Postsystolic thickening detected by Doppler myocardial imaging: A marker of viability or ischemia in patients with myocardial infarction

Background: Postsystolic thickening (PST) of ischemic myocardial segments has been reported to account for the characteristic heterogeneity or regional asynchrony of myocardial wall motion during acute ischemia. Hypothesis: Postsystolic thickening detected by Doppler myocardial imaging (DMI) could be a useful clinical index of myocardial viability or peri-infarction viability in patients with myocardial infarction (MI). Methods: Doppler myocardial imaging was recorded at each stage of a standard dobutamine stress echocardiogram (DSE) in 20 patients (16 male, 60 +/- 13 years) with an NIT in the territory of the left anterior descending artery. Myocardial velocity data were measured in the interventricular septum and apical inferior segment of the MI territory. Postsystolic thickening was identified if the absolute velocity of PST was higher than peak systolic velocity in the presence of either a resting PST > 2.0 cm/s or if PST doubled at low-dose dobutamine infusion. Results: Doppler myocardial imaging data could be analyzed in 38 ischemic segments (95%), and PST was observed in 21 segments (55%), including 3 segments showing PST only at low-dose dobutamine infusion. There was no significant difference of baseline wall motion score index (2.1 +/- 0.3 vs. 2.1 +/- 0.6, p = 0.77) or peak systolic velocity (1.1 +/- 1.1 vs. 1.9 +/- 2.0 cm/s, p = 0.05) between segments with and without PST Peri-infarction ischemia or viability during DSE was more frequently observed in segments with PST than in those without (86 vs. 24%, p < 0.05). The sensitivity and specificity of PST for prediction of peri-infarction viability or ischemia was 82 and 81%, respectively. Conclusions: Postsystolic thickening in the infarct territory detected by DMI is closely related with peri-infarction ischemia or viability at DSE.

HLS5, a novel RBCC (ring finger, B box, coiled-coil) family member isolated from a hemopoietic lineage switch, is a candidate tumor suppressor

Hemopoietic cells, apparently committed to one lineage, can be reprogrammed to display the phenotype of another lineage. The J2E erythroleukemic cell line has on rare occasions developed the features of monocytic cells. Subtractive hybridization was used in an attempt to identify genes that were up-regulated during this erythroid to myeloid transition. We report here on the isolation of hemopoietic lineage switch 5 (Hls5), a gene expressed by the monocytoid variant cells, but not the parental J2E cells. Hls5 is a novel member of the RBCC (Ring finger, B box, coiled-coil) family of genes, which includes Pml, Herf1, Tif-1alpha, and Rfp. Hls5 was expressed in a wide range of adult tissues; however, at different stages during embryogenesis, Hls5 was detected in the branchial arches, spinal cord, dorsal root ganglia, limb buds, and brain. The protein was present in cytoplasmic granules and punctate nuclear bodies. Isolation of the human cDNA and genomic DNA revealed that the gene was located on chromosome 8p21, a region implicated in numerous leukemias and solid tumors. Enforced expression of Hls5 in HeLa cells inhibited cell growth, clonogenicity, and tumorigenicity. It is conceivable that HLS5 is one of the tumor suppressor genes thought to reside at the 8p21 locus.

Genetic and economic analysis of a targeted marker-assisted wheat breeding strategy

The advent of molecular markers as a tool to aid selection has provided plant breeders with the opportunity to rapidly deliver superior genetic solutions to problems in agricultural production systems. However, a major constraint to the implementation of marker-assisted selection (MAS) in pragmatic breeding programs in the past has been the perceived high relative cost of MAS compared to conventional phenotypic selection. In this paper, computer simulation was used to design a genetically effective and economically efficient marker-assisted breeding strategy aimed at a specific outcome. Under investigation was a strategy involving the integration of both restricted backcrossing and doubled haploid (DH) technology. The point at which molecular markers are applied in a selection strategy can be critical to the effectiveness and cost efficiency of that strategy. The application of molecular markers was considered at three phases in the strategy: allele enrichment in the BC1F1 population, gene selection at the haploid stage and the selection for recurrent parent background of DHs prior to field testing. Overall, incorporating MAS at all three stages was the most effective, in terms of delivering a high frequency of desired outcomes and at combining the selected favourable rust resistance, end use quality and grain yield alleles. However, when costs were included in the model the combination of MAS at the BC1F1 and haploid stage was identified as the optimal strategy. A detailed economic analysis showed that incorporation of marker selection at these two stages not only increased genetic gain over the phenotypic alternative but actually reduced the over all cost by 40%.

