Differentiation of Mycobacterium ulcerans, M. marinum, and M. haemophilum: mapping of their relationships to M. tuberculosis by fatty acid profile analysis, DNA-DNA hybridization, and 16S rRNA gene sequence analysis.
Although Mycobacterium ulcerans, M. marinum, and M. haemophilum are closely related, their exact taxonomic placements have not been determined. We performed gas chromatography of fatty acids and alcohols, as well as DNA-DNA hybridization and 16S rRNA gene sequence analysis, to clarify their relationships to each other and to M. tuberculosis. M. ulcerans and M. marinum were most closely related to one another, and each displayed very strong genetic affinities to M. tuberculosis; they are actually the two mycobacterial species outside the M. tuberculosis complex most closely related to M. tuberculosis. M. haemophilum was more distinct from M. ulcerans and M. marinum, and it appeared to be as related to these two species as to M. tuberculosis. These results are important with regard to the development of diagnostic and epidemiological tools such as species-specific DNA probes and PCR assays for M. ulcerans, M. marinum, and M. haemophilum. In addition, the finding that M. ulcerans and M. marinum are more closely related to M. tuberculosis than are other pathogenic mycobacterial species suggests that they may be evaluated as useful models for studying the pathogenesis of M. tuberculosis. M. marinum may be particularly useful in this regard since strains of this species grow much more rapidly than M. tuberculosis and yet can cause systemic disease in immunocompromised hosts.


Effect of ACL sacrifice, retention, or substitution on kinematics after TKA.
Total knee arthroplasty (TKA) is an effective treatment for arthritic knee pain, but patients may not return to their desired recreational or functional activity level post-TKA. The difference in functional outcome between patients who underwent TKA and patients with normal (nonarthritic) knees may be related to differences in kinematics between the normal and replaced knee. Posterior cruciate-retaining TKAs are associated with paradoxical motion in which the tibia is subluxed anteriorly in extension and the femur translates anteriorly during knee flexion. However, unicompartmental and patellofemoral arthroplasties, which retain the anterior cruciate ligament (ACL), however provide relatively normal knee kinematics and favorable knee function compared with conventional TKAs, which sacrifice the ACL. Early results with a bicruciate-substituting TKA suggest that ACL function is necessary to achieve more normal kinematics after TKA.


Functional evaluation of gene silencing on macrophages derived from U937 cells using interference RNA (shRNA) in a model of macrophages infected with Leishmania (Viannia) braziliensis.
Leishmaniasis development is multifactorial; nonetheless, the establishment of the infection, which occurs by the survival and replication of the parasite inside its main host cell, the macrophage, is mandatory. Thus, the importance of studying the molecular mechanisms involved in the Leishmania-macrophage interaction is highlighted. The aim of this study was to characterize a cellular model of macrophages derived from U937 cells that would allow for the identification of infection phenotypes induced by genetic silencing with interference RNA in the context of macrophages infected with Leishmania (Viannia) braziliensis. The model was standardized by silencing an exogenous gene (gfp), an endogenous gene (lmna) and a differentially expressed gene between infected and non-infected macrophages (gro-β). The silencing process was successful for the three genes studied, obtaining reductions of 88·9% in the GFP levels, 87·5% in LMNA levels and 74·4% for Gro-β with respect to the corresponding control cell lines. The cell model revealed changes in the infection phenotype of the macrophages in terms of number of amastigotes per infected macrophage, number of amastigotes per sampled macrophage and percentage of infected macrophages as a result of gene silencing. Thus, this cell model constitutes a research platform for the study of parasite-host interactions and for the identification of potentially therapeutic targets.


Aroma profiles and preferences of Jasminum sambac L. flowers grown in Thailand.
Comparison of volatile constituents and odor preference of Jasminum sambac cultivated in Thailand was performed by enfleurage and solvent extractions. Enfleurage bases consisting of spermaceti wax, olive, sunflower, and rice bran oils were prepared. The defleurage flower was daily replaced with fresh jasmine for a period of 12 days. The absolute de pomades and extraits of each base were subjected to gas chromatography mass spectrometry (GC/MS) analysis, comparing with the concrete and absolute values obtained from maceration of jasmine in n-hexane for 24 h. Linalool, benzyl acetate, and α-farnesene were found as the main volatile compounds in the jasmine extracts. Spermaceti wax and olive oil gave the best quality base, exhibiting the most preferred resemblance of jasmine odor with the least difference from fresh jasmine, as evaluated by 103 Thai volunteers.


