Centre for Palaeogenetics

Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity1–4. Sparse taxon sampling has previously been proposed to confound phylogenetic inference5, and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families—including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species. A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.

BACKGROUND: Long-term exposure to ambient air pollution has been associated with premature mortality, but associations at concentrations lower than current annual limit values are uncertain. We analysed associations between low-level air pollution and mortality within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE). METHODS: ) from Europe-wide land use regression models at 100 m spatial resolution were assigned to baseline residential addresses. We applied cohort-specific Cox proportional hazard models with adjustment for area-level and individual-level covariates to evaluate associations with non-accidental mortality, as the main outcome, and with cardiovascular, non-malignant respiratory, and lung cancer mortality. Subset analyses of participants living at low pollutant concentrations (as per predefined values) and natural splines were used to investigate the concentration-response function. Cohort-specific effect estimates were pooled in a random-effects meta-analysis. FINDINGS: /m. INTERPRETATION: lower than current annual limit values was associated with non-accidental, cardiovascular, non-malignant respiratory, and lung cancer mortality in seven large European cohorts. Continuing research on the effects of low concentrations of air pollutants is expected to further inform the process of setting air quality standards in Europe and other global regions. FUNDING: Health Effects Institute.

Abstract Background Low levels of physical activity, sedentary behaviour and mental health problems are issues that have received considerable attention in the last decade. The aim of this systematic review and meta-analysis was to investigate effects of interventions targeting school-related physical activity or sedentary behaviour on mental health in children and adolescents and to identify the features of effective interventions. Methods Scientific articles published between January 2009 and October 2019 fulfilling the following criteria were included: general populations of children and adolescents between age 4 and 19, all types of school-related efforts to promote physical activity or reduce sedentary behaviour. Study selection, data extraction and quality assessment were done by at least two authors independently of each other. Data were analysed with a random effects meta-analysis and by narrative moderator analyses. Results The literature search resulted in 10265 unique articles. Thirty-one articles, describing 30 interventions, were finally included. Eleven relevant outcomes were identified: health-related quality of life, well-being, self-esteem and self-worth, resilience, positive effect, positive mental health, anxiety, depression, emotional problems, negative effect and internalising mental health problems. There was a significant beneficial effect of school-related physical activity interventions on resilience (Hedges’ g = 0.748, 95% CI = 0.326; 1.170, p = 0.001), positive mental health (Hedges’ g = 0.405, 95% CI = 0.208; 0.603, p = < 0.001), well-being (Hedges’ g = 0.877, 95% CI = 0.356; 1.398, p = < 0.001) and anxiety (Hedges’ g = 0.347, 95% CI = 0.072; 0.623, p = 0.013). Heterogeneity was moderate to high ( I 2 = 59–98%) between studies for all outcomes except positive effect, where heterogeneity was low ( I 2 = 2%). The narrative moderator analyses of outcomes based on 10 or more studies showed that age of the children moderated the effect of the intervention on internalising mental health problems. Interventions in younger children showed a significantly negative or no effect on internalising mental health problems while those in older children showed a significant positive or no effect. Moreover, studies with a high implementation reach showed a significant negative or no effect while those with a low level of implementation showed no or a positive effect. No signs of effect moderation were found for self-esteem, well-being or positive mental health. Risk of publication bias was evident for several outcomes, but adjustment did not change the results. Conclusions School-related physical activity interventions may reduce anxiety, increase resilience, improve well-being and increase positive mental health in children and adolescents. Considering the positive effects of physical activity on health in general, these findings may reinforce school-based initiatives to increase physical activity. However, the studies show considerable heterogeneity. The results should therefore be interpreted with caution. Future studies should report on implementation factors and more clearly describe the activities of the control group and whether the activity is added to or replacing ordinary physical education lessons in order to aid interpretation of results. Trial registration PROSPERO, CRD42018086757 .

Dogs were the first domestic animal, but little is known about their population history and to what extent it was linked to humans. We sequenced 27 ancient dog genomes and found that all dogs share a common ancestry distinct from present-day wolves, with limited gene flow from wolves since domestication but substantial dog-to-wolf gene flow. By 11,000 years ago, at least five major ancestry lineages had diversified, demonstrating a deep genetic history of dogs during the Paleolithic. Coanalysis with human genomes reveals aspects of dog population history that mirror humans, including Levant-related ancestry in Africa and early agricultural Europe. Other aspects differ, including the impacts of steppe pastoralist expansions in West and East Eurasia and a near-complete turnover of Neolithic European dog ancestry.

