In the 21st century this has come under attack, and the idea that

In the 21st century this has come under attack, and the idea that brain and hereditary information are stored as DNA is advocated. Thus, albeit without attribution, Butler’s idea is reinstated. Yet, while

check details the case is still open, the synaptic plasticity and DNA hypotheses have problems. Two broad alternatives remain on the table. Long term memory is located: (1) in the brain, either in some other macromolecular form (e.g. protein, lipid) or in some sub-molecular form (e.g. quantum computing and ‘brain as holograph’ hypotheses) or (2) outside the brain. The suggestion of the medieval physician Avicenna that the brain. cupboard’ is bare-Le. the brain is a perceptual, not storage, organ-is consistent with a mysterious,universe as holograph’ model. Understanding how Butler came to contribute could be heuristic for future progress in a field fraught with ‘fractionation and disunity’. (C) 2009 selleck chemicals Elsevier Ltd. All rights reserved.”
“The establishment of neural circuits involves both the precise positioning of cells within brain regions and projection of axons to specific target cells. In the cerebellum (Cb), the medial-lateral (M-L) and anterior-posterior (A-P) position of each Purkinje cell (PC) and the topography of its axon can be defined with respect to two coordinate systems within the Cb; one

based on the pattern of lobules and the other on PC gene expression in parasagittal clusters in

the embryo (e.g. Pcp2) and stripes in the adult (e.g. ZebrinII). The relationship between the embryonic clusters of molecularly defined PCs and particular adult PC stripes is not clear. Using a mouse genetic inducible fate mapping (GIFM) approach and a Pcp2-CreER-IRES-hAP transgene, we marked three bilateral clusters of PC clusters with myristolated green fluorescent protein (mGfp) on approximately embryonic day (E) 15 and followed their fate into adulthood. We found that these three clusters contributed specifically to ZebrinII-expressing PCs, including nine of the adult stripes. This result suggests that embryonic PCs maintain a particular Chlormezanone molecular identity, and that each embryonic cluster can contribute PCs to more than one adult M-L stripe. Each PC projects a primary axon to one of the deep cerebellar nuclei (DCN) or the vestibular nuclei in the brainstem in an organized fashion that relates to the position of the PCs along the M-L axis. We characterized when PC axons from the three M-L clusters acquire topographic projections. Using a combination of GIFM to mark the PC clusters with mGfp and staining for human placental alkaline phosphatase (hAP) in Pcp2-CreER-IRES-hAP transgenic embryos we found that axons from each embryonic PC cluster intermingled with neurons within particular DCN or projected out of the Cb toward the vestibular nuclei by E14.5.

The purpose of this article is to provide

The purpose of this article is to provide buy Thiazovivin an overview of experimental paradigms used to study habituation, integrate a theoretical approach to habituation to food based on memory and associative conditioning models, and review research on factors that influence habituation. Individual differences in habituation as

they relate to obesity and eating disorders are reviewed, along with research on how individual differences in memory can influence habituation. Other associative conditioning approaches to ingestive behavior are reviewed, as well as how habituation provides novel approaches to preventing or treating obesity. Finally, new directions for habituation research are presented. Habituation

provides a novel theoretical framework from which Selleck Belinostat to understand factors that regulate ingestive behavior.”
“This study was carried out to determine upper (CFMax) and lower (CTMin) thermal tolerance, acclimation response ratio (ARR) and thermal tolerance polygon of the European sea bass inhabiting the Iskenderun Bay, the most southeasterly part of the Mediterranean Sea, at three acclimation temperatures (15, 20, 25 degrees C). Acclimation temperature significantly affected the CTMin and CTMax values of the fish. At 0.3 degrees C min(-1) cooling or heating rate. CTMin ranged from 4.10 to 6.77 degrees C and CTMax ranged from 33.23 to 35.95 degrees C in three acclimation temperatures from 15 to 25 C. Thermal tolerance polygon for the juveniles at the tested acclimation temperatures was calculated to be 296.14 degrees C-2. In general, the current data show that our sea bass population possesses acclimation response ratio (ARR) values (0.25-0.27) similar to some tropical species. The cold tolerance values attained for this species ranged from 4.10 to 6.77 degrees C, suggesting that cold winter temperatures may not Methane monooxygenase pose danger during the culture of European sea bass in deep ponds or high water exchange rate systems. Upper thermal tolerance is more of a problem in the southern

