Estimating Dependency Structure as a Hidden Variable

This paper introduces a probability model, the mixture of trees that can account for sparse, dynamically changing dependence relationships. We present a family of efficient algorithms that use EM and the Minimum Spanning Tree algorithm to find the ML and MAP mixture of trees for a variety of priors, including the Dirichlet and the MDL priors. We also show that the single tree classifier acts like an implicit feature selector, thus making the classification performance insensitive to irrelevant attributes. Experimental results demonstrate the excellent performance of the new model both in density estimation and in classification.

Syntheses, structures, some reactions, and electrochemical oxidation of ferrocenylethynyl complexes of iron, ruthenium, and osmium

The syntheses and characterizations of several complexes containing ferrocenylethynyl and ferrocene-1,1'-bis(ethynyl) groups attached to M(PP)Cp'[M = Fe, Ru, PP = dppe, Cp'= Cp*; M = Ru, Os, PP = (PPh3)(2), dppe, Cp' = Cp] are described. Reactions with tetracyanoethene have given either tetracyanobuta-1,3-dienyl or eta(3)-allylic derivatives, while addition of Me+ afforded the corresponding vinylidene derivatives. Some electrochemical measurements are discussed in terms of electronic communication between the redox-active M(PP)Cp' groups through the ferrocene nucleus. The molecular structures of 14 of these complexes have been determined by crystallographic methods.

Comparison of the radiative properties and direct radiative effect of aerosols from a global aerosol model and remote sensing data over ocean

A global aerosol transport model (Oslo CTM2) with main aerosol components included is compared to five satellite retrievals of aerosol optical depth (AOD) and one data set of the satellite-derived radiative effect of aerosols. The model is driven with meteorological data for the period November 1996 to June 1997 which is the time period investigated in this study. The modelled AOD is within the range of the AOD from the various satellite retrievals over oceanic regions. The direct radiative effect of the aerosols as well as the atmospheric absorption by aerosols are in both cases found to be of the order of 20 Wm−2 in certain regions in both the satellite-derived and the modelled estimates as a mean over the period studied. Satellite and model data exhibit similar patterns of aerosol optical depth, radiative effect of aerosols, and atmospheric absorption of the aerosols. Recently published results show that global aerosol models have a tendency to underestimate the magnitude of the clear-sky direct radiative effect of aerosols over ocean compared to satellite-derived estimates. However, this is only to a small extent the case with the Oslo CTM2. The global mean direct radiative effect of aerosols over ocean is modelled with the Oslo CTM2 to be –5.5 Wm−2 and the atmospheric aerosol absorption 1.5 Wm−2.

Cancer classification using the Immunoscore: a worldwide task force

Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).

Predictors of oral health quality of life in older adults

There is limited information regarding oral health status and other predictors of oral health-related quality of life. An association between oral health status and perceived oral health-related quality of life (OHQOL) might help clinicians motivate patients to prevent oral diseases and improve the outcome of some dental public health programs. This study evaluated the relationship between older persons' OHQOL and their functional dentition, caries, periodontal status, chronic diseases, and some demographic characteristics. A group of 733 low-income elders (mean age 72.7 [SD = 4.71, 55.6% women, 55.1% members of ethnic minority groups in the U.S. and Canada) enrolled in the TEETH clinical trial were interviewed and examined as part of their fifth annual visit for the trial. OHQOL was measured by the Geriatric Oral Health Assessment Index (GOHAI); oral health and occlusal status by clinical exams and the Eichner Index; and demographics via interviews. Elders who completed the four-year assessment had an average of 21.5 teeth (SD = 6.9), with 8.5 occluding pairs (SD = 4.6), and 32% with occlusal contacts in all four occluding zones. Stepwise multiple regressions were conducted to predict total GOHAI and its subscores (Physical, Social, and Worry). Functional dentition was a less significant predictor than ethnicity and being foreign-born. These variables, together with gender, years since immigrating, number of carious roots, and periodontal status, could predict 32% of the variance in total GOHAI, 24% in Physical, 27% in Social, and 21% in the Worry subscales. These findings suggest that functional dentition and caries influence older adults' OHQOL, but that ethnicity and immigrant status play a larger role.