Size-exclusion chromatography of protected synthetic polypeptide tandems in an organic solvent.
A novel method for analytical and preparative size exclusion chromatography of large water-insoluble protected peptides in an organic solvent was developed. This method was applied to analysis and separation of protected synthetic peptide tandem repeats and to a control of the reaction of peptide fragment coupling. Columns containing Toyopearl HW-40, HW-50; HW-55 and HW-60 gels of Fine grade were used, and the selectivity of each sorbent, as well as the chromatographic behaviour of the peptides on them, were examined. Separation ranges of these gels applied to separation of protected peptides in DMF were shown to be much smaller (ca. 400-14,000 Da) than those of the same gels applied to protein separations in water buffers (100-1,000,000 Da). An initial evaluation of efficiency of Toyopearl HW Superfine grade gels with respect to similar separations was performed.


Deceptive nasal NK/T-cell lymphoma.
Nasal NK/T cell lymphoma is rare and it easily masquerades as chronic rhinosinusitis. It has a very poor prognosis and hence early diagnosis, although difficult, is necessary for better outcome. We present a case of a 30-year-old man who presented with nasal obstruction, facial oedema and crusts. High-resolution computed tomography found soft tissue in all sinuses and the nasal cavity. Endoscopic biopsy revealed necrotic and inflammatory tissue with fungi on culture. A diagnosis of fungal rhinosinusitis was made but the patient did not respond to antifungal drugs. A histopathology review with immunohistochemistry suggested nasal NK/T cell lymphoma. The patient was started on chemotherapy but died within 1 week.


Dynamic Contrast Enhanced MRI Assessing the Antiangiogenic Effect of Silencing HIF-1α with Targeted Multifunctional ECO/siRNA Nanoparticles.
Stabilization of hypoxia inducible factor 1α (HIF-1α), a biomarker of hypoxia, in hypoxic tumors mediates a variety of downstream genes promoting tumor angiogenesis and cancer cell survival as well as invasion, and compromising therapeutic outcome. In this study, dynamic contrast enhanced MRI (DCE-MRI) with a biodegradable macromolecular MRI contrast agent was used to noninvasively assess the antiangiogenic effect of RGD-targeted multifunctional lipid ECO/siHIF-1α nanoparticles in a mouse HT29 colon cancer model. The RGD-targeted ECO/siHIF-1α nanoparticles resulted in over 50% reduction in tumor size after intravenous injection at a dose of 2.0 mg of siRNA/kg every 3 days for 3 weeks compared to a saline control. DCE-MRI revealed significant decline in vascularity and over a 70% reduction in the tumor blood flow, permeability-surface area product, and plasma volume fraction vascular parameters in the tumor treated with the targeted ECO/siHIF-1α nanoparticles. The treatment with targeted ECO/siRNA nanoparticles resulted in significant silencing of HIF-1α expression at the protein level, which also significantly suppressed the expression of VEGF, Glut-1, HKII, PDK-1, LDHA, and CAIX, which are all important players in tumor angiogenesis, glycolytic metabolism, and pH regulation. By possessing the ability to elicit a multifaceted effect on tumor biology, silencing HIF-1α with RGD-targeted ECO/siHIF-1α nanoparticles has great promise as a single therapy or in combination with traditional chemotherapy or radiation strategies to improve cancer treatment.


Extended duration dual antiplatelet therapy in patients with myocardial infarction: A study-level meta-analysis of controlled randomized trials.
Whether dual antiplatelet therapy (DAPT) is beneficial beyond 1 year after myocardial infarction (MI) is not demonstrated; in particular, available studies may be individually underpowered for end points at low incidence, that is, major and fatal bleeding or mortality. We thus assessed the effectiveness and safety of prolonged DAPT after MI over the long term. We conducted a systematic search to identify randomized trials on the topic; 3 studies and 21,534 post-MI patients receiving placebo or aspirin plus P2Y12 inhibition for ≥2 years were included. Incidence of the following outcome measures was evaluated: major adverse cardiac events (MACE), major bleeding, fatal bleeding, and cardiovascular and noncardiovascular death. Occurrence of MACE was lower in patients treated with prolonged DAPT: 6.3% vs 7.9% in those without prolonged DAPT (odds ratios 0.74, 95% CI 0.60-0.91, P = .005); in the former, there was also a significant 16% reduction in cardiovascular mortality. Increase in major bleeding with extended duration DAPT was not significant in the overall analysis (1.5% vs 1.0%; P = .10), but became significant in the analysis restricted to patients receiving ticagrelor or prasugrel as second antiplatelet agent (odds ratios 2.16, 95% CI 1.63-2.86); prolonged use of DAPT did not raise rates of fatal bleeding or noncardiovascular mortality. Prolonged DAPT after MI reduces MACE and cardiovascular mortality over the long term; this was paralleled by higher risk of nonfatal major bleeding mainly with the newer, more potent P2Y12 antagonists. Tailoring duration of DAPT after MI on the comparative evaluation of both ischemic and bleeding risk is mandatory in this setting.


Plasma levels and urinary elimination of diftalone, paracetamol, and their metabolites after single oral administration in man.
The plasma levels of diftalone, its metabolite 7-hydroxydiftalone, unconjugated and total paracetamol have been assessed in 6 healthy volunteers after oral administration of diftalone 0.75 g and of paracetamol 1.0 g, given alone and in combination in a cross-over fashion. In the same subject the urinary elimination of 7-hydroxydiftalone, and of unconjugated and total paracetamol has also been estimated. The results provide some indication of a slight increase in the plasma levels of unconjugated and total paracetamol, when the drug is administered in combination with diftalone. The increase, however, does not reach the significance level. As to diftalone and its metabolite, the differences between the plasma levels obtained after administration of the compound alone and those obtained when it was given in combination were negligible. Furthermore, the urinary recoveries of 7-hydroxydiftalone and of unconjugated and total paracetamol were very similar after administration of each compound alone and of their combination. It is concluded that the administration of single doses of diftalone and paracetamol in combination does not produce any pharmacokinetic interaction likely to be of clinical relevance.


A fast sensor for in vivo quantification of cytosolic phosphate in Saccharomyces cerevisiae.
Eukaryotic metabolism consists of a complex network of enzymatic reactions and transport processes which are distributed over different subcellular compartments. Currently, available metabolite measurement protocols allow to measure metabolite whole cell amounts which hinder progress to describe the in vivo dynamics in different compartments, which are driven by compartment specific concentrations. Phosphate (Pi) is an essential component for: (1) the metabolic balance of upper and lower glycolytic flux; (2) Together with ATP and ADP determines the phosphorylation energy. Especially, the cytosolic Pi has a critical role in disregulation of glycolysis in tps1 knockout. Here we developed a method that enables us to monitor the cytosolic Pi concentration in S. cerevisiae using an equilibrium sensor reaction: maltose + Pi < = > glucose + glucose-1-phosphate. The required enzyme, maltose phosphorylase from L. sanfranciscensis was overexpressed in S. cerevisiae. With this reaction in place, the cytosolic Pi concentration was obtained from intracellular glucose, G1P and maltose concentrations. The cytosolic Pi concentration was determined in batch and chemostat (D = 0.1 h(-1) ) conditions, which was 17.88 µmol/gDW and 25.02 µmol/gDW, respectively under Pi-excess conditions. Under Pi-limited steady state (D = 0.1 h(-1) ) conditions, the cytosolic Pi concentration dropped to only 17.7% of the cytosolic Pi in Pi-excess condition (4.42 µmol/gDW vs. 25.02 µmol/gDW). In response to a Pi pulse, the cytosolic Pi increased very rapidly, together with the concentration of sugar phosphates. Main sources of the rapid Pi increase are vacuolar Pi (and not the polyPi), as well as Pi uptake from the extracellular space. The temporal increase of cytosolic Pi increases the driving force of GAPDH reaction of the lower glycolytic reactions. The novel cytosol specific Pi concentration measurements provide new insight into the thermodynamic driving force for ATP hydrolysis, GAPDH reaction, and Pi transport over the plasma and vacuolar membranes.