part of the Mediterranean as maximum water temperature in ponds may sometimes exceed 33-34 degrees C, during which underground cool-water should be used to lower ambient water temperature in the mid-summer. For successful culture of sea bass in ponds, temperature should be maintained around 25 degrees C throughout the year and this can be managed under greenhousing systems using underground well-waters, commonly available in the region. (C) 2011 Elsevier Ltd. All rights reserved.”
“Recent evidence indicates that Parkinson’s disease and diabetes, both age-related chronic diseases, share remarkably similar dysregulated pathways. Exposure to environmental factors and genetic susceptibility play a role in the etiology and progression of both diseases.

For evaluating antitumoral efficacy, woodchuck tumors were inject

For evaluating antitumoral efficacy, woodchuck tumors were injected with

increasing doses Gemcitabine research buy of SFV-enhIL-12, and tumor size was measured by ultrasonography following treatment. In five (83%) of six woodchucks, a dose-dependent, partial tumor remission was observed, with reductions in tumor volume of up to 80%, but tumor growth was restored thereafter. Intratumoral treatment further produced transient changes in WHV viremia and antigenemia, with >= 1.5-log(10) reductions in serum WHV DNA in half of the woodchucks. Antitumoral and antiviral effects were associated with T-cell responses to tumor and WHV antigens and with expression of CD4 and CD8 markers, gamma interferon, and tumor necrosis

factor alpha in peripheral blood mononuclear cells, suggesting that immune responses against WHV and HCC had been induced. These experimental observations suggest that intratumoral administration of SFV-enhIL-12 may represent a strategy for treatment of chronic HBV infection and associated HCC in humans but indicate that this approach could benefit from further improvements.”
“The RNA-dependent RNA polymerase 3D(pol) is required for the elongation of positive- and negative-stranded picornavirus RNA. During the course of investigating the effect of the transgenic expression of viral genes on the host immune response, we evaluated the viral load present in the host after infection. To our surprise, we found that 3D transgenic expression in genetically Methisazone susceptible FVB mice led to substantially lower viral Gefitinib loads after infection with Theiler’s murine encephalomyelitis virus (TMEV). As a result, spinal cord damage caused by chronic viral infection in the central nervous system was reduced in FVB mice that expressed 3D. This led to the preservation of large-diameter axons

and motor function in these mice. The 3D transgene also lowered early viral loads when expressed in FVB-Db mice resistant to persistent TMEV infection. The protective effect of 3D transgenic expression was not altered in FVB-Rag(-/-).3D mice that are deficient in T and B cells, thus ruling out a mechanism by which the overexpression of 3D enhanced the adaptive immune clearance of the virus. Understanding how endogenously overexpressed 3D polymerase inhibits viral replication may lead to new strategies for targeting therapies to all picornaviruses.”
“In the present study, sexual behavior of male rats was assessed following prolonged treatment with the CBI receptor agonist, HU-210 (0.1 mg/mg/day for 10 days) under conditions of drug maintenance, spontaneous withdrawal and precipitated withdrawal (induced via administration of the CB(1) receptor antagonist AM251; 1 mg/kg).

(c) 2008 Elsevier Ireland Ltd All rights reserved “
“Backgr

(c) 2008 Elsevier Ireland Ltd. All rights reserved.”
“Background. Functional evaluation is a cornerstone of multidimensional geriatric assessment; however, little is known of the clinical value of standardized performance-based assessment in the acute care setting. The aim of this study wits to evaluate the clinical correlates and short-teen predictive value of the Short Physical Performance Battery (SPPB) in older patients admitted to the hospital for an acute medical event.

Methods.

