Inference of chromosomal inversion dynamics from Pool-Seq data in natural and laboratory populations of Drosophila melanogaster.

Sequencing of pools of individuals (Pool-Seq) represents a reliable and cost-effective approach for estimating genome-wide SNP and transposable element insertion frequencies. However, Pool-Seq does not provide direct information on haplotypes so that, for example, obtaining inversion frequencies has not been possible until now. Here, we have developed a new set of diagnostic marker SNPs for seven cosmopolitan inversions in Drosophila melanogaster that can be used to infer inversion frequencies from Pool-Seq data. We applied our novel marker set to Pool-Seq data from an experimental evolution study and from North American and Australian latitudinal clines. In the experimental evolution data, we find evidence that positive selection has driven the frequencies of In(3R)C and In(3R)Mo to increase over time. In the clinal data, we confirm the existence of frequency clines for In(2L)t, In(3L)P and In(3R)Payne in both North America and Australia and detect a previously unknown latitudinal cline for In(3R)Mo in North America. The inversion markers developed here provide a versatile and robust tool for characterizing inversion frequencies and their dynamics in Pool-Seq data from diverse D. melanogaster populations.

Representational pseudoneglect and reference points both influence geographic location estimates

Our mental representation of the world is far from objective. For example, western Canadians estimate the locations of North American cities to be too far to the west. This bias could be due to a reference point effect, in which people estimate more space between places close to them than far from them, or to representational pseudoneglect, in which neurologically intact individuals favor the left side of space when asked to image a scene.We tested whether either or both of these biases influence the geographic world representations of neurologically intact young adults from Edmonton and Ottawa, which are in western and eastern Canada, respectively. Individuals were asked to locate NorthAmerican cities on a two-dimensional grid. Both groups revealed effects of representational pseudoneglect in this novel paradigm, but they also each exhibited reference point effects. These results inform theories in both cognitive psychology and neuroscience.

Evidence for adaptive radiation from a phylogenetic study of plant defenses.

One signature of adaptive radiation is a high level of trait change early during the diversification process and a plateau toward the end of the radiation. Although the study of the tempo of evolution has historically been the domain of paleontologists, recently developed phylogenetic tools allow for the rigorous examination of trait evolution in a tremendous diversity of organisms. Enemy-driven adaptive radiation was a key prediction of Ehrlich and Raven's coevolutionary hypothesis [Ehrlich PR, Raven PH (1964) Evolution 18:586-608], yet has remained largely untested. Here we examine patterns of trait evolution in 51 North American milkweed species (Asclepias), using maximum likelihood methods. We study 7 traits of the milkweeds, ranging from seed size and foliar physiological traits to defense traits (cardenolides, latex, and trichomes) previously shown to impact herbivores, including the monarch butterfly. We compare the fit of simple random-walk models of trait evolution to models that incorporate stabilizing selection (Ornstein-Ulenbeck process), as well as time-varying rates of trait evolution. Early bursts of trait evolution were implicated for 2 traits, while stabilizing selection was implicated for several others. We further modeled the relationship between trait change and species diversification while allowing rates of trait evolution to vary during the radiation. Species-rich lineages underwent a proportionately greater decline in latex and cardenolides relative to species-poor lineages, and the rate of trait change was most rapid early in the radiation. An interpretation of this result is that reduced investment in defensive traits accelerated diversification, and disproportionately so, early in the adaptive radiation of milkweeds.

Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa.

PURPOSE: Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes. METHODS: We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing. RESULTS: We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5' untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family. CONCLUSIONS: The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin.

Multiple introductions boosted genetic diversity in the invasive range of black cherry (Prunus serotina; Rosaceae).

BACKGROUND AND AIMS: Black cherry (Prunus serotina) is a North American tree that is rapidly invading European forests. This species was introduced first as an ornamental plant, then it was massively planted by foresters in many countries, but its origins and the process of invasion remain poorly documented. Based on a genetic survey of both native and invasive ranges, the invasion history of black cherry was investigated by identifying putative source populations and then assessing the importance of multiple introductions on the maintenance of gene diversity. METHODS: Genetic variability and structure of 23 populations from the invasive range and 22 populations from the native range were analysed using eight nuclear microsatellite loci and five chloroplast DNA regions. KEY RESULTS: Chloroplast DNA diversity suggests there were multiple introductions from a single geographic region (the north-eastern United States). A low reduction of genetic diversity was observed in the invasive range for both nuclear and plastid genomes. High propagule pressure including both the size and number of introductions shaped the genetic structure in Europe and boosted genetic diversity. Populations from Denmark, The Netherlands, Belgium and Germany showed high genetic diversity and low differentiation among populations, supporting the hypothesis that numerous introduction events, including multiple individuals and exchanges between sites, have taken place during two centuries of plantation. CONCLUSIONS: This study postulates that the invasive black cherry has originated from east of the Appalachian Mountains (mainly the Allegheny plateau) and its invasiveness in north-western Europe is mainly due to multiple introductions containing high numbers of individuals.

