Parameter inference for a stochastic kinetic model of expanded polyglutamine proteins.

The presence of protein aggregates in cells is a known feature of many human age-related diseases, such as Huntington's disease. Simulations using fixed parameter values in a model of the dynamic evolution of expanded polyglutaime (PolyQ) proteins in cells have been used to gain a better understanding of the biological system. However, there is considerable uncertainty about the values of some of the parameters governing the system. Currently, appropriate values are chosen by ad hoc attempts to tune the parameters so that the model output matches experimental data. The problem is further complicated by the fact that the data only offer a partial insight into the underlying biological process: the data consist only of the proportions of cell death and of cells with inclusion bodies at a few time points, corrupted by measurement error. Developing inference procedures to estimate the model parameters in this scenario is a significant task. The model probabilities corresponding to the observed proportions cannot be evaluated exactly, and so they are estimated within the inference algorithm by repeatedly simulating realizations from the model. In general such an approach is computationally very expensive, and we therefore construct Gaussian process emulators for the key quantities and reformulate our algorithm around these fast stochastic approximations. We conclude by highlighting appropriate values of the model parameters leading to new insights into the underlying biological processes.

The Chemical Complexity of e-Cigarette Aerosols Compared With the Smoke From a Tobacco Burning Cigarette.

Background: As e-cigarette popularity has increased, there is growing evidence to suggest that while they are highly likely to be considerably less harmful than cigarettes, their use is not free of risk to the user. There is therefore an ongoing need to characterise the chemical composition of e-cigarette aerosols, as a starting point in characterising risks associated with their use. This study examined the chemical complexity of aerosols generated by an e-cigarette containing one unflavored and three flavored e-liquids. A combination of targeted and untargeted chemical analysis approaches was used to examine the number of compounds comprising the aerosol. Contributions of e-liquid flavors to aerosol complexity were investigated, and the sources of other aerosol constituents sought. Emissions of 98 aerosol toxicants were quantified and compared to those in smoke from a reference tobacco cigarette generated under two different smoking regimes. Results: Combined untargeted and targeted aerosol analyses identified between 94 and 139 compounds in the flavored aerosols, compared with an estimated 72-79 in the unflavored aerosol. This is significantly less complex (by 1-2 orders of magnitude) than the reported composition of cigarette smoke. Combining both types of analysis identified 5-12 compounds over and above those found by untargeted analysis alone. Gravimetrically, 89-99% of the e-cigarette aerosol composition was composed of glycerol, propylene glycol, water and nicotine, and around 3% comprised other, more minor, constituents. Comparable data for the Ky3R4F reference tobacco cigarette pointed to 58-76% of cigarette smoke "tar" being composed of minor constituents. Levels of the targeted toxicants in the e-cigarette aerosols were significantly lower than those in cigarette smoke, with 68.5->99% reductions under ISO 3308 puffing conditions and 88.4->99% reductions under ISO 20778 (intense) conditions; reductions against the WHO TobReg 9 priority list were around 99%. Conclusion: These analyses showed that the e-cigarette aerosols contain fewer compounds and at significantly lower concentrations than cigarette smoke. The chemical diversity of an e-cigarette aerosol is strongly impacted by the choice of e-liquid ingredients.

Noncrop Host Plant Associations for Oversummering of Diuraphis noxia in the State of South Australia.