We enrolled 92 women and men 65 years old or older who were able to walk, who had a Mini-Mental State Examination (MMSE) score >= 18, and who were admitted to the hospital with a clinical diagnosis of congestive heart failure, pneumonia, chronic obstructive pulmonary disease (COPD), or minor stroke. The SPPB was assessed at hospital SB431542 admission and discharge. Self-report functional assessment included basic activities of daily living (ADL) and instrumental activities of daily living (IADL). Spearman’s rank

correlation coefficients and multivariable linear regression analyses were used to study the association of SPPB score and functional and clinical characteristics, including length of hospital stay.

Results. The mean age was 77.7 years (range 65-94 years), 49% were female, 64.1% had congestive heart failure, 16% COPD, 13.1% pneumonia, and 6.5% minor stroke. At hospital admission the mean SPPB score was 6.0 +/- 2.7. SPPB scores were inversely correlated with age, the severity of the index disease, and IADL and ADL difficulty 2 weeks before hospital admission

(p < .01), and were directly GSK2126458 order correlated with MMSE score (p = .002). On average, SPPB score increased I point ((+0.97, standard error of the mean = 0.2; p for paired t test < .001) from baseline to hospital discharge assessment. After adjustment for potential confounders, baseline SPPB score wits significantly associated with the length of hospital stay) < .007).

Conclusion. In older acute care inpatients, SPPB is a valid indicator of functional and clinical status. SPPB score at hospital admission is an independent predictor of the length of hospital stay.”
“Human serum Florfenicol albumin (HSA) is an effective therapeutic agent that protects neurons after cerebral ischemia or related injuries by means of its antioxidant capacity. Our aim was to test whether bovine serum albumin (BSA) might also provide protection, especially against DNA damage. Rat cortical neurons were cultured in both the presence and absence of BSA. To test the neuroprotective role of BSA against DNA damage and neuronal death, primary cultures were investigated using both gamma-H2AX and pATM immuno-cytochemistry, and the TUNEL assay, respectively. Quantitative analyses revealed that the cultures in the absence of BSA had a higher number of apoptotic neurons.


“Rapid and reductive cell divisions during embryogenesis r


“Rapid and reductive cell divisions during embryogenesis require that intracellular structures adapt to a wide range of cell sizes. The mitotic spindle presents a central example of this flexibility, scaling with the dimensions of the cell to mediate accurate chromosome segregation. To determine whether SAHA HDAC concentration spindle size regulation is achieved through a developmental program or is intrinsically

specified by cell size or shape, we developed a system to encapsulate cytoplasm from Xenopus eggs and embryos inside cell-like compartments of defined sizes. Spindle size was observed to shrink with decreasing compartment size, similar to what occurs during early embryogenesis, and this scaling trend depended on compartment volume rather than shape. Thus, the amount of cytoplasmic material provides a mechanism for regulating the size of intracellular structures.”
“The selleck compound quiescent center (QC) plays an essential role during root development by creating a microenvironment that preserves the stem cell fate of its surrounding cells. Despite being surrounded by highly mitotic active cells, QC cells self-renew at a low proliferation rate. Here, we identified the ERF115 transcription factor as a rate-limiting factor of QC cell division, acting as a transcriptional activator of the phytosulfokine PSK5 peptide hormone. ERF115 marks QC cell division but is restrained

through proteolysis by the APC/C-CCS52A2 ubiquitin ligase, whereas QC proliferation is driven by brassinosteroid-dependent ERF115 expression. Together, these two antagonistic mechanisms delimit ERF115 activity, which is called upon when surrounding stem cells are damaged, revealing a cell cycle regulatory mechanism accounting for stem cell niche Buspirone HCl longevity.”
“Bacterial invasion of host tissues triggers polymorphonuclear leukocytes to release DNA [neutrophil extracellular traps (NETs)], thereby immobilizing microbes for subsequent clearance by innate defenses including macrophage phagocytosis. We report here that Staphylococcus aureus escapes these defenses by converting NETs to deoxyadenosine, which triggers the caspase-3-mediated death of immune

cells. Conversion of NETs to deoxyadenosine requires two enzymes, nuclease and adenosine synthase, that are secreted by S. aureus and are necessary for the exclusion of macrophages from staphylococcal abscesses. Thus, the pathogenesis of S. aureus infections has evolved to anticipate host defenses and to repurpose them for the destruction of the immune system.”
“Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-delta syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110 delta protein, the catalytic subunit of phosphoinositide 3-kinase delta (PI3K delta), encoded by the PIK3CD gene.

