Large deviation theorems for empirical types of Markov chainsconstrained to thin sets

An irreducible Markov chain with stationary transition probabilities on a finite directed graph is considered. The probability of large deviations of the random variable denoting the empirical type of the first n transitions is investigated     

Train Tracks and Confluent Drawings

Confluent graphs capture the connection properties of train tracks, offering a very natural generalization of planar graphs, and—as the example of railroad maps shows—are an important tool in graph visualization. In this paper we continue the study of confluent graphs, introducing strongly confluent graphs and tree-confluent graphs. We show that strongly confluent graphs can be recognized in NP (the complexity of recognizing confluent graphs remains open). We also give a natural elimination ordering characterization of tree-confluent graphs, and we show that this class coincides with the (6,2)-chordal bipartite graphs. Finally, we define outerconfluent graphs and identify the bipartite permutation graphs as a natural subclass.     

Correlates of osteopenia in patients with cystic fibrosis

The responses to heat shock in Tritrichomonas mobilensis, a squirrel monkey parasite and Tritrichomonas augusta, an amphibian trichomonad, were evaluated by means of metabolic labeling with [35S]methionine. Electrophoretically separated trichomonad proteins synthesized at different temperatures were visualized by autoradiography and the label incorporation quantitated by a trichloroacetic acid precipitation procedure. A considerable difference in thermotolerance between the two species was found as the protein synthesis reached a maximum at 41 C in T. mobilensis and 37 C in T. augusta. The latter tolerated temperature increases 13 C above normal cultivation temperatures as compared to only 4 C thermotolerance range above normal in T. mobilensis. Major heat shock proteins (Hsps) were expressed in both T. mobilensis (with apparent Mr 94, 72, and 58 kDa) and T. augusta (Mr 94, 70, and 56 kDa) as revealed by autoradiography. Western blot analysis with polyclonal antibody against DnaK of Escherichia coli showed the presence of antigenic Hsp70 homologs in both trichomonads. Similarly, a polyclonal antibody against Hsp60 with broad interspecies cross-reactivity detected Hsp60 homologs in both T. mobilensis and T. augusta. The anti-DnaK antibody cross-reacted with a T. mobilensis protein localized in Golgi apparatus as demonstrated by immunoelectron microscopy. Immunocytochemistry on trichomonad frozen sections revealed the presence of the Hsp60 homolog in light-microscopic granules corresponding to hydrogenosomes.     

Semantic priming in schizophrenia: An examination of spreading activation using word pronunciation and multiple SOAs.

Semantic priming in word pronunciation was examined at 5 stimulus onset asynchronies (SOAs) in 75 medicated and 25 unmedicated people with schizophrenia (SCZ) and in 10 depressed and 28 normal controls. At SOAs     

An atomic model of the outer layer of the bluetongue virus core derived from X-ray crystallography and electron cryomicroscopy

BACKGROUND: Bluetongue virus (BTV), which belongs to the Reoviridae family and orbivirus genus, is a non-enveloped, icosahedral, double-stranded RNA virus. Several protein layers enclose its genome; upon cell entry the outer layer is stripped away leaving a core, the surface of which is composed of VP7. The structure of the trimeric VP7 molecule has previously been determined using X-ray crystallography. The articulated VP7 subunit consists of two domains, one which is largely alpha-helical and the other, smaller domain, is a beta barrel with jelly-roll topology. The relative orientations of these two domains vary in different crystal forms. The structure of VP7 and the organizations of 780 subunits of this molecule in the core of virus is central to the assembly and function of BTV. RESULTS: A 23 A resolution map of the core, determined using electron cryomicroscopy (cryoEM) data, reveals that the 260 trimers of VP7 are organized on a rather precise T = 13 laevo icosahedral lattice, in accordance with the theory of quasi-equivalence. The VP7 layer occupies a shell that is between 260 A and 345 A from the centre of the core. Below this radius (230-260 A) lies the T = 1 layer of 120 molecules of VP3. By fitting the X-ray structure of an individual VP7 trimer onto the cryoEM BTV core structure, we have generated an atomic model of the VP7 layer of BTV. This demonstrates that one of the molecular structures seen in crystals of the isolated VP7 corresponds to the in vivo conformation of the molecule in the core. CONCLUSIONS: The beta-barrel domains of VP7 are external to the core and interact with protein in the outer layer of the mature virion. The lower, alpha-helical domains of VP7 interact with VP3 molecules which form the inner layer of the BTV core. Adjacent VP7 trimer-trimer interactions in the T = 13 layer are mediated principally through well-defined regions in the broader lower domains, to form a structure that conforms well with that expected from the theory of quasi-equivalence with no significant conformational changes within the individual trimers. The VP3 layer determines the particle size and forms a rather smooth surface upon which the two-dimensional lattice of VP7 trimers is laid down.     