OBJECTIVE: Typologies of the cultural position of drinking from the social science literature are reviewed. METHOD: The article reviews significant studies and literature on the topic. RESULTS: Starting in the 1940s, two research traditions considered variations in the cultural position of drinking as explanations of rates of drinking problems. A "holocultural" tradition coded and analyzed ethnographic data on tribal and village societies, starting in the 1940s, with each study identifying a different social dimension as crucial. A "sociocultural" tradition distinguished abstinent cultures from prescriptive cultures, in which drinking was integrated with daily life, and expected, but drunkenness was prohibited. These types were implicitly contrasted with American drinking, which was variously characterized. Other dimensional and typological approaches in the literature are considered, including a little-known Jellinek typology. Problems with the widely used distinction between "wetter" and "drier" (or "temperance") cultures are discussed. CONCLUSIONS: Four ideal types of the cultural position of drinking can be readily distinguished: abstinent societies, constrained ritual drinking, banalized drinking and fiesta drunkenness. A large residual category remains, however, and a dimensional approach to typology building may be more fruitful. Two basic dimensions are proposed--regularity of drinking and extent of drunkenness--and further dimensions are described that may be added to fit the requirements of the particular study.

Abstract Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5 ), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5 , nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 µg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 µg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5 , nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 µg/m 3 an increase of 5 µg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.

Abstract The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics 1 . Here we show that particular lineages of methicillin-resistant Staphylococcus aureus —a notorious human pathogen—appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.

The skeletal fossils of the Early Cambrian Meishucunian Stage from two key localities (Meishucun, Jinning County, and Xianfeng, Xundian County) in eastern Yunnan Province, China, are described and illustrated in detail to provide a basis for improved palaeobiological and biostratigraphical work. About 1250 new SEM illustrations (including a large number of stereo-pairs) of well-preserved material are presented. The taxonomy is extensively revised. When biological and preservational variability are taken into account, the number of genera and species may be reduced through synonymy to about one third of that reported in the literature. Thirty-eight genera (2 of which are new) and 57 species (5 of which are new) are described. The biology and affinities of many of these taxa are also diseussed, but excursions into suprageneric taxonomy are generally restrained. The Meishucunian biotas of Yunnan consist of three successive assemblages with very few taxa in common. The first, the Anabarites-Protohertzina-Arthrochites Assemblage, is dominated by Anabarites and other sedentary tube-dwelling organisms, but non-sedentary benthic mollusc-like fossils (Canopoconus) and probable predators (Protohertzina) also occur. The key elements of this fauna have a wide geographical distribution and may be compared with the earliest skeietal faunas on the Siberian Platform, the Canadian Cordillera, and other regions. The second, the Siphogonuchites-Paragloborilus Assemblage, is characterized by a great diversity of vagile mollusc-like and multisclerite-bearing animals, but also sedentary tube-dwellers and some possible predators (Cyrtochitesand Yunnanodus) occur. This fauna is largely endemic. The third, the Lapworthella-Tannuolina-Sinosachites Assemblage, is mainly characterized by widely distributed taxa of multisclerite-bearing animals (chancelloriids, Halkieria, Tannuolina, and Lapworthella). It has elements in common with late Atdabanian faunas in other regions of the world.

BACKGROUND: ) with the incidence of stroke and acute coronary heart disease. METHODS: We did a pooled analysis of individual data from six population-based cohort studies within ELAPSE, from Sweden, Denmark, the Netherlands, and Germany (recruited 1992-2004), and harmonised individual and area-level variables between cohorts. Participants (all adults) were followed up until migration from the study area, death, or incident stroke or coronary heart disease, or end of follow-up (2011-15). Mean 2010 air pollution concentrations from centrally developed European-wide land use regression models were assigned to participants' baseline residential addresses. We used Cox proportional hazards models with increasing levels of covariate adjustment to investigate the association of air pollution exposure with incidence of stroke and coronary heart disease. We assessed the shape of the concentration-response function and did subset analyses of participants living at pollutant concentrations lower than predefined values. FINDINGS: . INTERPRETATION: Long-term air pollution exposure was associated with incidence of stroke and coronary heart disease, even at pollutant concentrations lower than current limit values. FUNDING: Health Effects Institute.