E138K restored viral replication capacity

E138K restored viral replication capacity selleck products (RC) in the presence of M184I/V, and this was confirmed in cell-free RT processivity assays. RT enzymes containing E138K, E138K/184I, or E138K/184V exhibited higher processivity than WT RT at low dNTP concentrations. Steady-state kinetic analysis demonstrated that the E138K mutation resulted in decreased K(m)s for dNTPs. In contrast, M184I/V resulted in an increased K(m) for dNTPs compared to those for WT RT. These

results indicate that the E138K mutation compensates for both the deficit in dNTP usage and impairment in replication capacity by M184I/V. Structural modeling shows that the addition of E138K to M184I/V promotes tighter dNTP binding.”
“Objective: Although the detrimental physical health effects of social isolation have been known for three decades, the answers to how and why social relationships generally improve health remain elusive. Social relationships are not always beneficial, and we examined a structural dimension that may bring about their salubrious effects: affiliative reciprocity during a stressor. Methods: In a lifespan study, female rats lived with their sisters and were tested for temperament, affiliative reciprocity during an everyday stressor at puberty, corticosterone response

to a stressor, mammary tumor development and diagnosis, and death. Results: Rats that affiliated more reciprocally during a mild group stressor survived longer (p = .0005), having exhibited a lower corticosterone peak in response to an acute novel stressor in late adulthood (p = .0015), and longer AG-120 in vivo time to the development of spontaneous mammary tumors (p = .02), These effects could not be explained solely by the number of affiliative interactions or individual Amisulpride temperament. Indeed, affiliative reciprocity and neophobia were independent and predicted mortality additively

(p = .0002). Conclusions: Affiliative reciprocity during a stressor, a structural quality of social interactions, protected females from early mammary tumor development (the primary pathology in Sprague-Dawley rats) and early all-cause mortality. Conversely, lack of reciprocity (whether disproportionately seeking or receiving attempted affiliation) was as potent a risk factor as neophobia. Thus a social role increased risk additively with individual temperament. Our data indicate that affiliative reciprocity functions as a buffer for everyday stressors and are likely mediated by attenuated reactivity of the hypothalamic-pituitary-adrenal axis.”
“Anodal stimulation of dorsolateral prefrontal cortex by transcranial Direct Current Stimulation (tDCS) has been shown to enhance performance on working memory tasks. However, it is not yet known precisely which aspects of working memory – a broad theoretical concept including short-term memory and various executive functions – are involved in such effects.

We further expound on the notion that chronic pain can be reformu

We further expound on the notion that chronic pain can be reformulated within the context of learning and memory, and demonstrate the relevance of the idea in the design of novel pharmacotherapies. Lastly, we integrate the human and

animal data into a unified working model outlining the mechanism by which acute pain transitions into a chronic state. It incorporates knowledge of underlying brain structures and their reorganization, and also includes specific variations as a function of pain persistence and injury type, thereby providing mechanistic descriptions of several unique chronic pain conditions within a single model. (C) 2008 Elsevier Ltd. All rights reserved.”
“During the past decade, it has been shown that circadian clock genes have more than a simple circadian time-keeping role. Clock genes also modulate motivational DMXAA manufacturer processes and have been implicated in the development of psychiatric disorders such as drug addiction. Recent studies indicate that casein-kinase 1 epsilon/delta (CK1 epsilon/delta)-one of the components of the circadian molecular clockwork-might be involved in the etiology of addictive behavior. The present study was initiated to study the specific role of CK1 epsilon/delta

