Search

Invasive mammals represent a critical threat to island biodiversity; eradications can result in ecological restoration yet may fail in the absence of key population parameters. Over-browsing by invasive Sitka black-tailed deer (Odocoileus hemionus sitkensis) is causing severe ecological and cultural impacts across the Haida Gwaii archipelago (Canada). Previous eradication attempts demonstrate forest regeneration upon deer removal, but reinvasion reverses conservation gains. Here we use restriction-site associated DNA sequencing (12,947 SNPs) to investigate connectivity and gene flow of invasive deer (n = 181) across 15 islands, revealing little structure throughout Haida Gwaii and identifying the large, central island of Moresby (2600 km

Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO2 inhalation challenge to induce panic symptoms. In the rat CO2 model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P 2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO2 exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

The secretin receptor (SCTR), a prototypical class B G protein-coupled receptor (GPCR), exerts its effects mainly by activating Gαs proteins upon binding of its endogenous peptide ligand secretin. SCTRs can be found in a variety of tissues and organs across species, including the pancreas, stomach, liver, heart, lung, colon, kidney, and brain. Beyond that, modulation of SCTR-mediated signaling has therapeutic potential for the treatment of multiple diseases, such as heart failure, obesity, and diabetes. However, no ligands other than secretin and its peptide analogs have been described to regulate SCTRs, probably due to inherent challenges in family B GPCR drug discovery. Here we report creation of a testing funnel that allowed targeted detection of SCTR small-molecule activators. Pursuing the strategy to identify positive allosteric modulators (PAMs), we established a unique primary screening assay employing a mixture of three orthosteric stimulators that was compared in a screening campaign testing 12,000 small-molecule compounds. Beyond that, we developed a comprehensive set of secondary assays, such as a radiolabel-free target engagement assay and a NanoBiT (NanoLuc Binary Technology)-based approach to detect β-arrestin-2 recruitment, all feasible in a high-throughput environment as well as capable of profiling ligands and hits regarding their effect on binding and receptor function. This combination of methods enabled the discovery of five promising scaffolds, four of which have been validated and further characterized with respect to their allosteric activities. We propose that our results may serve as starting points for developing the first in vivo active small molecules targeting SCTRs.

Objective Deer hunting includes various stimuli resulting in augmented sympathetic activity, increased heart rate (HR) response, and rhythm changes. Collectively, these superimposed stresses may increase an individual's risk for cardiovascular events. We undertook this study to evaluate HR and rhythm responses in multiple phases of deer hunting in men and women with and without cardiovascular disease (CVD). Methods Nineteen participants age 38.3 ± 13.8 years (mean ± SD) with body mass index 29.2 ± 6.9 kg/m 2 followed their normal hunting routine. HR and rhythm were recorded continuously during the hunt using a small leadless electrocardiogram (ECG) patch monitor. Results Data were collected on 13 of 19 hunters while hiking. Three hunters recorded HR ≥85% of their age-predicted heart rate maximum (HRmax) for 1 to 2 minutes. Arrhythmias were detected in both participants with CVD and in 8 without CVD. Recorded rhythms included premature atrial, junctional, and ventricular complexes. Six hunters climbed a tree stand; 3 of them recorded HR ≥85% HRmax with sustained elevated HR response for 2 to 3 minutes with premature junctional contractions. Four of 19 participants dragged deer carcasses. During the drag, 1 male hunter recorded an HR of 91% HRmax, and another male hunter without CVD recorded an exercise-induced ischemic ECG. Fifteen of 19 hunters experienced "buck fever" (acute extreme excitation), with 7 reaching ≥85% HRmax for up to 1 minute. Ventricular bigeminy and trigeminy and ventricular couplets were observed in 1 subject during buck fever. Conclusions Men and women with and without CVD recorded substantial increases in HR and clinically relevant arrhythmias while deer hunting.