The kākāpō is a flightless parrot endemic to New Zealand. Once common in the archipelago, only 201 individuals remain today, most of them descending from an isolated island population. We report the first genome-wide analyses of the species, including a high-quality genome assembly for kākāpō, one of the first chromosome-level reference genomes sequenced by the Vertebrate Genomes Project (VGP). We also sequenced and analyzed 35 modern genomes from the sole surviving island population and 14 genomes from the extinct mainland population. While theory suggests that such a small population is likely to have accumulated deleterious mutations through genetic drift, our analyses on the impact of the long-term small population size in kākāpō indicate that present-day island kākāpō have a reduced number of harmful mutations compared to mainland individuals. We hypothesize that this reduced mutational load is due to the island population having been subjected to a combination of genetic drift and purging of deleterious mutations, through increased inbreeding and purifying selection, since its isolation from the mainland ∼10,000 years ago. Our results provide evidence that small populations can survive even when isolated for hundreds of generations. This work provides key insights into kākāpō breeding and recovery and more generally into the application of genetic tools in conservation efforts for endangered species.

BACKGROUND: Data on the impact of functional dyspepsia on health-related quality of life in the general adult population are scarce. AIM: To explore the impact of functional dyspepsia applying the Rome III definition on health-related quality of life in the general population. METHOD: A random sample of an adult Swedish population (n=1001, The Kalixanda study) was invited to undergo an oesophagogastroduodenoscopy. An extended abdominal symptom questionnaire and Short Form-36 (SF-36) questionnaire, which includes eight domains measuring physical, mental and social aspects of quality of life, were completed at the clinic visit just before oesophagogastroduodenoscopy. RESULTS: Two hundred and two (20%) individuals reported uninvestigated dyspepsia (UID), 157 (16%) functional dyspepsia (FD), 52 (5%) epigastric pain syndrome (EPS) and 122 (12%) postprandial distress syndrome (PDS). UID, FD and PDS had a clinically meaningful (a ≥ 5 point) and statistically significant impact (P<0.05) on health-related quality of life in all SF-36 domains except for Role Emotional. EPS had a significant impact on Bodily Pain and Vitality. Overlap of FD with irritable bowel syndrome (IBS) had a significant impact on Bodily Pain (P=0.002) and General Health (P=0.02) while FD overlap with gastro-oesophageal reflux symptoms (GERS) had a significant impact on Bodily Pain (P=0.02) compared with FD without any overlap with IBS or GERS. CONCLUSION: Functional dyspepsia impacts all main domains describing physical, mental and social aspects of health-related quality of life in the general population. Overlap of functional dyspepsia with irritable bowel syndrome or gastro-oesophageal reflux symptoms impacts the domain related to bodily pain.

Advances in the isolation and sequencing of ancient DNA have begun to reveal the population histories of both people and dogs. Over the last 10,000 y, the genetic signatures of ancient dog remains have been linked with known human dispersals in regions such as the Arctic and the remote Pacific. It is suspected, however, that this relationship has a much deeper antiquity, and that the tandem movement of people and dogs may have begun soon after the domestication of the dog from a gray wolf ancestor in the late Pleistocene. Here, by comparing population genetic results of humans and dogs from Siberia, Beringia, and North America, we show that there is a close correlation in the movement and divergences of their respective lineages. This evidence places constraints on when and where dog domestication took place. Most significantly, it suggests that dogs were domesticated in Siberia by ∼23,000 y ago, possibly while both people and wolves were isolated during the harsh climate of the Last Glacial Maximum. Dogs then accompanied the first people into the Americas and traveled with them as humans rapidly dispersed into the continent beginning ∼15,000 y ago.

BACKGROUND: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. OBJECTIVES: We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. DATA SOURCES: Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. STUDY ELIGIBILITY CRITERIA: Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. METHODS: We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. RESULTS: Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. CONCLUSIONS: Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.

