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1.
Mol Cell ; 79(3): 488-503.e11, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32585128

RESUMO

Transcription elongation rates influence RNA processing, but sequence-specific regulation is poorly understood. We addressed this in vivo, analyzing RNAPI in S. cerevisiae. Mapping RNAPI by Miller chromatin spreads or UV crosslinking revealed 5' enrichment and strikingly uneven local polymerase occupancy along the rDNA, indicating substantial variation in transcription speed. Two features of the nascent transcript correlated with RNAPI distribution: folding energy and GC content in the transcription bubble. In vitro experiments confirmed that strong RNA structures close to the polymerase promote forward translocation and limit backtracking, whereas high GC in the transcription bubble slows elongation. A mathematical model for RNAPI elongation confirmed the importance of nascent RNA folding in transcription. RNAPI from S. pombe was similarly sensitive to transcript folding, as were S. cerevisiae RNAPII and RNAPIII. For RNAPII, unstructured RNA, which favors slowed elongation, was associated with faster cotranscriptional splicing and proximal splice site use, indicating regulatory significance for transcript folding.


Assuntos
RNA Polimerase III/genética , RNA Polimerase II/genética , RNA Polimerase I/genética , RNA Fúngico/química , Saccharomyces cerevisiae/genética , Elongação da Transcrição Genética , Composição de Bases , Sequência de Bases , Sítios de Ligação , Cromatina/química , Cromatina/metabolismo , DNA Ribossômico/genética , DNA Ribossômico/metabolismo , Regulação Fúngica da Expressão Gênica , Ligação Proteica , Dobramento de RNA , RNA Polimerase I/metabolismo , RNA Polimerase II/metabolismo , RNA Polimerase III/metabolismo , Sítios de Splice de RNA , Splicing de RNA , RNA Fúngico/genética , RNA Fúngico/metabolismo , Saccharomyces cerevisiae/metabolismo , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Termodinâmica
2.
Soft Matter ; 20(30): 5889-5903, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-38748245

RESUMO

Ouzo is a well-known drink in Mediterranean countries, with ingredients water, alcohol and trans-anethole oil. The oil is insoluble in water, but completely soluble in alcohol, so when water is added to the spirit, the available alcohol is depleted and the mixture exhibits spontaneous emulsification. This process is commonly known as the louche or ouzo effect. Although the phase boundaries of this archetypal ternary mixture are well known, the properties of coexisting phases have not previously been studied. Here, we present a detailed experimental investigation into the phase behaviour, including tie-lines connecting coexisting phases, determination of the critical point (also called the plait point in ternary systems) and measurements of the surface tension and density for varying alcohol concentrations. Additionally, we present a theory for the thermodynamics and phase diagram of the system. With suitable selection of the interaction parameters, the theory captures nearly all features of the experimental work. This simple model can be used to determine both bulk and non-uniform (e.g. interfacial) properties, paving the way for a wide range of future applications of the model to ternary mixtures in general. We show how our accurate equilibrium phase diagram can be used to provide improved understanding of non-equilibrium phenomena.

3.
J Chem Phys ; 159(15)2023 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-37846952

RESUMO

Modelling of many real-world processes, such as drug delivery, wastewater treatment, and pharmaceutical production, requires accurate descriptions of the dynamics of hard particles confined in complicated domains. In particular, when modelling sedimentation processes or systems with driven flows, it is important to accurately capture volume exclusion effects. This work applies Dynamic Density Functional Theory to the evolution of a particle density under diffusion, external forces, particle-particle interaction, and volume exclusion. Using a spectral element framework, for the first time it is possible to include all of these effects in dynamic simulations on complex domains. Moreover, this allows one to apply complicated no-flux, and other non-local, non-linear, boundary conditions. The methodology is also extended to control problems, addressing questions of how to enhance production set-up in industrially-motivated processes. In this work the relevant models are introduced, numerical methods are discussed, and several example problems are solved to demonstrate the methods' versatility. It is shown that incorporating volume exclusion is crucial for simulation accuracy and we illustrate that the choice of boundary conditions significantly impacts the dynamics.