Diuraphis noxia, Russian wheat aphid (Hemiptera: Aphididae), established in Australia since 2016, is dependent on grasses (Poales: Poaceae) to persist in the low-rainfall Australian wheat belt, where no crops are present during summer. To identify grasses as D. noxia hosts in Australia, plants were tested in greenhouse conditions as either whole plants collected from roadsides or grown from collected seed in 2017 and 2018. To determine actual field refugia, direct grass sampling and Berlese extraction of aphids were conducted from October 2018 to May 2020 throughout Southern Australia (2,285 samples). One hundred and twenty-six grass species were collected, 54 showed presence of D. noxia, of which 24 were considered host plants, including 16 species (9 Australian natives) not recorded as host plants previously. Hordeum leporinum (Link) Arcang. Poales:Poaceae and several Bromus species (Poales: Poaceae) showed the highest D. noxia detection frequency and aphid numbers, but these introduced grass species are not summer active in most of South Australia. The native Enneapogon nigricans (Poales: Poaceae) (R.Br.) is the most important summer refuge species because of its widespread distribution, summer growth, and an intermediate level of positive detections with low D. noxia populations. The late summer represents the main bottleneck for D. noxia with very few hosts available and very low D. noxia detections overall. Late summer rainfall (February) seems essential to have the main host grasses germinate for D. noxia populations to build up and potentially invade crops sown in autumn.

TimiRGeN: R/Bioconductor package for time series microRNA-mRNA integration and analysis.

MOTIVATION: The analysis of longitudinal datasets and construction of gene regulatory networks (GRNs) provide a valuable means to disentangle the complexity of microRNA (miRNA)-mRNA interactions. However, there are no computational tools that can integrate, conduct functional analysis and generate detailed networks from longitudinal miRNA-mRNA datasets. RESULTS: We present TimiRGeN, an R package that uses time point-based differential expression results to identify miRNA-mRNA interactions influencing signaling pathways of interest. miRNA-mRNA interactions can be visualized in R or exported to PathVisio or Cytoscape. The output can be used for hypothesis generation and directing in vitro or further in silico work such as GRN construction. AVAILABILITY AND IMPLEMENTATION: TimiRGeN is available for download on Bioconductor (https://bioconductor.org/packages/TimiRGeN) and requires R v4.0.2 or newer and BiocManager v3.12 or newer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Glyphosate exposure in pregnancy and shortened gestational length: a prospective Indiana birth cohort study.

BACKGROUND: Glyphosate (GLY) is the most heavily used herbicide worldwide but the extent of exposure in human pregnancy remains unknown. Its residues are found in the environment, major crops, and food items that humans, including pregnant women, consume daily. Since GLY exposure in pregnancy may also increase fetal exposure risk, we designed a birth-cohort study to determine exposure frequency, potential exposure pathways, and associations with fetal growth indicators and pregnancy length. METHOD: Urine and residential drinking water samples were obtained from 71 women with singleton pregnancies living in Central Indiana while they received routine prenatal care. GLY measurements were performed using liquid chromatography-tandem mass spectrometry. Demographic and survey information relating to food and water consumption, stress, and residence were obtained by questionnaire. Maternal risk factors and neonatal outcomes were abstracted from medical records. Correlation analyses were used to assess relationships of urine GLY levels with fetal growth indicators and gestational length. RESULTS: The mean age of participants was 29 years, and the majority were Caucasian. Ninety three percent of the pregnant women had GLY levels above the limit of detection (0.1 ng/mL). Mean urinary GLY was 3.40 ng/mL (range 0.5-7.20 ng/mL). Higher GLY levels were found in women who lived in rural areas (p = 0.02), and in those who consumed > 24 oz. of caffeinated beverages per day (p = 0.004). None of the drinking water samples had detectable GLY levels. We observed no correlations with fetal growth indicators such as birth weight percentile and head circumference. However, higher GLY urine levels were significantly correlated with shortened gestational lengths (r = - 0.28, p = 0.02). CONCLUSIONS: This is the first study of GLY exposure in US pregnant women using urine specimens as a direct measure of exposure. We found that > 90% of pregnant women had detectable GLY levels and that these levels correlated significantly with shortened pregnancy lengths. Although our study cohort was small and regional and had limited racial/ethnic diversity, it provides direct evidence of maternal GLY exposure and a significant correlation with shortened pregnancy. Further investigations in a more geographically and racially diverse cohort would be necessary before these findings could be generalized.

The burden of chronic spontaneous urticaria is substantial: Real-world evidence from ASSURE-CSU.

BACKGROUND: Chronic spontaneous urticaria (CSU) can be debilitating, difficult to treat, and frustrating for patients and physicians. Real-world evidence for the burden of CSU is limited. The objective of this study was to document disease duration, treatment history, and disease activity, as well as impact on health-related quality of life (HRQoL) and work among patients with inadequately controlled CSU, and to describe its humanistic, societal, and economic burden. METHODS: This international observational study assessed a cohort of 673 adult patients with CSU whose symptoms persisted for ≥12 months despite treatment. Demographics, disease characteristics, and healthcare resource use in the previous 12 months were collected from medical records. Patient-reported data on urticaria and angioedema symptoms, HRQoL, and work productivity and activity impairment were collected from a survey and a diary. RESULTS: Almost 50% of patients had moderate-to-severe disease activity as reported by Urticaria Activity Score. Mean (SD) Dermatology Life Quality Index and Chronic Urticaria Quality of Life Questionnaire scores were 9.1 (6.62) and 33.6 (20.99), respectively. Chronic spontaneous urticaria markedly interfered with sleep and daily activities. Angioedema in the previous 12 months was reported by 66% of enrolled patients and significantly affected HRQoL. More than 20% of patients reported ≥1 hour per week of missed work; productivity impairment was 27%. These effects increased with increasing disease activity. Significant healthcare resources and costs were incurred to treat CSU. CONCLUSIONS: Chronic spontaneous urticaria has considerable humanistic and economic impacts. Patients with greater disease activity and with angioedema experience greater HRQoL impairments.

Flow cytometric bacterial cell counts challenge conventional heterotrophic plate counts for routine microbiological drinking water monitoring.

Drinking water utilities and researchers continue to rely on the century-old heterotrophic plate counts (HPC) method for routine assessment of general microbiological water quality. Bacterial cell counting with flow cytometry (FCM) is one of a number of alternative methods that challenge this status quo and provide an opportunity for improved water quality monitoring. After more than a decade of application in drinking water research, FCM methodology is optimised and established for routine application, supported by a considerable amount of data from multiple full-scale studies. Bacterial cell concentrations obtained by FCM enable quantification of the entire bacterial community instead of the minute fraction of cultivable bacteria detected with HPC (typically < 1% of all bacteria). FCM measurements are reproducible with relative standard deviations below 3% and can be available within 15 min of samples arriving in the laboratory. High throughput sample processing and complete automation are feasible and FCM analysis is arguably less expensive than HPC when measuring more than 15 water samples per day, depending on the laboratory and selected staining procedure(s). Moreover, many studies have shown FCM total (TCC) and intact (ICC) cell concentrations to be reliable and robust process variables, responsive to changes in the bacterial abundance and relevant for characterising and monitoring drinking water treatment and distribution systems. The purpose of this critical review is to initiate a constructive discussion on whether FCM could replace HPC in routine water quality monitoring. We argue that FCM provides a faster, more descriptive and more representative quantification of bacterial abundance in drinking water.

Age-related changes in mesenchymal stem cells identified using a multi-omics approach.

Mesenchymal stem cells (MSC) are capable of multipotent differentiation into connective tissues and as such are an attractive source for autologous cell-based treatments for many clinical diseases and injuries. Ageing is associated with various altered cellular phenotypes coupled with a variety of transcriptional, epigenetic and translational changes. Furthermore, the regeneration potential of MSCs is reduced with increasing age and is correlated with changes in cellular functions. This study used a systems biology approach to investigate the transcriptomic (RNASeq), epigenetic (miRNASeq and DNA methylation) and protein alterations in ageing MSCs in order to understand the age-related functional and biological variations, which may affect their applications to regenerative medicine. We identified no change in expression of the cellular senescence markers. Alterations were evident at both the transcriptional and post-transcriptional level in a number of transcription factors. There was enrichment in genes involved in developmental disorders at mRNA and differential methylated loci (DML) level. Alterations in energy metabolism were apparent at the DML and protein level. The microRNA miR-199b-5p, whose expression was reduced in old MSCs, had predicted gene targets involved in energy metabolism and cell survival. Additionally, enrichment of DML and proteins in cell survival was evident. Enrichment in metabolic processes was revealed at the protein level and in genes identified as undergoing alternate splicing. Overall, an altered phenotype in MSC ageing at a number of levels implicated roles for inflamm-ageing and mitochondrial ageing. Identified changes represent novel insights into the ageing process, with implications for stem cell therapies in older patients.

A computer simulation approach to assessing therapeutic intervention points for the prevention of cytokine-induced cartilage breakdown.

OBJECTIVE: To use a novel computational approach to examine the molecular pathways involved in cartilage breakdown and to use computer simulation to test possible interventions for reducing collagen release. METHODS: We constructed a computational model of the relevant molecular pathways using the Systems Biology Markup Language, a computer-readable format of a biochemical network. The model was constructed using our experimental data showing that interleukin-1 (IL-1) and oncostatin M (OSM) act synergistically to up-regulate collagenase protein levels and activity and initiate cartilage collagen breakdown. Simulations were performed using the COPASI software package. RESULTS: The model predicted that simulated inhibition of JNK or p38 MAPK, and overexpression of tissue inhibitor of metalloproteinases 3 (TIMP-3) led to a reduction in collagen release. Overexpression of TIMP-1 was much less effective than that of TIMP-3 and led to a delay, rather than a reduction, in collagen release. Simulated interventions of receptor antagonists and inhibition of JAK-1, the first kinase in the OSM pathway, were ineffective. So, importantly, the model predicts that it is more effective to intervene at targets that are downstream, such as the JNK pathway, rather than those that are close to the cytokine signal. In vitro experiments confirmed the effectiveness of JNK inhibition. CONCLUSION: Our study shows the value of computer modeling as a tool for examining possible interventions by which to reduce cartilage collagen breakdown. The model predicts that interventions that either prevent transcription or inhibit the activity of collagenases are promising strategies and should be investigated further in an experimental setting.

The in vitro cytotoxicity and genotoxicity of cigarette smoke particulate matter with reduced toxicant yields.

Tobacco smoke contains more than 5600 constituents, of which approximately 150 are toxicants. This paper describes the activities in the Neutral Red uptake (NRU) assay, the Salmonella mutagenicity test (SAL), the mouse lymphoma mammalian cell mutation assay (MLA) and the in vitro micronucleus test (IVMNT) of Particulate Matter (PM) obtained from experimental cigarettes (ECs), designed to produce reduced levels of toxicants. The designs included tobacco substitute sheet (TSS) containing glycerol, which dilutes toxicants in smoke, or the incorporation of blend-treated (BT) tobacco to reduce the levels of nitrogenous toxicant precursors and some polyphenols. All samples were cytotoxic in the NRU, however TSS reduced PM cytotoxicity in this assay. All PMs were mutagenic in the SAL, MLA and IVMNT. Reductions in bacterial mutagenicity were observed in the SAL, for cigarettes with BT tobacco, compared with their respective controls. The quantitative changes in bacterial mutagenicity could be explained by analytical chemistry data on smoke generated from the ECs used in the study. These observations, and the absence of consistent qualitative differences in the activities of the experimental, control and reference cigarettes, suggest that reduced toxicity cigarettes, as measured by the tests described in this paper, may be developed without introducing any additional cytotoxic or genotoxic hazards, but the impact of this on human health risks remains unknown.

The effect of a novel tobacco process on the in vitro cytotoxicity and genotoxicity of cigarette smoke particulate matter.

Some of the toxic effects of smoking have been attributed to the combustion of nitrogenous protein in tobacco. The effects of a treatment which reduces tobacco's protein nitrogen level, on the in vitro cytotoxicity and genotoxicity of cigarette smoke particulate matter (PM), were measured. PMs were tested in the Neutral Red Uptake (NRU) test; the Salmonella mutagenicity assay (SAL); the mouse lymphoma mammalian cell mutation assay (MLA) and the in vitro micronucleus test (IVMNT). PMs from all of the cigarettes were cytotoxic and genotoxic. PM obtained from smoking treated tobacco, showed a small, consistent and statistically significant reduced mutagenicity (revertants/µg) in TA98 with post-mitochondrial supernatant (S9). No consistent quantitative or qualitative differences were detected in the other tests. The data are discussed in relation to published information on smoke chemistry obtained from cigarettes made of tobacco treated using this technique. The observations confirm that the method did not give rise to any new qualitative or quantitative cytotoxic or genotoxic effects, and may have reduced PM's bacterial mutagenicity in TA98 with S9. Further toxicity testing is warranted, to investigate the effects of the tobacco treatment in more detail and add to the data already obtained.

The extent and nature of need for mealtime support among adults with intellectual disabilities.

BACKGROUND: For many adults with an intellectual disability (ID), mealtimes carry significant health risks. While research and allied clinical guidance has focused mainly on dysphagia, adults with a range of physical and behavioural difficulties require mealtime support to ensure safety and adequate nutrition. The extent of need for and nature of such support within the wider ID population has yet to be reported. METHODS: In this study, we have estimated the prevalence of need for mealtime support among people with ID in the UK, using a population of 2230 adults known to specialist ID services (in Cambridgeshire, UK, total population 586,900). In a sample (n = 69, aged 19 to 79 years, with mild to profound ID), we characterised the support provided, using a structured proforma to consult support workers and carers providing mealtime support, and health and social care records. RESULTS: Mealtime support was found to be required by a significant minority of people with ID for complex and varied reasons. Prevalence of need for such support was estimated at 15% of adults known to specialist ID services or 56 per 100,000 total population. Within a sample, support required was found to vary widely in nature (from texture modification or environmental adaptation to enteral feeding) and in overall level (from minimal to full support, dependent on functional skills). Needs had increased over time in almost half (n = 34, 49.3%). Reasons for support included difficulties getting food into the body (n = 56, 82.2%), risky eating and drinking behaviours (n = 31, 44.9%) and slow eating or food refusal (n = 30, 43.5%). These proportions translate into crude estimates of the prevalence of these difficulties within the known ID population of 11.9%, 6.6% and 6.4% respectively. Within the sample of those requiring mealtime support, need for support was reported to be contributed to by the presence of additional disability or illness (e.g. visual impairment, poor dentition and dementia; n = 45, 65.2%) and by psychological or behavioural issues (e.g. challenging behaviour, emotional disturbance; n = 36, 52.2%). CONCLUSIONS: These findings not only highlight the need for a multidisciplinary approach to mealtime interventions (paying particular attention to psychological and environmental as well as physical issues), but also signal the daily difficulties faced by carers and paid support workers providing such support and illustrate their potentially crucial role in managing the serious health risks associated with eating and drinking difficulties in this population.

Design and chemical evaluation of reduced machine-yield cigarettes.

Experimental cigarettes (ECs) were made by combining technological applications that individually reduce the machine measured yields of specific toxicants or groups of toxicants in mainstream smoke (MS). Two tobacco blends, featuring a tobacco substitute sheet or a tobacco blend treatment, were combined with filters containing an amine functionalised resin (CR20L) and/or a polymer-derived, high activity carbon adsorbent to generate three ECs with the potential for generating lower smoke toxicant yields than conventional cigarettes. MS yields of smoke constituents were determined under 4 different smoking machine conditions. Health Canada Intense (HCI) machine smoking conditions gave the highest MS yields for nicotine-free dry particulate matter and for most smoke constituents measured. Toxicant yields from the ECs were compared with those from two commercial comparator cigarettes, three scientific control cigarettes measured contemporaneously and with published data on 120 commercial cigarettes. The ECs were found to generate some of the lowest machine yields of toxicants from cigarettes for which published HCI smoke chemistry data are available; these comparisons therefore confirm that ECs with reduced MS machine toxicant yields compared to commercial cigarettes can be produced. The results encourage further work examining human exposure to toxicants from these cigarettes, including human biomarker studies.

The use of a novel tobacco-substitute sheet and smoke dilution to reduce toxicant yields in cigarette smoke.

The Institute of Medicine encouraged the pursuit and development of potential reduced-exposure products, tobacco products that substantially reduce exposure to one or more tobacco toxicants and can reasonably be expected to reduce the risk of one or more specific diseases or other adverse health effects. One approach to reducing smoke toxicant yields is to dilute the smoke with glycerol. We report chemical, biological and human exposure data related to experimental cigarettes containing up to 60% of a novel glycerol containing "tobacco-substitute" sheet. Analysis of mainstream smoke from experimental cigarettes showed reductions in yields of most measured constituents, other than some volatile species. In vitro toxicological tests showed reductions in the activity of smoke particulates in proportion to their glycerol content. Human exposure to nicotine was reduced by a mean of 18% as determined by filter studies and by 14% using 24h urinary biomarker analysis. Smoke particulate exposures were reduced by a mean of 29% in filter studies and NNK exposure by similar amounts based on urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol concentrations. These results show that reducing exposure to some smoke toxicants is possible using a tobacco-substitute sheet, although some smoke toxicants, and the sensory attributes of the smoke, remain as technical challenges.

Modelling the checkpoint response to telomere uncapping in budding yeast.

One of the DNA damage-response mechanisms in budding yeast is temporary cell-cycle arrest while DNA repair takes place. The DNA damage response requires the coordinated interaction between DNA repair and checkpoint pathways. Telomeres of budding yeast are capped by the Cdc13 complex. In the temperature-sensitive cdc13-1 strain, telomeres are unprotected over a specific temperature range leading to activation of the DNA damage response and subsequently cell-cycle arrest. Inactivation of cdc13-1 results in the generation of long regions of single-stranded DNA (ssDNA) and is affected by the activity of various checkpoint proteins and nucleases. This paper describes a mathematical model of how uncapped telomeres in budding yeast initiate the checkpoint pathway leading to cell-cycle arrest. The model was encoded in the Systems Biology Markup Language (SBML) and simulated using the stochastic simulation system Biology of Ageing e-Science Integration and Simulation (BASIS). Each simulation follows the time course of one mother cell keeping track of the number of cell divisions, the level of activity of each of the checkpoint proteins, the activity of nucleases and the amount of ssDNA generated. The model can be used to carry out a variety of in silico experiments in which different genes are knocked out and the results of simulation are compared to experimental data. Possible extensions to the model are also discussed.

Neurofunctional imaging of the pancreas utilizing the cholinergic PET radioligand [18F]4-fluorobenzyltrozamicol.

The pancreas is one of the most heavily innervated peripheral organs in the body. Parasympathetic and sympathetic neurons terminate in the pancreas and provide tight control of endocrine and exocrine functions. The aim of this study was to determine whether the pancreas can be imaged with a radioligand that binds to specific neuroreceptors. Using fluorine-18 4-fluorobenzyltrozamicol (FBT), which binds to the presynaptic vesicular acetylcholine transporter, positron emission tomography scans were performed in four adult mice, two adult rhesus monkeys, and one adult human. In these mammals, the pancreas is intensely FBT avid, with uptake greater than in any other organ at 30, 60, and 90 min. The maximum standardized uptake value (SUV) ratios of pancreas to liver, for example, ranged from 1.4 to 1.7 in rhesus monkeys (mean 1.6; median 1.7) and from 1.9 to 4.7 (mean 3.24; median 3.02) in mice. The maximum SUV ratio of pancreas to liver in the human was 1.8. These data suggest that neuroreceptor imaging of the pancreas in vivo is feasible in animal models and humans. This imaging could allow researchers to interrogate functions under control of the autonomic nervous system in the pancreas, with applications possible in transplanted and native pancreata. Also, as beta cell function is intimately related to parasympathetic cholinergic input, FBT activity in the pancreas may correlate with insulin-producing beta cell mass. This could ultimately provide a method of in vivo imaging in animal models and humans for diabetes research.

Modelling antipredator vigilance and flight response in group foragers when warning signals are ambiguous.

The trade-off between feeding and vigilance in flocks of birds has been extensively studied and modelled. An assumption of many models is that if one bird spots the predator, it gives a signal and the rest of the flock takes flight. However, it has been observed that birds do not always respond to signals and in fact many signals turn out to be false alarms. Since taking flight is both costly in time and energy, it may be advantageous for birds not to respond to all alarm calls. A model is developed to show under what circumstances birds should respond to a signal. The model predicts that under most, but not all, circumstances, birds should respond to multiple detections but not to single detections. The model also predicts that if birds respond to all flights, they will have to compensate for the time lost to feeding and the greater energy requirement of spending more time in flight, by being less vigilant, and they have a lower probability of survival than birds which only respond to multiple detections.

Synthesis and in vivo evaluation of (E)-N-[(11)C]Methyl-4- (3-pyridinyl)-3-butene-1-amine ([(11)C]metanicotine) as a nicotinic receptor radioligand.

(E)-N-[(11)C]Methyl-4-(3-pyridinyl)-3-butene-1-amine ([(11)C]metanicotine), a high affinity (K(i) = 16 nM) CNS-selective nicotinic agonist, was prepared by the [(11)C]alkylation of the desmethyl precursor with [(11)C]methyl trifluoromethanesulfonate. In vivo distribution studies in mice demonstrated good blood brain permeability but essentially uniform regional brain distribution and no evidence of specific binding to nicotinic cholinergic receptors. Identical results were obtained in an imaging study performed in a monkey brain. Therefore, despite literature reports supporting the use of metanicotine as a cognition enhancing nicotinic agonist, (E)-N-[(11)C]methyl-4-(3-pyridinyl)-3-butene-1-amine does not appear to be a suitable candidate for in vivo imaging studies of nicotinic acetylcholine receptors in the mammalian brain.

A spatial model of antipredator vigilance.

Many species of animals have to perform two contradictory tasks: feeding, and avoiding becoming food for others. A large number of theoretical and empirical studies have investigated the trade-off between feeding and antipredator vigilance, especially in birds. An important factor which has been neglected in these studies is that of the area occupied by the flock. If individuals feed close together, competition increases and feeding rates decrease. However, if individuals space themselves widely, then vigilance efficiency goes down and there is an increased predation risk. We develop a vigilance model which allows birds to control the area the flock occupies as well as their vigilance rate. The optimal strategy is found for the birds under a variety of environmental conditions. In particular the effect of each environmental parameter on this optimum is considered in turn. How the model can be adapted for different bird species is also investigated.

Synthesis and evaluation of 6-[11C]methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2- benzisoxazole as an in vivo radioligand for acetylcholinesterase.

6-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole is a high affinity (K(i) = 8.2 nM) reversible inhibitor of acetylcholinesterase (AChE). The carbon-11 labeled form was prepared in high (>97%) radiochemical purity and with specific activities of 37+/-20 GBq/micromol at end of synthesis, by the alkylation of the desmethyl precursor with [11C]methyl trifluoromethanesulfonate in N,N-dimethyl-formamide at room temperature. In vivo studies in mice demonstrated good blood brain permeability but essentially uniform regional brain distribution. Thus, despite in vitro and in vivo activity as an AChE inhibitor, 6-[11C]methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzis oxa zole does not appear to be a good candidate for in vivo imaging studies of AChE in the mammalian brain.