Abstract The grey wolf ( Canis lupus ) was the first species to give rise to a domestic population, and they remained widespread throughout the last Ice Age when many other large mammal species went extinct. Little is known, however, about the history and possible extinction of past wolf populations or when and where the wolf progenitors of the present-day dog lineage ( Canis familiaris ) lived 1–8 . Here we analysed 72 ancient wolf genomes spanning the last 100,000 years from Europe, Siberia and North America. We found that wolf populations were highly connected throughout the Late Pleistocene, with levels of differentiation an order of magnitude lower than they are today. This population connectivity allowed us to detect natural selection across the time series, including rapid fixation of mutations in the gene IFT88 40,000–30,000 years ago. We show that dogs are overall more closely related to ancient wolves from eastern Eurasia than to those from western Eurasia, suggesting a domestication process in the east. However, we also found that dogs in the Near East and Africa derive up to half of their ancestry from a distinct population related to modern southwest Eurasian wolves, reflecting either an independent domestication process or admixture from local wolves. None of the analysed ancient wolf genomes is a direct match for either of these dog ancestries, meaning that the exact progenitor populations remain to be located.

Our ability to assess the threat posed by the genetic load to small and declining populations has been greatly improved by advances in genome sequencing and computational approaches. Yet, considerable confusion remains around the definitions of the genetic load and its dynamics, and how they impact individual fitness and population viability. We illustrate how both selective purging and drift affect the distribution of deleterious mutations during population size decline and recovery. We show how this impacts the composition of the genetic load, and how this affects the extinction risk and recovery potential of populations. We propose a framework to examine load dynamics and advocate for the introduction of load estimates in the management of endangered populations.

Significance The microbiome plays key roles in human health, but little is known about its evolution. We investigate the evolutionary history of the African hominid oral microbiome by analyzing dental biofilms of humans and Neanderthals spanning the past 100,000 years and comparing them with those of chimpanzees, gorillas, and howler monkeys. We identify 10 core bacterial genera that have been maintained within the human lineage and play key biofilm structural roles. However, many remain understudied and unnamed. We find major taxonomic and functional differences between the oral microbiomes of Homo and chimpanzees but a high degree of similarity between Neanderthals and modern humans, including an apparent Homo -specific acquisition of starch digestion capability in oral streptococci, suggesting microbial coadaptation with host diet.

We describe an update of MirGeneDB, the manually curated microRNA gene database. Adhering to uniform and consistent criteria for microRNA annotation and nomenclature, we substantially expanded MirGeneDB with 30 additional species representing previously missing metazoan phyla such as sponges, jellyfish, rotifers and flatworms. MirGeneDB 2.1 now consists of 75 species spanning over ∼800 million years of animal evolution, and contains a total number of 16 670 microRNAs from 1549 families. Over 6000 microRNAs were added in this update using ∼550 datasets with ∼7.5 billion sequencing reads. By adding new phylogenetically important species, especially those relevant for the study of whole genome duplication events, and through updating evolutionary nodes of origin for many families and genes, we were able to substantially refine our nomenclature system. All changes are traceable in the specifically developed MirGeneDB version tracker. The performance of read-pages is improved and microRNA expression matrices for all tissues and species are now also downloadable. Altogether, this update represents a significant step toward a complete sampling of all major metazoan phyla, and a widely needed foundation for comparative microRNA genomics and transcriptomics studies. MirGeneDB 2.1 is part of RNAcentral and Elixir Norway, publicly and freely available at http://www.mirgenedb.org/.

