Quantitative Measurable Concepts to Visualize Business Process Improvement

Business process improvement evaluation enables performance indicators to be used alongside process improvement techniques in order to quantitatively compare measurement information between the as-is and to-be processes. Limitations of the present methods of business process improvement indicate there is scope for looking at the problem in a different way. Business processes are commonly modelled as diagrams which at their fundamental level are complex networks. This suggests the question as to whether complex network analysis (CNA) has anything to contribute to business process improvement. We develop a technique of projecting a business process model onto the sub-space of a complex network and identify the measurable concepts that can be useful in business process improvement. The measurable concepts from CNA are combined with Time and Cost metrics from the simulation technique to visualize and track improvement efforts and satisfy improvement requirements

Human TRIM Gene Expression in Response to Interferons

Tripartite motif (TRIM) proteins constitute a family of proteins that share a conserved tripartite architecture. The recent discovery of the anti-HIV activity of TRIM5α in primate cells has stimulated much interest in the potential role of TRIM proteins in antiviral activities and innate immunity.To test if TRIM genes are up-regulated during antiviral immune responses, we performed a systematic analysis of TRIM gene expression in human primary lymphocytes and monocyte-derived macrophages in response to interferons (IFNs, type I and II) or following FcγR-mediated activation of macrophages. We found that 27 of the 72 human TRIM genes are sensitive to IFN. Our analysis identifies 9 additional TRIM genes that are up-regulated by IFNs, among which only 3 have previously been found to display an antiviral activity. Also, we found 2 TRIM proteins, TRIM9 and 54, to be specifically up-regulated in FcγR-activated macrophages.Our results present the first comprehensive TRIM gene expression analysis in primary human immune cells, and suggest the involvement of additional TRIM proteins in regulating host antiviral activities

Behavioural effects of chemogenetic dopamine neuron activation

Various psychiatric disorders, including schizophrenia, attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder, have been associated with altered dopamine signalling in the brain. However, it remains unclear which specific changes in dopamine activity are related to specific psychiatric symptoms. Recent clinical studies have proposed that aberrant dopamine neuronal activity may play a vital role in the pathophysiology of, amongst others, schizophrenia and ADHD. In this thesis, we have tested the behavioural effects of increased dopamine neuronal activity. To do so, we used the recently developed Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, also called chemogenetics, in TH::Cre transgenic rats. This approach enables us to directly and transiently enhance the excitability of selective populations of dopamine cells. We determined the impact of chemogenetic dopamine neuron activation on behavioural domains that are disturbed in psychiatric disorders, including hyperactivity, motivation and attention. Our findings show that activation of dopamine neurons in the ventral tegmental area (VTA) induced locomotor hyperactivity, increased motivational behaviour, disrupted feeding patterns, and impaired sustained attention. In follow-up experiments we selectively targeted different VTA neuronal pathways, and found that these effects were reproduced by chemogenetic activation of VTA mesolimbic neurons, projecting to ventral striatum. Chemogenetic activation of dopamine neurons in the substantia nigra pars compacta (SNc) yielded a wholly different phenotype, including a modest increase in locomotion, no effect on motivation or feeding, yet pronounced deficits in performance of an attentional task. Dopamine neurons in the SNc project primarily to the dorsal striatum. Our findings show that dopamine neuronal activity in the VTA and SNc are differentially involved in the regulation of psychiatry-related behaviours, including locomotor activity, motivation and attentional processes. We propose that enhanced mesolimbic VTA dopamine neuronal activity promotes behavioural activation, resulting in a hyperactive and distracted phenotype. In contrast, increased SNc dopamine neuron activity seems to disrupt selection of appropriate motor actions, resulting in attentional deficits. These findings have implications for understanding the role of dopamine neuronal activity in psychiatric disorders, and may contribute to the development of novel, target-specific treatments

Behavioural effects of chemogenetic dopamine neuron activation

Various psychiatric disorders, including schizophrenia, attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder, have been associated with altered dopamine signalling in the brain. However, it remains unclear which specific changes in dopamine activity are related to specific psychiatric symptoms. Recent clinical studies have proposed that aberrant dopamine neuronal activity may play a vital role in the pathophysiology of, amongst others, schizophrenia and ADHD. In this thesis, we have tested the behavioural effects of increased dopamine neuronal activity. To do so, we used the recently developed Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, also called chemogenetics, in TH::Cre transgenic rats. This approach enables us to directly and transiently enhance the excitability of selective populations of dopamine cells. We determined the impact of chemogenetic dopamine neuron activation on behavioural domains that are disturbed in psychiatric disorders, including hyperactivity, motivation and attention. Our findings show that activation of dopamine neurons in the ventral tegmental area (VTA) induced locomotor hyperactivity, increased motivational behaviour, disrupted feeding patterns, and impaired sustained attention. In follow-up experiments we selectively targeted different VTA neuronal pathways, and found that these effects were reproduced by chemogenetic activation of VTA mesolimbic neurons, projecting to ventral striatum. Chemogenetic activation of dopamine neurons in the substantia nigra pars compacta (SNc) yielded a wholly different phenotype, including a modest increase in locomotion, no effect on motivation or feeding, yet pronounced deficits in performance of an attentional task. Dopamine neurons in the SNc project primarily to the dorsal striatum. Our findings show that dopamine neuronal activity in the VTA and SNc are differentially involved in the regulation of psychiatry-related behaviours, including locomotor activity, motivation and attentional processes. We propose that enhanced mesolimbic VTA dopamine neuronal activity promotes behavioural activation, resulting in a hyperactive and distracted phenotype. In contrast, increased SNc dopamine neuron activity seems to disrupt selection of appropriate motor actions, resulting in attentional deficits. These findings have implications for understanding the role of dopamine neuronal activity in psychiatric disorders, and may contribute to the development of novel, target-specific treatments