Inflammation suppressor genes: please switch out all the lights

An effective immune system requires rapid and appropriate activation of inflammatory mechanisms but equally rapid and effective resolution of the inflammatory state. A review of the canonical host response to gram-negative bacteria, the lipopolysaccharide-Toll-like receptor 4 signaling cascade, highlights the induction of repressors that act at each step of the activation process. These inflammation suppressor genes are characterized by their induction in response to pathogen, typically late in the macrophage activation program, and include an expanding class of dominant-negative proteins derived from alternate splicing of common signaling components. Despite the expanse of anti-inflammatory mechanisms available to an activated macrophage, the frailty of this system is apparent in the large numbers of genes implicated in chronic inflammatory diseases. This apparent lack of redundancy between inflammation suppressor genes is discussed with regard to evolutionary benefits in generating a heterogeneous population of immune cells and consequential robustness in defense against new and evolving pathogens.

Olfactory marker protein modulates primary olfactory axon overshooting in the olfactory bulb

Olfactory marker protein (OMP) is expressed by mature primary olfactory sensory neurons during development and in adult mice. In mice that lack OMP, olfactory sensory neurons have perturbed electrophysiological activity, and the mice exhibit altered responses and behavior to odor stimulation. To date, defects in axon guidance in mice that lack OMP have not been investigated. During development of the olfactory system in mouse, primary olfactory axons often overshoot their target glomerular layer and project into the deeper external plexiform layer. These aberrant axonal projections are normally detected within the external plexiform layer up to postnatal day 12. We have examined the projections of primary olfactory axons in OMP-tau:LacZ mice and OMP-GFP mice, two independent lines in which the OMP coding region has been replaced by reporter molecules. We found that axons overshoot their target layer and grow into the external plexiform layer in these OMP null mice as they do in wild-type animals. However, in the absence of OMP, overshooting axons are more persistent and remain prominent until 5 weeks postnatally, after which their numbers decrease. Overshooting axons are still present in these mice even at 8 months of age. In heterozygous mice, axons also overshoot into the external plexiform layer; however, there are fewer axons, and they project for shorter distances, compared with those in a homozygous environment. Our results suggest that perturbed electrophysiological responses, caused by loss of OMP in primary olfactory neurons, reduce the ability of primary olfactory axons to recognize their glomerular target. © 2005 Wiley-Liss, Inc.

E2F suppression and Sp1 overexpression are sufficient to induce the differentiation-specific marker, transglutaminase type 1, in a squamous cell carcinoma cell line

Recently, E2F function has expanded to include the regulation of differentiation in human epidermal keratinocytes (HEKs). We extend these findings to report that in HEKs, Sp1 is a differentiation-specific activator and a downstream target of E2F-mediated suppression of the differentiation-specific marker, transglutaminase type 1 (TG-1). Deletion of elements between -0.084 to -0.034 kb of the TG-1 promoter disabled E2F1-induced suppression of promoter activity. Electrophoretic mobility shift assays (EMSAs) demonstrated that Sp1 and Sp3 bound this region. Protein expression analysis suggested that squamous differentiation was accompanied by increased Sp1/Sp3 ratio. Cotransfection of proliferating HEKs or the squamous cell carcinoma (SCC) cell line, KJD-1/SV40, with an E2F inhibitor (E2Fd/n) and Sp1 expression plasmid was sufficient to activate the TG-1 promoter. The suppression of Sp1 activity by E2F in differentiated cells appeared to be indirect since we found no evidence of an Sp1/E2F coassociation on the TG-1 promoter fragment. Moreover, E2F inhibition in the presence of a differentiation stimulus induced Sp1 protein. These data demonstrate that (i) Sp1 can act as a differentiation stimulus, (ii) E2F-mediated suppression of differentiation-specific markers is indirect via Sp1 inhibition and (iii) a combination of E2F inhibition and Sp1 activation could form the basis of a differentiation therapy for SCCs.