in alcohol relapse-like drinking using the ‘Alcohol Deprivation Effect’ model. The effect of CK1 epsilon/delta inhibition was tested on alcohol consumption SRT1720 cell line in long-term alcohol-drinking rats upon re-exposure to alcohol Thalidomide after deprivation using a four-bottle free-choice paradigm with water, 5%, 10%, and 20% ethanol solutions, as well as on saccharin preference in alcohol-naive rats. The inhibition of CK1 epsilon/delta with systemic PF-670462 (0, 10, and 30 mg/kg) injections dose-dependently decreased, and at a higher dosage prevented the alcohol deprivation effect, as compared with vehicle-treated rats. The impact of the treatment was further characterized using nonlinear regression analyses on the daily profiles of drinking and locomotor activity. We reveal that CK1 epsilon/delta inhibition blunted the high

daytime alcohol intake typically observed upon alcohol re-exposure, and induced a phase shift of locomotor activity toward daytime. Only the highest dose of PF-670462 shifted the saccharin intake daily rhythm toward daytime during treatment, and decreased saccharin preference after treatment. Our data suggest that CK1 inhibitors may be candidates for drug treatment development for alcoholism. Neuropsychopharmacology ( 2012) 37, 2121-2131; doi:10.1038/npp.2012.62; published online 2 May 2012″
“Sustained vascular smooth muscle contraction can be mediated by several mechanisms, including the influx of extracellular Ca2+ through L-type voltage-gated Ca2+ channels (LTCCs) and by RhoA/Rho-associated kinase (ROCK)-dependent Ca2+ sensitization of the contractile machinery.

The hydrogen bond H186-R155 partially contributes to the structur

The hydrogen bond H186-R155 partially contributes to the structural stability of rabbit prion protein.

Conclusions: Rabbit prion protein was found to own the structural stability, the salt bridges D177-R163, D201-R155 greatly contribute and

the hydrogen bond H186-R155 partially contributes to this structural stability. The comparison of the structural stability of prion proteins from the three species rabbit, human and Torin 1 research buy mouse showed that the human and mouse prion protein structures were not affected by the removing these two salt bridges. Dima et al. (Biophysical Journal 83 (2002) 1268-1280 and Proceedings of the National Academy of Sciences of the United States of America 101 (2004) 15335-15340) also confirmed this point and pointed out that “”correlated mutations that reduce the frustration in the second half of helix 2 in mammalian prion proteins could

inhibit the formation of PrP(Sc)”". (C) 2010 Elsevier Ltd. All rights reserved.”
“The distinctive function of nitric oxide (NO) in biology is to transmit cellular signals through membranes and regulate cellular functions in adjacent cells. NO conveys signals as a second messenger from a cell where NO is generated to contiguous cells in two ways: one is as gaseous molecule by free diffusion resulting in an activation of soluble guanylate cyclase (NO/cGMP pathway), and another form is by binding with a molecule such as cysteine or protein thiol through S-nitrosylation (SNO pathway). Both pathways see more transmit much of the biological influence

of NO from cell where other messenger molecules but NO are confined, through the plasma membrane to the adjacent cells. Since SNO pathway cannot utilize free-diffusion mechanism to get through the membrane as the molecular size is significantly larger than NO molecule, it utilizes amino acid transporter to convey signals as a form of S-nitrosylated cysteine (CysNO). Although S-nitrosylated glutathione (GSNO) is the molecule which act as a determinant of the total S-nitrosothiol level in cell, transnitrosylation reaction from GSNO STK38 to CysNO is an initial requirement to pass through signal through the membrane. Thus, multiplexed combination of these steps and the regulatory factors involved in this system conform and modify the outcome from stimulus-response coupling via the SNO pathway. (C) 2011 Elsevier Inc. All rights reserved.”
“In population biology, loop analysis is a method of decomposing a life cycle graph into life history pathways so as to compare the relative contributions of pathways to the population growth rate across species and populations. We apply loop analysis to the transmission graph of five pathogens known to infect the black-legged tick, Ixodes scapularis. In this context loops represent repeating chains of transmission that could maintain the pathogen. They hence represent completions of the life cycle, in much the same way as loops in a life cycle graph do for plants and animals.

