The plasma level of 7α-hydroxy-4-cholesten-3-one reflects the activity of hepatic cholesterol 7α-hydroxylase in man

AbstractCirculating levels of 7α-hydroxy-4-cholesten-3-one have been compared with activities of the rate-limiting enzyme in bile acid synthesis, microsomal cholesterol 7α-hydroxylase, measured in liver biopsies obtained from patients undergoing surgery for gallstone disease. Some patients were treated with cholestyramine or bile acids prior to operation in order to alter the feed-back inhibition of the enzyme. The levels of the sterol were similar in untreated patients and in patients treated with ursodeoxycholic acid (median concentration 17 and 13 ng/ml, respectively), and so were the activities of the enzyme (median activity 7.0 and 5.5 pmol/min/mg protein, respectively). The sterol levels and enzyme activities were significantly increased in patients treated with cholestyramine (91 ng/ml and 45 pmol/min/mg protein) and decreased in patients treated with chenodeoxycholic acid (<2.0 ng/ml and 0.7 pmol/min/mg protein). There was a strong positive correlation (r=0.90, P<0.00001) between levels of 7α-hydroxy-4-cholesten-3-one in plasma and the activities of cholesterol 7α-hydroxylase in the whole patient group. The results show that analysis of 7α-hydroxy-4-cholesten-3-one in plasma is a sensitive and convenient method to determine relative rates of bile acid production in man

7α-Hydroxylation of 26-hydroxycholesterol, 3β-hydroxy-5-cholestenoic acid and 3β-hydroxy-5-cholenoic acid by cytochrome P-450 in pig liver microsomes

AbstractPig liver microsomes were found to catalyze the 7α-hydroxylation of several potential bile acid precursors besides cholesterol. 26-Hydroxycholesterol, 3β-hydroxy-5-cholestenoic acid and 3β-hydroxy-5-cholenoic acid were all efficiently converted into the 7α-hydroxylated products. Two cytochrome P-450 fractions showing 7α-hydroxylase activity could be isolated. One fraction catalyzed 7α-hydroxylation of 26-hydroxycholesterol. 3β-hydroxy-5-cholestenoic acid and 3β-hydroxy-5-cholenoic acid but was inactive towards cholesterol. The other fraction catalyzed 7α-hydroxylation of cholesterol in addition to the other substrates. 26-Hydroxycholesterol in equimolar concentration did not inhibit the cholesterol 7α-hydroxylase activity of this fraction. It is concluded that liver microsomes contain a cytochrome P-450 catalyzing 7α-hydroxylation of 26-hydroxycholesterol, 3β-hydroxy-5-cholestenoic acid and 3β-hydroxy-5-cholenoic acid. The results indicate that this cytochrome P-450 is different from that catalyzing 7α-hydroxylation of cholesterol

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Caring More About EQ Than IQ : Automatic Equalizing of Audio Signals

In this bachelor thesis, the possiblity to correct for room acousticsbased on frequency analysis is studied. A software to calculate transferfunctions online was constructed and tested. This was done using a ver-sion of the Maximum Length Sequence method, which is a method thatrequires long sequences for rooms with long reverberation. During theproject, it was noted that zero padding the sequences improved the ac-curacy greatly, it was also noted that the length of the zero pad aectedthe results. The software was tested both in computer simulations andin practice. While testing in practice, it was noted that the system haslimitations on which rooms it would work in. All testsignals were recordedand afterwards, compared to the original recording. The constructed soft-ware showed, that it is possible to correct for unknown transfer functionsusing only frequency analysis, to some extent. Further, it does correct forthe room's transfer function, but it is dicult to say if it this is valid forall rooms and transfer functions

Distribution of Control Effort in Multi-Agent Systems : Autonomous systems of the world, unite!

