Epidemiology and Heritability of Major Depressive Disorder,Stratified by Age of Onset,Sex, and Illness Course in Generation Scotland: Scottish Family Health Study (GS:SFHS)

The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.     

Earth Observation,Spatial Data Quality,and Neglected Tropical Diseases

Earth observation (EO) is the use of remote sensing and in situ observations to gather data on the environment. It finds increasing application in the study of environmentally modulated neglected tropical diseases (NTDs). Obtaining and assuring the quality of the relevant spatially and temporally indexed EO data remain challenges. Our objective was to review the Earth observation products currently used in studies of NTD epidemiology and to discuss fundamental issues relating to spatial data quality (SDQ), which limit the utilization of EO and pose challenges for its more effective use. We searched Web of Science and PubMed for studies related to EO and echinococossis, leptospirosis, schistosomiasis, and soil-transmitted helminth infections. Relevant literature was also identified from the bibliographies of those papers. We found that extensive use is made of EO products in the study of NTD epidemiology; however, the quality of these products is usually given little explicit attention. We review key issues in SDQ concerning spatial and temporal scale, uncertainty, and the documentation and use of quality information. We give examples of how these issues may interact with uncertainty in NTD data to affect the output of an epidemiological analysis. We conclude that researchers should give careful attention to SDQ when designing NTD spatial-epidemiological studies. This should be used to inform uncertainty analysis in the epidemiological study. SDQ should be documented and made available to other researchers.     

Mapping the Risk of Soil-Transmitted Helminthic Infections in the Philippines

BackgroundIn order to increase the efficient allocation of soil-transmitted helminth (STH) disease control resources in the Philippines, we aimed to describe for the first time the spatial variation in the prevalence of A. lumbricoides, T. trichiura and hookworm across the country, quantify the association between the physical environment and spatial variation of STH infection and develop predictive risk maps for each infection.Conclusions/SignificanceThis analysis revealed significant spatial variation in STH infection prevalence within provinces of the Philippines. This suggests that a spatially targeted approach to STH interventions, including mass drug administration, is warranted. When financially possible, additional STH surveys should be prioritized to high-risk areas identified by our study in Luzon.     

Acinetobacter baumannii Repeatedly Evolves a Hypermutator Phenotype in Response to Tigecycline That Effectively Surveys Evolutionary Trajectories to Resistance

The evolution of hypermutators in response to antibiotic treatment in both clinical and laboratory settings provides a unique context for the study of adaptive evolution. With increased mutation rates, the number of hitchhiker mutations within an evolving hypermutator population is remarkably high and presents substantial challenges in determining which mutations are adaptive. Intriguingly however, hypermutators also provide an opportunity to explore deeply the accessible evolutionary trajectories that lead to increased organism fitness, in this case the evolution of antibiotic resistance to the clinically relevant antibiotic tigecycline by the hospital pathogen Acinetobacter baumannii. Using a continuous culture system, AB210M, a clinically derived strain of A. baumannii, was evolved to tigecycline resistance. Analysis of the adapted populations showed that nearly all the successful lineages became hypermutators via movement of a mobile element to inactivate mutS. In addition, metagenomic analysis of population samples revealed another 896 mutations that occurred at a frequency greater than 5% in the population, while 38 phenotypically distinct individual colonies harbored a total of 1712 mutations. These mutations were scattered throughout the genome and affected ~40% of the coding sequences. The most highly mutated gene was adeS, a known tigecycline-resistance gene; however, adeS was not solely responsible for the high level of TGC resistance. Sixteen other genes stood out as potentially relevant to increased resistance. The five most prominent candidate genes (adeS, rpsJ, rrf, msbA, and gna) consistently re-emerged in subsequent replicate population studies suggesting they are likely to play a role in adaptation to tigecycline. Interestingly, the repeated evolution of a hypermutator phenotype in response to antibiotic stress illustrates not only a highly adaptive strategy to resistance, but also a remarkably efficient survey of successful evolutionary trajectories.     

Revisiting the phylogeography and demography of European badgers (Meles meles) based on broad sampling,multiple markers and simulations

Although the phylogeography of European mammals has been extensively investigated since the 1990s, many studies were limited in terms of sampling distribution, the number of molecular markers used and the analytical techniques employed, frequently leading to incomplete postglacial recolonisation scenarios. The broad-scale genetic structure of the European badger (Meles meles) is of interest as it may result from historic restriction to glacial refugia and/or recent anthropogenic impact. However, previous studies were based mostly on samples from western Europe, making it difficult to draw robust conclusions about the location of refugia, patterns of postglacial expansion and recent demography. In the present study, continent-wide sampling and analyses with multiple markers provided evidence for two glacial refugia (Iberia and southeast Europe) that contributed to the genetic variation observed in badgers in Europe today. Approximate Bayesian computation provided support for a colonisation of Scandinavia from both Iberian and southeastern refugia. In the whole of Europe, we observed a decline in genetic diversity with increasing latitude, suggesting that the reduced diversity in the peripheral populations resulted from a postglacial expansion processes. Although MSVAR v.1.3 also provided evidence for recent genetic bottlenecks in some of these peripheral populations, the simulations performed to estimate the method''s power to correctly infer the past demography of our empirical populations suggested that the timing and severity of bottlenecks could not be established with certainty. We urge caution against trying to relate demographic declines inferred using MSVAR with particular historic or climatological events.     

