Visual perception in a snapshot.
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Attention↗
Biomedical subjects
Mark Elliott
Publications and source records attributed to Mark Elliott.
Characterization of preexisting humoral immunity specific for two cancer-testis antigens overexpressed at the mRNA level in non-small cell lung cancer.
In order to establish a rationale for immunotherapy for lung cancer, we have investigated immunological characteristics of tumor-associated antigens (TAAs) discovered through molecular approaches. Preexisting Abs specific to these predicted TAAs were examined using specimens of lung pleural effusions (LPEs) and sera in non-small cell lung cancer (NSCLC) patients. The novel cancer-testis (CT) antigens L514S and L552S were highly expressed in approximately half of the NSCLC tissues and established cell lines examined. When lung cancer patients in the USA and Japan were screened, 13%, 17%, and 5% were found to have Abs specific to recombinant L514S, L552S, and NY-ESO-1 proteins, respectively, whereas 48 normal donors had no Abs to these three CT antigens. The Ab titers specific to recombinant L552S and L514S proteins were similar to, and slightly lower than, Abs specific to NY-ESO-1 in stage IV NSCLC patients. To further characterize the preexisting specific Abs, the epitopes were analyzed using 20-aa length peptides entirely covering both antigens. An epitope common to the patients' L514S-specific Abs was identified as aa 85-100 and multiple epitopes, including a major epitope (aa 141-160), were identified for L552S-specific Abs. The Ab epitopes thus identified are not found in human, animal, or bacterial proteins, other than L514S, L552S, or XAGE-1. These data clearly demonstrate that both molecularly defined CT antigens L514S and L552S are immunogenic, at least in terms of humoral responses, suggesting that both CT antigens are promising candidates for immunotherapy.
Amino Acid Sequence↗
Use of semiconductor-based oligonucleotide microarrays for influenza a virus subtype identification and sequencing.
In the face of concerns over an influenza pandemic, identification of virulent influenza A virus isolates must be obtained quickly for effective responses. Rapid subtype identification, however, is difficult even in well-equipped virology laboratories or is unobtainable in the field under more austere conditions. Here we describe a genome assay and microarray design that can be used to rapidly identify influenza A virus hemagglutinin subtypes 1 through 15 and neuraminidase subtypes 1 through 9. Also described is an array-based enzymatic assay that can be used to sequence portions of both genes or any other sequence of interest.
Gene Expression Profiling↗
Diversity of the CD8+ T-cell response to herpes simplex virus type 2 proteins among persons with genital herpes.
Cytolytic T cells play a major role in controlling herpes simplex virus type 2 (HSV-2) infections in humans. In an effort to more thoroughly evaluate the response to HSV-2 directly, ex vivo, we developed an enzyme-linked immunospot (ELISPOT) assay that utilized pools of overlapping synthetic peptides presented by autologous dendritic cells to purified CD8(+) T cells. Donor response rates to individual open reading frames (ORFs) ranged from fewer than 5% responding to as many as 70% responding, with the greatest frequency of responses (by ORF) being directed against UL39, UL25, UL27, ICP0, UL46, and UL47 in descending order of frequency. HSV-2-seropositive subjects responded to as few as 3 or as many as 46 of the 48 ORFs tested, with a median of 11 ORFs recognized. HLA-B*07 expression correlated with stronger responses overall that were directed primarily against UL49 and UL46. Cumulative precursor frequencies in the blood ranged from 500 to almost 6,000 HSV-2 spot-forming units/10(6) CD8(+) T cells. The magnitude and breadth of the response in the infected population were greater than previously appreciated. Whether this variability in the CD8(+) T-cell response within individuals is associated with the frequency of viral reactivation warrants further study.
CD8-Positive T-Lymphocytes↗
Evidence-based ethics?
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Biomedical Research↗
Levels-of-processing effect on frontotemporal function in schizophrenia during word encoding and recognition.
OBJECTIVE: Patients with schizophrenia improve episodic memory accuracy when given organizational strategies through levels-of-processing paradigms. This study tested if improvement is accompanied by normalized frontotemporal function. METHOD: Event-related blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) was used to measure activation during shallow (perceptual) and deep (semantic) word encoding and recognition in 14 patients with schizophrenia and 14 healthy comparison subjects. RESULTS: Despite slower and less accurate overall word classification, the patients showed normal levels-of-processing effects, with faster and more accurate recognition of deeply processed words. These effects were accompanied by left ventrolateral prefrontal activation during encoding in both groups, although the thalamus, hippocampus, and lingual gyrus were overactivated in the patients. During word recognition, the patients showed overactivation in the left frontal pole and had a less robust right prefrontal response. CONCLUSIONS: Evidence of normal levels-of-processing effects and left prefrontal activation suggests that patients with schizophrenia can form and maintain semantic representations when they are provided with organizational cues and can improve their word encoding and retrieval. Areas of overactivation suggest residual inefficiencies. Nevertheless, the effect of teaching organizational strategies on episodic memory and brain function is a worthwhile topic for future interventional studies.
Adult↗
Securing the healthcare border.
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Computer Communication Networks↗
Isolation and characterization of the human tRNA-(N1G37) methyltransferase (TRM5) and comparison to the Escherichia coli TrmD protein.