A probabilistic switch model of information flow in social networks: Application for virtual circuits to organizational design

Network building and exchange of information by people within networks is crucial to the innovation process. Contrary to older models, in social networks the flow of information is noncontinuous and nonlinear. There are critical barriers to information flow that operate in a problematic manner. New models and new analytic tools are needed for these systems. This paper introduces the concept of virtual circuits and draws on recent concepts of network modelling and design to introduce a probabilistic switch theory that can be described using matrices. It can be used to model multistep information flow between people within organisational networks, to provide formal definitions of efficient and balanced networks and to describe distortion of information as it passes along human communication channels. The concept of multi-dimensional information space arises naturally from the use of matrices. The theory and the use of serial diagonal matrices have applications to organisational design and to the modelling of other systems. It is hypothesised that opinion leaders or creative individuals are more likely to emerge at information-rich nodes in networks. A mathematical definition of such nodes is developed and it does not invariably correspond with centrality as defined by early work on networks.

Alpha B-crystallin, a new independent marker for poor prognosis in head and neck cancer

Objectives. Gene expression profiling has provided many insights into tumor progression but translation to clinical practice has been limited. We have previously identified a list of potential markers by the differences of expression profiling of seven matched head and neck cancer (HNSCC) tumors with autologous normal oral mucosa (NOM). Alpha B-crystallin (CRYAB) was in the top 5% of genes identified with statistically significant differences in expression between tumor and NOM at the mRNA level. The objective was to confirm this in routine paraffin sections at the protein level. Study Design: The level of alpha B-crystallin was determined in tumors of 62 HNSCC patients whose prognosis was known for 5 years. Methods. Immunohistochemical detection of alpha B-crystallin expression was performed on HNSCC paraffin sections. Results. Univariate survival analysis identified lack of alpha B-crystallin staining as an independent prognostic marker for disease-free interval (P < 0.001) and overall survival (P < 0.002) of HNSCC patients over the 5-year observation period. Notably, all 13 patients (100%), including 5 patients with nodal disease whose tumors lacked alpha B-crystallin had no recurrences (P < 0.001). Nineteen of 27 node-negative patients stained positive for alpha B-crystallin and seven of the 19 (36.8%) had recurrences. Conclusion: Presence or absence of expression of alpha B-crystallin was a powerful marker for prognosis in this series of patients.

A Genetic Marker to Separate Emiliania Huxleyi (Prymnesiophyceae) Morphotypes

Emiliania huxleyi (Lohm.) Hay and Mohler is a ubiquitous unicellular marine alga surrounded by an elaborate covering of calcite platelets called coccoliths. It is an important primary producer involved in oceanic biogeochemistry and climate regulation. Currently, E. huxleyi is separated into five morphotypes based on morphometric, physiological, biochemical, and immunological differences. However, a genetic marker has yet to be found to characterize these morphotypes. With the use of sequence analysis and denaturing gradient gel electrophoresis, we discovered a genetic marker that correlates significantly with the separation of the most widely recognized A and B morphotypes. Furthermore, we reveal that the A morphotype is composed of a number of distinct genotypes. This marker lies within the 3' untranslated region of a coccolith associated protein mRNA, which is implicated in regulating coccolith calcification. Consequently, we tentatively termed this marker the coccolith morphology motif.

