Pediatric Erythroid Sarcoma Diagnostically Confirmed by Identification of a Recurrent NFIA::CBFA2T3 Fusion.

Erythroid sarcoma (ES) is exceedingly rare in the pediatric population with only a handful of reports of de novo cases, mostly occurring in the central nervous system (CNS) or orbit. It is clinically and pathologically challenging and can masquerade as a nonhematopoietic small round blue cell tumor. Clinical presentation of ES without bone marrow involvement makes diagnosis particularly difficult. We describe a 22-month-old female with ES who presented with a 2-cm mass involving the left parotid region and CNS. The presence of crush/fixation artifact from the initial biopsy made definitive classification of this highly proliferative and malignant neoplasm challenging despite an extensive immunohistochemical workup. Molecular studies including RNA-sequencing revealed a NFIA::CBFA2T3 fusion. This fusion has been identified in several cases of de novo acute erythroid leukemia (AEL) and gene expression analysis comparing this case to other AELs revealed a similar transcriptional profile. Given the diagnostically challenging nature of this tumor, clinical RNA-sequencing was essential for establishing a diagnosis.

Selection of endurance capabilities and the trade-off between pressure and volume in the evolution of the human heart.

Chimpanzees and gorillas, when not inactive, engage primarily in short bursts of resistance physical activity (RPA), such as climbing and fighting, that creates pressure stress on the cardiovascular system. In contrast, to initially hunt and gather and later to farm, it is thought that preindustrial human survival was dependent on lifelong moderate-intensity endurance physical activity (EPA), which creates a cardiovascular volume stress. Although derived musculoskeletal and thermoregulatory adaptations for EPA in humans have been documented, it is unknown if selection acted similarly on the heart. To test this hypothesis, we compared left ventricular (LV) structure and function across semiwild sanctuary chimpanzees, gorillas, and a sample of humans exposed to markedly different physical activity patterns. We show the human LV possesses derived features that help augment cardiac output (CO) thereby enabling EPA. However, the human LV also demonstrates phenotypic plasticity and, hence, variability, across a wide range of habitual physical activity. We show that the human LV's propensity to remodel differentially in response to chronic pressure or volume stimuli associated with intense RPA and EPA as well as physical inactivity represents an evolutionary trade-off with potential implications for contemporary cardiovascular health. Specifically, the human LV trades off pressure adaptations for volume capabilities and converges on a chimpanzee-like phenotype in response to physical inactivity or sustained pressure loading. Consequently, the derived LV and lifelong low blood pressure (BP) appear to be partly sustained by regular moderate-intensity EPA whose decline in postindustrial societies likely contributes to the modern epidemic of hypertensive heart disease.

Comparative analysis of MBD-seq and MeDIP-seq and estimation of gene expression changes in a rodent model of schizophrenia.

We conducted a comparative study of multiplexed affinity enrichment sequence methodologies (MBD-seq and MeDIP-seq) in a rodent model of schizophrenia, induced by in utero methylazoxymethanol acetate (MAM) exposure. We also examined related gene expression changes using a pooled sample approach. MBD-seq and MeDIP-seq identified 769 and 1771 differentially methylated regions (DMRs) between F2 offspring of MAM-exposed rats and saline control rats, respectively. The assays showed good concordance, with ~56% of MBD-seq-detected DMRs being identified by or proximal to MeDIP-seq DMRs. There was no significant overlap between DMRs and differentially expressed genes, suggesting that DNA methylation regulatory effects may act upon more distal genes, or are too subtle to detect using our approach. Methylation and gene expression gene ontology enrichment analyses identified biological processes important to schizophrenia pathophysiology, including neuron differentiation, prepulse inhibition, amphetamine response, and glutamatergic synaptic transmission regulation, reinforcing the utility of the MAM rodent model for schizophrenia research.

Novel epigenetic determinants of type 2 diabetes in Mexican-American families.

Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.

Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression.

