) is the result of an 801-bp deletion within the extracellular domain of wild-type EGF-R and is expressed by breast carcinomas, but not by normal breast tissues. EGF-RvIII is expressed both on the surface and in the cytoplasm of tumor cells. Thus, EGF-RvIII is a potential tumor-specific target for both Abs and T cells. However, it is not known whether breast cancer patients can raise immune responses to EGF-RvIII expressed by their tumors. The demonstration of EGF-RvIII-specific immune responses in patients would suggest that immunization of patients with EGF-RvIII vaccines is feasible, because these vaccines may boost a pre-existing immune response. We have evaluated humoral and cellular immune responses to EGF-RvIII in 16 breast cancer patients and three healthy donors. Seven of 16 patients developed EGF-RvIII-specific Abs that bound to isolated EGF-RvIII protein or the protein expressed by EGF-RvIII-transfected mouse fibroblasts. The Abs that bound to EGF-RvIII did not bind to wild-type EGF-R, and anti-EGF-RvIII Abs were not found in the sera of healthy donors. Three patients had EGF-RvIII peptide-specific lymphoproliferative responses, and two of these patients also had humoral immune responses. Humoral and cellular immune responses correlated with EGF-RvIII expression by patients' tumors in most cases. These studies demonstrate that breast cancer patients specifically recognize EGF-RvIII with an overall immune response rate of 50%, suggesting that patients may benefit from vaccination against EGF-RvIII, boosting pre-existing immune responses.

Adult↗
PubMed2004

Partial recovery of brain metabolism in methamphetamine abusers after protracted abstinence.

OBJECTIVE: Methamphetamine is a highly addictive drug of abuse that is neurotoxic to dopamine terminals. The authors recently reported that decreases in dopamine transporters (used as markers of dopamine terminals) in the striatum of methamphetamine abusers recover with protracted abstinence and that relative to comparison subjects, recently detoxified methamphetamine abusers have lower metabolism in the striatum and thalamus. In this study, the authors assessed whether metabolism recovers with protracted abstinence. METHOD: Brain glucose metabolism was measured with positron emission tomography and [18F]fluorodeoxyglucose in five methamphetamine abusers who were evaluated after both a short (<6 months) and protracted (12-17 months) abstinence interval, eight methamphetamine abusers tested only after protracted abstinence, and 11 comparison subjects who were not drug users. RESULTS: Significantly greater thalamic, but not striatal, metabolism was seen following protracted abstinence relative to metabolism assessed after a short abstinence interval, and this increase was associated with improved performance in motor and verbal memory tests. Relative to the comparison subjects, the methamphetamine abusers tested after protracted abstinence had lower metabolism in the striatum (most accentuated in the caudate and nucleus accumbens) but not in the thalamus. CONCLUSIONS: The persistent decreases in striatal metabolism in methamphetamine abusers could reflect long-lasting changes in dopamine cell activity, and decreases in the nucleus accumbens could account for the persistence of amotivation and anhedonia in detoxified methamphetamine abusers. The recovery of thalamic metabolism could reflect adaptation responses to compensate for the dopamine deficits, and the associated improvement in neuropsychological performance further indicates its functional significance. These results suggest that while protracted abstinence may reverse some of the methamphetamine-induced alterations in brain function, other deficits persist.

Adaptation, Physiological↗
PubMed2003

Synchronous loss of quasispecies memory in parallel viral lineages: a deterministic feature of viral quasispecies.

Viral quasispecies are endowed with a memory of their past evolutionary history in the form of minority genomes of their mutant spectra. To determine the fate of memory genomes in evolving viral quasispecies, we have measured memory levels of antigenic variant of foot-and-mouth disease virus (FMDV) RED, which includes an Arg-Glu-Asp (RED) at a surface antigenic loop of the viral capsid. The RED reverted to the standard Arg-Gly-Asp (RGD), and the RED remained as memory in the evolving quasispecies. In four parallel evolutionary lineages, memory reduction followed a strikingly similar pattern, and at passage 60 memory levels were indistinguishable from those of control populations (devoid of memory). Nucleotide sequence analyses indicated that memory loss occurred synchronously despite its ultimate molecular basis being the stochastic occurrence of mutations in the evolving quasispecies. These results on the kinetics of memory levels have unveiled a deterministic feature of viral quasispecies. Molecular mechanisms that may underlie synchronous memory loss are the averaging of noise signals derived from mutational input, and constraints to genome diversification imposed by a nucleotide sequence context in the viral genome. Possible implications of the behaviour of complex, adaptive viral systems as experimental models to address primary mechanisms of neurological memory are discussed.

Amino Acid Sequence↗
PubMed2002

Relationships among brain metabolites, cognitive function, and viral loads in antiretroviral-naïve HIV patients.

This study aims to determine the relationship among cerebral metabolite concentrations (on proton magnetic resonance spectroscopy or (1)H MRS), cognitive function, and clinical variables (CD4, plasma and CSF viral loads, and lipids) in antiretroviral medication-nai;ve HIV patients. We hypothesized that the probable glial markers myo-inositol [MI] and choline compounds [CHO] would correlate with cognitive function, CD4 count, and viral loads, but not with serum lipids. Forty-five antiretroviral-drug-nai;ve HIV patients and 25 control subjects were evaluated. Frontal lobe [MI], [CHO], and total creatine [CR] were elevated, while basal ganglia [CR] were decreased, with increasing dementia severity. As a group, HIV patients showed slowing on fine motor (Grooved Pegboard) and psychomotor function (Trails A & B), and deficits on executive function (Stroop tasks). Lower CD4 counts and elevated plasma viral loads were associated with elevated frontal white matter [MI], which in turn correlated with the Stroop tasks. These findings suggest that systemic factors (resulting from suppressed immune function and higher plasma viral load) may lead to glial proliferation (elevated [MI], [CHO], and [CR]) in the frontal white matter, which in turn may contribute to deficits on executive function in HIV. Studying antiretroviral-nai;ve patients minimized the confounding effects of antiretroviral treatment on the clinical, MRS, and neuropsychological variables, and allowed for a more accurate assessment of the relationships among these measurements. Metabolite concentrations, rather than metabolite ratios, should be measured since [CR], a commonly used reference for metabolite ratios, varies with disease severity in both frontal lobe and basal ganglia.

AIDS Dementia Complex↗