A human TRM5 cDNA has been cloned and recombinant tRNA-N(1)G37 methyltransferase was produced. The recombinant enzyme methylates the N1 position of guanosine 37 (G37) in selected tRNA transcripts utilizing S-adenosyl methionine. The effects of RNA sequence and structure on the methylation reaction in comparison between the Escherichia coli TrmD and human TRM5 recombinant enzymes are presented. G37-methylation by TRM5 occurs regardless of the nature of the nucleotide at position 36. TRM5 also methylates inosine at position 37 unlike TrmD, which recognizes the G36pG37 motif preferentially and does not methylate inosine. New evidence is presented concerning TrmD showing that with some tRNA species, A at position 36 is also recognized. The TRM5 enzyme is sensitive to subtle changes in the tRNA-protein tertiary interaction leading to loss of activity. The TrmD enzyme is more tolerant of alterations in tRNA-protein tertiary interactions as long as the core tRNA structure and the G36pG37 are present. The TRM5 enzyme does not have an absolute requirement for magnesium ions, whereas TrmD requires magnesium to express activity. TRM5 demonstrates much higher affinity for substrates with K(m) values for tRNA that are nanomolar. TrmD has K(m) values for tRNA in the micromolar range. Recombinant TRM5 appears to function as a 60 772 Da monomer, while recombinant TrmD functions as a homodimer of 30 586 Da subunits. Bioinformatic analysis of the human TRM5 genomic locus (KIAA1393) have identified TRM5 homologues in eukaryotes and archaea; however, no significantly homologous regions were identified in any prokaryotes including the TrmD gene.
Base Sequence↗
Event-related fMRI of frontotemporal activity during word encoding and recognition in schizophrenia.
OBJECTIVE: Neuropsychological studies have demonstrated verbal episodic memory deficits in schizophrenia during word encoding and retrieval. This study examined neural substrates of memory in an analysis that controlled for successful retrieval. METHOD: Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation during word encoding and recognition in 14 patients with schizophrenia and 15 healthy comparison subjects. An unbiased multiple linear regression procedure was used to model the BOLD response, and task effects were detected by contrasting the signal before and after stimulus onset. RESULTS: Patients attended during encoding and had unimpaired reaction times and normal response biases during recognition, but they had lower recognition discriminability scores, compared with the healthy subjects. Analysis of contrasts was restricted to correct items. Previous findings of a deficit in bilateral prefrontal cortex activation during encoding in patients were reproduced, but patients showed greater parahippocampal activation rather than deficits in temporal lobe activation. During recognition, left dorsolateral prefrontal cortex activation was lower in the patients and right anterior prefrontal cortex activation was preserved, as in the authors' previous study using positron emission tomography. Successful retrieval was associated with greater right dorsolateral prefrontal cortex activation in the comparison subjects, whereas orbitofrontal, superior frontal, mesial temporal, middle temporal, and inferior parietal regions were more active in the patients during successful retrieval. CONCLUSIONS: The pattern of prefrontal cortex underactivation and parahippocampal overactivation in the patients suggests that functional connectivity of dorsolateral prefrontal and temporal-limbic structures is disrupted by schizophrenia. This disruption may be reflected in the memory strategies of patients with schizophrenia, which include reliance on rote rehearsal rather than associative semantic processing.
Adult↗
Type II estrogen binding site agonist: synthesis and biological evaluation of the enantiomers of methyl-para-hydroxyphenyllactate (MeHPLA).
A high-affinity ligand for the type II estrogen binding site (EBS) was identified. Methyl para-hydroxyphenyllactate (MeHPLA) was observed to suppress the cellular proliferation of estrogen-sensitive MCF-7 breast cancer cells in vitro and to suppress the growth of rat uteri in vivo. The high affinity of MeHPLA for the type II EBS suggests that this interaction is responsible for the observed suppression of cell growth. In this study, the enantiomers of MeHPLA were synthesized and separated by three methods and evaluated for biological activity. When the methods were compared, it was found that the method using an optically pure amine to form the diastereomers of the enantiomers gave the superior yield. Binding studies for the enantiomers to the type II EBS showed that the S-MeHPLA had a higher affinity for the binding site. However, higher binding affinity did not translate into superior cell growth suppression. Both enantiomers suppressed cell growth equally.
Animals↗
Effects of muscle activation on fatigue and metabolism in human skeletal muscle.
Increasing stimulation frequency has been shown to increase fatigue but not when the changes in force associated with changes in frequency have been controlled. An effect of frequency, independent of force, may be associated with the metabolic cost resulting from the additional activations. Here, two separate experiments were performed on human medial gastrocnemius muscles. The first experiment (n = 8) was designed to test the effect of the number of pulses on fatigue. The declines in force during two repetitive, 150-train stimulation protocols that produced equal initial forces, one using 80-Hz trains and the other using 100-Hz trains, were compared. Despite a difference of 600 pulses (23.5%), the protocols produced similar rates and amounts of fatigue. In the second experiment, designed to test the effect of the number of pulses on the metabolic cost of contraction, 31P-NMR spectra were collected (n = 6) during two ischemic, eight-train stimulation protocols (80- and 100-Hz) that produced comparable forces despite a difference of 320 pulses (24.8%). No differences were found in the changes in P(i) concentration, phosphocreatine concentration, and intracellular pH or in the ATP turnover produced by the two trains. These results suggest that the effect of stimulation frequency on fatigue is related to the force produced, rather than to the number of activations. In addition, within the range of frequencies tested, increasing total activations did not increase metabolic cost.
Adenosine Triphosphate↗