Platelet nitric oxide responsiveness - A novel prognostic marker in acute coronary syndromes

Objectives - Nitric oxide (NO) is critically important in the regulation of vascular tone and the inhibition of platelet aggregation. We have shown previously that patients with acute coronary syndromes (ACS) or stable angina pectoris have impaired platelet responses to NO donors when compared with normal subjects. We tested the hypotheses that platelet hyporesponsiveness to NO is a predictor of (1) cardiovascular readmission and/or death and (2) all-cause mortality in patients with ACS (unstable angina pectoris or non-Q-wave myocardial infarction). Methods and Results - Patients (n = 51) with ACS had evaluation of platelet aggregation within 24 hours of coronary care unit admission using impedance aggregometry. Patients were categorized as having normal (>= 32% inhibition of ADP-induced aggregation with the NO donor sodium nitroprusside; 10 mu mol/L; n = 18) or impaired (>= 32% inhibition of ADP-induced aggregation; n = 33) NO responses. We then compared the incidence of cardiovascular readmission and death during a median of 7 years of follow-up in these 2 groups. Using a Cox proportional hazards model adjusting for age, sex, index event, postdischarge medical treatment, revascularization status, left ventricular systolic dysfunction, concurrent disease states, and cardiac risk factors, impaired NO responsiveness was associated with an increased risk of the combination of cardiovascular readmission and/or death (relative risk, 2.7; 95% CI, 1.03 to 7.10; P = 0.041) and all-cause mortality (relative risk, 6.3; 95% CI, 1.09 to 36.7; P = 0.033). Conclusions - Impaired platelet NO responsiveness is a novel, independent predictor of increased mortality and cardiovascular morbidity in patients with high-risk ACS.

Mapping the I-3 gene for resistance to Fusarium wilt in tomato: application of an I-3 marker in tomato improvement and progress towards the cloning of I-3

Fusarium wilt of tomato, caused by the fungal pathogen, Fusarium oxysporum f. sp. lycopersici (Fol), is an economically damaging disease that results in huge losses in Australia and other countries worldwide. The I-3 gene, which confers resistance to Fol race 3, has been described in wild tomato, Lycopersicon pennellii, accessions LA716 and PI414773. We are pursuing the isolation of I-3 from LA716 by map-based cloning. We have constructed a high-resolution map of the I-3 region and have identified markers closely flanking I-3 as well as markers co-segregating with I-3. In addition, construction of a physical map based on these markers has been initiated. This review describes the context of our research and our progress towards isolating the I-3 gene. It also describes some important practical outcomes of our work, including the development and use of a PCR-based marker for marker-assisted selection for I-3, and the finding that the I-3 gene from LA716 is different to that from PI1414773, which we have now designated I-7. Tomato varieties combining I-3 and I-7 have been developed and are currently being introduced into commercial production to further safeguard tomato crops against Fusarium wilt.

Stochastic models for regulatory networks of the genetic toggle switch

Bistability arises within a wide range of biological systems from the A phage switch in bacteria to cellular signal transduction pathways in mammalian cells. Changes in regulatory mechanisms may result in genetic switching in a bistable system. Recently, more and more experimental evidence in the form of bimodal population distributions indicates that noise plays a very important role in the switching of bistable systems. Although deterministic models have been used for studying the existence of bistability properties under various system conditions, these models cannot realize cell-to-cell fluctuations in genetic switching. However, there is a lag in the development of stochastic models for studying the impact of noise in bistable systems because of the lack of detailed knowledge of biochemical reactions, kinetic rates, and molecular numbers. in this work, we develop a previously undescribed general technique for developing quantitative stochastic models for large-scale genetic regulatory networks by introducing Poisson random variables into deterministic models described by ordinary differential equations. Two stochastic models have been proposed for the genetic toggle switch interfaced with either the SOS signaling pathway or a quorum-sensing signaling pathway, and we have successfully realized experimental results showing bimodal population distributions. Because the introduced stochastic models are based on widely used ordinary differential equation models, the success of this work suggests that this approach is a very promising one for studying noise in large-scale genetic regulatory networks.