An expert system for choosing the best combination of options in a general purpose program for Automated Design Synthesis

An expert system called EXADS has been developed to aid users of the Automated Design Synthesis (ADS) general purpose optimization program. ADS has approximately 100 combinations of strategy, optimizer, and one-dimensional search options from which to choose. It is difficult for a nonexpert to make this choice. This expert system aids the user in choosing the best combination of options based on the users knowledge of the problem and the expert knowledge stored in the knowledge base. The knowledge base is divided into three categories; constrained problems, unconstrained problems, and constrained problems being treated as unconstrained problems. The inference engine and rules are written in LISP, contains about 200 rules, and executes on DEC-VAX (with Franz-LISP) and IBM PC (with IQ-LISP) computers.     

A Histone Deacetylase (HDAC) Inhibitor with Pleiotropic In Vitro Anti-Toxoplasma and Anti-Plasmodium Activities Controls Acute and Chronic Toxoplasma Infection in Mice

Toxoplasmosis is a highly prevalent human disease, and virulent strains of this parasite emerge from wild biotopes. Here, we report on the potential of a histone deacetylase (HDAC) inhibitor we previously synthesized, named JF363, to act in vitro against a large panel of Toxoplasma strains, as well as against the liver and blood stages of Plasmodium parasites, the causative agents of malaria. In vivo administration of the drug significantly increases the survival of mice during the acute phase of infection by T. gondii, thus delaying its spreading. We further provide evidence of the compound’s efficiency in controlling the formation of cysts in the brain of T. gondii-infected mice. A convincing docking of the JF363 compound in the active site of the five annotated ME49 T. gondii HDACs was performed by extensive sequence–structure comparison modeling. The resulting complexes show a similar mode of binding in the five paralogous structures and a quite similar prediction of affinities in the micromolar range. Altogether, these results pave the way for further development of this compound to treat acute and chronic toxoplasmosis. It also shows promise for the future development of anti-Plasmodium therapeutic interventions.     

Evaluation of atrial septal defects with 4D flow MRI—multilevel and inter-reader reproducibility for quantification of shunt severity

Purpose

With the hypothesis that 4D flow can be used in evaluation of cardiac shunts, we seek to evaluate the multilevel and interreader reproducibility of measurements of the blood flow, shunt fraction and shunt volume in patients with atrial septum defect (ASD) in practice at multiple clinical sites.

Materials and methods

Four-dimensional flow MRI examinations were performed at four institutions across Europe and the US. Twenty-nine patients (mean age, 43 years; 11 male) were included in the study. Flow measurements were performed at three levels (valve, main artery and periphery) in both the pulmonary and systemic circulation by two independent readers and compared against stroke volumes from 4D flow anatomic data. Further, the shunt ratio (Q_p/Q_s) was calculated. Additionally, shunt volume was quantified at the atrial level by tracking the atrial septum.

Results

Measurements of the pulmonary blood flow at multiple levels correlate well whether measuring at the valve, main pulmonary artery or branch pulmonary arteries (r = 0.885–0.886). Measurements of the systemic blood flow show excellent correlation, whether measuring at the valve, ascending aorta or sum of flow from the superior vena cava (SVC) and descending aorta (r = 0.974–0.991). Intraclass agreement between the two observers for the flow measurements varies between 0.96 and 0.99. Compared with stroke volume, pulmonic flow is underestimated with 0.26 l/min at the main pulmonary artery level, and systemic flow is overestimated with 0.16 l/min at the ascending aorta level. Direct measurements of ASD flow are feasible in 20 of 29 (69%) patients.

Conclusion

Blood flow and shunt quantification measured at multiple levels and performed by different readers are reproducible and consistent with 4D flow MRI.

     

Selective incorporation of docosahexaenoic acid into lysobisphosphatidic acid in cultured THP-1 macrophages

Lysobisphosphatidic acid (LBPA) is highly accumulated in specific domains of the late endosome and is involve in the biogenesis and function of this organelle. Little is known about the biosynthesis and metabolism of this lipid. We examined its FA composition and the incorporation of exogenous FA into LBPA in the human monocytic leukemia cell line THP-1. The LBPA FA composition in THP-1 cells exhibits an elevated amount of oleic acid (18∶1n−9) and enerichment of PUFA, especially DHA (22∶6n−3). DHA supplemented to the medium was efficiently incorporated into LBPA. In contrast, arachidonic acid (20∶4n−6) was hardly esterified to LBPA under the same experimental conditions. The turnover of DHA in LBPA was similar to that in other phospholipids. Specific incorporation of DHA into LBPA was also observed in baby hamster kidney fibroblasts, although LBPA in these cells contains very low endogenous levels of DHA in normal growth conditions. Our results, together with published observations, suggest that the specific incorporation of DHA into LBPA is a common phenomenon in mammalian cells. The physiological significance of DHA-enriched LBPA is discussed.     