The use of easily accessible peripheral samples, such as blood or saliva, to investigate neurological and neuropsychiatric disorders is well-established in genetic and epigenetic research, but the pathological implications of such biomarkers are not easily discerned. To better understand the relationship between peripheral blood- and brain-based epigenetic activity, we conducted a pilot study on captive baboons (Papio hamadryas) to investigate correlations between miRNA expression in peripheral blood mononuclear cells (PBMCs) and 14 different cortical and subcortical brain regions, represented by two study groups comprised of 4 and 6 animals. Using next-generation sequencing, we identified 362 miRNAs expressed at ≥ 10 read counts in 80% or more of the brain samples analyzed. Nominally significant pairwise correlations (one-sided P < 0.05) between peripheral blood and mean brain expression levels of individual miRNAs were observed for 39 and 44 miRNAs in each group. When miRNA expression levels were averaged for tissue type across animals within the groups, Spearman's rank correlations between PBMCs and the brain regions are all highly significant (r s = 0.47-0.57; P < 2.2 × 10-16), although pairwise correlations among the brain regions are markedly stronger (r s = 0.86-0.99). Principal component analysis revealed differentiation in miRNA expression between peripheral blood and the brain regions for the first component (accounting for ∼75% of variance). Linear mixed effects modeling attributed most of the variance in expression to differences between miRNAs (>70%), with non-significant 7.5% and 13.1% assigned to differences between blood and brain-based samples in the two study groups. Hierarchical UPGMA clustering revealed a major co-expression branch in both study groups, comprised of miRNAs globally upregulated in blood relative to the brain samples, exhibiting an enrichment of miRNAs expressed in immune cells (CD14+, CD15+, CD19+, CD3+, and CD56 + leukocytes) among the top blood-brain correlates, with the gene MYC, encoding a master transcription factor that regulates angiogenesis and neural stem cell activation, representing the most prevalent miRNA target. Although some differentiation was observed between tissue types, these preliminary findings reveal wider correlated patterns between blood- and brain-expressed miRNAs, suggesting the potential utility of blood-based miRNA profiling for investigating by proxy certain miRNA activity in the brain, with implications for neuroinflammatory and c-Myc-mediated processes.

Genomic and systems evolution in Vibrionaceae species.

BACKGROUND: The steadily increasing number of prokaryotic genomes has accelerated the study of genome evolution; in particular, the availability of sets of genomes from closely related bacteria has facilitated the exploration of the mechanisms underlying genome plasticity. The family Vibrionaceae is found in the Gammaproteobacteria and is abundant in aquatic environments. Taxa from the family Vibrionaceae are diversified in their life styles; some species are free living, others are symbiotic, and others are human pathogens. This diversity makes this family a useful set of model organisms for studying bacterial evolution. This evolution is driven by several forces, among them gene duplication and lateral gene transfer, which are believed to provide raw material for functional redundancy and novelty. The resultant gene copy increase in one genome is then detected as lineage-specific expansion (LSE). RESULTS: Here we present the results of a detailed comparison of the genomes of eleven Vibrionaceae strains that have distinct life styles and distinct phenotypes. The core genome shared by all eleven strains is composed of 1,882 genes, which make up about 31%-50% of the genome repertoire. We further investigated the distribution and features of genes that have been specifically expanded in one unique lineage of the eleven strains. Abundant duplicate genes have been identified in the eleven Vibrionaceae strains, with 1-11% of the whole genomes composed lineage specific radiations. These LSEs occurred in two distinct patterns: the first type yields one or more copies of a single gene; we call this a single gene expansion. The second pattern has a high evolutionary impact, as the expansion involves two or more gene copies in a block, with the duplicated block located next to the original block (a contiguous block expansion) or at some distance from the original block (a discontiguous block expansion). We showed that LSEs involve genes that are tied to defense and pathogenesis mechanisms as well as in the fundamental life cycle of Vibrionaceae species. CONCLUSION: Our results provide evidence of genome plasticity and rapid evolution within the family Vibrionaceae. The comparisons point to sources of genomic variation and candidates for lineage-specific adaptations of each Vibrionaceae pathogen or nonpathogen strain. Such lineage specific expansions could reveal components in bacterial systems that, by their enhanced genetic variability, can be tied to responses to environmental challenges, interesting phenotypes, or adaptive pathogenic responses to host challenges.

Assessment of right ventricular function by real-time three-dimensional echocardiography improves accuracy and decreases interobserver variability compared with conventional two-dimensional views.