Doxorubicin (DOX) is a potent and widely used antineoplastic agent. Despite the efficacy of DOX, its clinical use is limited by a dose-dependent cardiotoxicity. Chronic exercise training has been shown to protect against DOX-induced cardiotoxicity. It is less clear whether short-term exercise can attenuate DOX-induced dysfunction. The purposes of this study were to determine if short-term wheel running and treadmill exercise training can attenuate the cardiac dysfunction that accompanies DOX treatment and to investigate possible mechanisms that may be involved with any protective effects of exercise. Male Sprague-Dawley rats engaged in a short-term 5-day voluntary wheel running (WR) or treadmill exercise (TM) regimen. Following the exercise preconditioning period, animals received either 10 or 15 mg/kg of DOX or an equivalent volume of saline (SAL). Five days after DOX/SAL exposure, cardiac function was examined. Western immunoblotting was used to quantify left ventricular sarcoendoplasmic reticulum calcium-ATPase 2a (SERCA2a) protein expression. Exercise preconditioning attenuated in vivo and ex vivo cardiac dysfunction observed with DOX treatment alone. Specifically, short-term treadmill exercise (TM + DOX10, 56 ± 4 %; TM + DOX15, 48 ± 5 %) and voluntary wheel running (WR + DOX10, 51 ± 5 %; WR + DOX15, 45 ± 3 %) consistently preserved fractional shortening when compared to sedentary (SED) animals treated with DOX (SED + DOX10, 48 ± 4 %; SED + DOX15, 39 ± 6 %). Likewise, both exercise protocols preserved left ventricular developed pressure (TM + DOX10, 115 ± 6 mmHg; TM + DOX15, 85 ± 5 mmHg; WR + DOX10, 92 ± 12 mmHg; WR + DOX15, 91 ± 8 mmHg) when compared to SED animals treated with DOX (SED + DOX10, 79 ± 6 mmHg; SED + DOX15, 69 ± 7 mmHg). SERCA2a expression was also preserved in TM + DOX and WR + DOX. These findings suggest that short-term exercise prior to DOX treatment may be a valuable adjuvant therapy to offset acute cardiotoxicities and that maintaining calcium handling in cardiomyocytes may be responsible, in part, for the preservation in cardiac function.

The preclinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochemical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (34), are described herein.

Orexins (OXs) are peptides produced by perifornical (PeF) and lateral hypothalamic neurons that exert a prominent role in arousal-related processes, including stress. A critical role for the orexin-1 receptor (OX1R) in complex emotional behavior is emerging, such as overactivation of the OX1R pathway being associated with panic or anxiety states. Here we characterize a brain-penetrant, selective, and high-affinity OX1R antagonist, compound 56 [N-({3-[(3-ethoxy-6-methylpyridin-2-yl)carbonyl]-3-azabicyclo[4.1.0]hept-4-yl}methyl)-5-(trifluoromethyl)pyrimidin-2-amine]. Ex vivo receptor binding studies demonstrated that, after subcutaneous administration, compound 56 crossed the blood-brain barrier and occupied OX1Rs in the rat brain at lower doses than standard OX1R antagonists GSK-1059865 [5-bromo-N-({1-[(3-fluoro-2-methoxyphenyl)carbonyl]-5-methylpiperidin-2-yl}methyl)pyridin-2-amine], SB-334867 [1-(2-methyl-1,3-benzoxazol-6-yl)-3-(1,5-naphthyridin-4-yl)urea], and SB-408124 [1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea]. Although compound 56 did not alter spontaneous sleep in rats and in wild-type mice, its administration in orexin-2 receptor knockout mice selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. In a rat model of psychological stress induced by cage exchange, the OX1R antagonist prevented the prolongation of sleep onset without affecting sleep duration. In a rat model of panic vulnerability (involving disinhibition of the PeF OX region) to threatening internal state changes (i.e., intravenous sodium lactate infusion), compound 56 attenuated sodium lactate-induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. In conclusion, OX1R antagonism represents a novel therapeutic strategy for the treatment of various psychiatric disorders associated with stress or hyperarousal states.

In group-living mammals, the eviction of subordinate females from breeding groups by dominants may serve to reduce feeding competition or to reduce breeding competition. Here, we combined both correlational and experimental approaches to investigate whether increases in food intake by dominant females reduces their tendency to evict subordinate females in wild meerkats ($\textit{Suricata suricatta}$). We used 20 years of long-term data to examine the association between foraging success and eviction rate, and provisioned dominant females during the second half of their pregnancy, when they most commonly evict subordinates. We show that rather than reducing the tendency for dominants to evict subordinates, foraging success of dominant females is positively associated with the probability that pregnant dominant females will evict subordinate females and that experimental feeding increased their rates of eviction. Our results suggest that it is unlikely that the eviction of subordinate females serves to reduce feeding competition and that its principal function may be to reduce reproductive competition. The increase in eviction rates following experimental feeding also suggests that rather than feeding competition, energetic constraints may normally constrain eviction rates.

Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX-induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague–Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg·(kg body mass)–1·d–1 by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (–21% and –27%), maximal rate of pressure development (–29% and –32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective.

There is growing concern regarding the long-term negative side effects of chemotherapy in childhood cancer survivors. Doxorubicin (DOX) is commonly used in the treatment of childhood cancers and has been shown to be both cardiotoxic and osteotoxic. It is unclear whether exercise can attenuate the negative skeletal effects of this chemotherapy. Rat pups were treated with saline or DOX. Animals remained sedentary or voluntarily exercised. After 10 weeks, femoral bone mineral content and bone mineral density were measured using dual-energy x-ray absorptiometry. Cortical and cancellous bone architecture was then evaluated by microcomputed tomography. DOX had a profound negative effect on all measures of bone mass and cortical and cancellous bone architecture. Treatment with DOX resulted in shorter femora and lower femoral bone mineral content and bone mineral density, lower cross-sectional volume, cortical volume, marrow volume, cortical thickness, and principal (IMAX, IMIN) and polar (IPOLAR) moments of inertia in the femur diaphysis, and lower cancellous bone volume/tissue volume, trabecular number, and trabecular thickness in the distal femur metaphysis. Exercise failed to protect bones from the damaging effects of DOX. Other modalities may be necessary to mitigate the deleterious skeletal effects that occur in juveniles undergoing treatment with anthracyclines.

The use of exercise to minimize doxorubicin (DOX)-induced cardiotoxicity is gaining attention. However, very few clinically relevant reports exist investigating the effects of exercise performed during and following DOX treatments. The purpose of this study, therefore, was to examine the effects of voluntary wheel running during and following DOX treatment using two models of late-onset DOX cardiotoxicity in the rat. Female Sprague-Dawley rats received either DOX or saline injections using one of two separate treatment regimens. These regimens involved either daily or weekly DOX injections with cumulative doses for both protocols totaling 15 mg/kg. Daily DOX injections were 1 mg/kg and lasted for 15 consecutive days while weekly DOX injections were 2.5 mg/kg and lasted for six consecutive weeks with control animals receiving matched saline injection regimens. Immediately following the initial DOX/saline injection, animals were randomly housed in cages with voluntary running wheels or standard rat cages throughout DOX/saline treatments and continued until reaching 10 weeks. Cardiac function was then assessed using echocardiography and an isolated working heart model, and myosin heavy chain (MHC) isoform distribution was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When compared wth controls, daily DOX treatment resulted in reduced running wheel distances at weeks 2-10 (P < 0.05), and weekly DOX treatment resulted in reduced running wheel distances at weeks 2, 6 and 10 (P < 0.05). Nonetheless, wheel running during and following daily and weekly DOX dosing protected against DOX-induced cardiotoxicity by preserving maximal mitral and aortic blood flow velocities, left ventricular developed pressure and MHC isoform expression. In conclusion, the overall reduced volume of activity during and following daily and weekly DOX treatments attenuated DOX-induced cardiac dysfunction suggesting that low-volume endurance training may be an effective rehabilitative approach in minimizing DOX cardiotoxicity in cancer patients.

We describe the synthesis of a novel class of brain penetrating P2X7 antagonists with high potency at both the rat and human P2X7 receptors. Disclosed herein are druglike molecules with demonstrated target engagement of the rat P2X7 receptors after an oral dose. Specifically, compound 20 occupied the P2X7 receptors >80% over the 6 h time course as measured by an ex vivo radioligand binding experiment. In a dose–response assay, this molecule has a plasma EC50 of 8 ng/mL. Overall, 20 has suitable druglike properties and pharmacokinetics in rat and dog. This molecule and others disclosed herein will serve as additional tools to elucidate the role of the P2X7 receptor in neuropsychiatric disorders.

Acute doxorubicin (DOX) cardiotoxicity can be attenuated by exercise preconditioning, but little is known of whether this cardioprotection continues beyond 10 days post-DOX administration. The purpose of this study was to determine the effects of exercise preconditioning on early chronic DOX-induced cardiotoxicity. Male rats were randomly assigned to sedentary, treadmill, or wheel running groups. Treadmill and wheel running animals participated in a progressive treadmill training protocol or voluntary wheel running, respectively, for 10 weeks. Following the intervention, animals were further randomized to receive either DOX (sedentary + DOX, treadmill + DOX, wheel running + DOX) or saline (sedentary + saline, treadmill + saline, wheel running + saline). All animals then remained sedentary for 4 weeks. A 22% reduction in fractional shortening was observed in left ventricles from previously sedentary animals receiving DOX when compared with sedentary + saline. This degree of decline was not observed in treadmill + DOX and wheel running + DOX. Sedentary + DOX possessed significantly depressed mitral and aortic valve blood flow velocities when compared with sedentary + saline, but these decrements were not observed in treadmill + DOX and wheel running + DOX. Ex vivo analysis revealed that left ventricular developed pressure and maximal rate of pressure development were significantly lower in sedentary + DOX when compared to sedentary + saline. Treadmill and wheel running prior to DOX treatment protected against these decrements. Exercise cardioprotection was associated with preserved myosin heavy chain but not sarcoendoplasmic reticulum Ca2+ ATPase 2a expression. In conclusion, 10 weeks of prior exercise protected against early chronic DOX cardiotoxicity suggesting that training status may be a determining factor in the degree of late-onset cardiotoxicity experienced by cancer patients undergoing treatment with DOX.

Doxorubicin (DOX) is an effective antineoplastic agent with well-characterized cardiotoxic effects. Although exercise has been shown to protect against DOX cardiotoxicity, a clear and concise mechanism to explain its cardioprotective effects is lacking. The purpose of this study was to determine if exercise training reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity.Sprague-Dawley rats were randomly assigned to 1 of 3 primary experimental groups: sedentary (n = 77), wheel running (n = 65), or treadmill (n = 65). Animals in wheel running and treadmill groups completed 10 weeks of exercise before DOX treatment. DOX was administered 24 hours after the last training session as a bolus intraperitoneal injection at 10 mg/kg. Subgroups of rats from each primary group were killed at 1, 3, 5, 7, and 9 days after DOX exposure to assess cardiac function and DOX accumulation.Ten weeks of exercise preconditioning reduced myocardial DOX accumulation, and this reduction in accumulation was associated with preserved cardiac function.These data suggest that the cardioprotective effects of exercise against DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.

The orexin, or hypocretin, neuropeptides (orexin-A and orexin-B) are produced on neurons in the hypothalamus which project to key areas of the brain that control sleep-wake states, modulation of food intake, panic, anxiety, emotion, reward and addictive behaviors. These neuropeptides exert their effects on a pair of G-protein coupled receptors termed the orexin-1 (OX1) and orexin-2 (OX2) receptors. Emerging biology suggests the involvement of these receptors in psychiatric disorders as they are thought to play a key role in the regulation of multiple systems. This review is intended to highlight key selective OX1 or OX2 small-molecule antagonists.

A high-fat diet has been shown to exacerbate the cardiotoxicity associated with the chemotherapy drug doxorubicin (DOX); however, it is unknown whether switching from a high-fat diet to a low-fat diet can attenuate the intensified DOX cardiotoxicity. The purpose of this study was to investigate the effects of a low-fat diet on DOX-induced cardiotoxicity in rats previously fed a high-fat diet.Male rats were randomly assigned to consume a Western diet or a low-fat diet for 6 weeks. Western diet-fed rats were then further randomized to switch to the low-fat diet (WD-LF) or continue with the Western diet (WD). One week later, WD-LF and WD received 1 mg/kg DOX per day for 10 consecutive days and continued with their diets (WD-LF + DOX, WD + DOX). LF was further randomized to receive 1 mg/kg DOX per day for 10 consecutive days (LF + DOX) or saline injections as a control (LF + SAL). Four weeks following the first injection, cardiac function was analyzed, and left ventricles were analyzed for cardiotoxicity indices.When compared to LF + SAL and LF + DOX, WD + DOX exhibited an enhanced cardiotoxicity as evidenced by reduced septal wall thickness, fractional shortening, and sarco-endoplasmic reticulum Ca(2+) ATPase expression as well as increased left ventricular cavity dimensions, lipid peroxidation, and β-myosin heavy-chain expression. This exacerbated cardiotoxicity was not observed in WD-LF + DOX.Switching to a low-fat diet 1 week prior to, during, and following DOX treatment attenuated the exacerbated cardiotoxicity observed in the previously Western diet-fed rats.

Doxorubicin (DOX)-induced muscle dysfunction may contribute to patient fatigue, but the nature of this myotoxicity remains unclear. The purpose of this study was to characterize the muscle function dose-response to DOX. A secondary purpose was to compare the degree of DOX-induced muscle dysfunction to the observed cardiac dysfunction.Rats received DOX at 10 mg/kg (DOX1), 12.5 mg/kg (DOX2), or 15 mg/kg (DOX3). Muscle and cardiac function were assessed 5 days, post injection.Compared to controls, DOX2 and DOX3 soleus and DOX3 extensor digitorum longus (EDL) had lower maximal twitch force (p0.05). Soleus fatigue rate was altered by DOX, but EDL fatigue rate was not. Additionally, fractional shortening was lower in DOX2 and DOX3 compared to controls (p0.05).DOX impaired muscle function in a dose-dependent manner. The degree of dysfunction was greater in the soleus and was consistent with the observed cardiac dysfunction.

Childhood cancer survivors are at greater risk of cardiovascular complications once they reach adulthood. Anthracyclines may be a major contributor to these delayed-onset complications, yet their use continues because of favorable clinical outcomes. Exercise has been shown to protect against anthracycline cardiotoxicity, yet it is unclear whether exercise can protect against delayed-onset cardiotoxicity when treatment is initiated in childhood. The aim of the present study was to determine if exercise training provides cardioprotection in a juvenile rat model of delayed-onset anthracycline cardiotoxicity.At 25 days of age, male Sprague-Dawley rat pups were subjected to a treatment regimen with the anthracycline doxorubicin (DOX). Pups received DOX at 2 mg/kg on 7 consecutive days (cumulative dose 14 mg/kg) or saline as a control. At the time DOX treatment began, pups remained sedentary or were allowed to voluntarily exercise. Ten weeks after the initiation of exercise, cardiac function was assessed both in vivo and ex vivo.DOX treatment stunted normal growth and significantly impaired cardiac function. While voluntary exercise did not offset changes in the growth curve, it did provide significant cardioprotection against DOX-induced cardiotoxicity.Exercise training, initiated at the time treatment begins, can protect against delayed-onset anthracycline-induced cardiotoxicity in adult rats that were treated with anthracyclines as juveniles.

