Mixture modeling
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We describe a novel approach of reaction representation as a combination of two mixtures: a mixture of reactants and a mixture of products. In turn, each mixture can be encoded using an earlier reported approach involving simplex descriptors (SiRMS). The feature vector representing these two mixtures results from either concatenated product and reactant descriptors or the difference between descriptors of products and reactants. This reaction representation doesn't need an explicit labeling of a reaction center. The rigorous "product-out" cross-validation (CV) strategy has been suggested. Unlike the naïve "reaction-out" CV approach based on a random selection of items, the proposed one provides with more realistic estimation of prediction accuracy for reactions resulting in novel products. The new methodology has been applied to model rate constants of E2 reactions. It has been demonstrated that the use of the fragment control domain applicability approach significantly increases prediction accuracy of the models. The models obtained with new "mixture" approach performed better than those required either explicit (Condensed Graph of Reaction) or implicit (reaction fingerprints) reaction center labeling.
V experimentálnej práci u 5 zdravých králikov plemena Novozélandsky biely sa zisťujú a hodnotia zmeny VOT a pupily po aplikácii do spojovkového vaku ľavého oka zmesi amínokyseliny 10% L-arginínu.HCl rozpusteného v 0,5% Timoptole. Pravé oko bolo kontrolné. Preukázalo sa, že zmes 0,5% Timoptolu s 10% L-arginínom. HCl počas celého pokusu signifikantne znížila VOT oproti kontrolnému oku Maximálne zníženie VOT o 20,1 % bolo v 60 min. (o 4 tory) a v 240 min o 10,7% (o 2,1 torov). V porovnaní s účinkom zmesi oboch látok samotný 10% L-arginin.HCl a samotný 0,5% Timoptol len nesignifikantne znížili VOT. Veľkosť pupily počas celého merania ostala na oboch očiach identická (7–7,5 mm). Predpokladáme, že interakciou L-argininu s Timoptolom vzniká nový metabolit, ktorý predstavuje vlastne hotový produkt, pôsobiaci zníženie produkciekomorovéhomoku vráskovcom čo vedie aj ku zníženiuVOTuž vo fyziologických podmienkach. Využitie tohto poznatku v klinických podmienkach by mohlo prispieť k lepšiemu využitiu a bezpečnejšiemu použitiu antiglaukomatík v liečbe glaukómového ochorenia. Preto účinok tohto metabolitu v lokálnej aplikácii je v ďalšom potrebné ešte dlhodobo sledovať.
- Klíčová slova
- TIMOPTOL,
- MeSH
- aminokyseliny bazické aplikace a dávkování farmakologie MeSH
- beta blokátory aplikace a dávkování farmakologie metabolismus MeSH
- finanční podpora výzkumu jako téma MeSH
- glaukom farmakoterapie MeSH
- králíci MeSH
- modely nemocí na zvířatech MeSH
- nitrooční tlak účinky léků MeSH
- timolol aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
Surface water can contain countless organic micropollutants, and targeted chemical analysis alone may only detect a small fraction of the chemicals present. Consequently, bioanalytical tools can be applied complementary to chemical analysis to detect the effects of complex chemical mixtures. In this study, bioassays indicative of activation of the aryl hydrocarbon receptor (AhR), activation of the pregnane X receptor (PXR), activation of the estrogen receptor (ER), adaptive stress responses to oxidative stress (Nrf2), genotoxicity (p53) and inflammation (NF-κB) and the fish embryo toxicity test were applied along with chemical analysis to water extracts from the Danube River. Mixture-toxicity modeling was applied to determine the contribution of detected chemicals to the biological effect. Effect concentrations for between 0 to 13 detected chemicals could be found in the literature for the different bioassays. Detected chemicals explained less than 0.2% of the biological effect in the PXR activation, adaptive stress response, and fish embryo toxicity assays, while five chemicals explained up to 80% of ER activation, and three chemicals explained up to 71% of AhR activation. This study highlights the importance of fingerprinting the effects of detected chemicals.