Mendelian randomization supports causality between gut microbiota and chronic hepatitis B.
Observational studies have provided evidence of a close association between gut microbiota and the progression of chronic hepatitis B (CHB). However, establishing a causal relationship between gut microbiota and CHB remains a subject of investigation. Genome-wide association study (GWAS) summary data of gut microbiota came from the MiBioGen consortium, while the GWAS summary data of CHB came from the Medical Research Council Integrative Epidemiology Unit (IEU) Open GWAS project. Based on the maximum likelihood (ML), Mendelian randomization (MR)-Egger regression, inverse variance weighted (IVW), MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and weighted-mode and weighted-median methods, we conducted a bidirectional, two-sample, MR analysis to explore the causal relationship between the gut microbiota and CHB. Additionally, we evaluated the genetic associations between individual gut microbes and CHB using the Linkage disequilibrium score regression (LDSC) program. According to the IVW method estimates, genetically predicted class Alphaproteobacteria (odds ratio [OR] = 0.57; 95% confidence interval [CI], 0.34-0.96; false discovery rate [FDR] = 0.046), genus Family XIII AD3011 group (OR = 0.60; 95% CI, 0.39-0.91; FDR = 0.026), genus Prevotella 7 (OR = 0.73; 95% CI, 0.56-0.94; FDR = 0.022) exhibited a protective effect against CHB. On the other hand, family Family XIII (OR = 1.79; 95% CI, 1.03-3.12; FDR = 0.061), genus Eggerthella group (OR = 1.34; 95% CI, 1.04-1.74; FDR = 0.043), genus Eubacterium ventriosum group (OR = 1.59; 95% CI, 1.01-2.51; FDR = 0.056), genus Holdemania (OR = 1.35; 95% CI, 1.00-1.82; FDR = 0.049), and genus Ruminococcus gauvreauii group (OR = 1.69; 95% CI, 1.10-2.61; FDR = 0.076) were associated with an increased risk of CHB. The results from LDSC also indicated a significant genetic correlation between most of the aforementioned gut microbiota and CHB. Our reverse MR analysis demonstrated no causal relationship between genetically predicted CHB and gut microbiota, and we observed no significant horizontal pleiotropy or heterogeneity of instrumental variables (IVs). In this study, we identified three types of gut microbiota with a protective effect on CHB and five types with an adverse impact on CHB. We postulate that this information will facilitate the clinical prevention and treatment of CHB through fecal microbiota transplantation.


Implant reversible complications: classification and treatments.
Failures of dental implants are detrimental to both patients and dental providers. These failures are often preceded by complications at various levels of the treatment phases. Early detection of the complications that are amenable to rescue therapies may reverse the fate of the implant. This review article discusses diagnosis, classification, and treatment aspects of the reversible complications commonly encountered during routine dental implant-related procedures.


The human embryo: a scientist's point of view.
...Thus, my judgement is that a human embryo is not a human person, and so we may do experiments on it which involve killing it. But my judgement is also that a human embryo has the potential to become a human being. The consequence of this attribute is that it imposes limits on the kinds of experiments which may be performed on human embryos. It is this which sets the boundaries. Experiments which may harm the embryo while still allowing it subsequently to realise its potential, and become a person, should not be permitted. It is the potentiality of the human embryo which governs our behaviour towards it. Its potential makes it special, and radically different from any other human tissue. This potential which the early embryo has means that great respect must always be accorded it, and great thought and care must surround any dealings with it....


Transcriptional analysis of the Pseudomonas aeruginosa genes algR, algB, and algD reveals a hierarchy of alginate gene expression which is modulated by algT.
Strains of Pseudomonas aeruginosa which colonize and infect the lungs of cystic fibrosis patients have a mucoid colony morphology due to the overproduction of the exopolysaccharide alginate. The response regulators AlgB and AlgR are required for the transcription of algD, a tightly regulated gene encoding GDP-mannose dehydrogenase, which is critical for P. aeruginosa alginate biosynthesis. Previous studies indicated that mutations in the algT gene of mucoid FRD1 P. aeruginosa result in nonmucoid derivatives. However, the specific role for algT in alginate gene regulation has not been elucidated. In this study, transcription of algB, algD, and algR was characterized by gene fusion and primer extension analysis. Expression of algR and algD was abolished in P. aeruginosa strains containing algT::Tn501 insertions because of lack of transcription initiation at the algR and algD promoters. An algR mutation was constructed in FRD1, and this resulted in the loss of alginate production and a dramatic decrease in algD transcription. RNA and gene fusion analysis revealed that algB is not required for algR expression, nor is algR necessary for transcription of algB. Thus, with the exception of a requirement for AlgT, the AlgB and AlgR pathways appear to be independent of each other. In gel band mobility shift assays, a protein(s) present in extracts from mucoid and algB and algR mutant P. aeruginosa strains formed a specific complex with algD sequences located immediately upstream of the start of transcription. No binding to these sequences was observed when extracts from algT mutant strains were examined. A model proposed suggests that a hierarchy of alginate gene expression exists in which AlgT is required for transcription of the response regulators algB and algR, which in turn are necessary for algD expression. AlgT or a protein under algT control also binds to sequences located within the algD promoter.