As more industrial processes, transportation and appliances have been automated or equipped with some level of artificial intelligence, the number and scale of interconnected systems has grown in the recent past. This is a development which can be expected to continue and therefore the research in performance of interconnected systems and networks is growing. Due to increased automation and sheer scale of networks, dynamically scaling networks is an increasing field and research into scalable performance measures is advancing. Recently, the notion gamma-robustness, a scalable network performance measure, was introduced as a measurement of interconnected systems robustness with respect to external disturbances. This thesis aims to investigate how the distribution of control effort and cost, within interconnected system, affects network performance, measured with gamma-robustness. Further, we introduce a notion of fairness and a measurement of unfairness in order to quantify the distribution of network properties and performance. With these in place, we also present distributed algorithms with which the distribution of control effort can be controlled in order to achieve a desired network performance. We close with some examples to show the strengths and weaknesses of the presented algorithms.I och med att fler och fler system och enheter blir utrustade med olika grader av intelligens så växer både förekomsten och omfattningen av sammankopplade system, även kallat Multi-Agent Systems. Sådana system kan vi se exempel på i traffikledningssystem, styrning av elektriska nätverk och fordonståg, vi kan också hitta fler och fler exempel på så kallade sensornätverk i och med att Internet of Things och Industry 4.0 används och utvecklas mer och mer. Det som särskiljer sammankopplade system från mer traditionella system med flera olika styrsignaler och utsignaler är att dem sammankopplade systemen inte styrs från en central styrenhet. Istället styrs dem sammankopplade systemen på ett distribuerat sätt i och med att varje agent styr sig själv och kan även ha individuella mål som den försöker uppfylla. Det här gör att analysen av sammankopplade system försvåras, men tidigare forskning har hittat olika regler och förhållninssätt för agenterna och deras sammankoppling för att uppfylla olika krav, såsom stabilitet och robusthet. Men även om dem sammankopplade systemen är både robusta och stabila så kan dem ha egenskaper som vi vill kunna kontrollera ytterligare. Specifikt kan ett sådant prestandamått vara systemens motståndskraft mot påverkan av yttre störningar och i vanliga olänkade system finns det en inneboende avvägning mellan kostnad på styrsignaler och resiliens mot yttre störningar. Samma avvägning hittar vi i sammankopplade system, men i dessa system hittar vi också ytterligare en dimension på detta problem. I och med att ett visst mått av en nätverksprestanda inte nödvändigtvis betyder att varje agent i nätverket delar samma mått kan agenterna i ett nätverk ha olika utväxling mellan styrsignalskostnad och resiliens mot yttre störningar. Detta gör att vissa agenter kan ha onödigt höga styrsignalskonstander, i den mening att systemen skulle uppnå samma nätverksprestanda men med lägre styrsignalskostnad om flera av agenterna skulle vikta om sina kontrollinsatser. I det här examensarbetet har vi studerat hur olika val av kontrollinsats påverkar ett sammankopplat systems prestanda. Vi har gjort detta för att undersöka hur autonoma, men sammankopplade, agenter kan ändra sin kontrollinsats, men med bibehållen nätverksprestanda, och på det sättet minska sina kontrollkostnader. Detta har bland annat resulterat i en distruberad algoritm för att manipulera agenternas kontrollinsats så att skillnaderna mellan agenternas resiliens mot yttre störningar minskar och nätverksprestandan ökar. Vi avslutar rapporten med att visa ett par exempel på hur system anpassade med hjälp av den framtagna algoritmen får ökad prestanda. Avslutningsvis följer en diskussion kring hur vissa antaganden kring systemstruktur kan släppas upp, samt kring vilka områden framtida forskning skulle kunna fortsätta med

Distribution of Control Effort in Multi-Agent Systems : Autonomous systems of the world, unite!