- MeSH
- biotest MeSH
- chemické látky znečišťující vodu analýza toxicita MeSH
- ekotoxikologie metody MeSH
- embryo nesavčí účinky léků MeSH
- NF-kappa B MeSH
- organické látky analýza toxicita MeSH
- receptory aromatických uhlovodíků metabolismus MeSH
- receptory pro estrogeny metabolismus MeSH
- řeky chemie MeSH
- ryby embryologie MeSH
- steroidní receptory metabolismus MeSH
- techniky in vitro MeSH
- teoretické modely MeSH
- testy genotoxicity metody MeSH
- testy toxicity metody MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chemicals in the environment occur in mixtures rather than as individual entities. Environmental quality monitoring thus faces the challenge to comprehensively assess a multitude of contaminants and potential adverse effects. Effect-based methods have been suggested as complements to chemical analytical characterisation of complex pollution patterns. The regularly observed discrepancy between chemical and biological assessments of adverse effects due to contaminants in the field may be either due to unidentified contaminants or result from interactions of compounds in mixtures. Here, we present an interlaboratory study where individual compounds and their mixtures were investigated by extensive concentration-effect analysis using 19 different bioassays. The assay panel consisted of 5 whole organism assays measuring apical effects and 14 cell- and organism-based bioassays with more specific effect observations. Twelve organic water pollutants of diverse structure and unique known modes of action were studied individually and as mixtures mirroring exposure scenarios in freshwaters. We compared the observed mixture effects against component-based mixture effect predictions derived from additivity expectations (assumption of non-interaction). Most of the assays detected the mixture response of the active components as predicted even against a background of other inactive contaminants. When none of the mixture components showed any activity by themselves then the mixture also was without effects. The mixture effects observed using apical endpoints fell in the middle of a prediction window defined by the additivity predictions for concentration addition and independent action, reflecting well the diversity of the anticipated modes of action. In one case, an unexpectedly reduced solubility of one of the mixture components led to mixture responses that fell short of the predictions of both additivity mixture models. The majority of the specific cell- and organism-based endpoints produced mixture responses in agreement with the additivity expectation of concentration addition. Exceptionally, expected (additive) mixture response did not occur due to masking effects such as general toxicity from other compounds. Generally, deviations from an additivity expectation could be explained due to experimental factors, specific limitations of the effect endpoint or masking side effects such as cytotoxicity in in vitro assays. The majority of bioassays were able to quantitatively detect the predicted non-interactive, additive combined effect of the specifically bioactive compounds against a background of complex mixture of other chemicals in the sample. This supports the use of a combination of chemical and bioanalytical monitoring tools for the identification of chemicals that drive a specific mixture effect. Furthermore, we demonstrated that a panel of bioassays can provide a diverse profile of effect responses to a complex contaminated sample. This could be extended towards representing mixture adverse outcome pathways. Our findings support the ongoing development of bioanalytical tools for (i) compiling comprehensive effect-based batteries for water quality assessment, (ii) designing tailored surveillance methods to safeguard specific water uses, and (iii) devising strategies for effect-based diagnosis of complex contamination.
Body-focused repetitive behavior disorders (BFRBs) include Trichotillomania (TTM; Hair pulling disorder) and Excoriation (Skin Picking) Disorder (SPD). These conditions are prevalent, highly heterogeneous, under-researched, and under-treated. In order for progress to be made in optimally classifying and treating these conditions, it is necessary to identify meaningful subtypes. 279 adults (100 with TTM, 81 with SPD, 40 with both TTM and SPD, and 58 controls) were recruited for an international, multi-center between-group comparison using mixture modeling, with stringent correction for multiple comparisons. The main outcome measure was to examine distinct subtypes (aka latent classes) across all study participants using item-level data from gold-standard instruments assessing detailed clinical measures. Mixture models identified 3 subtypes of TTM (entropy 0.98) and 2 subtypes of SPD (entropy 0.99) independent of the control group. Significant differences between these classes were identified on measures of disability, automatic and focused symptoms, perfectionism, trait impulsiveness, and inattention and hyperactivity. These data indicate the existence of three separate subtypes of TTM, and two separate subtypes of SPD, which are distinct from controls. The identified clinical differences between these latent classes may be useful to tailor future treatments by focusing on particular traits. Future work should examine whether these latent subtypes relate to treatment outcomes, or particular psychobiological findings using neuroimaging techniques.