Initial Reliability of the Diagnostic Interview for Narcissism Adapted for Preadolescents: Parent Version (P-DIN).
the Diagnostic Interview for Narcissism, an instrument developed by Gunderson and associates to assess pathological narcissistic traits in adults, has been adapted for use with parents of preadolescents as a semi-structured interview. A sixth section has been added to assess the parental narcissistic investment of the child. the sample consists of 21 parents of children (aged 8-13 years) at risk for narcissistic personality disorder. An interviewer-observer design, with independent interview evaluation, was used to assess inter-rater reliabilities. Both raters were blind to diagnostic information. Very good inter-rater reliabilities (ranging from .85 to 1.00) were obtained for all 35 statements of this Parent version of the DIN (P-DIN). Good internal consistencies a=0.82, a=0.88, a=0.69, respectively) were obtained for the first three Sections of the P-DIN, which include all the DSM-IV criteria for Narcissistic Personality Disorder. Section V, Social/Moral Adaptation (a=0.54), and Section VI, Parental Narcissistic Investment of the Child (a=0.62), had weaker internal consistencies. Section IV, Mood States, had the lowest internal consistency (a=0.50). Finally, a high reliability coefficient was obtained for the total scale (a=0.92, 32 statements for Sections I to V). present results of this pilot study justify further research into the P-DIN psychometric properties.


Antinutrients and metabolomic compounds of Bambara groundnut (Vigna subterranean) as affected by traditional processing by smallholder farmers.
Bambara groundnut (BG) (Vigna subterranean) is an underutilized, indigenous crop in South Africa that has nutritional and associated health benefits. Decreasing the antinutrients in food sources can potentially increase the digestibility of proteins and mineral absorption. To determine the effect of traditional processing (cooking) on the antinutrient content and metabolome of this crop, BG was sampled from 12 rural farms in three districts of the Mpumalanga province, South Africa. The four main colors that were identified (cream, orange, brown, and purple) were pooled together according to the district they were obtained from. One-half of each color sample obtained from each of the three districts was dehulled, color sorted, milled, and subjected to subsequent antinutrient and metabolome analyses, while the other half was cooked, air-dried, and milled prior to analyses. Samples were analyzed for phytate and tannins (antinutrients) by hydrochloric acid extraction methods as well as metabolome constituents by ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Phytate, tannins, as well as other metabolomic constituents, namely, catechin, epicatechin, procyanidin, as well as citric acid, were identified in all raw and cooked BG samples. The cooking process resulted in a significant decrease (p < 0.05) in the phytate and tannin content as well as an increase in the health-associated phenolic compounds.


Vibration analysis of healthy skin: toward a noninvasive skin diagnosis methodology.
Several noninvasive imaging techniques have been developed to monitor the health of skin and enhance the diagnosis of skin diseases. Among them, skin elastography is a popular technique used to measure the elasticity of the skin. A change in the elasticity of the skin can influence its natural frequencies and mode shapes. We propose a technique to use the resonant frequencies and mode shapes of the skin to monitor its health. Our study demonstrates how the resonant frequencies and mode shapes of skin can be obtained using numerical and experimental analysis. In our study, natural frequencies and mode shapes are obtained via two methods: (1) finite element analysis: an eigensolution is performed on a finite element model of normal skin, including stratum corneum, epidermis, dermis, and subcutaneous layers and (2) digital image correlation (DIC): several in-vivo measurements have been performed using DIC. The experimental results show a correlation between the DIC and FE results suggesting a noninvasive method to obtain vibration properties of the skin. This method can be further examined to be eventually used as a method to differentiate healthy skin from diseased skin. Prevention, early diagnosis, and treatment are critical in helping to reduce the incidence, morbidity, and mortality associated with skin cancer; thus, making the current study significant and important in the field of skin biomechanics.


Altered tuning in primary motor cortex does not account for behavioral adaptation during force field learning.
Although primary motor cortex (M1) is intimately involved in the dynamics of limb movement, its inputs may be more closely related to higher-order aspects of movement and multi-modal sensory feedback. Motor learning is thought to result from the adaption of internal models that compute transformations between these representations. While the psychophysics of motor learning has been studied in many experiments, the particular role of M1 in the process remains the subject of debate. Studies of learning-related changes in the spatial tuning of M1 neurons have yielded conflicting results. To resolve the discrepancies, we recorded from M1 during curl field adaptation in a reaching task. Our results suggest that aside from the addition of the load itself, the relation of M1 to movement dynamics remains unchanged as monkeys adapt behaviorally. Accordingly, we implemented a musculoskeletal model to generate synthetic neural activity having a fixed dynamical relation to movement and showed that these simulated neurons reproduced the observed behavior of the recorded M1 neurons. The stable representation of movement dynamics in M1 suggests that behavioral changes are mediated through progressively altered recruitment of M1 neurons, while the output effect of those neurons remained largely unchanged.