AIMS: Two-dimensional echocardiographic (2DE) assessment of right ventricular (RV) function is difficult, often resulting in inconsistent RV evaluation. Real-time three-dimensional echocardiography (RT3DE) allows the RV to be viewed in multiple planes, which can potentially improve RV assessment and limit interobserver variability when compared with 2DE. METHODS AND RESULTS: Twenty-five patients underwent 2DE and RT3DE. Views of 2DE (RV inflow, RV short axis, and apical four-chamber) were compared with RT3DE views by four readers. RT3DE data sets were sliced from anterior-posterior (apical view) and from base to apex (short axis) to obtain six standardized planes. Readers recorded the RV ejection fraction (RVEF) from 2DE and RT3DE images. RVEF recorded by RT3DE (RVEF(3D)) and 2D (RVEF(2D)) were compared with RVEF by disc summation (RVEF(DS)), which was used as a reference. Interobserver variability among readers of RVEF(3D) and RVEF(2D) was then compared. Overall, mean RVEF(DS), RVEF(3D), and RVEF(2D) were 37 +/- 11%, 38 +/- 10%, 41 +/- 10%, respectively. The mean difference of RVEF(3D)-RVEF(DS) was significantly less than RVEF(2D)-RVEF(DS) (3.7 +/- 4% vs. 7.1 +/- 5%, P = 0.0066, F-test). RVEF(3D) correlated better with RVEF(DS) (r = 0.875 vs. r = 0.69, P = 0.028, t-test). RVEF(3D) was associated with a 39% decrease in interobserver variability when compared with RVEF(2D) [standard deviation of mean difference: 3.7 vs. 5.1, (RT3DE vs. 2DE), P = 0.018, t-test]. CONCLUSIONS: RT3DE provides improved accuracy of RV function assessment and decreases interobserver variability when compared with 2D views.

Endurance exercise training attenuates natriuretic peptide release during maximal effort exercise: biochemical correlates of the "athlete's heart".

Endurance exercise training (ET) stimulates eccentric left ventricular hypertrophy (LVH) with left atrial dilation. To date, the biochemical correlates of exercise-induced cardiac remodeling (EICR) remain incompletely understood. Collegiate male rowers (n = 9) were studied with echocardiography and maximal-effort cardiopulmonary exercise testing (MECPET) before and after 90 days of ET intensification. Midregional proatrial natriuretic peptide (MR-proANP), NH2-terminal pro B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T were measured at rest, peak MECPET, and 60 min post-MECPET at both study time points. Endurance exercise training resulted in eccentric LVH (LV mass = 102 ± 8 vs. 110 ± 11 g/m2, P = 0.001; relative wall thickness = 0.36 ± 0.04 vs. 0.37 ± 0.04, P = 0.103), left atrial dilation (74 ± 18 vs. 84 ± 15 ml, P < 0.001), and increased exercise capacity (peak V̇o2 = 53.0 ± 5.9 vs. 67.3 ± 8.2 ml·kg-1·min-1, P < 0.001). Left ventricular remodeling was characterized by an ~7% increase in LV wall thickness but only a 3% increase in LV chamber radius. The magnitude of natriuretic peptide release, examined as percent change from rest to peak exercise, was significantly lower for both MR-proANP (115 [95,127]% vs. 78 [59,87]%, P = 0.04) and NT-proBNP (46 [31,70]% vs. 27 [25,37]%, P = 0.02) after ET. Rowing-based ET and corollary EICR appear to result in an attenuated natriuretic peptide response to maximal effort exercise. This may occur as a function of decreased cardiac wall stress after ET as seen by disproportionally higher ventricular wall thickening compared with chamber dilation.NEW & NOTEWORTHY Using longitudinal pre- and postendurance training natriuretic peptide measurements, we demonstrate that the development of exercise-induced cardiac remodeling results in an attenuated natriuretic peptide response to acute bouts of maximal intensity exercise. Exercise-induced cardiac remodeling was associated with a disproportionally higher ventricular wall thickening compared with chamber dilation, a pattern that reduces cardiac wall stress. These observations advance our understanding of both the structural and biochemical adaptations that underlie the cardiovascular response to endurance training.

