Inferring Past Pesticide Exposures: A Matrix of Individual Active Ingredients in Home and Garden Pesticides Used in Past Decades

BACKGROUND: In retrospective studies of the health effects of home and garden pesticides, self-reported information typically forms the basis for exposure assessment. Study participants generally find it easier to remember the types of pests treated than the specific pesticides used. However, if the goal of the study is to assess disease risk from specific chemicals, the investigator must be able to link the pest type treated with specific chemicals or products. OBJECTIVES: Our goal was to develop a “pesticide–exposure matrix” that would list active ingredients on the market for treating different types of pests in past years, and provide an estimate of the probability that each active ingredient was used. METHODS: We used several different methods for deriving the active ingredient lists and estimating the probabilities. These methods are described in this article, along with a sample calculation and data sources for each. RESULTS: The pesticide–exposure matrix lists active ingredients and their probabilities of use for 96 distinct scenarios defined by year (1976, 1980, 1990, 2000), applicator type (consumer, professional), and pest type (12 categories). Calculations and data sources for all 96 scenarios are provided online. CONCLUSIONS: Although we are confident that the active ingredient lists are reasonably accurate for most scenarios, we acknowledge possible sources of error in the probability estimates. Despite these limitations, the pesticide–exposure matrix should provide valuable information to researchers interested in the chronic health effects of residential pesticide exposure

Determination of muscle shape deformations of the tibialis anterior during dynamic contractions using 3D ultrasound

PurposeIn this paper, we introduce a novel method for determining 3D deformations of the human tibialis anterior (TA) muscle during dynamic movements using 3D ultrasound.Materials and MethodsAn existing automated 3D ultrasound system is used for data acquisition, which consists of three moveable axes, along which the probe can move. While the subjects perform continuous plantar- and dorsiflexion movements in two different controlled velocities, the ultrasound probe sweeps cyclically from the ankle to the knee along the anterior shin. The ankle joint angle can be determined using reflective motion capture markers. Since we considered the movement direction of the foot, i.e., active or passive TA, four conditions occur: slow active, slow passive, fast active, fast passive. By employing an algorithm which defines ankle joint angle intervals, i.e., intervals of range of motion (ROM), 3D images of the volumes during movement can be reconstructed.ResultsWe found constant muscle volumes between different muscle lengths, i.e., ROM intervals. The results show an increase in mean cross-sectional area (CSA) for TA muscle shortening. Furthermore, a shift in maximum CSA towards the proximal side of the muscle could be observed for muscle shortening. We found significantly different maximum CSA values between the fast active and all other conditions, which might be caused by higher muscle activation due to the faster velocity.ConclusionIn summary, we present a method for determining muscle volume deformation during dynamic contraction using ultrasound, which will enable future empirical studies and 3D computational models of skeletal muscles

Fiber-tip spintronic terahertz emitters

Spintronic terahertz emitters promise terahertz sources with an unmatched broad frequency bandwidth that are easy to fabricate and operate, and therefore easy to scale at low cost. However, current experiments and proofs of concept rely on free-space ultrafast pump lasers and rather complex benchtop setups. This contrasts with the requirements of widespread industrial applications, where robust, compact, and safe designs are needed. To meet these requirements, we present a novel fiber-tip spintronic terahertz emitter solution that allows spintronic terahertz systems to be fully fiber-coupled. Using single-mode fiber waveguiding, the newly developed solution naturally leads to a simple and straightforward terahertz near-field imaging system with a 90%-10% knife-edge-response spatial resolution of 30 ${\mu}m$

Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase.

Protein tyrosine kinases differ widely in their propensity to undergo rearrangements of the N-terminal Asp-Phe-Gly (DFG) motif of the activation loop, with some, including FGFR1 kinase, appearing refractory to this so-called 'DFG flip'. Recent inhibitor-bound structures have unexpectedly revealed FGFR1 for the first time in a 'DFG-out' state. Here we use conformationally selective inhibitors as chemical probes for interrogation of the structural and dynamic features that appear to govern the DFG flip in FGFR1. Our detailed structural and biophysical insights identify contributions from altered dynamics in distal elements, including the αH helix, towards the outstanding stability of the DFG-out complex with the inhibitor ponatinib. We conclude that the αC-β4 loop and 'molecular brake' regions together impose a high energy barrier for this conformational rearrangement, and that this may have significance for maintaining autoinhibition in the non-phosphorylated basal state of FGFR1.This work was funded as part of the AstraZeneca Internal Postdoctoral program. All authors with the exception of G.S.T. are employees (and stockholders) of AstraZeneca UK Ltd or MedImmune LLC, or were at the time that this study was conducted.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncomms887

Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium

Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan). The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (< 2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer. Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52). These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation

“Be Sustainable”: EOSC-Life Recommendations for Implementation of FAIR Principles in Life Science Data Handling

The main goals and challenges for the life science communities in the Open Science framework are to increase reuse and sustainability of data resources, software tools, and workflows, especially in large-scale data-driven research and computational analyses. Here, we present key findings, procedures, effective measures and recommendations for generating and establishing sustainable life science resources based on the collaborative, cross-disciplinary work done within the EOSC-Life (European Open Science Cloud for Life Sciences) consortium. Bringing together 13 European life science research infrastructures, it has laid the foundation for an open, digital space to support biological and medical research. Using lessons learned from 27 selected projects, we describe the organisational, technical, financial and legal/ethical challenges that represent the main barriers to sustainability in the life sciences. We show how EOSC-Life provides a model for sustainable data management according to FAIR (findability, accessibility, interoperability, and reusability) principles, including solutions for sensitive- and industry-related resources, by means of cross-disciplinary training and best practices sharing. Finally, we illustrate how data harmonisation and collaborative work facilitate interoperability of tools, data, solutions and lead to a better understanding of concepts, semantics and functionalities in the life sciences

The first myriapod genome sequence reveals conservative arthropod gene content and genome organisation in the centipede Strigamia maritima.

Myriapods (e.g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.This work was supported by the following grants: NHGRIU54HG003273 to R.A.G; EU Marie Curie ITN #215781 “Evonet” to M.A.; a Wellcome Trust Value in People (VIP) award to C.B. and Wellcome Trust graduate studentship WT089615MA to J.E.G; Marine rhythms of Life” of the University of Vienna, an FWF (http://www.fwf.ac.at/) START award (#AY0041321) and HFSP (http://www.hfsp.org/) research grant (#RGY0082/2010) to KT-­‐R; MFPL Vienna International PostDoctoral Program for Molecular Life Sciences (funded by Austrian Ministry of Science and Research and City of Vienna, Cultural Department -­‐Science and Research to T.K; Direct Grant (4053034) of the Chinese University of Hong Kong to J.H.L.H.; NHGRI HG004164 to G.M.; Danish Research Agency (FNU), Carlsberg Foundation, and Lundbeck Foundation to C.J.P.G.; U.S. National Institutes of Health R01AI55624 to J.H.W.; Royal Society University Research fellowship to F.M.J.; P.D.E. was supported by the BBSRC via the Babraham Institute;This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pbio.100200

Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia

Expression levels of long non-coding RNA (lncRNA) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNA in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged <60 years) with CN-AML, who were comprehensively characterized with regard to clinical outcome. We used available genomic databases and stringent filters to annotate genetic variants unequivocally located in the non-coding transcriptome of AML patients. We detected 981 variants, which are recurrently present in lncRNA that are expressed in leukemic blasts. Among these variants, we identified a cytosine-to-thymidine variant in the lncRNA RP5-1074L1.4 and a cytosine-to-thymidine variant in the lncRNA SNHG15, which independently associated with longer survival of CN-AML patients. The presence of the SNHG15 cytosine-to-thymidine variant was also found to associate with better outcome in an independent dataset of CN-AML patients, despite differences in treatment protocols and RNA sequencing techniques. In order to gain biological insights, we cloned and overexpressed both wild-type and variant versions of the SNHG15 lncRNA. In keeping with its negative prognostic impact, overexpression of the wild-type SNHG15 associated with higher proliferation rate of leukemic blasts when compared with the cytosine-to-thymidine variant. We conclude that recurrent genetic variants of lncRNA that are expressed in the leukemic blasts of CN-AML patients have prognostic and potential biological significance

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies