The koala immunological toolkit: Sequence identification and comparison of key markers of the koala (Phascolarctos cinereus) immune response

The koala (Phascolarctos cinereus) is an Australian marsupial that continues to experience significant population declines. Infectious diseases caused by pathogens such as Chlamydia are proposed to have a major role. Very few species-specific immunological reagents are available, severely hindering our ability to respond to the threat of infectious diseases in the koala. In this study, we utilise data from the sequencing of the koala transcriptome to identify key immunological markers of the koala adaptive immune response and cytokines known to be important in the host response to chlamydial infection in other species. This report describes the identification and preliminary sequence analysis of (1) T lymphocyte glycoprotein markers (CD4, CD8); (2) IL-4, a marker for the Th2 response; (3) cytokines such as IL-6, IL-12 and IL-1β, that have been shown to have a role in chlamydial clearance and pathology in other hosts; and (4) the sequences for the koala immunoglobulins, IgA, IgG, IgE and IgM. These sequences will enable the development of a range of immunological reagents for understanding the koala’s innate and adaptive immune responses, while also providing a resource that will enable continued investigations into the origin and evolution of the marsupial immune system.

Archiving primary data: Solutions for long-term studies

The recent trend for journals to require open access to primary data included in publications has been embraced by many biologists, but has caused apprehension amongst researchers engaged in long-term ecological and evolutionary studies. A worldwide survey of 73 principal investigators (Pls) with long-term studies revealed positive attitudes towards sharing data with the agreement or involvement of the PI, and 93% of PIs have historically shared data. Only 8% were in favor of uncontrolled, open access to primary data while 63% expressed serious concern. We present here their viewpoint on an issue that can have non-trivial scientific consequences. We discuss potential costs of public data archiving and provide possible solutions to meet the needs of journals and researchers.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5–89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

Efficient parameter estimation in longitudinal data analysis using a hybrid GEE method

The method of generalized estimating equations (GEEs) provides consistent estimates of the regression parameters in a marginal regression model for longitudinal data, even when the working correlation model is misspecified (Liang and Zeger, 1986). However, the efficiency of a GEE estimate can be seriously affected by the choice of the working correlation model. This study addresses this problem by proposing a hybrid method that combines multiple GEEs based on different working correlation models, using the empirical likelihood method (Qin and Lawless, 1994). Analyses show that this hybrid method is more efficient than a GEE using a misspecified working correlation model. Furthermore, if one of the working correlation structures correctly models the within-subject correlations, then this hybrid method provides the most efficient parameter estimates. In simulations, the hybrid method's finite-sample performance is superior to a GEE under any of the commonly used working correlation models and is almost fully efficient in all scenarios studied. The hybrid method is illustrated using data from a longitudinal study of the respiratory infection rates in 275 Indonesian children.

Early stopping by using stochastic curtailment in a three-arm sequential trial

Summary. Interim analysis is important in a large clinical trial for ethical and cost considerations. Sometimes, an interim analysis needs to be performed at an earlier than planned time point. In that case, methods using stochastic curtailment are useful in examining the data for early stopping while controlling the inflation of type I and type II errors. We consider a three-arm randomized study of treatments to reduce perioperative blood loss following major surgery. Owing to slow accrual, an unplanned interim analysis was required by the study team to determine whether the study should be continued. We distinguish two different cases: when all treatments are under direct comparison and when one of the treatments is a control. We used simulations to study the operating characteristics of five different stochastic curtailment methods. We also considered the influence of timing of the interim analyses on the type I error and power of the test. We found that the type I error and power between the different methods can be quite different. The analysis for the perioperative blood loss trial was carried out at approximately a quarter of the planned sample size. We found that there is little evidence that the active treatments are better than a placebo and recommended closure of the trial.

An extension of the continual reassessment method using decision theory

The primary goal of a phase I trial is to find the maximally tolerated dose (MTD) of a treatment. The MTD is usually defined in terms of a tolerable probability, q*, of toxicity. Our objective is to find the highest dose with toxicity risk that does not exceed q*, a criterion that is often desired in designing phase I trials. This criterion differs from that of finding the dose with toxicity risk closest to q*, that is used in methods such as the continual reassessment method. We use the theory of decision processes to find optimal sequential designs that maximize the expected number of patients within the trial allocated to the highest dose with toxicity not exceeding q*, among the doses under consideration. The proposed method is very general in the sense that criteria other than the one considered here can be optimized and that optimal dose assignment can be defined in terms of patients within or outside the trial. It includes as an important special case the continual reassessment method. Numerical study indicates the strategy compares favourably with other phase I designs.

Bias reduction using stochastic approximation

The paper studies stochastic approximation as a technique for bias reduction. The proposed method does not require approximating the bias explicitly, nor does it rely on having independent identically distributed (i.i.d.) data. The method always removes the leading bias term, under very mild conditions, as long as auxiliary samples from distributions with given parameters are available. Expectation and variance of the bias-corrected estimate are given. Examples in sequential clinical trials (non-i.i.d. case), curved exponential models (i.i.d. case) and length-biased sampling (where the estimates are inconsistent) are used to illustrate the applications of the proposed method and its small sample properties.

Jukka Ruohomäen sävellystuotanto ja tyylipiirteet 1970-luvulla : Esimerkkianalyysi teoksesta Pisces

Tutkimuksessani olen keskittynyt tarkastelemaan säveltäjä Jukka Ruohomäen (s.1947) 1970-luvun sävellystuotantoa ja teosten tyylipiirteitä sekä Ruohomäen toimintaa elektroakustisen musiikin parissa. Ruohomäen 1970-luvun teokset kuuluvat elektroakustisen nauhamusiikin lajiin. Aiempaa tutkimusta hänen musiikistaan ei ole tehty. Tutkimuksen kohteen tarkastelua varten työssä luodaan kuva elektroakustisen musiikin historian, kulttuurin ja analyysin kehitykseen sekä elektroakustisen musiikin terminologiaan ja työtapoihin. Elektroakustisen musiikin historiallista kehitystä seurataan 1800-luvulta 1960- ja 1970-lukujen taitteeseen asti, jotta voidaan ymmärtää, mihin kulttuurihistorialliseen kontekstiin Ruohomäen ensimmäisen sävellyskauden (1970–1978) tuotanto on syntynyt. Historiallisesta näkökulmasta tutkimus on kartoittavaa perustutkimusta. Elektroakustisen musiikin analyysimenetelmiä esittelevässä osassa esitellään ne keskeiset menetelmät, joita tässä työssä käytetään Ruohomäen tuotannon analysointiin. Analyysin pääpaino on teosten äänimateriaalien ja rakenteen tarkastelussa. Tähän tarkasteluun valittuja analyysimenetelmiä ovat Simon Emmersonin elektroakustisten teosten jaottelu äänimateriaalien narratiivisuuden ja syntaktisten piirteiden suhteen, Denis Smalleyn spektromorfologia ja Robert Coganin musiikin kuvaamiseen esittelemä sonogrammikuvaaja. Ruohomäen 1970-luvun teosten esittelyn lisäksi tarkemman analyysin kohteeksi on valittu sävellys Pisces (1975–76). Teosesittelyjen pohjalta muodostetaan kuva Ruohomäen ensimmäisen sävellyskauden vaikutteista ja sävellystyylin muuttumisesta. Ruohomäki painottaa sävellysprosessissa kuuntelun merkitystä ja hänen teoksensa syntyvät pikemminkin vuorovaikutuksessa äänimateriaalin ja sävellysteknologian kanssa kuin tarkan etukäteissuunnitelman ohjaamina. Varhaisten teosten populaarimusiikkivaikutteista Ruohomäen musiikki kehittyi 1970-luvulla kohti puhtaampaa konkreettisen musiikin traditiota. Minimalistiset ja stokastisen musiikin ideat ovat kuultavissa kaikissa ensimmäisen sävellyskauden teoksissa. Analyysi teoksesta Pisces tarkentaa kuvaa Ruohomäen sävellysten tyylipiirteistä. Teosanalyysissä luodaan pohjaa myös Ruohomäen kahden sävellyskauden vertailuun. Jatkotutkimuksen kannalta mielenkiintoiseksi kysymykseksi nousee Ruohomäen kahden sävellyskauden vertailu sekä sävellysteknologian kehityksen ja elektroakustisen musiikin estetiikan suhteen tarkastelu tämän vertailun avulla.

Kantauralin murteutuminen vokaalivastaavuuksien valossa

Tässä työssä käsittelen kolmen läntisimmän (saame, itämerensuomi ja mordva) ja kolmen itäisimmän kielihaaran (mansi, hanti ja samojedi) ensitavun vokaalivastaavuuksia aineistonani Pekka Sammallahden sanalista artikkelista Historical phonology of the Uralic Languages (kirjasta The Uralic languages, 1988, toimittanut Denis Sinor). Keskiset kielihaarat marin, permin ja unkarin olen tässä työssä jättänyt systemaattisen tarkastelun ulkopuolelle, koska pohjustustyön aikana selvisi kaksi tendenssiä: yhtäältä monella näiden kielihaarojen vokaaleista on taustallaan useita eri kantauralin vokaaleja, ja toisaalta monilla kantauralin vokaaleilla on jatkajinaan erilaisia vokaaleja kyseisissä kielihaaroissa. Lisäksi jättämällä näiden kielten vokaaliston systemaattisen selvittämisen myöhempiin tutkimuksiin minun on mahdollista koetella lopputyössä esittämiäni hypoteeseja. Tarkasteluni perusteella sana-aineisto antaa mahdollisuuden sellaiselle uudelleentulkinnalle, että kantauralin ensitavun vokaaliparadigma olisikin ollut aiemmin oletettua rikkaampi. Itäisissä kielihaaroissa on säilynyt enemmän distinktiivisiä vokaalifoneemeja kuin läntisissä, ja vaikka läntisissä kielihaaroissa vokaalifoneemien kokonaislukumäärä on lähtökohtaisesti pienempi, selittyvät eräissä sanaryhmissä esiintyvät vokaalivastaavuussarjat luontevimmin niin, että vokaalit ovat lännessä langenneet yhteen, mutta eri kielihaaroissa eri tavalla. Toisin sanoen itäisten kielihaarojen distinktiivisiä vokaaleja vastaavat systemaattisella tavalla läntisten kielihaarojen epäsäännöllisinä pidetyt vastaavuussarjat. Nähdäkseni tässä työssä esittämiäni seikkoja ei ole aikaisemmin havaittu johtuen menetelmän sisäänrakennetuista rajoituksista: yksittäisiä vokaaleja vertaamalla on mahdollista löytää säännölliset vastineet vain niin monelle vokaalille kuin löytyy kummastakin (tai jokaisesta) vertailtavasta kielestä. Pääsääntöisesti vertailu tavoittaa siis vain sen määrän distinktiivisiä yksiköitä kuin löytyy siitä kielestä, jossa yksikköjen lukumäärä on pienin. Tämän vertailevan menetelmän rajoituksen ylitettyäni esitänkin lopputyössäni kantauraliin kahta uutta vokaalia, jotka vastaavat uralistiikassa vanhastaan tunnettuja redusoituneita vokaaleja (etinen ja takainen labiaalisuudeltaan redusoitunut vokaali). Tarkastelussani perustelen myös, miksi äännetaso on luotettavin murteutumisen osoittaja ja että äänteellisin perustein ei ole löydettävissä tukea samojedihaaran varhaiselle erolle muun kielikunnan yhteydestä; pikemminkin samojedi jakaa eräitä äänteellisiä uudennoksia (sekä vokaaliston että konsonantiston osalta) ugrilaisten kielten kanssa. Lisäksi toisin kuin on perinteisesti ajateltu, yhteisen sanaston lukumäärä ei voi aukottomasti todistaa varhaisesta diakronisesta kuilusta kielihaarojen välillä: sanastoeroille on löydettävissä muitakin mahdollisia selityksiä, kuten vaikkapa tiiviit kielikontaktit. Sen sijaan äännetasoa voidaan pitää luotettavana silloin kun useat kielikuntaa jakavat äänteelliset isoglossit osuvat samaan kohtaan. Tällä perusteella näyttää alustavasti siltä, että varhaisin kantauralin jälkeinen murreraja osuisi suomalais-permiläisten ja ugrilais-samojedilaisten kielten väliin.

100 Years of U.S. Consumer Spending: Data for the Nation, New York City, and Boston

[From Preface] The Consumer Expenditure Survey is among the oldest publications of the Bureau of Labor Statistics. With information on the expenditures, incomes, and demographic characteristics of households, the survey documents the spending patterns and economic status of American families. This report offers a new approach to the use of Consumer Expenditure Survey data. Normally, the survey presents an indepth look at American households at a specific point in time, the reference period being a calendar year. Here, the authors use consumer expenditure data longitudinally and draw on information from decennial census reports to present a 100-year history of significant changes in consumer spending, economic status, and family demographics in the country as a whole, as well as in New York City and Boston.

Solutions for archiving data in long-term studies: A reply to Whitlock et al.

In our recent paper [1], we discussed some potential undesirable consequences of public data archiving (PDA) with specific reference to long-term studies and proposed solutions to manage these issues. We reaffirm our commitment to data sharing and collaboration, both of which have been common and fruitful practices supported for many decades by researchers involved in long-term studies. We acknowledge the potential benefits of PDA (e.g., [2]), but believe that several potential negative consequences for science have been underestimated [1] (see also 3 and 4). The objective of our recent paper [1] was to define practices to simultaneously maximize the benefits and minimize the potential unwanted consequences of PDA.

Developing and communicating strategies for controlling virus diseases in vegetable cucurbit crops

Virus diseases cause serious yield and quality losses in field grown cucurbit crops worldwide. In Australia, the main viruses of cucurbits are Papaya ringspot virus (PRSV), Squash mosaic virus (SqMV), Watermelon mosaic virus (WMV) and Zucchini yellow mosaic virus (ZYMV). Plants infected early have severely distorted fruit. High infection incidences, of ZYMV and PRSV in crops cause losses of marketable fruit of up to 100% and infected crops are often abandoned. Two new alternative hosts of ZYMV were identified, the native cucurbit Cucumis maderaspatanus and wild legume Rhyncosia minima. No new alternative hosts of PRSV, SqMV or WMV were found in Western Australia or Queensland. Seed transmission of ZYMV (0.7%) was found in seedlings grown from ZYMV-infected fruit of zucchini but not of pumpkin. None was detected with PRSV or SqMV in zucchini or pumpkin seedlings, respectively. ZYMV spread to pumpkins by aphids was greater downwind than upwind of a virus source. Delaying sowing by 2 weeks decreased ZYMV spread. Millet non-host barriers between pumpkin plantings slowed ZYMV infection. Host resistance gene (zym) in cucumber cultivars was effective against ZYMV. Pumpkin cultivars with resistance gene (Zym) became infected under high virus pressure but leaf symptoms were milder and infected plants higher yielding with more market-acceptable fruit than those without Zym. Most zucchini cultivars with Zym developed severe leaf and fruit symptoms. ZYMV, PRSV, WMV and SqMV spread readily from infected to healthy cucurbit plants by direct leaf contact. ZYMV survives and remains infective on diverse surfaces for up to 6 hours but can be inactivated by some disinfectants. Phylogenetic analysis indicates at least three separate introductions of ZYMV into Australia, with new introductions rarely occurring. ZYMV isolates clustered into three groups according to collection location i) Kununurra, ii) Northern Territory and iii) Carnarvon, Qld and Vic. A multiplex Real-Time PCR was developed which distinguished between the three groups of Australian isolates. Integrated disease management (IDM) strategies for virus diseases of vegetable cucurbit crops grown in the field were improved incorporating the new information gathered. These strategies are aimed at causing using minimal extra expense, labour demands and disruption to normal practices.

Integrated viral disease management in vegetable crops

Integrated viral disease management in vegetable crops.

Protecting the Australian citrus industry from HLB (greening) disease

Protecting the Australian citrus industry from HLB (greening) disease.

Management of virus diseases in vegetables

• To undertake an audit of management systems used for tomato spotted wilt virus (TSWV) in greenhouse and field production with the aim of improving disease management determining knowledge gaps in virus-vector relationships. • To investigate the basis for the development of resistance breaking strains of TSWV in capsicums and apply this to virus management in capsicums. • To further develop effective virus management systems in vegetable cucurbit crops. Aspects to be investigated include value of barrier crops, non-insecticide products and cultivar tolerance to virus. • To further develop and assess the adoption and impact of integrated viral disease management systems in field grown and protected cropping systems as part of the vegetable industry development plan.