Ciel': V predkladanej práci autoři venujú pozornost' ovplyvneniu fyziologických hodnot vnútroočného tlaku po aplikácii zmesi 10% L-lyzínu.2HCL.2H2O v 0,5% Timoptole. Metody: Do spojovkového vaku Favého oka 5 dospělých králikov (samiciach plemena Novozélandský biely) sa instiloval v týždňovom odstupe 10% L-lyzín.2HCL.2H2O, 0,5% Timoptol a zmes 10% L-lyzínu.2HCL.2H2O v 0,5% Timoptole. VOT a šířka pupily sa merali 5,15, 30, 60,120,180 a 240 minut po in-stilácii. Pravé oko bolo kontrolně. Výsledky; Bolo zistené, že: a) aminokyselina 10% L-lyzín.2HC1.2H2O neovplyvní fyziologickú hodnotu VOT; b) 0.5% Timoptol v porovnaní s kontrolným okom počas styroch hodin experimentu nesignifikantne sa znížil VOT; c) zmes oboch látok znižuje fyziologický VOT v dvoch fázach. Prvá fáza nesignifikantného zníženia trvá od aplikácie až po 60. minutu. V tomto období zhodný priebeh bol aj u kontrolného oka. Druhá fáza trvá od 60. minuty do konca experimentu (do styroch hodin), kedy pozorovat' oproti kontrolnému oku vysoko signifikantný účinok uvedenej zmesi. Prejaví sa 3,3-torrovým poklesom fyziologickej hodnoty VOT, pósobenie na tejto úrovni má rovnoměrný a priamociary charakter. Na kontrolnom oku sa druhá fáza poklesu VOT neprejaví. Závěry; Výsledky dokazujú, že samotný Timolol len nesignifikantne znižuje fyziologické hodnoty VOT, aminokyselina L-lyzín.2HC1.2H2O na VOT nepósobí. V práci sa potvrdilo, že v zmesi 10% L-lyzín. 2HC1.2H2O v 0,5% Timoptole inter-akciou vzniká nová látka, specifické „bio-antiglaukomatikum", ktoré vysoko signifikantně znižuje fyziologickú hodnotu VOT.
Objective: In this article authors focused to influence the physiologic IOP values after application of the aminoacid 10% L-lysine.2HC1.2H2O in 0.5 % Timoptol eye drops mixture in experiments. Methods: 0.5% Timoptol, followed by 10% L-lysine.2HC1.2H2O and mixture of 10% L-lysine.2HC1.2H2O with 0.5 % Timoptol was instilled weekly into the left conjunctival sac of 5 adult rabbits (females of the New Zealand White species). The IOP and pupilar diameter were measured in 5,15,30,60,120,180 and 240 min. after instillation. The right eye was ušed as control. Results: In experiments authors observed that: a) the aminoacid 10% L-lysi-ne.2HC1.2H2O is without influence on the physiologic value of the IOP; b) 0.5 % Timoptol compared with control eye nonsignifícantly decreased the rabbit IOP; c) after instillation of 10% L-lysine.2HC1.2H2O and 0.5 % Timoptol mixture the IOP showed decrease of the physiologic IOP in two periods. The initial non-significant period of the IOP decrease was measured after application up to the 60th min. The identical values were also in the control eye. However, the major decrease of the IOP compared with control eye was observed during the second period starting from 60th min. up to the end of experiments (to the 4th hour) after instillation of this mixture. The mean value of this significant decrease was 3.3 torrs of the physiologic IOP value showing regular and linear effecti-vity in the experimental eye. In the control eye the second period was without decrease of the IOP. Conclusions: The results demonstrate that the Timolol alone decreased the physiologic IOP no significantly, the aminoacid L-lysine.2HCl.2H2O is without influence on the physiologic value of the IOP. In experiments we confirmed that in a mixture of aminoacid L-lysine.2HCl.2H2O with antiglaucomatic 0.5 % Timoptol a new substance was created, a new "bio-antiglaucomatic", respon-sible for more significant decrease of the physiologic IOP.