Hospital admissions for CHF and ambient air pollution data for Ta

Hospital admissions for CHF and ambient air pollution data for Taipei were obtained

for the period from 1996 to 2004. The relative risk of hospital admission was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. In the single-pollutant model, the number of CHF admissions was significantly associated with the environmental presence of the contaminants particulate matter (PM(10)), nitrogen dioxide (NO(2)), carbon monoxide (CO), and ozone (O(3)) on warm days (> 20 degrees C). However, statistically significant positive effects on increased CHF admissions on cool days (< 20 degrees GS-4997 purchase C) was observed only for CO levels. For the two-pollutant model, NO(2) and O(3) were significant in combination with each of the other four pollutants MI-503 chemical structure on warm days for enhanced CHF admissions. This study provides evidence that higher levels of ambient air pollutants increase the risk of hospital admissions for CHF.”
“The development of static and dynamic perception for stimuli requiring different levels of neural analysis was assessed

by measuring orientation-identification and direction-identification thresholds for both lower-level [or first-order (FO)] and higher-level [or second-order (SO)] stimuli as a function of age. Results demonstrate that both lower-level and higher-level perception continue to develop during school-age years in both dynamic and static domains. When compared with adult levels, dynamic performance for 5-6-year-olds HAS1 is significantly decreased for SO, but not for the FO perception; however, type of stimulus (FO vs. SO) did not affect the development of static perception. We therefore suggest that levels of stimulus complexity should be considered an important variable when assessing and making inferences regarding the typical and atypical development of static and dynamic perception.”
“Aluminum smelters produce in excess thousand of tons

of spent pot lining (SPL) each year. CAlSiFrit technology is a recycling process in which spent pot lining (SPL) is recovered and transformed into commercial value-added products. Since SPL contains beryllium (Be), exposures encountered by workers may result in adverse effects. This study aimed to establish the level at which Be is present in the CAlSiFrit and to determine the chemical and physical characteristics of the Be-containing particles. Three samples of CAlSiFrit powder supplied by the recycling industry were analyzed using several methods in order to (1) detect and characterize Be-containing particles, (2) identify the Be chemical form, and (3) quantify the amount of other major chemical elements present. These methods were: inductively coupled plasma mass spectrometry, instrumental neutron activation analysis, time-of-flight secondary-ion mass spectrometry (TOF-SIMS), analytical transmission electron microscopy (ATEM), and x-ray diffraction.

Low doses of N/OFQ and NOP receptor antagonists promoted movement

Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by amisulpride. Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic D2

receptors, mice lacking the D2 receptor (D2R(-/-)) or its long isoform (D2L(-/-) )were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R-/- and D2L-/- mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion

was observed in both genotypes. We demonstrate that motor selleck actions of NOP receptor ligands rely on the modulation of endogenous Abemaciclib mouse dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the D2 presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists

on motor function reflect the blockade next of this endogenous N/OFQ tone. (C) 2013 Elsevier Ltd. All rights reserved.”
“Tobacco withdrawal is characterized by a negative mood state and relatively mild somatic symptoms. Increased noradrenergic transmission has been reported to play an important role in opioid withdrawal, but little is known about the role of noradrenergic transmission in nicotine withdrawal.

The aim of these experiments was to investigate the effects of prazosin, clonidine, and propranolol on the negative mood state and somatic signs associated with nicotine withdrawal in rats.

A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function.

In all the experiments, the nicotinic acetylcholine receptor antagonist mecamylamine (3 mg/kg) elevated the brain reward thresholds of the nicotine-treated rats and did not affect those of the control rats. The alpha 1-adrenergic receptor antagonist prazosin (0.0625 and 0.125 mg/kg) dose-dependently attenuated the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. The alpha 2-adrenergic receptor agonist clonidine (10-40 mu g/kg) and the nonselective beta-adrenergic receptor antagonist propranolol (2.