Effects of conjunctival hyperosmolar challenge in allergic subjects and normal controls.
Nonspecific hyperreactivity to a number of physical, chemical and pharmacological agents in a common characteristics of allergic subjects, which is strictly related to the inflammatory events consequent to an allergic reaction. Hyperosmolar stimulus has previously been shown to cause an inflammatory response inducing mast cell activation and subsequent mediator release. We investigated the clinical and cytological events following conjunctival challenge using a hyperosmolar agent (i.e. glucose solution) in patients with allergy due to pollen, in patients with allergy due to mites and in healthy individuals in order to investigate the possible existence of 'conjunctival hyperreactivity', similar to the well-known nasal and bronchial nonspecific hyperreactivity in allergic patients. Hyperosmolar stimulus was able to produce an immediate inflammatory response evidenced by clinical symptomatology, inflammatory cell infiltrate and CD54 expression on conjunctival epithelium in all allergic subjects and healthy volunteers. House dust mite-sensitive subjects, but not pollen-sensitive subjects studied out of pollen season, showed conjunctival hyperreactivity as shown by histamine challenge, in that they required lower glucose concentrations to elicit the conjunctival reaction. This is probably related to an underlying although mild, inflammation.


La Crosse virus neuroinvasive disease: the kids are not alright.
La Crosse virus (LACV) is the most common cause of neuroinvasive mosquito-borne disease in children within the United States. Despite more than 50 years of recognized endemicity in the United States, the true burden of LACV disease is grossly underappreciated, and there remain severe knowledge gaps that inhibit public health interventions to reduce morbidity and mortality. Long-standing deficiencies in disease surveillance, clinical diagnostics and therapeutics, actionable entomologic and environmental risk indices, case response capacity, public awareness, and availability of community support groups clearly frame LACV disease as neglected. Here we synthesize salient prior research and contextualize our findings as an assessment of current gaps and opportunities to develop a framework to prevent, detect, and respond to LACV disease. The persistent burdens of LACV disease clearly require renewed public health attention, policy, and action.


Penalized logistic regression based on L1/2 penalty for high-dimensional DNA methylation data.
DNA methylation is a molecular modification of DNA that is vital and occurs in gene expression. In cancer tissues, the 5'-C-phosphate-G-3'(CpG) rich regions are abnormally hypermethylated or hypomethylated. Therefore, it is useful to find out the diseased CpG sites by employing specific methods. CpG sites are highly correlated with each other within the same gene or the same CpG island. Based on this group effect, we proposed an efficient and accurate method for selecting pathogenic CpG sites. Our method aimed to combine a L1/2 regularized solver and a central node fully connected network to penalize group constrained logistic regression model. Consequently, both sparsity and group effect were brought in with respect to the correlated regression coefficients. Extensive simulation studies were used to compare our proposed approach with existing mainstream regularization in respect of classification accuracy and stability. The simulation results show that a greater predictive accuracy was attained in comparison to previous methods. Furthermore, our method was applied to over 20000 CpG sites and verified using the ovarian cancer data generated from Illumina Infinium HumanMethylation 27K Beadchip. In the result of the real dataset, not only the indicators of predictive accuracy are higher than the previous methods, but also more CpG sites containing genes are confirmed pathogenic. Additionally, the total number of CpG sites chosen is less than other methods and the results show higher accuracy rates in comparison to other methods in simulation and DNA methylation data. The proposed method offers an advanced tool to researchers in DNA methylation and can be a powerful tool for recognizing pathogenic CpG sites.


Oncogenesis and mutagenesis of pituitary tumors.
Although pituitary tumors may be present in up to 10% of the population, the pathophysiology of these lesions is not well characterized. Pituitary tumors are composed of monoclonal cell populations with disrupted control of replication pathways. The oncogenes and tumor suppressor genes that are common in other malignancies (i.e. jun, fos, myc, and p53) are rarely involved in the development of these tumors. However, oncogenes, such as gsp, can be present in up to 40% of hormonally active adenomas. The process of pituitary oncogenesis further appears to involve oncogenes such as cyclin E, cyclin D1, and the pituitary tumor transforming gene (PTTG). Finally, the cAMP signaling cascade plays a significant role in generation of both benign and malignant pituitary tumors. In this review, the biology of pituitary adenomas is explored with a special emphasis on potential targets for the development of targeted therapeutics.