15-series prostaglandins (PGE₂s) and isoprostanes (isoPGE₂s) are robust biomarkers of oxidative stress, possess potent biological activity, and may be derived through cyclooxygenase or free radical pathways. Thus, their quantification is critical in understanding many biological processes where PG, isoPG, or oxidative stress are involved. LC/MS/MS methods allow a highly selective, sensitive, simultaneous analysis for prostanoids without derivatization. However, the LC/MS/MS methods currently used do not allow for simultaneous separation of the major brain PGE₂/D₂) and isoPGE₂ without derivatization and multiple HPLC separations. The developed LC/MS/MS method allows for the major brain PGE₂/PGD₂/isoPGE₂ such as PGE₂, entPGE₂, 8-isoPGE₂, 11β-PGE₂, PGD₂, and 15(R)-PGD₂ to be separated and quantified without derivatization. The method was validated by analyzing free and esterified isoPGE₂ in mouse brains fixed with head-focused microwave irradiation before or after global ischemia. Using the developed method, we report for the first time the esterified isoPGE₂ levels in brain tissue under basal conditions and upon global ischemia and demonstrate a nonreleasable pool of esterified isoPG upon ischemia. In addition, we demonstrated that PGE₂s found esterified in the sn-2 position in phospholipids are derived from a free radical nonenzymatic pathway under basal conditions. Our method for brain PG analysis provides a high level of selectivity to detect changes in brain PG and isoPG mass under both basal and pathological conditions.

Doxorubicin (DOX) and goserelin acetate (GA), when administered individually, can lead to impaired cardiac function via different mechanisms. Combining GA and DOX (GA + DOX), however, could potentially exacerbate cardiac dysfunction when compared to GA and DOX treatments administered individually. Therefore, the first purpose of this study was to investigate the effects of GA + DOX on cardiac function. Additionally, since exercise training has been shown to protect against GA- and DOX-induced cardiac dysfunction when administered individually, the second purpose of this study was to examine the effects of exercise during GA + DOX on cardiac function. Female rats were randomly assigned to control (CON), GA, DOX, GA + DOX, or exercise training during GA + DOX (EX GA + DOX). Following 56 days, cardiac function was analyzed in vivo using echocardiography and ex vivo using an isolated working heart model. GA + DOX had significantly lower mitral valve maximal and mean blood flow velocities and aortic valve maximal blood flow velocity than CON (in vivo analysis, P

The synthesis and SAR for a novel series of 2-alkyl-4-aryl-tetrahydro-pyrido-pyrimidines and 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines is described. Representative compounds were shown to be subtype selective 5-HT(2A) antagonists. Optimal placement of a basic nitrogen relative to the pyrimidine and the presence of a 4-fluorophenyl group in the pyrimidine 4-position was found to have a profound effect on affinity and selectivity.

Functional interpretations of helping behaviour suggest that it has evolved because helpers increase their direct or indirect fitness by helping. However, recent critiques have suggested that helping may be an unselected extension of normal parental behaviour, pointing to evidence that all mature individuals commonly respond to begging young (whether they are parents, relatives or non-relatives) as well as to the lack of evidence that cooperative activities have appreciable costs to helpers. Here we provide an example of one form of cooperative behaviour that is seldom performed by parents and has substantial energetic costs to helpers. In the cooperative mongoose, Suricata suricatta, non-breeding adults commonly babysit young pups at the natal burrow for a day at a time, foregoing feeding for 24 hours. Parents rarely contribute to babysitting, and babysitting has substantial energetic costs to helpers. Members of small groups compensate for the reduced number of participants by babysitting more frequently, and neither the proportion of time that babysitters are present nor the survival of litters vary with group size.

“Limited control” models of reproductive skew in cooperative societies suggest that the frequency of breeding by subordinates is determined by the outcome of power struggles with dominants. In contrast, “optimal skew” models suggest that dominants have full control of subordinate reproduction and allow subordinates to breed only when this serves to retain subordinates' assistance with rearing dominants' own litters. The results of our 7-year field study of cooperative meerkats, Suricata suricatta , support the predictions of limited control models and provide no indication that dominant females grant reproductive concessions to subordinates to retain their assistance with future breeding attempts.

Evolutionary explanations of cooperative breeding based on kin selection have predicted that the individual contributions made by different helpers to rearing young should be correlated with their degree of kinship to the litter or brood they are raising. In the cooperative mongoose or meerkat, Suricata suricatta, helpers babysit pups at the natal burrow for the first month of pup life and frequent babysitters suffer substantial weight losses over the period of babysitting. Large differences in contributions exist between helpers, which are correlated with their age, sex and weight but not with their kinship to the young they are raising. Provision of food to some group members raises the contributions of individuals to babysitting. We discuss the implications of these results for evolutionary explanations of cooperative behaviour.