Promoting Precision Addiction Management (PAM) to Combat the Global Opioid Crisis.

It is universally agreed that dopamine is a major neurotransmitter in terms of reward dependence, however, there remains controversy regarding how to modulate its role clinically to treat and prevent relapse for both substance and non-substance-related addictive behaviors. It is also agreed by most that there is a need to provide early genetic identification possibly through a novel researched technology referred to Genetic Addiction Risk Score(GARS).™ The existing FDA-approved medications promote blocking dopamine, however, we argue that a more prudent paradigm shift should be biphasic-short-term blockade and long-term upregulation, enhancing functional connectivity of brain reward. It is critical to understand that the real phenotype is not any specific drug or non -drug addictive behavior, but instead is Reward Deficiency Syndrome (RDS). Thus the true phenotype of all addictive behaviors is indeed RDS. Finally, we are suggesting that one way to combat the current out of control Opioid /Alcohol crisis worldwide is to seriously reconsider treating RDS by simply supplying powerful narcotic agents (e.g. Buprenorphine). This type of treatment will only keep people addicted. A more reasonable solution involving genetic testing, urine drug screens using Comprehensive Analysis of Reported Drugs (CARD) and dopamine homeostasis we call " Precision Addiction Management" ™ seems parsonomiuos.

The Benefits of Genetic Addiction Risk Score (GARS™) Testing in Substance Use Disorder (SUD).

Following 25 years of extensive research by many scientists worldwide, a panel of ten reward gene risk variants, called the Genetic Addiction Risk Score (GARS), has been developed. In unpublished work, when GARS was compared to the Addiction Severity Index (ASI), which has been used in many clinical settings, GARS significantly predicted the severity of both alcohol and drug dependency. In support of early testing for addiction and other RDS subtypes, parents caught up in the current demographic of 127 people, both young and old, dying daily from opiate/opioid overdose, need help. In the past, families would have never guessed that their loved ones would die or could be in real danger due to opiate addiction. Author, Bill Moyers, in Parade Magazine, reported that as he traveled around the United States, he found many children with ADHD and other spectrum disorders like Autism, and noted that many of these children had related conditions like substance abuse. He called for better ways to identify these children and treat them with approaches other than addictive pharmaceuticals. To our knowledge, GARS is the only panel of genes with established polymorphisms reflecting the Brain Reward Cascade (BRC), which has been correlated with the ASI-MV alcohol and drug risk severity score. While other studies are required to confirm and extend the GARS test to include other genes and polymorphisms that associate with an hypodopaminergic trait, these results provide clinicians with a non-invasive genetic test. Genomic testing, such as GARS, can improve clinical interactions and decision-making. Knowledge of precise polymorphic associations can help in the attenuation of guilt and denial, corroboration of family gene-o-grams; assistance in risk-severity-based decisions about appropriate therapies, including pain medications and risk for addiction; choice of the appropriate level of care placement (i.e., inpatient, outpatient, intensive outpatient, residential); determination of the length of stay in treatment; determination of genetic severity-based relapse and recovery liability and vulnerability; determination of pharmacogenetic medical monitoring for better clinical outcomes (e.g., the A1 allele of the DRD2 gene reduces the binding to opioid delta receptors in the brain, thus, reducing Naltrexone's clinical effectiveness); and supporting medical necessity for insurance scrutiny.

GLOBAL OPIOID EPIDEMIC: DOOMED TO FAIL WITHOUT GENETICALLY BASED PRECISION ADDICTION MEDICINE (PAM™): LESSONS LEARNED FROM AMERICA.