Biologic aspects of thrombopoietins and the development of therapeutic agents.
Thrombopoiesis is a multistage process beginning with pluripotent hematopoietic stem cells, progressing through proliferating cells committed to megakaryocytopoiesis, to megakaryocytes, and eventually ending with the shedding of platelets from megakaryocytes. Many growth factors stimulate thrombopoiesis; this review addresses those that act through binding to the thrombopoietin receptor. The cloning of thrombopoietin in 1994 greatly accelerated progress in understanding the biology of thrombopoiesis and of hematopoiesis in general. Detailed structural and functional studies of the thrombopoietin receptor, coupled with novel molecular pharmacology approaches, have led to new classes of thrombopoietic mimetics. Initial clinical trials with recombinant thrombopoietins faltered as they encountered significant neutralizing antibodies or difficulty finding a significant clinical niche in support of chemotherapy. Ongoing studies with the new thrombopoietic agents have invigorated the field, with positive results now reported in idiopathic thrombocytopenic purpura.


Evaluation of seismic performance and effectiveness of multiple slim-type damper system for seismic response control of building structures.
This paper presents the evaluation of seismic performance and cost-effectiveness of a multiple slim-type damper system developed for the vibration control of earthquake excited buildings. The multiple slim-type damper (MSD) that consists of several small slim-type dampers and linkage units can control damping capacity easily by changing the number of small dampers. To evaluate the performance of the MSD, dynamic loading tests are performed with three slim-type dampers manufactured at a real scale. Numerical simulations are also carried out by nonlinear time history analysis with a ten-story earthquake excited building structure. The seismic performance and cost-effectiveness of the MSD system are investigated according to the various installation configurations of the MSD system. From the results of numerical simulation and cost-effectiveness evaluation, it is shown that combinations of the MSD systems can effectively improve the seismic performance of earthquake excited building structures.


Health worker preferences for community-based health insurance payment mechanisms: a discrete choice experiment.
In 2004, a community-based health insurance scheme (CBI) was introduced in Nouna health district, Burkina Faso. Since its inception, coverage has remained low and dropout rates high. One important reason for low coverage and high dropout is that health workers do not support the CBI scheme because they are dissatisfied with the provider payment mechanism of the CBI. A discrete choice experiment (DCE) was used to examine CBI provider payment attributes that influence health workers' stated preferences for payment mechanisms. The DCE was conducted among 176 health workers employed at one of the 34 primary care facilities or the district hospital in Nouna health district. Conditional logit models with main effects and interactions terms were used for analysis. Reimbursement of service fees (adjusted odds ratio (aOR) 1.49, p < 0.001) and CBI contributions for medical supplies and equipment (aOR 1.47, p < 0.001) had the strongest effect on whether the health workers chose a given provider payment mechanism. The odds of selecting a payment mechanism decreased significantly if the mechanism included (i) results-based financing (RBF) payments made through the local health management team (instead of directly to the health workers (aOR 0.86, p < 0.001)) or (ii) RBF payments based on CBI coverage achieved in the health worker's facility relative to the coverage achieved at other facilities (instead of payments based on the numbers of individuals or households enrolled at the health worker's facility (aOR 0.86, p < 0.001)). Provider payment mechanisms can crucially determine CBI performance. Based on the results from this DCE, revised CBI payment mechanisms were introduced in Nouna health district in January 2011, taking into consideration health worker preferences on how they are paid.


Growth rate of Enterobacteriaceae at elevated temperatures: limitation by methionine.
The effect of elevated temperatures on growth rate was studied in five strains of Enterobacteriaceae. In all the strains tested a shift to the elevated temperature resulted in an immediate decrease in growth rate which was due to limitation in the availability of endogenous methionine. The first biosynthetic enzyme of the methionine pathway-homoserine transsuccinylase-was studied in extracts of Aerobacter aerogenes, Salmonella typhimurium, and Escherichia coli and was shown to be temperature sensitive in all of them.