Modelling parasite aggregation: disentangling statistical and ecological approaches

The overdispersion in macroparasite infection intensity among host populations is commonly simulated using a constant negative binomial aggregation parameter. We describe an alternative to utilising the negative binomial approach and demonstrate important disparities in intervention efficacy projections that can come about from opting for pattern-fitting models that are not process-explicit. We present model output in the context of the epidemiology and control of soil-transmitted helminths due to the significant public health burden imposed by these parasites, but our methods are applicable to other infections with demonstrable aggregation in parasite numbers among hosts.     

Trio under threat: can we secure the future of rhinos,elephants and tigers in Malaysia?

Three of Malaysia’s endangered large mammal species are experiencing contrasting futures. Populations of the Sumatran rhino (Dicerorhinus sumatrensis) have dwindled to critically low numbers in Peninsular Malaysia (current estimates need to be revised) and the state of Sabah (less than 40 individuals estimated). In the latter region, a bold intervention involving the translocation of isolated rhinos is being developed to concentrate them into a protected area to improve reproduction success rates. For the Asian elephant (Elephas maximus), recently established baselines for Peninsular Malaysia (0.09 elephants/km² estimated from one site) and Sabah (between 0.56 and 2.15 elephants/km² estimated from four sites) seem to indicate globally significant populations based on dung count surveys. Similar surveys are required to monitor elephant population trends at these sites and to determine baselines elsewhere. The population status of the Malayan tiger (Panthera tigris jacksoni) in Peninsular Malaysia, however, remains uncertain as only a couple of scientifically defensible camera-trapping surveys (1.66 and 2.59 tigers/100 km² estimated from two sites) have been conducted to date. As conservation resources are limited, it may be prudent to focus tiger monitoring and protection efforts in priority areas identified by the National Tiger Action Plan for Malaysia. Apart from reviewing the conservation status of rhinos, elephants and tigers and threats facing them, we highlight existing and novel conservation initiatives, policies and frameworks that can help secure the long-term future of these iconic species in Malaysia.     

Major histocompatibility complex variation and evolution at a single, expressed DQA locus in two genera of elephants

Genes of the vertebrate major histocompatibility complex (MHC) are crucial to defense against infectious disease, provide an important measure of functional genetic diversity, and have been implicated in mate choice and kin recognition. As a result, MHC loci have been characterized for a number of vertebrate species, especially mammals; however, elephants are a notable exception. Our study is the first to characterize patterns of genetic diversity and natural selection in the elephant MHC. We did so using DNA sequences from a single, expressed DQA locus in elephants. We characterized six alleles in 30 African elephants (Loxodonta africana) and four alleles in three Asian elephants (Elephas maximus). In addition, for two of the African alleles and three of the Asian alleles, we characterized complete coding sequences (exons 1–5) and nearly complete non-coding sequences (introns 2–4) for the class II DQA loci. Compared to DQA in other wild mammals, we found moderate polymorphism and allelic diversity and similar patterns of selection; patterns of non-synonymous and synonymous substitutions were consistent with balancing selection acting on the peptides involved in antigen binding in the second exon. In addition, balancing selection has led to strong trans-species allelism that has maintained multiple allelic lineages across both genera of extant elephants for at least 6 million years. We discuss our results in the context of MHC diversity in other mammals and patterns of evolution in elephants.     

Angiotensin II-dependent growth of vascular smooth muscle cells requires transactivation of the epidermal growth factor receptor via a cytosolic phospholipase A2-mediated release of arachidonic acid

Angiotensin (Ang) II stimulates vascular smooth muscle cell (VSMC) growth via activation of cytosolic phospholipase A₂ (cPLA₂), release of arachidonic acid (ArAc) and activation of mitogen-activated protein kinase (MAPK). The mechanism linking AT₁ receptor stimulation of ArAc release with MAPK activation may involve transactivation of the epidermal growth factor receptor (EGFR). In this study, Ang II increased phosphorylation of the EGFR and MAPK in cultured VSMC and these effects were attenuated by the cPLA₂ inhibitor arachidonyl trifluoromethyl ketone (AACOCF₃), and restored by addition of ArAc. Ang II- or ArAc-induced phosphorylation of the EGFR and MAPK were abolished by the EGFR kinase inhibitor AG1478. Ang II or ArAc also stimulated VSMC growth that was blocked by AG1478 or the MAPK kinase (MEK) inhibitor PD98059. Thus, it appears that the cPLA₂-dependent release of ArAc may provide a mechanism for the transactivation between the AT₁ receptor and the EGFR signaling cascade.