It is a reality that globally opioid deaths have soared for men and women of all social, economic status and age from heroin and fentanyl overdoses. Specifically, in the United States, deaths from narcotic overdoses have reached alarming metrics since 2010. In fact, the Fentanyl rise is driven by drug dealers who sell it as heroin or who use it to lace cocaine or to make illegal counterfeit prescription opioids. The President's Commission on the crisis has linked the death toll as equivalent to "September 11th every three weeks." In fact, The U.S. Centre for Disease Control (CDC) released data showing that opioid-related overdoses were up 15% in the first three quarters of 2016 compared to 2015. Various governmental organizations including NIDA, are actively seeking solutions. However, we argue that unless the scientific community embraces genetic addiction risk coupled with potential precision or personalized medicine to induce "dopamine homeostasis" it will fail. We now have evidence that a ten-gene and eleven single nucleotide polymorphism (SNP) panel predicts Addiction Severity Index (ASI) for both alcohol and drugs of abuse (e.g., Opioids). In a large multi-addiction centre study involving seven diverse treatment programs, the genetic addiction risk score (GARS™) was shown to have a predictive relationship with ASI-MV derived alcohol (≥ seven alleles), and other drugs (≥ 4 alleles) severity risk scores. In a number of neuroimaging studies, we also display that in both animal (bench) and abstinent Chinese severe heroin-dependent patients (bedside), BOLD dopamine activation across the brain reward circuitry revealed increases in resting state functional connectivity as well volume connectivity. It is also known that published nutrigenomic (coupling gene polymorphisms with altered KB220z) studies reveal improved clinical outcomes related to obesity.

"Dopamine homeostasis" requires balanced polypharmacy: Issue with destructive, powerful dopamine agents to combat America's drug epidemic.

The well-researched pro-dopamine regulator KB220 and variants result in increased functional connectivity in both animal and human brains, and prolonged neuroplasticity (brain cell repair) having been observed in rodents. Moreover, in addition to increased functional connectivity, recent studies show that KB220Z increases overall brain connectivity volume, enhances neuronal dopamine firing, and eliminates lucid dreams in humans over a prolonged period. An unprecedented number of clinical studies validating this patented nutrigenomic technology in re-balancing brain chemistry and optimizing dopamine sensitivity and function have been published. On another note, it is sad that unsuspecting consumers could be deceived and endangered by false promises of knock-off marketers with look- and- sound-alike products. Products containing ingredients having potential dangers (i.e., combinations of potent D2 agonists including L-Dopa and L-Theanine) threaten the credibility and reputation of validated, authentic, and ethical products. We encourage clinicians and neuroscientists to continue to embrace the concept of "dopamine homeostasis" and search for safe, effective, validated and authentic means to achieve a lifetime of recovery, instead of reverting to anti-dopaminergic agents doomed to fail in the war against the devastating drug epidemic, or promoting powerful D2 agonists that compromise needed balance.

Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia.

Both environmental and genetic factors contribute to schizophrenia; however, the exact etiology of this disorder is not known. Animal models are utilized to better understand the mechanisms associated with neuropsychiatric diseases, including schizophrenia. One of these involves gestational administration of methylazoxymethanol acetate (MAM) to induce a developmental disruption, which in turn produces a schizophrenia-like phenotype in post-pubertal rats. The mechanisms by which MAM produces this phenotype are not clear; however, we now demonstrate that MAM induces differential DNA methylation, which may be heritable. Here we demonstrate that a subset of both second (F2) and third (F3) filial generations of MAM-treated rats displays a schizophrenia-like phenotype and hypermethylation of the transcription factor, Sp5. Specifically, ventral tegmental area of dopamine neuron activity was examined using electrophysiology as a correlate for the dopamine hyperfunction thought to underlie psychosis in patients. Interestingly, only a subset of F2 and F3 MAM rats exhibited increases in dopamine neuron population activity, indicating that this may be a unique model with a susceptibility to develop a schizophrenia-like phenotype. An increase in dopamine system function in rodent models has been previously associated with decreases in hippocampal GABAergic transmission. In line with these observations, we found a significant correlation between hippocampal parvalbumin expression and dopamine neuron activity in F2 rats. These data therefore provide evidence that offspring born from MAM-treated rats possess a susceptibility to develop aspects of a schizophrenia-like phenotype and may provide a useful tool to investigate gene-environment interactions.

Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families.