- Klíčová slova
- Timoptol,
- MeSH
- aminokyseliny aplikace a dávkování chemie metabolismus MeSH
- beta blokátory aplikace a dávkování farmakologie MeSH
- finanční podpora výzkumu jako téma MeSH
- glaukom s otevřeným úhlem farmakoterapie MeSH
- králíci MeSH
- lysin aplikace a dávkování metabolismus MeSH
- modely u zvířat MeSH
- nitrooční tlak fyziologie účinky léků MeSH
- pupila fyziologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
OBJECTIVE: While many individuals gamble responsibly, some develop maladaptive symptoms of a gambling disorder. Gambling problems often first occur in young people, yet little is known about the longitudinal course of such symptoms and whether this course can be predicted. The aim of this study was to identify latent subtypes of disordered gambling based on symptom presentation and identify predictors of persisting gambling symptoms over time. METHODS: 575 non-treatment seeking young adults (mean age [SD] = 22.3 [3.6] years; 376 (65.4%) male) were assessed at baseline and annually, over three years, using measures of gambling severity. Latent subtypes of gambling symptoms were identified using latent mixture modeling. Baseline differences were characterized using analysis of variance and binary logistic regression respectively. RESULTS: Three longitudinal phenotypes of disordered gambling were identified: high harm group (N = 5.6%) who had moderate-severe gambling disorder at baseline and remained symptomatic at follow-up; intermediate harm group (19.5%) who had problem gambling reducing over time; and low harm group (75.0%) who were essentially asymptomatic. Compared to the low harm group, the other two groups had worse baseline quality of life, elevated occurrence of other mental disorders and substance use, higher body mass indices, and higher impulsivity, compulsivity, and cognitive deficits. Approximately 5% of the total sample showed worsening of gambling symptoms over time, and this rate did not differ significantly between the groups. CONCLUSIONS: Three subtypes of disordered gambling were found, based on longitudinal symptom data. Even the intermediate gambling group had a profundity of psychopathological and untoward physical health associations. Our data indicate the need for large-scale international collaborations to identify predictors of clinical worsening in people who gamble, across the full range of baseline symptom severity from minimal to full endorsement of current diagnostic criteria for gambling disorder.
V práci sú dokumentované výsledky experimentov s ovplyvnením fyziologických hodnot VOT po aplikácii COSOPT očných kvapiek (dvojkombinácie bbb-blokátora a inhibítora karboanhydrázy, aminokyseliny 10% L-arginínu.HCl a ich zmesi u králikov. Metody: Do spojovkového vaku lavého oka 5 dospělých králikov (samiciach plemena Novozélandský biely sa instiloval v týždňovom odstupe COSOPT, 10% L-arginín.HCl a zmes 10% L-arginínu.HCl v COSOPT-e. VOT a šířka pupily sa merali 5, 15, 30, 60, 120, 180 a 240 min, resp. 24 hod. po instilácii. Pravé oko bolo kontrolně. Výsledky: COSOPT za in vivo podmienok počas 24 hodin znížil hodnoty VOT v očiach králikov nesignifikantne (v priemere o 1,85 %). Aminokyselina 10% L-arginín.HCl znížila VOT signifikantně, v priemere o 16,03 % (s maximom v 60. a 180. min.). Po instilácii zmesi 10% L-arginínu s COSOPT-om VOT signifikantně klesol, v priemere o 9,64 % (okrem 5. min. a 24. hod.). Oproti kontrolnému oku najváčší pokles VOT (o 17,98 %) bol v 240. min. Avšak ešte 24 hodin po instilácii VOT nedosiahol hodnotu kontrolného oka a došlo aj ku zníženiu VOT kontrolného oka. Závěry: Předpokládáme, že v dvojkombinácii antiglaukomatík v COSOPT-e vznikla nová látka, ktorá za in vitro podmienok interagovala s aminokyselinou 10% L-arginínom.HCl. Tým v zmesi oboch látok vzniklo nové „bio- antiglaukomatikum", ktoré lepšie prestúpilo do cielovej oblasti. To sa prejavilo priekaznejším znížením VOT po aplikácii zmesi ako samotného COSOPT-u. Přítomnost aminokyseliny móže brzdit' aj nežiadúce účinky antiglaukomatík a móže mať aj neuroprotektívne pósobenie.