In March 2004, two important documents on alcohol policy were published by the British government. One is an Alcohol Harm Reduction Strategy for England (UK Cabinet Office 2004). This document has received more attention, but is arguably of less import. As we shall see, what it offers is a recipe for ineffectiveness at the national level. The second document, the kind which only a lawyer could love, is entitled Draft Guidance issued under Section 182 of the Licensing Act 2003 (UK Ministry of Culture, Media & Sport 2004). The consequences of this document are likely to be much more serious for public health and safety, as it is intended to eviscerate any possibility of effective action on alcohol issues at the local level. In the same month, then, the Blair government has managed to accomplish not only a missed chance at the national level but also a thoroughgoing neutralization of local powers to control the alcohol market in the interests of public health and safety. This deliberate effort to disable the public interest applies directly only to parts of the United Kingdom, but it is of wider significance. As will be discussed, the same government also holds important powers for the whole of the United Kingdom, and there is nowhere else to look for policy decisions on such matters. Further, the UK government has an important voice in the European Union, and in this context has generally sided, as in the Strategy, with British alcohol industry interests at the expense of public health and safety. More generally, in an international context the effort is worth holding up to the light for detailed examination as a textbook case of how industry interests can be brought to bear, through an ideologically friendly central government, to thwart local efforts to deal with the problems which enthusiastic and unchecked alcohol marketing can bring at the street level. In 1998, the government of the United Kingdom stated that it was ‘preparing a new strategy on alcohol’ (UK Department of Health 1998, §9.14), and the next year added that ‘we expect to publish our strategy . . . early in the year 2000’ (UK Department of Health 1999, §2.23). In 2003, a PowerPoint presentation entitled the Interim Analytical Report was published on the web (UK Cabinet Office, 2003). As noted, the strategy has now finally been published (UK Cabinet Office 2004). Prepared by the Prime Minister's Strategy Unit, the strategy carries a foreword signed by Tony Blair himself. Although originally billed to be a National Strategy, the final document is a strategy only for England. This presumably partly covers any embarrassment from the fact that, by the time it appeared, every other part of the United Kingdom, including the Isle of Man, already had its alcohol or its drug and alcohol strategy. The downshifting of focus may also reflect that the strategy, as we shall discuss, largely avoids recommending any measures (such as changes in excise tax or in blood–alcohol level for drink-driving) which would require action at a broader level than England. This begs the question of the need still for an alcohol strategy for the United Kingdom, covering the aspects of alcohol policy which can be enacted only by the UK government. Both England and the rest of the United Kingdom are in trouble with respect to alcohol. The Interim Analytical Report and the Strategy itself each document this as best they can, given the spotty nature of available British statistics of alcohol consumption and alcohol-related harms. A further accounting can be found in a recent report from the Academy of Medical Sciences (2004; it should be noted that I was a member of that report's working group). The Strategy's proposals for how to respond to a bad and worsening situation can best be described as bathetic. If one takes the listing at the back of Alcohol—No Ordinary Commodity (Babor et al. 2003), for instance, where preventive measures are ranked roughly on the evidence of their effectiveness, there is an almost total correspondence between the measures proposed in the Strategy's recommendations and the measures which are ranked in the listing as ‘ineffective’. They are all there in the Strategy: school education, voluntary advertising codes, even a half-hearted discussion of alternative entertainment for youth. Conversely, the Strategy eschews almost all the strategies ranked as ‘effective’. For those from the effective end of the list which it does advocate—for instance, brief interventions in primary health care—no new resources are provided, and the problem of actually getting health workers to conduct brief interventions (Roche & Freeman 2004) is not addressed. Concerning drink-driving, the one concrete initiative mentioned is a designated-driver publicity campaign run by an alcohol industry group; again the Strategy chooses a measure for which there is no evidence of effectiveness. The Strategy mentions that the United Kingdom's blood alcohol limit of 0.08% is among the highest in Europe, but does not broach the idea of reducing the limit to 0.05% to match most of the rest of Europe, nor other effective measures such as intensive random breath-testing. Again, the Strategy steers away from any measure with a reasonable track-record of effectiveness. The Strategy acknowledges that ‘there is a clear association between price, availability and consumption’ (p. 23). However, it eschews any proposals either on excise taxes or on controls of availability, with the explanation that ‘our analysis showed that the drivers of consumption are much more complex than merely price and availability’. While this statement is true (although no back-up analysis for it is offered), it is irrelevant: that the aetiology of emphysema is more complicated than just cigarette smoking is not an argument against doing something about the smoking. The Strategy also mentions ‘evidence [which] suggested that using price as a key lever risked major unintended side-effects’. No such evidence is given, but presumably potential rises in cross-channel purchases and smuggling are what is meant. A discussion of these issues would have been a good opportunity to raise the issue of whether the United Kingdom should attempt to change EU rules on alcohol in the Single Market which undercut public health. Indeed, an indication of the parochial quality of the Strategy is that the European Union (EU) is mentioned only once (in connection with seeking permission from the EU to require warning labels on alcoholic beverage containers; p. 33). After implying that price and availability policies would be unpopular, the Strategy offers its capping argument for looking away from price and availability: ‘measures to control price and availability are already built into the system’ (p. 23). The idea the Strategy can thus ignore a whole arena of action because it is ‘already built into the system’ is a breathtaking contradiction with the Strategy's general thrust, which points