BACKGROUND: There is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (≥95 cm in males and ≥80 cm in females) combined with high serum triglyceride concentration (≥2.0 mmol/L in males and ≥1.5 mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease. However, the prevalence of this phenotype in high-risk populations, its association with T2D, and the genetic or epigenetic influences on HTGW are not well explored. Using data from large, extended families of Mexican Americans (a high-risk minority population in the USA) we aimed to: (1) estimate the prevalence of this phenotype, (2) test its association with T2D and related traits, and (3) dissect out the genetic and epigenetic associations with this phenotype using genome-wide and epigenome-wide studies, respectively. RESULTS: Data for this study was from 850 Mexican American participants (representing 39 families) recruited under the ongoing San Antonio Family Heart Study, 26 % of these individuals had HTGW. This phenotype was significantly heritable (h (2) r = 0.52, p = 1.1 × 10(-5)) and independently associated with T2D as well as fasting glucose levels and insulin resistance. We conducted genome-wide association analyses using 759,809 single nucleotide polymorphisms (SNPs) and epigenome-wide association analyses using 457,331 CpG sites. There was no evidence of any SNP associated with HTGW at the genome-wide level but two CpG sites (cg00574958 and cg17058475) in CPT1A and one CpG site (cg06500161) in ABCG1 were significantly associated with HTGW and remained significant after adjusting for the closely related components of metabolic syndrome. CPT1A holds a cardinal position in the metabolism of long-chain fatty acids while ABCG1 plays a role in triglyceride metabolism. CONCLUSIONS: Our results reemphasize the value of HTGW as a marker of T2D. This phenotype shows association with DNA methylation within CPT1A and ABCG1, genes involved in fatty acid and triglyceride metabolism. Our results underscore the importance of epigenetics in a clinically informative phenotype.

The feasibility, diagnostic yield, and learning curve of portable echocardiography for out-of-hospital cardiovascular disease screening.

BACKGROUND: The reduction in the size of full-capability echocardiographic machines facilitates "out-of-hospital" transthoracic echocardiography (TTE). Data documenting the feasibility, yield, and logistical considerations of out-of-hospital TTE for preparticipation evaluation of athletes are sparse. METHODS: A multiyear study was conducted to examine the role of 12-lead electrocardiography for athlete screening in which TTE was used to document or exclude underlying structural heart disease. Using a commercially available portable transthoracic echocardiographic system, the rate of technically adequate imaging, diagnostic yield, and the time required for the completion of TTE (including setup, performance, and interpretation) were examined. TTE was performed in university medical offices and at "out-of-office" athletic facilities. Measurements were recorded during each year of the study to determine the impact of targeted attempts to improve efficiency. RESULTS: Four hundred sixty-seven of 510 participants had transthoracic echocardiographic images that were technically adequate for complete interpretation (imaging success rate, 92%). Echocardiographic evidence of physiologic, exercise-induced cardiac remodeling was observed in 110 of 510 (22%). Cardiac abnormalities with relevance to sports participation risk were detected in 11 of 508 participants (2.2%). Over 3 years, the average time for the completion of TTE (including setup, imaging, and interpretation) decreased (year 1, 17.4 ± 3 min; year 2, 14.0 ± 2.1 min; year 3, 11.0 ± 1.8 min; P < .001). This was driven by a significant decrease in the time required for TTE at out-of-office athletic facilities. CONCLUSIONS: Community-based TTE in athletes is feasible and is associated with a high rate of technically adequate imaging. Importantly, there appears to be a significant learning curve associated with out-of-hospital TTE.

Genome evolution and functional divergence in Yersinia.

The steadily increasing number of prokaryotic genomes has accelerated the study of genome evolution; in particular, the availability of sets of genomes from closely related bacteria has made exploration of questions surrounding the evolution of pathogenesis tractable. Here we present the results of a detailed comparison of the genomes of Yersinia pseudotuberculosis IP32593 and three strains of Yersinia pestis (CO92, KIM10, and 91001). There appear to be between 241 and 275 multigene families in these organisms. There are 2,568 genes that are identical in the three Y. pestis strains, but differ from the Y. pseudotuberculosis strain. The changes found in some of these families, such as the kinases, proteases, and transporters, are illustrative of how the evolutionary jump from the free-living enteropathogen Y. pseudotuberculosis to the obligate host-borne blood pathogen Y. pestis was achieved. We discuss the composition of some of the most important families and discuss the observed divergence between Y. pseudotuberculosis and Y. pestis homologs.