P2Y₂ Nucleotide Receptors Expressed Heterologously in Sympathetic Neurons Inhibit Both N-Type Ca²⁺ and M-Type K⁺ Currents

The P2Y₂ receptor is a uridine/adenosine triphosphate (UTP/ATP)-sensitive G-protein-linked nucleotide receptor that previously has been reported to stimulate the phosphoinositide signaling pathway. Messenger RNA for this receptor has been detected in brain tissue. We have investigated the coupling of the molecularly defined rat P2Y₂ receptor to neuronal N-type Ca²⁺ channels and to M-type K⁺ channels by heterologous expression in rat superior cervical sympathetic (SCG) neurons. After the injection of P2Y₂cRNA, UTP inhibited the currents carried by both types of ion channel. As previously reported [Filippov AK, Webb TE, Barnard EA, Brown DA (1997) Inhibition by heterologously expressed P2Y₂nucleotide receptors of N-type calcium currents in rat sympathetic neurones. Br J Pharmacol 121:849–851], UTP inhibited the Ca²⁺ current (I_{Ca(N)} by up to 64%, with an IC₅₀ of ∼0.5 μm. We now find that UTP also inhibited the K⁺_{M} current (I_{K(M)} by up to 61%, with an IC₅₀ of ∼1.5 μm. UTP had no effect on either current in neurons not injected with P2Y₂ cRNA. Structure–activity relations for the inhibition of I_{Ca(N)} and I_{K(M)} in P2Y₂ cRNA-injected neurons were similar, with UTP ≥ ATP > ITP ≫ GTP,UDP. However, coupling to these two channels involved different G-proteins: pretreatment withPertussis toxin (PTX) did not affect UTP-induced inhibition of I_{K(M)} but reduced inhibition of I_{Ca(N)} by ∼60% and abolished the voltage-dependent component of this inhibition. In unclamped neurons, UTP greatly facilitated depolarization-induced action potential discharges. Thus, the single P2Y₂ receptor can couple to at least two G-proteins to inhibit both Ca²⁺_{N} and K⁺_{M} channels with near-equal facility. This implies that the P2Y₂ receptor may induce a broad range of effector responses in the nervous system

Change in commute mode and BMI: longitudinal, prospective evidence from UK Biobank

BACKGROUND: Insufficient physical activity is a determinant of obesity and cardiovascular disease. Active travel to work has declined in high-income countries in recent decades. We aimed to determine which socioeconomic and demographic characteristics predicted switching to or from active commuting, whether switching from passive to active commuting (or the reverse) independently predicts change in objectively measured body-mass index (BMI), and to ascertain whether any association is attenuated by socioeconomic, demographic, or behavioural factors. METHODS: This study used longitudinal data from UK Biobank. Baseline data collection occurred at 22 centres between March, 2006, and July, 2010, with a repeat assessment at one centre (Stockport) between August, 2012, and June, 2013, for a subset of these participants. Height and weight were objectively measured at both timepoints. We included individuals present at both timepoints with complete data in the analytic sample. Participants were aged 40–69 years and commuted from home to a workplace on a regular basis at both baseline and follow-up. Two exposures were investigated: transition from car commuting to active or public transport commuting and transition from active or public transport to car commuting. Change in BMI between baseline and repeat assessment was the outcome of interest, assessed with bivariate and multivariate logistic regression models. FINDINGS: 502 656 individuals provided baseline data, with 20 346 participating in the repeat assessment after a median of 4·4 years (IQR 3·7–4·9). 5861 individuals were present at both timepoints and had complete data for all analytic variables. Individuals who transitioned from car commuting at baseline to active or public transportation modes at follow-up had a decrease in BMI of −0·30 kg/m2 (95% CI −0·47 to −0·13; p=0·0005). Conversely, individuals who transitioned from active commuting at baseline to car commuting at follow-up had a BMI increase of 0·32 kg/m2 (0·13 to 0·50; p=0·008). These effects were not attenuated by adjustment for hypothesised confounders. Change in household income emerged as a determinant of commute mode transitions. INTERPRETATION: Incorporation of increased levels of physical activity as part of the commute to work could reduce obesity among middle-aged adults in the UK. FUNDING: UK Medical Research Council

Narrowing the wingless-2 mutation to a 227 kb candidate region on chicken chromosome 12.

Wingless-2 (wg-2) is an autosomal recessive mutation in chicken that results in an embryonic lethal condition. Affected individuals exhibit a multisystem syndrome characterized by absent wings, truncated legs, and craniofacial, kidney, and feather malformations. Previously, work focused on phenotype description, establishing the autosomal recessive pattern of Mendelian inheritance and placing the mutation on an inbred genetic background to create the congenic line UCD Wingless-2.331. The research described in this paper employed the complementary tools of breeding, genetics, and genomics to map the chromosomal location of the mutation and successively narrow the size of the region for analysis of the causative element. Specifically, the wg-2 mutation was initially mapped to a 7 Mb region of chromosome 12 using an Illumina 3 K SNP array. Subsequent SNP genotyping and exon sequencing combined with analysis from improved genome assemblies narrowed the region of interest to a maximum size of 227 kb. Within this region, 3 validated and 3 predicted candidate genes are found, and these are described. The wg-2 mutation is a valuable resource to contribute to an improved understanding of the developmental pathways involved in chicken and avian limb development as well as serving as a model for human development, as the resulting syndrome shares features with human congenital disorders

Exploring the Phenotypes of Individuals with Midline Brain Defects

Background The prevalence, aetiology and optimal management of the behavioural and cognitive difficulties, and circadian rhythm disturbances in children with midline brain abnormalities including isolated growth hormone deficiency (IGHD), isolated optic nerve hypoplasia (ONH) and septo-optic dysplasia (SOD) have to date not been adequately addressed. Aims and Methods This thesis aims to assess the prevalence of cognitive/behavioural problems and circadian rhythm abnormalities in children with midline brain abnormalities, and to further investigate any problems identified using high resolution MRI brain, actigraphy and melatonin profiling. Results Children with IGHD have significant impairments in motor skills and lower cognitive function scores, and children with ONH have significantly higher scores on the child behavioural checklist than controls. Children with SOD have significant sleep abnormalities. In IGHD corticospinal tract and corpus callosum fractional anisotropy (FA) and specific neural volumes are significantly lower than in controls, with neural abnormalities correlating significantly with IQ and motor skills scores. In ONH ventral cingulum, corpus callosum and optic radiation FA are significantly reduced, with right ventral 13 cingulum FA correlating significantly with behavioural assessment scores. In SOD melatonin production was absent in one child in association with a fragmented sleep pattern. Three children had normal melatonin profiles, one with an arrhythmic and two with fragmented sleep patterns. The remaining child had fragmented sleep and a modest increase in daytime melatonin concentrations. Conclusions These studies suggest that the GH-IGF-1 axis plays a role in brain and cognitive development. They also show that children with ONH require behavioural assessment, not previously part of routine clinical care, and that the behavioural abnormalities identified in children with ONH may be related to underlying whiter matter abnormalities. We have also demonstrated that the aetiology of the sleep disturbances found in SOD is complex, and not solely due to abnormal nocturnal melatonin production

Gabapentin and pregabalin: do the benefits outweigh the harms?

Gabapentin and pregabalin prescribing in Scotland has increased substantially over recent years. Evidence suggests that prescribers may be advocating the use of these medicines off-label to avoid prescribing opioid analgesics. The evidence to support gabapentin and pregabalin use in non-neuropathic pain disorders indicates they are less effective than several other licensed non-opioid analgesics. Notably, patients may not benefit from gabapentin and pregabalin but remain at risk of adverse drug reactions. Furthermore, greater availability has resulted in increased diversion of gabapentin and pregabalin; creating problems within the opioid misuse population and prison service. As a consequence, both gabapentin and pregabalin may soon be controlled under the Misuse of Drugs Act 1971. Prescribers should be aware of the very limited clinical evidence for use of gabapentin and pregabalin outside their licensed indications, as well as their capacity to do harm

Life history of the coppertail skink (Ctenotus taeniolatus)in southeastern australia

© 2020. David A. Pike All Rights Reserved. —The global decline of reptiles is a serious problem, but we still know little about the life histories of most species, making it difficult to predict which species are most vulnerable to environmental change and why they may be vulnerable. Life history can help dictate resilience in the face of decline, and therefore understanding attributes such as sexual size dimorphism, site fidelity, and survival rates are essential. Australia is well-known for its diversity of scincid lizards, but we have little detailed knowledge of the life histories of individual scincid species. To examine the life history of the Coppertail Skink (Ctenotus taeniolatus), which uses scattered surface rocks as shelter, we estimated survival rates, growth rates, and age at maturity during a three-year capture-mark-recapture study. We captured mostly females (>84%), and of individuals captured more than once, we captured 54.3% at least twice beneath the same rock, and of those, 64% were always beneath the same rock (up to five captures). Our growth model estimated that males can reach sexual maturity in as few as 8 mo, whereas females delay maturity until they reach 17 or more months of age. The large body size of females in our population suggests that many individuals were three or more years old. Average monthly survival rate was 86%, which is within the range reported for lizard species in other families. We now have a baseline with which to compare the life histories of other populations of this widespread species, which ranges from temperate to tropical environments. These findings also provide a baseline for examining effects of disturbance or environmental change on life-history traits