out how fragmented alcohol issues are between government departments, with ‘no clear focus for policymaking’ (p. 82). A document cannot be accepted seriously as taking ‘a strategic approach to addressing alcohol issues’ (p. 82) if it rules out of consideration some of the most effective available strategies. Having offered its arguments for steering away from price and availability, the Strategy continues: ‘So we believe that a more effective strategy would be to provide the industry with further opportunities to work in partnership with the government to reduce alcohol-related harm’ (p. 23). No evidence is offered of why this would be ‘a more effective strategy’; again, the evaluation research literature would not support the belief. My reading of the sentence is that it must have been written with a wink, essentially as a statement that ‘our political masters decided that the Strategy's approach would be to work with the alcohol beverage industry, and vetoed recommendations on matters like price and availability which would upset the industry’. This reading of the sentence is supported by the most ludicrous item in the Strategy—the model of actors and responsibilities for reducing harms from drinking (pp. 24–25). Three sets of actors are named. The first are ‘individuals and families’, who are responsible through ‘their own choices about what they and those for whom they are responsible drink, where and how’, including being responsible for actions while intoxicated. The third actor is ‘government’, which is responsible for informing consumers, ‘supporting those who suffer adverse consequences’, protecting others from the drinker, ‘ensuring a fair balance between the interests of all stakeholders’ and ‘providing the right strategic framework’. Also mentioned is ‘protecting against harms caused by the supply of alcohol where appropriate, and for regulating to the minimum necessary to achieve this’. (One can guess which qualifiers in this sentence were insisted upon by industry interests.) Between the individual and family and the government is another actor, the ‘Alcoholic drinks industry’, which is assigned responsibilities for giving accurate information and warning about consequences of drinking, for ‘supplying its products in a way which minimizes harm’ and for working with national agencies and local partners. So much for civil society. No other intermediate actor is mentioned in the chart, whether professions, institutions, voluntary associations or—notably—local governments. There is simply the individual drinker or family, the government and the alcoholic beverage industry. It is a telling and indeed a rather totalitarian picture, and an utterly inadequate representation of reality in a complex society such as the United Kingdom. As noted, in the same month another major British alcohol policy document was released, the Draft Guidance issued under Section 182 of the Licensing Act 2003 (UK Ministry of Culture, Media & Sport 2004). This document was also the result of a long process of consideration. In May 2001, the Home Office published its proposals on alcohol licensing ‘reform’ (UK Home Office 2001), the culmination of a review and consultation process dating back to 1998. A notable feature was a provision to eliminate any national closing hours for pubs and nightclubs. After an intervening election, legislation based on the proposals was finally passed in 2003. The Draft Guidance, which must be passed by Parliament, begins the process of actually implementing the new legislation. After the election, responsibility for alcohol licensing matters was transferred to the Ministry of Culture, Media and Sport. This transfer, which of course further fragmented government responsibility for alcohol matters, has tended to provide the industry with a more reliable governmental ally (alcohol licensing falls under the ‘tourism’ section of the ministry's portfolio). A 2002 speech by the Culture Secretary to an alcohol trade group, for instance, essentially promised that the reforms would increase alcohol sales: ‘the reforms would be good for the economy, opening the way to new and more diverse markets, providing new investment opportunities and creating new employment’ (UK Ministry of Culture, Media & Sport 2002). A major change in the new licensing law is the abolition of the centuries-old system of ‘licensing justices’ and their replacement by a licensing committee drawn from the local elected council. This can be seen as a positive change in terms of governance and accountability, making the licensing authorities responsible to the community which elects them. However, this is precisely what has greatly worried alcohol industry interests, which fear that such local authorities may be less co-optable: ‘They have a vested interest in the people that vote for them’, a board member of the Restaurant Association complained (Restaurant industry speaks out . . . 2002). As troubles with drinking in the core city area have increased, a number of British municipal governments have become activist in their licensing policies, and some have been looking to charge the trade for the extra policing, street-cleaning and late-night transport that later closing hours would require (BISL hits out . . . 2002). The trade became worried that the shift in structure might mean a more restrictive rather than a weakened licence regime, including in some places a reduction rather than an increase in opening hours. The task for industry interests, thus, has been to lobby the central government to impose severe constraints on what actions local licensing boards can take, in the form of ‘guidance’ from the central government on how the boards can act. The March 23 document gives evidence of the trade's very considerable success in this effort. From the perspective of an outsider, the result is astonishing. The instructions on what may and may not be carried out are, after at local who have presumably been elected to their as people of and It is to such an taking to the of the which in its as if at As for the the is to the of any local of the document is on the of the of the licensing which are to ‘the of and public the of public and the of from harm’ (p. is no for the licensing to a the which is merely it must be For may not be which to the health of rather than their (p. public is with the of the people using the and not with the public with is with in other (p. licensing authorities are to look no further than the of the in question in terms of which might result in on the to cannot to the of once they are the of the licence and or (p. to public caused by the of once they are the control of the licence . . . cannot be . . . the of the these are matters for responsibility of under the (p. from in the street the cannot be into by in a of (p. licensing authorities may not impose which the of as to the of should be to . . . It will be the responsibility of the licence as an and not the licensing to that at the are and and licensing authorities must that they not their powers and (p. are to be essentially as an which must be from or (p. or even in terms of a of (p. This applies even to issued to or of even ‘a deal of time may (p. the are will be important for investment and that no new are the actually (p. While licensing authorities are to policies to which the of new in a may only be into a new licence or change in an one is being it cannot be into even in a review of an licence (p. policies be as a for an licence are received about problems with those (p. licensing authorities should not with the of the The of by the licensing is no a consideration. the for another or or This is not a for the licensing . . . is a for and the (p. 23). problems from a or licence is The for advertising that an has been is to one on the (p. only and but also are to be from consideration for which would have been the for the licence was first and which were by of the of a licence (p. It is that the on whether a is thus not to be be to of the licensing committee (p. This that political is as an of decisions on a not be on the of any political which would a approach to the This may be for from their own (p. and the is in For instance, on of it in general that and be to alcohol at any time which they to The document in the British government that and early closing are ‘a key of and of are to This in the of the research literature (Babor et al. 2003, and . . 2002). opening in for instance, in in and in The work was more the but this a change in shift to the new work at et al. 2002). One to the problem of the pubs at the same it would might be closing licensing authorities should also not to closing by for closing . . . In the this would only to the of and . . . with a of . . . and would not be necessary to the licensing The general should be to support later opening that for a (p. 82). I found for a the of the document ‘licensing authorities should not closing for (p. this would a key of the 2003 (p. are licensing authorities to reduce opening hours in the to the new licensing regime, even in the case of with permission to for hours. the even more ‘a licensing is from . . . which would have the of opening hours to more hours than the (p. the other any idea of the public responsibilities as a of public to be ‘there is no . . . to for the . . . for a public has no trade on a the licence is entitled to the (p. The end result of the Guidance, if it into will be a the new local licensing authorities will be with and but will be almost to the licensing to the or of of the alcohol in their for local to have to alcohol licensing is also not For instance, the in that there was local the licensing system was In such the for in some local control alcohol has been through their and In for instance, have good of which essentially impose controls on hours and of through the system & The UK Guidance that the local process is also in local control of alcohol In it the argument that local authorities should provide control and licensing will be to and (p. it is to how is to However, the of the has arguments that the local powers in England cannot work as a for licensing powers 2003). A for the Prime Minister's Office of the of a measure by the government in to local gives support to this that ‘the local authorities the of about by of the is about the for and drinking in ‘the of public that has in This a market that has been by the central constraints on local is by authorities to have the of and to have given to because of the number of people in one area and by in the (UK Ministry of Culture, Media & Sport 2001, As the report on the there is a problem in British and with alcohol and the & et al. 2003). The powers of local governments have been they cannot provide a The Guidance on the new Licensing to that licensing cannot provide a and there is in the Strategy which is likely to have much in reducing these The which is of a central government which is to be with respect to alcohol and which effort to any by local government to effective alcohol This is a which England has to at the end of of efforts on the Strategy and on the Licensing The one feature of the is that the because this gives some to the that there has been the government the is I itself is a very and is to alcohol industry In recent some have of the The supply of to was to have between and A member of noted ‘a rather change in the The most of the while the of drinking are . . . I have there are now more people than who in the in a 2002). Media have also to drinking among a on Home Office proposals to by it just the and suggested that the Home Secretary was by the of the Home 2002). Alcohol industry interests are in and in the government. The is the at with of and industry interests to have as an on this government as they on the governments which In March for instance, the government that it was on its dating from to reduce the blood–alcohol limit for from 0.08% to the general level of the European Union, to this the with the which is by the drinks industry and reducing the The Department of on research by the A of noted that ‘the with that of the alcohol industry but is by local the the British Medical the the for the of the and the for (UK of 2002). The of the of a noted that by the of the drinks 2002). The also general of the Blair government. has a to problems in individual to the in pubs and on the street to be seen as a of and the are individual and from or a law for the to on the for and This from the Prime with but up again in the Strategy as a of to be by the and (p. in the is thus in terms of steering away from the and in which the trouble as more to than any government . . . It that it has been to to the more than any of its It would be to of a more of than the of the Blair government on alcohol the end of the Strategy, under the ‘ensuring the is there is an attempt to the are to the industry to its to by best that in the should be voluntary . . . the next if industry actions are not to an in reducing will the case for including legislation. However, in the light of the it is to much to this There was a not long was of on alcohol It is to the new Strategy with the report on Alcohol in in the final of the government, by the The report was but published in in the of the Act the Strategy, the review noted the of alcohol issues UK government departments, by the for the for for However, the of the not much further than The review on the literature a of alcohol consumption to of in the and not the It proposed that ‘the should a positive on the in consumption and on the reduction of alcohol-related (p. It the of alcohol taxes as an of alcohol with the at a minimum being level with changes in the price licensing should not be further it should be and in respect to under drinking its ‘the on drinking and should be and legislation (p. A the review still a than the document for a British strategy on alcohol.