Objective: The article documents results of experiments focused to influence the physiological IOP values after application of the COSOPT eye drops (double combination of bbb-blocker and carbonic anhydrase inhibitor), aminoacid 10% L-arginin.HCl and their mixture in rabbits. Methods: COSOPT followed by 10% L-arginin.HCl and mixture of 10% L-arginin.HCl with COSOPT was instilled weekly into the left conjunctival sac of 5 adult rabbits (females of the New Zealand White species). The IOP and pupilar diameter were measured in 5, 15, 30, 60, 120, 180, 240 min. and 24 hours after instillation. The right eye was ušed as control. Results: The antiglaucomatic COSOPT no significantly decreased the rabbit IOP during 24 hours (mean value 1.85 %) in vivo. The aminoacid 10 % L-arginin.HCl achieved significant decrease of the IOP: the mean value was 16.03 % reaching maximum in 60th and 180th min. After instillation of the 10% L-arginin.HCl and COSOPT mixture in the IOP showed significant decrease with mean value of 9,64 % (except values in 5th min. and 24th hour). Compared with control eye, the major decrease of the IOP was measured in 240th min. (mean value 17.98 %). However even in 24 hours after instillation the IOP was not reaching the values of the control eye, shoving also the IOP decrease. Conclusion: We assume that in a double combination of antiglaucomatics in COSOPT a new substance was created. This substance interacted in vitro with the aminoacid 10% L-arginin.HCl resulting in a new "bio-antiglaucomatis" better penetrating into the target area. This new substance was responsible for more significant decrease after the mixture application compared with COSOPT alone. The presence of aminoacid can slow down the undesirable effect of the antiglaucomatics together with the possible neuroprotection.
- Klíčová slova
- Trusopt,
- MeSH
- aminokyseliny aplikace a dávkování farmakologie MeSH
- arginin aplikace a dávkování farmakologie MeSH
- finanční podpora výzkumu jako téma MeSH
- glaukom farmakoterapie MeSH
- konjunktiva účinky léků MeSH
- králíci MeSH
- lékové roztoky aplikace a dávkování farmakologie chemie MeSH
- modely u zvířat MeSH
- nitrooční tlak účinky léků MeSH
- pilokarpin MeSH
- timolol MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
OBJECTIVES: Apart from infections and habitat loss, environmental pollution is another major factor of global decline of amphibians. Using the model of Xenopus laevis embryos, we test the hypothesis that combined exposure of amphibians to natural toxins and anthropogenic pollutants induces more pronounced adverse effects than single exposures. METHODS: Experimental procedures adhered to Frog Embryo Teratogenesis Assay - Xenopus standards (FETAX). Exposure groups included controls, solvent (dimethyl sulfoxide) controls, and embryos exposed for 96 h to single, double and triple action of paraoxon (P), bromadiolone (B), and microcystin-LR (M), added to the FETAX medium at a dose of 300, 350, and 500 μg.L(-1), respectively. Studied responses of X. laevis embryos included mortality and malformations, head-to-tail length, total antioxidant capacity, lipid peroxidation, and caspase-3 activity. RESULTS: The triple combination induced the highest mortality. Malformations in embryos significantly prevailed only in B-, and B+P-exposure groups. Apart from the single exposure to B, the tested substances and their combinations inhibited the embryonic growth. Triple exposure had the most pronounced effect both on the growth inhibition and total antioxidant capacity. Lipid peroxidation was increased after B+M exposure, while single and combined exposures to B and P had an opposite effect. CONCLUSIONS: This study helps to understand adverse effects of environmental pollution by natural toxins and agrochemicals in amphibians. The results allow for risk assessment of environmental pollution and findings of low concentrations of contaminants in aquatic environments. Further research to address issues such as mixture toxicity to metamorphosing and adult amphibians is necessary.
- MeSH
- 4-hydroxykumariny toxicita MeSH
- abnormality vyvolané léky * MeSH
- antikoagulancia toxicita MeSH
- cholinesterasové inhibitory toxicita MeSH
- embryo nesavčí účinky léků embryologie MeSH
- inhibitory enzymů toxicita MeSH
- kaspasa 3 účinky léků MeSH
- mikrocystiny toxicita MeSH
- paraoxon toxicita MeSH
- peroxidace lipidů účinky léků MeSH
- testy toxicity MeSH
- velikost těla účinky léků MeSH
- Xenopus laevis embryologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