Does colonoscopic polypectomy reduce the incidence of colorectal carcinoma?

The study's objective was to examine whether there is evidence that colonoscopic polypectomy reduces the incidence of colorectal cancer. The records of all patients who underwent colonoscopic polypectomy by a single surgeon between 1974 and 1991 were reviewed. Patients with colorectal cancer diagnosed at the initial colonoscopy, with a history of colorectal cancer, inflammatory bowel disease or familial adenomatous polyposis or with only hyperplastic polyps were excluded. There were 1008 remaining patients, of whom 645 have attended at least one follow-up colonoscopic examination, and these 645 patients from the basis of the study, because the incidence of cancer is known exactly in this group. The mean period of follow up was 4.4 years and the mean number of follow-up colonoscopic examinations was 2.2. There was a total of 2847 person-years of colonoscopic follow up. The expected incidence of cancer, age and sex adjusted, is calculated using Australian epidemiological figures. The observed incidence of cancer was 3 cases (all asymptomatic) per 2847 person-years, which is indistinguishable from the general population's risk of 3.75 cases per 2847 person-years. Analysis of previous publications suggests that patients with adenomas are at an increased risk of developing colorectal cancer of about 2.5 times the general population's risk. If correct, then the observed incidence of 3 cases per 2847 person-years is less than the expected incidence of 9.4 cases per 2847 person-years. This analysis suggests colonoscopic polypectomy does reduce the incidence of colorectal cancer.     

Method for determining musculotendon parameters in subject-specific musculoskeletal models of children developed from MRI data

Accurate knowledge of muscle-tendon parameters in biomechanical models is critical for accurate simulation and analyses of human movement. An excellent example of this is the creation of subject-specific models from magnetic resonance imaging (MRI). When Hill-type muscle models are used to calculate muscle forces, the determination of muscle attachment points, optimal fiber length, tendon slack length and maximum isometric force all have a significant influence on the joint moment-angle behavior of the model. In the present study a method was developed for customizing the values of muscle-tendon parameters in a generic model to create subject-specific biomechanical models from MRI. The method was applied by generating musculoskeletal models for the biomechanical simulation platform OpenSim, but the workflow is equally well applicable to other simulation platforms. New computational algorithms are described for identifying joint centers and for reconstructing the centroids of the muscle bellies from MRI. A?process is also described for the extraction of the muscle paths and for identifying the positions of ??via-points?? used to model muscles wrapping over bones. Finally, a new algorithm is described for adjusting the values of optimal fiber length, tendon slack length and maximum isometric force based on a comparison of the model results with experiment. We tested our computational algorithms by developing subject-specific biomechanical models of five typically developed children (age 9.5±1.7?years) from MRI. The joint moment-angle relationships calculated for the subject-specific models were similar to those determined for corresponding scaled generic models. The results indicate that the proposed methodology is suitable for developing subject-specific models of healthy children. Future studies should investigate how abnormalities of the musculoskeletal system, such as tibial torsion and muscle spasticity, can be integrated into the modeling process.     

Energy Metabolites as Biomarkers in Ischemic and Dilated Cardiomyopathy

With more than 25 million people affected, heart failure (HF) is a global threat. As energy production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM (p = 1.7 × 10⁻⁶). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting enzymes of these pathways could also be found and validated in our second stage of metabolite assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades that potentially represent suitable intervention targets.     

Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.