Tubular sprouting in angiogenesis relies on division of labour between endothelial tip cells, leading and guiding the sprout, and their neighboring stalk cells, which divide and form the vascular lumen. We previously learned how the graded extracellular distribution of heparin-binding vascular endothelial growth factor (VEGF)-A orchestrates and balances tip and stalk cell behavior. Recent data now provided insight into the regulation of tip cell numbers, illustrating how delta-like (DII)4-Notch signalling functions to limit the explorative tip cell behavior induced by VEGF-A. These data also provided a first answer to the question why not all endothelial cells stimulated by VEGF-A turn into tip cells. Here we review this new model and discuss how VEGF-A and DII4/Notch signalling may interact dynamically at the cellular level to control vascular patterning.

Research on organizational interventions needs to meet the objectives of both researchers and participating organizations. This duality means that real-world impact has to be considered throughout the research process, simultaneously addressing both scientific rigour and practical relevance. This discussion paper aims to offer a set of principles, grounded in knowledge from various disciplines that can guide researchers in designing, implementing, and evaluating organizational interventions. Inspired by Mode 2 knowledge production, the principles were developed through a transdisciplinary, participatory and iterative process where practitioners and academics were invited to develop, refine and validate the principles. The process resulted in 10 principles: 1) Ensure active engagement and participation among key stakeholders; 2) Understand the situation (starting points and objectives); 3) Align the intervention with existing organizational objectives; 4) Explicate the program logic; 5) Prioritize intervention activities based on effort-gain balance; 6) Work with existing practices, processes, and mindsets; 7) Iteratively observe, reflect, and adapt; 8) Develop organizational learning capabilities; 9) Evaluate the interaction between intervention, process, and context; and 10) Transfer knowledge beyond the specific organization. The principles suggest how the design, implementation, and evaluation of organizational interventions can be researched in a way that maximizes both practical and scientific impact.