Potential health-care service utilization substitution effects induced by case management for emergency department frequent users

BACKGROUND: In most of the emergency departments (ED) in developed countries, a subset of patients visits the ED frequently. Despite their small numbers, these patients are the source of a disproportionally high number of all ED visits, and use a significant proportion of healthcare resources. They place a heavy economic burden on hospital and healthcare systems budgets overall. Several interventions have been carried out to improve the management of these ED frequent users. Case management has been shown in some North American studies to reduce ED utilization and costs. In these studies, cost analyses have been carried out from the hospital perspective without examining the costs induced by healthcare consumed in the community. However, case management might reduce ED visits and costs from the hospital's perspective, but induce substitution effects, and increase health service utilization outside the hospital. This study examined if an interdisciplinary case-management intervention-compared to standard ED care -reduced costs generated by frequent ED users not only from the hospital perspective, but also from the healthcare system perspective-that is, from a broader perspective taking into account the costs of healthcare services used outside the hospital. METHODS: In this randomized controlled trial, 250 adult frequent emergency department users (5 or more visits during the previous 12 months) who visited the ED of the University Hospital of Lausanne, Switzerland, between May 2012 and July 2013 were allocated to one of two groups: case management intervention (CM) or standard ED care (SC), and followed up for 12 months. Depending on the perspective of the analysis, costs were evaluated differently. For the analysis from the hospital's perspective, the true value of resources used to provide services was used as a cost estimate. These data were obtained from the hospital's analytical accounting system. For the analysis from the health-care system perspective, all health-care services consumed by users and charged were used as an estimate of costs. These data were obtained from health insurance providers for a subsample of participants. To allow comparisons in a same time period, individual monthly average costs were calculated. Multivariate linear models including a fixed effect "group" were run using socio-demographic characteristics and health-related variables as controlling variables (age, gender, educational level, citizenship, marital status, somatic and mental health problems, and risk behaviors).

Transient ocular motor nerve palsies associated with presumed cranial nerve schwannomas.

BACKGROUND: Cranial nerve schwannomas are radiologically characterized by nodular cranial nerve enhancement on magnetic resonance imaging (MRI). Schwannomas typically present with gradually progressive symptoms, but isolated reports have suggested that schwannomas may cause fluctuating symptoms as well. METHODS: This is a report of ten cases of presumed cranial nerve schwannoma that presented with transient or recurring ocular motor nerve deficits. RESULTS: Schwannomas of the third, fourth, and fifth nerves resulted in fluctuating deficits of all 3 ocular motor nerves. Persistent nodular cranial nerve enhancement was present on sequential MRI studies. Several episodes of transient oculomotor (III) deficts were associated with headaches, mimicking ophthalmoplegic migraine. CONCLUSIONS: Cranial nerve schwannomas may result in relapsing and remitting cranial nerve symptoms.

Police work and new 'security devices' : a tale from the beat

Mobile technologies have brought about major changes in police equipment and police work. If a utopian narrative remains strongly linked to the adoption of new technologies, often formulated as 'magic bullets' to real occupational problems, there are important tensions between their 'imagined' outcomes and the (unexpected) effects that accompany their daily 'practical' use by police officers. This article offers an analysis of police officers' perceptions and interactions with security devices. In so doing, it develops a conceptual typology of strategies for coping with new technology inspired by Le Bourhis and Lascoumes: challenging, neutralizing and diverting. To that purpose, we adopt an ethnographic approach that focuses on the discourses, practices and actions of police officers in relation to three security devices: the mobile digital terminal, the mobile phone and the body camera. Based on a case study of a North American municipal police department, the article addresses how these technological devices are perceived and experienced by police officers on the beat.

Continental faunal exchange and the asymmetrical radiation of carnivores.

Lineages arriving on islands may undergo explosive evolutionary radiations owing to the wealth of ecological opportunities. Although studies on insular taxa have improved our understanding of macroevolutionary phenomena, we know little about the macroevolutionary dynamics of continental exchanges. Here we study the evolution of eight Carnivora families that have migrated across the Northern Hemisphere to investigate if continental invasions also result in explosive diversification dynamics. We used a Bayesian approach to estimate speciation and extinction rates from a substantial dataset of fossil occurrences while accounting for the incompleteness of the fossil record. Our analyses revealed a strongly asymmetrical pattern in which North American lineages invading Eurasia underwent explosive radiations, whereas lineages invading North America maintained uniform diversification dynamics. These invasions into Eurasia were characterized by high rates of speciation and extinction. The radiation of the arriving lineages in Eurasia coincide with the decline of established lineages or phases of climate change, suggesting differences in the ecological settings between the continents may be responsible for the disparity in diversification dynamics. These results reveal long-term outcomes of biological invasions and show that the importance of explosive radiations in shaping diversity extends beyond insular systems and have significant impact at continental scales.