TAP-independent delivery of antigenic peptides to the endoplasmic reticulum: therapeutic potential and insights into TAP-dependent antigen processing.
We have taken several approaches to investigate the capacity of the secretory pathway to liberate major histocompatibility complex (MHC) class I-restricted antigenic peptides from precursor polypeptides. Cells lacking the peptide transporter (TAP) are unable to deliver peptides from cytosolic antigens to class I molecules. TAP can be bypassed by targeting peptides directly to the endoplasmic reticulum (ER) using NH2-terminal signal sequences. This results in the generation of enormous numbers of MHC class I complexes (50,000 peptides/cell), and recombinant vaccinia viruses expressing such peptides are highly immunogenic. In contrast to signal sequence-targeted peptides, peptides are liberated very inefficiently from internal locations in ER-targeted full-length proteins, indicating that the secretory pathway has a limited capacity for generating antigenic peptides from most polypeptide contexts. We have, however, identified a location in proteins from which peptides can be liberated in numerous contexts in the secretory pathway. Placing a number of different peptides at the COOH termini of a secreted protein and two proteins with type II membrane anchors resulted in their TAP-independent presentation. These findings demonstrate that the secretory compartment possesses proteases able to liberate COOH-terminal antigenic peptides from virtually any context, entirely consistent with a role for these proteases in the processing of TAP-transported antigenic peptide precursors.


Controlling aqueous silica nanoparticle synthesis in the 10-100 nm range.
We describe the control of size and homogeneity in silica nanoparticle dispersions, prepared by a two-phase arginine catalysed aqueous method, through varying the upper organic solvent phase. The final particle dispersion characteristics can be controlled by varying features including solvent type and interfacial area, related to the rate of monomer transfer at the TEOS/water interface.


Hidden-Markov Factor analysis as a spatiotemporal model for electrocorticography.
We present a new approach to extracting low-dimensional neural trajectories that summarize the electrocorticographic (ECoG) signals recorded with high-channel-count electrode arrays implanted subdurally. In our approach, Hidden-Markov Factor Analysis (HMFA), a finite set of factor analyzers are used to model the relationship between the high-dimensional ECoG neural space and a low-dimensional latent neural space; the factor analyzers at different time points are in turn linked together with a hidden Markov model. The recorded ECoG signals were band-pass filtered such that our analysis was focused on a sub-band (76-100Hz) of high gamma. HMFA affords the quantization of the ECoG neural space and dimensionality reduction in a common probabilistic space. We applied this method to the ECoG recordings of 2 subjects who responded with button presses to audiovisual stimuli in an experimental task. Using a goodness-of-fit metric that measures how well the ECoG activity of each electrode can be predicted by all the other electrodes, we found that HMFA performed best when compared with Gaussian-Process Factor Analysis (GPFA) and other related spatiotemporal modeling techniques. In contradistinction to HMFA, GPFA and the other techniques integrate temporal smoothing with dimensionality reduction. We believe that this method will provide a powerful tool for relating high-channel-count ECoG signals to the perception and behavior of subjects.


Psychological distress of patients with advanced cancer: influence and contribution of pain severity and pain interference.
The growing interest in the psychological distress and the multidimensionality of pain in patients with cancer has been the major reason for the conduction of this study. The aims were to evaluate psychological distress and pain in patients with advanced cancer and the impact of pain severity and pain interference dimensions on the anxiety and depression. One hundred twenty patients with advanced cancer were surveyed at a palliative care unit in Athens, Greece. Greek versions of the Hospital Anxiety and Depression (G-HAD) scale and the Brief Pain Inventory were administered. Information concerning patients' treatment received was acquired from the medical records, whereas physicians recorded their clinical condition. The analysis showed that significant associations were found between pain interference to "mood" and HAD-A (anxiety) (r = 0.252, P = .005) and between pain interference to "relations with other people" and HAD-A (r = 0.474, P < .0005). Multiple regression analyses showed that "average pain" (P < .05), pain interference to "walking ability" (P < .05), "normal work" (P < .05, and "relations with other people" are significant predictors of HAD-anxiety (HAD-A) (P < .0005), explaining 46.2% of total variance. For depression (HAD-D), the Greek version of the Brief Pain Inventory dimension that serve as predictor is "enjoyment of life," as well as the demographic variables of "age," and "gender" (P < .05), explaining 22.2% of variance. Moreover, a further analysis of the pain severity and pain interference scales showed that they differentiate the anxiety of the patients with cancer. In this patient sample, pain interference and, to a lesser extent, pain severity was significantly associated with psychological distress (anxiety and pain), whereas pain interference to "walking ability," "normal work," and "relations with other people" was found to be more prominent and troublesome to patients' anxiety than that to patients' depression.