Collaboration and competition: ethics in toxicology

From animal research through adverse events in clinical trials to health scares around food contamination, toxicology has frequently been a focus of scientific and societal concern. As these concerns shift with each new drug, new technology or public health scare, how can toxicology stay current, relevant and ethical? Two of the biggest ethical challenges in pharmaceutical toxicology are the use of animals in testing and the high safety-related attrition rates in new drug development. Both of these require progress in the discipline that will only be driven by research funding. Yet, very little is invested in these two fields compared with investment in new efficacy models, new disease targets and new technologies. How can this be addressed? Here, we explore current paradigms in toxicology that may have the potential for perceived or actual unethical ramifications. We discuss the underpinnings of such practices and make recommendations for change around peer review, resourcing, transparency and data sharing. These ideas build on the analysis presented in the 2004 Paton Prize lecture (Purchase, 2004) where issues around conflict of interest (COI), collaboration and competition in the context of ethical behaviours were highlighted. These areas are clearly relevant to many aspects of scientific research but here we focus on toxicology and specifically toxicology in the pharmaceutical industry

Gradient flux measurements of sea–air DMS transfer during the Surface Ocean Aerosol Production (SOAP) experiment

Direct measurements of marine dimethylsulfide (DMS) fluxes are sparse, particularly in the Southern Ocean. The Surface Ocean Aerosol Production (SOAP) voyage in February–March 2012 examined the distribution and flux of DMS in a biologically active frontal system in the southwest Pacific Ocean. Three distinct phytoplankton blooms were studied with oceanic DMS concentrations as high as 25 nmol L−1. Measurements of DMS fluxes were made using two independent methods: the eddy covariance (EC) technique using atmospheric pressure chemical ionization–mass spectrometry (API-CIMS) and the gradient flux (GF) technique from an autonomous catamaran platform. Catamaran flux measurements are relatively unaffected by airflow distortion and are made close to the water surface, where gas gradients are largest. Flux measurements were complemented by near-surface hydrographic measurements to elucidate physical factors influencing DMS emission. Individual DMS fluxes derived by EC showed significant scatter and, at times, consistent departures from the Coupled Ocean–Atmosphere Response Experiment gas transfer algorithm (COAREG). A direct comparison between the two flux methods was carried out to separate instrumental effects from environmental effects and showed good agreement with a regression slope of 0.96 (r2 = 0.89). A period of abnormal downward atmospheric heat flux enhanced near-surface ocean stratification and reduced turbulent exchange, during which GF and EC transfer velocities showed good agreement but modelled COAREG values were significantly higher. The transfer velocity derived from near-surface ocean turbulence measurements on a spar buoy compared well with the COAREG model in general but showed less variation. This first direct comparison between EC and GF fluxes of DMS provides confidence in compilation of flux estimates from both techniques, as well as in the stable periods when the observations are not well predicted by the COAREG model

The very energetic, broad-lined Type Ic supernova 2010ah (PTF10bzf) in the context of GRB/SNe

SN 2010ah, a very broad-lined Type Ic supernova (SN) discovered by the Palomar Transient Factory, was interesting because of its relatively high luminosity and the high velocity of the absorption lines, which was comparable to that of gamma-ray burst (GRB)/SNe, suggesting a high explosion kinetic energy. However, no GRB was detected in association with the SN. Here, the properties of SN 2010ah are determined with higher accuracy than previous studies through modelling. New Subaru telescope photometry is presented. A bolometric light curve is constructed taking advantage of the spectral similarity with SN 1998bw. Radiation transport tools are used to reproduce the spectra and the light curve. The results thus obtained regarding ejecta mass, composition and kinetic energy are then used to compute a synthetic light curve. This is in reasonable agreement with the early bolometric light curve of SN 2010ah, but a high abundance of 56Ni at high velocity is required to reproduce the early rise, while a dense inner core must be used to reproduce the slow decline at late phases. The high-velocity 56Ni cannot have been located on our line of sight, which may be indirect evidence for an off-axis, aspherical explosion. The main properties of SN 2010ah are: ejected mass Mej ≈ 3 M⊙; kinetic energy Ekin ≈ 1052 erg, M(56Ni) ≈ 0.25 M⊙. The mass located at v ≳ 0.1 c is ∼0.2 M⊙. Although these values, in particular the Ekin, are quite large for a Type Ic SN, they are all smaller (especially Mej) than those typical of GRB/SNe. This confirms the tendency for these quantities to correlate, and suggests that there are minimum requirements for a GRB/SN, which SN 2010ah may not meet although it comes quite close. Depending on whether a neutron star or a black hole was formed following core collapse, SN 2010ah was the explosion of a CO core of ∼5 to 6 M⊙, pointing to a progenitor mass of ∼24–28 M⊙

Methanethiol, dimethyl sulfide and acetone over biologically productive waters in the southwest Pacific Ocean

Atmospheric methanethiol (MeSHa), dimethyl sulfide (DMSa) and acetone (acetonea) were measured over biologically productive frontal waters in the remote southwest Pacific Ocean in summertime 2012 during the Surface Ocean Aerosol Production (SOAP) voyage. MeSHa mixing ratios varied from below the detection limit (<10ppt) up to 65ppt and were 3%–36% of parallel DMSa mixing ratios. MeSHa and DMSa were correlated over the voyage(R2=0.3,slope=0.07)with a stronger correlation over a coccolithophore-dominated phytoplankton bloom (R2= 0.5, slope 0.13). The diurnal cycle for MeSHa shows similar behaviour to DMSa with mixing ratios varying by a factor of ∼2 according to time of day with the minimum levels of both MeSHa and DMSa occurring at around 16:00LT (local time, all times in this paper are in local time). A positive flux of MeSH out of the ocean was calculated for three different nights and ranged from 3.5 to 5.8µmolm−2 d−1, corresponding to 14%–24% of the DMS flux (MeSH/(MeSH+DMS)). Spearman rank correlations with ocean biogeochemical parameters showed a moderate to-strong positive, highly significant relationship between both MeSHa and DMSa with seawater DMS (DMSsw) and a moderate correlation with total dimethylsulfoniopropionate (total DMSP). A positive correlation of acetonea with water temperature and negative correlation with nutrient concentrations are consistent with reports of acetone production in warmer subtropical waters. Positive correlations of acetonea with cryptophyte and eukaryotic phytoplankton numbers, and high-molecular-weight sugars and chromophoric dissolved organic matter (CDOM), suggest an organic source. This work points to a significant ocean source of MeSH, highlighting the need for further studies into the distribution and fate of MeSH, and it suggests links between atmospheric acetone levels and biogeochemistry over the midlatitude ocean. In addition, an intercalibration of DMSa at ambient levels using three independently calibrated instruments showed ∼15%–25% higher mixing ratios from an atmospheric pressure ionisation chemical ionisation mass spectrometer (mesoCIMS) compared to a gas chromatograph with a sulfurchemiluminescencedetector(GC-SCD)and proton transfer reaction mass spectrometer (PTR-MS). Some differences were attributed to the DMSa gradient above the sea surface and differing approaches of integrated versus discrete measurements. Remaining discrepancies were likely due to different calibrationscales,suggesting that further investigation of the stability and/or absolute calibration of DMSstandards used at sea is warranted

A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells

Viral mutational escape can reduce or abrogate recognition by the T cell receptor (TCR) of virus-specific CD8+ T cells. However, very little is known about the impact of cytotoxic T lymphocyte (CTL) epitope mutations on interactions between peptide–major histocompatibility complex (MHC) class I complexes and MHC class I receptors expressed on other cell types. Here, we analyzed a variant of the immunodominant human leukocyte antigen (HLA)-B2705–restricted HIV-1 Gag KK10 epitope (KRWIILGLNK) with an L to M amino acid substitution at position 6 (L6M), which arises as a CTL escape variant after primary infection but is sufficiently immunogenic to elicit a secondary, de novo HIV-1–specific CD8+ T cell response with an alternative TCR repertoire in chronic infection. In addition to altering recognition by HIV-1–specific CD8+ T cells, the HLA-B2705–KK10 L6M complex also exhibits substantially increased binding to the immunoglobulin-like transcript (ILT) receptor 4, an inhibitory MHC class I–specific receptor expressed on myelomonocytic cells. Binding of the B2705–KK10 L6M complex to ILT4 leads to a tolerogenic phenotype of myelomonocytic cells with lower surface expression of dendritic cell (DC) maturation markers and co-stimulatory molecules. These data suggest a link between CTL-driven mutational escape, altered recognition by innate MHC class I receptors on myelomonocytic cells, and functional impairment of DCs, and thus provide important new insight into biological consequences of viral sequence diversificatio

Evaluation of the stock structure of cobia (Rachycentron canadum) in the southeastern United States by using dart-tag and genetics data