Crossing the road in time: Inequalities in older people's walking speeds

Pedestrian crossings in the UK and US require people to walk at 1.2 m/s to cross the road in time; however a large proportion of older people do not walk this fast, potentially discouraging walking or putting older people at risk of injury. We use longitudinal data to investigate changes in walking speed, and ability to cross the road in time, at older ages. 31,015 walking speed measurements were taken from 10,249 men and women aged 60+ years in waves 1–7 of the English Longitudinal Study of Ageing (2002–2014). Growth curve analyses were used to model how walking speed changes with increasing age, and predicted probabilities of being able to cross the road in time were estimated. 10% of measured walking speeds were fast enough to cross the road in time. Walking speed declined with age (−5.7×10$^{−3}$m/s/yr (95% CI −7.6×10$^{−3}$, −3.9×10$^{−3}$)), and the decline accelerated with increasing age (−0.3 ×10$^{−3}$m/s/yr (−0.4 ×10$^{−3}$, −0.3 ×10$^{−3}$)). Female, less wealthy and less healthy older people had slower walking speeds. For instance, predicted probability of crossing the road in time at age 60 was 14.8% (10.1, 18.5) and 2.7% (1.5, 3.8) for the richest and poorest men and 8.4% (6.0, 1.1) and 1.5% (0.9, 2.2) for the richest and poorest women, and at age 80 they were 7.1% (3.6, 10.5) and 1.0% (0.3, 1.7) for the richest and poorest men and 3.7% (1.6, 5.9) and 0.5% (0.1, 0.9) for the richest and poorest women. Most older people do not walk fast enough to cross the road in time. Even the majority of the wealthiest and healthiest people aged 60 years and older do not walk fast enough to cross pedestrian crossings in the allocated time. Crossing times should be increased to allow for older peoples’ slower walking speeds or other policies considered to improve walkability, and to help avoid injuries and social isolation.This work was supported by the UK Economic and Social Research Council (grant number ES/J019119/1 to EW), the European Research Council (grant number ERC-StG-2012-309337 to SB and ERC-2011-StG_20101124 to RL) and the UK Medical Research Council/Alcohol Research UK (grant number MR/M006638/1 to SB)

Increasing condom use in heterosexual men: development of a theory-based interactive digital intervention

Increasing condom use to prevent sexually transmitted infections is a key public health goal. Interventions are more likely to be effective if they are theory- and evidence-based. The Behaviour Change Wheel (BCW) provides a framework for intervention development. To provide an example of how the BCW was used to develop an intervention to increase condom use in heterosexual men (the MenSS website), the steps of the BCW intervention development process were followed, incorporating evidence from the research literature and views of experts and the target population. Capability (e.g. knowledge) and motivation (e.g. beliefs about pleasure) were identified as important targets of the intervention. We devised ways to address each intervention target, including selecting interactive features and behaviour change techniques. The BCW provides a useful framework for integrating sources of evidence to inform intervention content and deciding which influences on behaviour to target

Reduced ventral cingulum integrity and increased behavioral problems in children with isolated optic nerve hypoplasia and mild to moderate or no visual impairment.

To assess the prevalence of behavioral problems in children with isolated optic nerve hypoplasia, mild to moderate or no visual impairment, and no developmental delay. To identify white matter abnormalities that may provide neural correlates for any behavioral abnormalities identified

Predicting consumer biomass, size-structure, production, catch potential, responses to fishing and associated uncertainties in the world's marine ecosystems

Existing estimates of fish and consumer biomass in the world’s oceans are disparate. This creates uncertainty about the roles of fish and other consumers in biogeochemical cycles and ecosystem processes, the extent of human and environmental impacts and fishery potential. We develop and use a size-based macroecological model to assess the effects of parameter uncertainty on predicted consumer biomass, production and distribution. Resulting uncertainty is large (e.g. median global biomass 4.9 billion tonnes for consumers weighing 1 g to 1000 kg; 50% uncertainty intervals of 2 to 10.4 billion tonnes; 90% uncertainty intervals of 0.3 to 26.1 billion tonnes) and driven primarily by uncertainty in trophic transfer efficiency and its relationship with predator-prey body mass ratios. Even the upper uncertainty intervals for global predictions of consumer biomass demonstrate the remarkable scarcity of marine consumers, with less than one part in 30 million by volume of the global oceans comprising tissue of macroscopic animals. Thus the apparently high densities of marine life seen in surface and coastal waters and frequently visited abundance hotspots will likely give many in society a false impression of the abundance of marine animals. Unexploited baseline biomass predictions from the simple macroecological model were used to calibrate a more complex size- and trait-based model to estimate fisheries yield and impacts. Yields are highly dependent on baseline biomass and fisheries selectivity. Predicted global sustainable fisheries yield increases ≈4 fold when smaller individuals (< 20 cm from species of maximum mass < 1kg) are targeted in all oceans, but the predicted yields would rarely be accessible in practice and this fishing strategy leads to the collapse of larger species if fishing mortality rates on different size classes cannot be decoupled. Our analyses show that models with minimal parameter demands that are based on a few established ecological principles can support equitable analysis and comparison of diverse ecosystems. The analyses provide insights into the effects of parameter uncertainty on global biomass and production estimates, which have yet to be achieved with complex models, and will therefore help to highlight priorities for future research and data collection. However, the focus on simple model structures and global processes means that non-phytoplankton primary production and several groups, structures and processes of ecological and conservation interest are not represented. Consequently, our simple models become increasingly less useful than more complex alternatives when addressing questions about food web structure and function, biodiversity, resilience and human impacts at smaller scales and for areas closer to coasts