As more industrial processes, transportation and appliances have been automated or equipped with some level of artificial intelligence, the number and scale of interconnected systems has grown in the recent past. This is a development which can be expected to continue and therefore the research in performance of interconnected systems and networks is growing. Due to increased automation and sheer scale of networks, dynamically scaling networks is an increasing field and research into scalable performance measures is advancing. Recently, the notion gamma-robustness, a scalable network performance measure, was introduced as a measurement of interconnected systems robustness with respect to external disturbances. This thesis aims to investigate how the distribution of control effort and cost, within interconnected system, affects network performance, measured with gamma-robustness. Further, we introduce a notion of fairness and a measurement of unfairness in order to quantify the distribution of network properties and performance. With these in place, we also present distributed algorithms with which the distribution of control effort can be controlled in order to achieve a desired network performance. We close with some examples to show the strengths and weaknesses of the presented algorithms.I och med att fler och fler system och enheter blir utrustade med olika grader av intelligens så växer både förekomsten och omfattningen av sammankopplade system, även kallat Multi-Agent Systems. Sådana system kan vi se exempel på i traffikledningssystem, styrning av elektriska nätverk och fordonståg, vi kan också hitta fler och fler exempel på så kallade sensornätverk i och med att Internet of Things och Industry 4.0 används och utvecklas mer och mer. Det som särskiljer sammankopplade system från mer traditionella system med flera olika styrsignaler och utsignaler är att dem sammankopplade systemen inte styrs från en central styrenhet. Istället styrs dem sammankopplade systemen på ett distribuerat sätt i och med att varje agent styr sig själv och kan även ha individuella mål som den försöker uppfylla. Det här gör att analysen av sammankopplade system försvåras, men tidigare forskning har hittat olika regler och förhållninssätt för agenterna och deras sammankoppling för att uppfylla olika krav, såsom stabilitet och robusthet. Men även om dem sammankopplade systemen är både robusta och stabila så kan dem ha egenskaper som vi vill kunna kontrollera ytterligare. Specifikt kan ett sådant prestandamått vara systemens motståndskraft mot påverkan av yttre störningar och i vanliga olänkade system finns det en inneboende avvägning mellan kostnad på styrsignaler och resiliens mot yttre störningar. Samma avvägning hittar vi i sammankopplade system, men i dessa system hittar vi också ytterligare en dimension på detta problem. I och med att ett visst mått av en nätverksprestanda inte nödvändigtvis betyder att varje agent i nätverket delar samma mått kan agenterna i ett nätverk ha olika utväxling mellan styrsignalskostnad och resiliens mot yttre störningar. Detta gör att vissa agenter kan ha onödigt höga styrsignalskonstander, i den mening att systemen skulle uppnå samma nätverksprestanda men med lägre styrsignalskostnad om flera av agenterna skulle vikta om sina kontrollinsatser. I det här examensarbetet har vi studerat hur olika val av kontrollinsats påverkar ett sammankopplat systems prestanda. Vi har gjort detta för att undersöka hur autonoma, men sammankopplade, agenter kan ändra sin kontrollinsats, men med bibehållen nätverksprestanda, och på det sättet minska sina kontrollkostnader. Detta har bland annat resulterat i en distruberad algoritm för att manipulera agenternas kontrollinsats så att skillnaderna mellan agenternas resiliens mot yttre störningar minskar och nätverksprestandan ökar. Vi avslutar rapporten med att visa ett par exempel på hur system anpassade med hjälp av den framtagna algoritmen får ökad prestanda. Avslutningsvis följer en diskussion kring hur vissa antaganden kring systemstruktur kan släppas upp, samt kring vilka områden framtida forskning skulle kunna fortsätta med

A novel polymorphic cytochrome P450 formed by splicing of CYP3A7 and the pseudogene CYP3AP1.

The cytochrome P450 3A7 (CYP3A7) is the most abundant CYP in human liver during fetal development and first months of postnatal age, playing an important role in the metabolism of endogenous hormones, drugs, differentiation factors, and potentially toxic and teratogenic substrates. Here we describe and characterize a novel enzyme, CYP3A7.1L, encompassing the CYP3A7.1 protein with the last four carboxyl-terminal amino acids replaced by a unique sequence of 36 amino acids, generated by splicing of CYP3A7 with CYP3AP1 RNA. The corresponding CYP3A7-3AP1 mRNA had a significant expression in liver, kidney, and gastrointestinal tract, and its presence was found to be tissue-specific and dependent on the developmental stage. Heterologous expression in yeast revealed that CYP3A7.1L was a functional enzyme with a specific activity similar to that of CYP3A7.1 and, in some conditions, a different hydroxylation specificity than CYP3A7.1 using dehydroepiandrosterone as a substrate. CYP3A7.1L was found to be polymorphic due to a mutation at position -6 of the first splicing site of CYP3AP1 (CYP3A7_39256T-->A), which abrogates the pseudogene splicing. This polymorphism had pronounced interethnic differences and was in linkage disequilibrium with other functional polymorphisms described in the CYP3A locus: CYP3A7*2 and CYP3A5*1. Therefore, the resulting CYP3A haplotypes express different sets of enzymes within the population. In conclusion, a novel mechanism, consisting of the splicing of the pseudogene CYP3AP1 to CYP3A7, causes the formation of the novel CYP3A7.1L having a different tissue distribution and functional properties than the parent CYP3A7 enzyme, with possible developmental, physiological, and toxicological consequences.S

Potent inhibitory effect of the cyclolignan picropodophyllin (PPP) on human adrenocortical carcinoma cells proliferation

Adrenocortical carcinoma (ACC) is a very aggressive tumor with a poor prognosis. Available treatments for this type of cancer are far from being satisfactory. The IGF signalling pathway represents an important mechanism for ACT growth and constitutes a relevant therapeutic target. We investigated the effect of picropodophyllin (PPP), a member of the cyclolignan family and a new inhibitor of IGF-1R, on proliferation of human adrenocortical cell lines H295R and SW-13. PPP inhibits proliferation and induces an important accumulation in G2/M phase and apoptosis of H295R and SW-13 cells. Our data suggest that PPP may be a promising candidate for drug development for adrenocortical carcinoma