Available tag-recapture and population genetics data for cobia (Rachycentron canadum) in the south-eastern United States were evaluated to provide information on population structure and determine the geographic boundary between stocks in the Gulf of Mexico and the Atlantic Ocean. The movements of 1750 cobia were evaluated on the basis of assigned tagging and recapture zones. Genetic samples from an additional 2796 cobia collected during the presumed spawning season were genotyped at 10 microsatellite loci, and standard population genetic statistical analyses were applied to the resulting sample data set. Tag- recapture results indicate that cobia tagged south of Cape Canaveral, Florida, primarily move between that area and the Gulf of Mexico and that cobia tagged north of Georgia have little interaction with the area south of Cape Canaveral. Cobia tagged at Cape Canaveral distributed widely throughout the entire southeastern coast of the United States. Genetic analysis results agree, indicating separate stocks that occur from Texas through Hobe Sound on the east coast of Florida and from Savannah, Georgia, to the Chesapeake Bay in Virgina, with distinct genetic groupings within the Atlantic Ocean stock. The results indicate a transition area that occurs from Cape Canaveral through northern Georgia, and additional data from this region are necessary to further refine the stock boundary

Maintained physical activity and physiotherapy in the management of distal upper limb pain – a protocol for a randomised controlled trial (the arm pain trial)

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Distal upper limb pain (pain affecting the elbow, forearm, wrist, or hand) can be non-specific, or can arise from specific musculoskeletal disorders. It is clinically important and costly, the best approach to clinical management is unclear. Physiotherapy is the standard treatment and, while awaiting treatment, advice is often given to rest and avoid strenuous activities, but there is no evidence base to support these strategies. This paper describes the protocol of a randomised controlled trial to determine, among patients awaiting physiotherapy for distal arm pain, (a) whether advice to remain active and maintain usual activities results in a long-term reduction in arm pain and disability, compared with advice to rest; and (b) whether immediate physiotherapy results in a long-term reduction in arm pain and disability, compared with physiotherapy delivered after a seven week waiting list period.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods/Design&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Between January 2012 and January 2014, new referrals to 14 out-patient physiotherapy departments were screened for potential eligibility. Eligible and consenting patients were randomly allocated to one of the following three groups in equal numbers: 1) advice to remain active, 2) advice to rest, 3) immediate physiotherapy. Patients were and followed up at 6, 13, and 26 weeks post-randomisation by self-complete postal questionnaire and, at six weeks, patients who had not received physiotherapy were offered it at this time. The primary outcome is the proportion of patients free of disability at 26 weeks, as determined by the modified DASH (Disabilities of the Arm, Shoulder and Hand) questionnaire.&lt;p&gt;&lt;/p&gt; We hypothesise (a) that advice to maintain usual activities while awaiting physiotherapy will be superior than advice to rest the arm; and (b) that fast-track physiotherapy will be superior to normal (waiting list) physiotherapy. These hypotheses will be examined using an intention-to-treat analysis.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Discussion&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Results from this trial will contribute to the evidence base underpinning the clinical management of patients with distal upper limb pain, and in particular, will provide guidance on whether they should be advised to rest the arm or remain active within the limits imposed by their symptoms

Diminished temperature and vegetation seasonality over northern high latitudes

Global temperature is increasing, especially over northern lands (>50° N), owing to positive feedbacks1. As this increase is most pronounced in winter, temperature seasonality (ST)—conventionally defined as the difference between summer and winter temperatures—is diminishing over time2, a phenomenon that is analogous to its equatorward decline at an annual scale. The initiation, termination and performance of vegetation photosynthetic activity are tied to threshold temperatures3. Trends in the timing of these thresholds and cumulative temperatures above them may alter vegetation productivity, or modify vegetation seasonality (SV), over time. The relationship between ST and SV is critically examined here with newly improved ground and satellite data sets. The observed diminishment of ST and SV is equivalent to 4° and 7° (5° and 6°) latitudinal shift equatorward during the past 30 years in the Arctic (boreal) region. Analysis of simulations from 17 state-of-the-art climate models4 indicates an additional STdiminishment equivalent to a 20° equatorward shift could occur this century. How SV will change in response to such large projected ST declines and the impact this will have on ecosystem services5 are not well understood. Hence the need for continued monitoring6 of northern lands as their seasonal temperature profiles evolve to resemble thosefurther south.Lopullinen vertaisarvioitu käsikirjoitu