Does activation of midbrain dopamine neurons promote or reduce feeding?

BACKGROUND: Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced DA activity. On the other hand, psychostimulant drugs that increase DA signalling suppress food intake. This poses the questions of how endogenous DA neuronal activity regulates feeding, and whether enhancing DA neuronal activity would either promote or reduce food intake. METHODS: Here, we used designer receptors exclusively activated by designer drugs (DREADD) technology to determine the effects of enhancing DA neuronal activity on feeding behaviour. We chemogenetically activated selective midbrain DA neuronal subpopulations and assessed the effects on feeding microstructure in rats. RESULTS: Treatment with the psychostimulant drug amphetamine or the selective DA reuptake inhibitor GBR 12909 significantly suppressed food intake. Selective chemogenetic activation of DA neurons in the ventral tegmental area (VTA) was found to reduce meal size, but had less impact on total food intake. Targeting distinct VTA neuronal pathways revealed that specific activation of the mesolimbic pathway towards nucleus accumbens (NAc) resulted in smaller and shorter meals. In addition, the meal frequency was increased, rendering total food intake unaffected. The disrupted feeding patterns following activation of VTA DA neurons or VTA to NAc projection neurons were accompanied by locomotor hyperactivity. Activation of VTA neurons projecting towards prefrontal cortex or amygdala, or of DA neurons in the substantia nigra, did not affect feeding behaviour. CONCLUSIONS: Chemogenetic activation of VTA DA neurons or VTA to NAc pathway disrupts feeding patterns. Increased activity of mesolimbic DA neurons appears to both promote and reduce food intake, by facilitating both the initiation and cessation of feeding behaviou

Long-Term Neurodevelopmental Follow-up of Children Exposed to Pravastatin in-Utero

BACKGROUND: Preeclampsia, especially when preterm, increases risk of child neurodevelopmental adverse outcomes. Biological plausibility, preclinical studies, and pilot clinical trials conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development-Obstetrics Fetal Pharmacology Research Centers Network support the safety and utility of pravastatin to prevent preeclampsia. OBJECTIVE: To determine the effect of antenatal pravastatin treatment in high-risk pregnant individuals on their child\u27s health, growth, and neurodevelopment. STUDY DESIGN: We conducted an ancillary follow-up cohort study of children born to mothers who participated in the Obstetrics Fetal Pharmacology Research Centers Network pilot trials of pravastatin vs. placebo in individuals at high-risk of preeclampsia. (Clinicaltrials.gov Identifier NCT01717586). After obtaining written informed consent (and assent as appropriate), the parent was instructed to complete the Child Behavior Checklist. To assess the child\u27s motor, cognitive, and developmental outcomes, a certified and blinded study psychologist completed child motor, cognitive, emotional, and behavioral assessment using validated tools. Given the small numbers of individuals in the studies, the 10 and 20mg of pravastatin were combined into one group and compared with those in the placebo group. RESULTS: Out of the 40 children born to mothers in the original trial, 30 (15 exposed in-utero to pravastatin and 15 to placebo) were enrolled in this follow-up study. The time of follow-up, which was 4.7 [2.5-6.9] years, was not different between those in the pravastatin or placebo groups. There were no differences in child\u27s body mass index percentiles per sex and corrected age, rates of extremes of body mass index percentiles or the report of any other medical or developmental complications between the two groups. No child born in the pravastatin group had any limitation in motor assessment compared with two (13.3%) children who walked with difficulty and four (26.7%) children who had reduced manual abilities in the placebo group. Moreover, children born to mothers who received pravastatin had non-significant higher general mean conceptual ability score (98.2 ± 16.7 vs. 89.7 ± 11.0, p=0.13) and a non-significant lower frequency (15.4% vs. 35.7%, p=0.38) of having a score below 85 (i.e., one standard deviation lower than the mean) compared with those in the placebo group. Lastly, there no significant differences in the parents\u27 report on the Child Behavior Checklist between the two groups. CONCLUSIONS: To our knowledge, this is the first report on the long-term neuromotor, cognitive, and behavioral outcomes among children exposed to pravastatin in-utero during the 2 and 3 trimesters of pregnancy. Although the data are limited by the original trial\u27s sample size, no identifiable long-term neurodevelopmental safety signal was evident with the use of pravastatin during pregnancy. This favorable neonatal risk-benefit analysis justifies continued research using pravastatin in clinical trials