4.
Phys Rev E ; 109(2-1): 024801, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38491689

RESUMO

We present a theory for the interfacial wetting phase behavior of binary liquid mixtures on rigid solid substrates, applicable to both miscible and immiscible mixtures. In particular, we calculate the binding potential as a function of the adsorptions, i.e., the excess amounts of each of the two liquids at the substrate. The binding potential fully describes the corresponding interfacial thermodynamics. Our approach is based on classical density functional theory. Binary liquid mixtures can exhibit complex bulk phase behavior, including both liquid-liquid and vapor-liquid phase separation, depending on the nature of the interactions among all the particles of the two different liquids, the temperature, and the chemical potentials. Here we show that the interplay between the bulk phase behavior of the mixture and the properties of the interactions with the substrate gives rise to a wide variety of interfacial phase behaviors, including mixing and demixing situations. We find situations where the final state is a coexistence of up to three different phases. We determine how the liquid density profiles close to the substrate change as the interaction parameters are varied and how these determine the form of the binding potential, which in certain cases can be a multivalued function of the adsorptions. We also present profiles for sessile droplets of both miscible and immiscible binary liquids.

5.
Phys Rev Lett ; 109(12): 120603, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-23005931

RESUMO

We study the dynamics of a colloidal fluid including inertia and hydrodynamic interactions, two effects which strongly influence the nonequilibrium properties of the system. We derive a general dynamical density functional theory which shows very good agreement with full Langevin dynamics. In suitable limits, we recover existing dynamical density functional theories and a Navier-Stokes-like equation with additional nonlocal terms.


Assuntos
Coloides/química , Modelos Químicos , Hidrodinâmica
6.
Pharmacol Res ; 64(4): 364-70, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21745571

RESUMO

The aim of this study was to explore the psychopharmacological characteristics of opioid-induced conditioned reinforcement using oxycodone, a potent mu-opioid receptor agonist with known abuse potential. In differed groups of rats, passive intravenous infusions of oxycodone (100 infusions/3 h×6 sessions in total; 0, 0.01, 0.05 and 0.1 mg/kg/inf) were paired with an audio-visual stimulus and, subsequently, operant responding maintained by this conditioned stimulus was tested in extinction conditions. It was found that the oxycodone-paired stimulus maintained operant responding and that this effect was dependent on the number of conditioning sessions and on the conditioning dose. Responding maintained the oxycodone-paired stimulus could also be reinstated by both foot-shock stress and by oxycodone priming (0.25 mg/kg, SC). A conditioned place preference experiment (3 drug and 3 vehicle injections over 6 days; oxycodone: 0, 0.25, 2 and 5 mg/kg, SC) confirmed that stimuli associated with lower doses of oxycodone induce conditioned approach. Finally, two control experiments performed with chlordiazepoxide ruled out an interpretation of the oxycodone data based on drug-induced amnesia, and confirmed that operant responding for a drug-conditioned stimulus is observed only when the drug possesses unconditioned reinforcing properties. Therefore, the intravenous conditioned reinforcement procedure appears a useful method to study how opioid drugs impart reinforcing value to discrete environmental stimuli.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Entorpecentes/administração & dosagem , Oxicodona/administração & dosagem , Reforço Psicológico , Animais , Masculino , Entorpecentes/farmacologia , Oxicodona/farmacologia , Psicofarmacologia/métodos , Ratos , Ratos Sprague-Dawley , Esquema de Reforço
7.
Phys Rev Lett ; 103(21): 213001, 2009 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-20366031

RESUMO

In the case of one nuclear degree of freedom, we derive an explicit formula for the nuclear wave function transmitted through an avoided crossing, and show that it agrees to high accuracy with precise numerical calculations.

8.
AMIA Jt Summits Transl Sci Proc ; 2019: 127-135, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258964

RESUMO

Neonatal sepsis, a blood infection occurring in infants younger than 90 days old, represents a significant source of mortality and morbidity among infants.1 Mortality rates increase with postnatal age and can be as high as 52% (36% in newborns aged 8-14 days and 52% in those aged 15-28 days).2 While sepsis in adults has a generally accepted definition, the definition for clinical diagnosis in infants is less well defined. Using the Medical Information Mart for Intensive Care database (MIMIC-III), patient diagnoses and microbiology results records were processed with an artificial neural network trained using unsupervised learning known as a self-organizing map (SOM). The results of this feasibility study suggest a low degree of overlap between the presentation of sepsis in neonate and adult intensive care unit populations. As a consequence, it supports the need for dedicated research in neonatal sepsis, which may manifest differently than adult sepsis.