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Challenges to patient-centred care in a general internal medicine context: findings from an exploratory study

Introduction. If we are to promote more patient-centred approaches in care delivery, we have to better characterize the situations in which being patient-centred is difficult to achieve. Data from professionals in health and social care are important because they are the people charged with operationalizing patient-centred care (PCC) in their daily practice. However, empirical accounts from frontline care providers are still lacking, and it is important to gather experiences not only from doctors but also from the other care providers. Indeed, experiences from different professions can help inform our understanding of patient care, which is expected to be both patient-centred and collaborative. Methods. This study was based on the following research question: What factors make the provision of PCC difficult to achieve? Sample and setting. A purposeful sampling technique was used, allowing for a series of choices about the participants and their professional affiliation. Because patient-centredness is the focus, 3 professions appeared to be of special interest: general internists, nurses and social workers. The study was undertaken in the General Internal Medicine Division of a teaching hospital located in a North American context. Data Collection. To answer the research question, a methodological approach based on a theory called phenomenology was chosen. Accordingly, semi-structured interviews were used since they generate understanding of the meanings different individuals have of their lived world. Interviews with 8 physicians, 10 nurses and 10 social workers were eventually conducted. Data analysis. An inductive thematic analysis was employed to make sense of the interview data. Results. The thematic analysis allowed identifying various types of challenges to PCC. Although most of the challenges were perceived by all three groups of professionals, they were perceived to a different degree across the professions, which likely reflected the scope of practice of each profession. The challenges and their distribution across the professions are illustrated in Table 1. Examples of challenges are provided in Table 2. Discussion. There is a tension between what is supposed to be done - what stands in the philosophy of patient -centredness - and what is currently done - the real life with all the challenges to PCC. According to some participants' accounts, PCC clearly risks becoming a mere illusion for health care professionals on which too great pressures are imposed.

Genomics of clinal variation in Drosophila: disentangling the interactions of selection and demography.

Clines in phenotypes and genotype frequencies across environmental gradients are commonly taken as evidence for spatially varying selection. Classical examples include the latitudinal clines in various species of Drosophila, which often occur in parallel fashion on multiple continents. Today, genomewide analysis of such clinal systems provides a fantastic opportunity for unravelling the genetics of adaptation, yet major challenges remain. A well-known but often neglected problem is that demographic processes can also generate clinality, independent of or coincident with selection. A closely related issue is how to identify true genic targets of clinal selection. In this issue of Molecular Ecology, three studies illustrate these challenges and how they might be met. Bergland et al. report evidence suggesting that the well-known parallel latitudinal clines in North American and Australian D. melanogaster are confounded by admixture from Africa and Europe, highlighting the importance of distinguishing demographic from adaptive clines. In a companion study, Machado et al. provide the first genomic comparison of latitudinal differentiation in D. melanogaster and its sister species D. simulans. While D. simulans is less clinal than D. melanogaster, a significant fraction of clinal genes is shared between both species, suggesting the existence of convergent adaptation to clinaly varying selection pressures. Finally, by drawing on several independent sources of evidence, Bo?ičević et al. identify a functional network of eight clinal genes that are likely involved in cold adaptation. Together, these studies remind us that clinality does not necessarily imply selection and that separating adaptive signal from demographic noise requires great effort and care.

Genomic evidence for adaptive inversion clines in Drosophila melanogaster.

Clines in chromosomal inversion polymorphisms-presumably driven by climatic gradients-are common but there is surprisingly little evidence for selection acting on them. Here we address this long-standing issue in Drosophila melanogaster by using diagnostic single nucleotide polymorphism (SNP) markers to estimate inversion frequencies from 28 whole-genome Pool-seq samples collected from 10 populations along the North American east coast. Inversions In(3L)P, In(3R)Mo, and In(3R)Payne showed clear latitudinal clines, and for In(2L)t, In(2R)NS, and In(3R)Payne the steepness of the clinal slopes changed between summer and fall. Consistent with an effect of seasonality on inversion frequencies, we detected small but stable seasonal fluctuations of In(2R)NS and In(3R)Payne in a temperate Pennsylvanian population over 4 years. In support of spatially varying selection, we observed that the cline in In(3R)Payne has remained stable for >40 years and that the frequencies of In(2L)t and In(3R)Payne are strongly correlated with climatic factors that vary latitudinally, independent of population structure. To test whether these patterns are adaptive, we compared the amount of genetic differentiation of inversions versus neutral SNPs and found that the clines in In(2L)t and In(3R)Payne are maintained nonneutrally and independent of admixture. We also identified numerous clinal inversion-associated SNPs, many of which exhibit parallel differentiation along the Australian cline and reside in genes known to affect fitness-related traits. Together, our results provide strong evidence that inversion clines are maintained by spatially-and perhaps also temporally-varying selection. We interpret our data in light of current hypotheses about how inversions are established and maintained.