Chlorhexidine and preservation of sound tooth structure in older adults. A placebo-controlled trial

The Trial to Enhance Elderly Teeth Health (TEETH) was designed to test the impact of regular rinsing with a 0.12% chlorhexidine (CHX) solution on tooth loss, and the causes of tooth loss (caries, periodontal disease and trauma) were also investigated. This paper reports on the effectiveness of a 0.12% CHX solution for controlling caries using a tooth surface (coronal and root) survival analysis. A total of 1,101 low income elders in Seattle (United States) and Vancouver (Canada), aged 60-75 years, were recruited for a double-blind clinical trial and assigned to either a CHX (n = 550) or a placebo (n = 551) mouth rinse. Subjects alternated between daily rinsing for 1 month, followed by weekly rinsing for 5 months. All sound coronal and root surfaces at baseline were followed annually for up to 5 years. At each follow-up examination, those tooth surfaces with caries, restored, or extracted were scored as 'carious'. The hazard ratio associated with CHX for a sound surface to become filled, decayed, or extracted was 0.87 for coronal surfaces (95% confidence interval: 0.71-1.14, p = 0.20) and 0.91 for root surfaces (95% confidence interval: 0.73-1.14, p = 0.41). These findings suggest that regular rinsing with CHX does not have a substantial effect on the preservation of sound tooth structure in older adults.

Brain mechanisms of quantity are similar in 5-year-old children and adults

Both 5-year-old children and adults determine the quantity of a number by the use of a similar parietal lobe mechanism. Event related potentials indicate that input from Arabic digits and from dot patterns reach areas involved in determining quantity about 200 ms after input. However, voluntary key presses indicating the relation of the input to the quantity five take almost three times as long in children. The ability to trace the networks of brain areas involved in the learning of school subjects should aid in the design and testing of educational methods.

Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes

To discover genes involved in von Hippel-Lindau (VHL)-mediated carcinogenesis, we used renal cell carcinoma cell lines stably transfected with wild-type VHL-expressing transgenes. Large-scale RNA differential display technology applied to these cell lines identified several differentially expressed genes, including an alpha carbonic anhydrase gene, termed CA12. The deduced protein sequence was classified as a one-pass transmembrane CA possessing an apparently intact catalytic domain in the extracellular CA module. Reintroduced wild-type VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines. Similar results were obtained with CA9, encoding another transmembrane CA with an intact catalytic domain. Although both domains of the VHL protein contribute to regulation of CA12 expression, the elongin binding domain alone could effectively regulate CA9 expression. We mapped CA12 and CA9 loci to chromosome bands 15q22 and 17q21.2 respectively, regions prone to amplification in some human cancers. Additional experiments are needed to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth.

Inactivation of calcium-activated chloride channels in smooth muscle by calcium/calmodulin-dependent protein kinase

To determine the mechanisms responsible for the termination of Ca2+-activated Cl− currents (ICl(Ca)), simultaneous measurements of whole cell currents and intracellular Ca2+ concentration ([Ca2+]i) were made in equine tracheal myocytes. In nondialyzed cells, or cells dialyzed with 1 mM ATP, ICl(Ca) decayed before the [Ca2+]i decline, whereas the calcium-activated potassium current decayed at the same rate as [Ca2+]i. Substitution of AMP-PNP or ADP for ATP markedly prolonged the decay of ICl(Ca), resulting in a rate of current decay similar to that of the fall in [Ca2+]i. In the presence of ATP, dialysis of the calmodulin antagonist W7, the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor KN93, or a CaMKII-specific peptide inhibitor the rate of ICl(Ca) decay was slowed and matched the [Ca2+]i decline, whereas H7, a nonspecific kinase inhibitor with low affinity for CaMKII, was without effect. When a sustained increase in [Ca2+]i was produced in ATP dialyzed cells, the current decayed completely, whereas in cells loaded with 5′-adenylylimidodiphosphate (AMP-PNP), KN93, or the CaMKII inhibitory peptide, ICl(Ca) did not decay. Slowly decaying currents were repeatedly evoked in ADP- or AMP-PNP-loaded cells, but dialysis of adenosine 5′-O-(3-thiotriphosphate) or okadaic acid resulted in a smaller initial ICl(Ca), and little or no current (despite a normal [Ca2+]i transient) with a second stimulation. These data indicate that CaMKII phosphorylation results in the inactivation of calcium-activated chloride channels, and that transition from the inactivated state to the closed state requires protein dephosphorylation.

Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II

The classically recognized functions of the renin–angiotensin system are mediated by type 1 (AT1) angiotensin receptors. Whereas man possesses a single AT1 receptor, there are two AT1 receptor isoforms in rodents (AT1A and AT1B) that are products of separate genes (Agtr1a and Agtr1b). We have generated mice lacking AT1B (Agtr1b −/−) and both AT1A and AT1B receptors (Agtr1a −/−Agtr1b −/−). Agtr1b −/− mice are healthy, without an abnormal phenotype. In contrast, Agtr1a −/−Agtr1b −/− mice have diminished growth, vascular thickening within the kidney, and atrophy of the inner renal medulla. This phenotype is virtually identical to that seen in angiotensinogen-deficient (Agt−/−) and angiotensin-converting enzyme-deficient (Ace −/−) mice that are unable to synthesize angiotensin II. Agtr1a −/−Agtr1b −/− mice have no systemic pressor response to infusions of angiotensin II, but they respond normally to another vasoconstrictor, epinephrine. Blood pressure is reduced substantially in the Agtr1a −/− Agtr1b −/− mice and following administration of an angiotensin converting enzyme inhibitor, their blood pressure increases paradoxically. We suggest that this is a result of interruption of AT2-receptor signaling. In summary, our studies suggest that both AT1 receptors promote somatic growth and maintenance of normal kidney structure. The absence of either of the AT1 receptor isoforms alone can be compensated in varying degrees by the other isoform. These studies reaffirm and extend the importance of AT1 receptors to mediate physiological functions of the renin–angiotensin system.

Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation

Jaagsiekte sheep retrovirus (JSRV) can induce rapid, multifocal lung cancer, but JSRV is a simple retrovirus having no known oncogenes. Here we show that the envelope (env) gene of JSRV has the unusual property that it can induce transformation in rat fibroblasts, and thus is likely to be responsible for oncogenesis in animals. Retrovirus entry into cells is mediated by Env interaction with particular cell-surface receptors, and we have used phenotypic screening of radiation hybrid cell lines to identify the candidate lung cancer tumor suppressor HYAL2/LUCA2 as the receptor for JSRV. HYAL2 was previously described as a lysosomal hyaluronidase, but we show that HYAL2 is actually a glycosylphosphatidylinositol (GPI)-anchored cell-surface protein. Furthermore, we could not detect hyaluronidase activity associated with or secreted by cells expressing HYAL2, whereas we could easily detect such activity from cells expressing the related serum hyaluronidase HYAL1. Although the function of HYAL2 is currently unknown, other GPI-anchored proteins are involved in signal transduction, and some mediate mitogenic responses, suggesting a potential role of HYAL2 in JSRV Env-mediated oncogenesis. Lung cancer induced by JSRV closely resembles human bronchiolo-alveolar carcinoma, a disease that is increasing in frequency and now accounts for ≈25% of all lung cancer. The finding that JSRV env is oncogenic and the identification of HYAL2 as the JSRV receptor provide tools for further investigation of the mechanism of JSRV oncogenesis and its relationship to human bronchiolo-alveolar carcinoma.

Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma

Transthyretin (TTR) tetramer dissociation and misfolding facilitate assembly into amyloid fibrils that putatively cause senile systemic amyloidosis and familial amyloid polyneuropathy. We have previously discovered more than 50 small molecules that bind to and stabilize tetrameric TTR, inhibiting amyloid fibril formation in vitro. A method is presented here to evaluate the binding selectivity of these inhibitors to TTR in human plasma, a complex biological fluid composed of more than 60 proteins and numerous small molecules. Our immunoprecipitation approach isolates TTR and bound small molecules from a biological fluid such as plasma, and quantifies the amount of small molecules bound to the protein by HPLC analysis. This approach demonstrates that only a small subset of the inhibitors that saturate the TTR binding sites in vitro do so in plasma. These selective inhibitors can now be tested in animal models of TTR amyloid disease to probe the validity of the amyloid hypothesis. This method could be easily extended to evaluate small molecule binding selectivity to any protein in a given biological fluid without the necessity of determining or guessing which other protein components may be competitors. This is a central issue to understanding the distribution, metabolism, activity, and toxicity of potential drugs.