9.
Neuropsychopharmacology ; 31(7): 1462-74, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16237390

RESUMO

Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.


Assuntos
Encéfalo/efeitos dos fármacos , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Metadona/farmacologia , Entorpecentes/farmacologia , Receptores Opioides mu/metabolismo , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Expressão Gênica/efeitos dos fármacos , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/genética , Autoadministração
10.
Pharmacol Biochem Behav ; 83(4): 540-6, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16682073

RESUMO

The aim of the present experiment was to investigate the effects of cocaine primes and exposure to foot shock stress on reinstatement of operant responding maintained by a cocaine-conditioned stimulus in rats never trained to actively self-administer cocaine. Following a baseline session of responding for a light-buzzer compound stimulus, rats underwent classical conditioning whereby the compound stimulus was paired with passive intravenous infusions of cocaine (vehicle, 0.5 or 1.0 mg/kg/inf). On subsequent test sessions, operant responding for the compound stimulus was re-assessed in the absence of cocaine. Finally, rats received a cocaine prime (20 mg/kg, i.p.) and foot shock stress prior to two separate test sessions assessing lever pressing for the cocaine-conditioned stimulus. It was found that the animals conditioned with cocaine displayed sustained responding on the lever activating the cocaine-conditioned stimulus. In addition, priming injections of cocaine reinstated responding for the light-buzzer compound stimulus, and this effect was proportional to the dose of cocaine received during classical conditioning. Foot shock stress also reinstated responding, but its effect was smaller and observed only in animals conditioned with the highest dose of cocaine. These findings suggest that cocaine primes and stress can induce reinstatement by reactivating the motivational value of cocaine-conditioned cues.


Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Reforço Psicológico , Animais , Masculino , Ratos , Ratos Sprague-Dawley
11.
J Addict ; 2013: 394064, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24826360

RESUMO

Although it is well established that drug conditioned stimuli produce a variety of conditioned responses, it is not known whether such stimuli can also reinforce an arbitrary operant response and thus serve as conditioned reinforcers. Volunteers (n = 39) recruited from a residential treatment center for substance dependence were tested on a task in which presses on computer keys activated images of drugs/drug paraphernalia on a progressive ratio schedule of reinforcement. They also completed a personalized craving questionnaire and a personalized Implicit Association Test. A significant bias in responding was found for images of preferred drugs/route of drug administration. Craving, however, was low and the images generated negative evaluative reactions. Two additional studies were performed to ascertain the generalizability of the effects to a different population of drug-using individuals (i.e., students who drink) and to incentive stimuli of a different nature (i.e., sexual). The additional studies partially replicated and extended the central findings of the main study. Therefore, although these data should be considered preliminary in light of small group sizes, it is concluded that cue specificity and availability of the unconditioned stimuli (drugs and sex) plays a role in modulating responding maintained by conditioned reinforcers.

12.
Eur Neuropsychopharmacol ; 19(4): 238-49, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18990547

RESUMO

To elucidate the effects of steady-state methadone exposure on responding to cocaine conditioned stimuli and on cocaine-induced alterations in central opioid, hypocretin/orexin, and D2 receptor systems, male Sprague-Dawley rats received intravenous infusions of 1 mg/kg/inf cocaine paired with an audiovisual stimulus over three days of conditioning. Then, mini pumps releasing vehicle or 30 mg/kg/day methadone were implanted (SC), and lever pressing for the stimulus was assessed in the absence of cocaine and after a cocaine prime (20 mg/kg, IP). It was found that rats treated with vehicle, but not methadone, responded for the cocaine conditioned stimulus and displayed elevated mu-opioid receptor mRNA expression in the nucleus accumbens core and basolateral amygdala, reduced hypocretin/orexin mRNA in the lateral hypothalamus, and reduced D2 receptor mRNA in the caudate-putamen. This is the first demonstration that steady-state methadone administered after cocaine exposure blocks cocaine-induced behavioral and neural adaptations.


Assuntos
Analgésicos Opioides/administração & dosagem , Encéfalo/efeitos dos fármacos , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Metadona/administração & dosagem , Estimulação Acústica/métodos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Esquema de Medicação , Sistemas de Liberação de Medicamentos/métodos , Dinorfinas/genética , Dinorfinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Orexinas , Estimulação Luminosa/métodos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo
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