Delivering scalable video with QoS to the home

User satisfaction is a key factor in the success of novel multimedia services. Yet, to enable service providers and network operators to control and maximize the quality (QoS, QoE) of delivered video streams, quite some challenges remain. In this paper, we particularly focus on three of them. First of all, objectively measuring video quality requires appropriate quality metrics and methods of assessing them in a real-time fashion. Secondly, the recent Scalable Video Coding (SVC) format opens opportunities for adapting video to the available (network) resources, yet the appropriate configuration of video encoding as well as real-time streaming adaptation are largely unaddressed research areas. Thirdly, while bandwidth reservation mechanisms in access/core networks do exist, service providers lack a means for guaranteeing QoS in the increasingly complex home networks (which they are not in full control of). In this paper we offer a broad view on these interrelated issues, by presenting the developments originating in a Flemish research project (including proof-of-concept demonstrations). From a developmental perspective, we propose an architecture combining a real-time video quality monitoring platform, on-the-fly adaptation (optimizing the video quality) and QoS reservation in a heterogeneous home network based on UPnP QoS?v3. From a research perspective, we propose a new subjective test procedure that revealed user preference for temporal scalability over quality scalability. In addition, an extensive study on optimizing HD SVC encoding in IPTV scenarios with fluctuating bandwidth showed that under certain bandwidth constraints (prohibiting sufficient fidelity) spatial scalability is a better option than quality scalability.     

Critical Role of Estrogens on Bone Homeostasis in Both Male and Female: From Physiology to Medical Implications

Bone is a multi-skilled tissue, protecting major organs, regulating calcium phosphate balance and producing hormones. Its development during childhood determines height and stature as well as resistance against fracture in advanced age. Estrogens are key regulators of bone turnover in both females and males. These hormones play a major role in longitudinal and width growth throughout puberty as well as in the regulation of bone turnover. In women, estrogen deficiency is one of the major causes of postmenopausal osteoporosis. In this review, we will summarize the main clinical and experimental studies reporting the effects of estrogens not only in females but also in males, during different life stages. Effects of estrogens on bone involve either Estrogen Receptor (ER)α or ERβ depending on the type of bone (femur, vertebrae, tibia, mandible), the compartment (trabecular or cortical), cell types involved (osteoclasts, osteoblasts and osteocytes) and sex. Finally, we will discuss new ongoing strategies to increase the benefit/risk ratio of the hormonal treatment of menopause.     

mtDNA replicative potential remains constant during ageing: polymerase gamma activity does not correlate with age related cytochrome oxidase activity decline in platelets

Progressive age-related oxidative phosphorylation (OxPhos) decline is well known in human tissues. Depletion of mitochondrial DNA (mtDNA) causes OxPhos defects in patients with myopathic syndromes and deficient mtDNA replication has been observed in cells cultured from patients with mitochondrial disease. Patients undergoing treatment for AIDS develop OxPhos defects via mtDNA depletion resulting from inhibition of mtDNA polymerase gamma (Polgamma) by 2'-deoxy 3'-azido thymidine. These findings by others give rise to a possible link between mtDNA replication and bioenergetic decline in disease and during ageing. We have designed an in vitro assay for Polgamma function in small tissue samples to explore this possible link. Platelet homogenate Polgamma showed an activity with a K m of 150 microM (dTTP), a V max of 11.8 pmol/min/mg, inhibited (41% inhibition; 50 microM) by ethidium bromide. Determination of several storage characteristics showed that platelets were a convenient source of Polgamma for assay. Polgamma activity in 45 subjects did not coincide with significant age-related decline (P<0.002; P) observed in cytochrome oxidase (CytOx) activity or with citrate synthase activity. Of the activities studied, the only significant age-wise variation was a 24% CytOx deficiency in elderly (>50; n = 19) compared to young (<51; n = 24) individuals (P<0.01; t). These results suggest a maintenance of total cellular mtDNA Polgamma processive levels during ageing, largely independent of total cellular bioenergetic status or mitochondrial number/density. The processive component of Polgamma is therefore unlikely to make a major contribution to age-related bioenergetic activity decline. This does not, however, preclude the possibility that transient periods of inhibition at crucial points of the cell cycle or development may augment existing intracellular deficiencies. The assay described here greatly facilitates study of Polgamma activity in patients with conditions involving mtDNA depletion or rearrangement.     

Expression of Ly-6, a marker for highly malignant murine tumor cells, is regulated by growth conditions and stress

Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10(-10)-10(-8) M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10(-6) M). Bradykinin (>10(-7) M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9[Leu8]bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.     

Widowhood and illness: A comparison of social network characteristics in France, Germany, Japan, and the United States.

This study examined social network characteristics of adults aged 70 to 90 years in relation to widowhood and illness in France, Germany, Japan, and the United States. Participants were drawn from representative samples from each of the 4 countries (total N?=?1,331). Resource deficit profiles based on whether respondents were widowed, ill, both, or neither were directly related to social network characteristics for German and Japanese adults, were differentially related by gender and age for French adults, and were not related to social networks of Americans. Country, gender, and age differences in total network size, proportion of close network members, and frequency of contact with network members are reported. Similarities and differences found in the associations between normative late-life deficits and social network characteristics in the 4 countries point to the importance of investigating sociocultural factors that mediate the impact of resource loss and afford life quality in very old age. (PsycINFO Database Record (c) 2010 APA, all rights reserved)