Allostatic load and preterm birth

Preterm birth is a universal health problem that is one of the largest unmet medical needs contributing to the global burden of disease. Adding to its complexity is that there are no means to predict who is at risk when pregnancy begins or when women will actually deliver. Until these problems are addressed, there will be no interventions to reduce the risk because those who should be treated will not be known. Considerable evidence now exists that chronic life, generational or accumulated stress is a risk factor for preterm delivery in animal models and in women. This wear and tear on the body and mind is called allostatic load. This review explores the evidence that chronic stress contributes to preterm birth and other adverse pregnancy outcomes in animal and human studies. It explores how allostatic load can be used to, firstly, model stress and preterm birth in animal models and, secondly, how it can be used to develop a predictive model to assess relative risk among women in early pregnancy. Once care providers know who is in the highest risk group, interventions can be developed and applied to mitigate their risk

Microzooplankton community structure investigated with imaging flow cytometry and automated live-cell staining

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Marine Ecology Progress Series 550 (2016): 65-81, doi:10.3354/meps11687.Protozoa play important roles in grazing and nutrient recycling, but quantifying these roles has been hindered by difficulties in collecting, culturing, and observing these often-delicate cells. During long-term deployments at the Martha’s Vineyard Coastal Observatory (Massachusetts, USA), Imaging FlowCytobot (IFCB) has been shown to be useful for studying live cells in situ without the need to culture or preserve. IFCB records images of cells with chlorophyll fluorescence above a trigger threshold, so to date taxonomically resolved analysis of protozoa has presumably been limited to mixotrophs and herbivores which have eaten recently. To overcome this limitation, we have coupled a broad-application ‘live cell’ fluorescent stain with a modified IFCB so that protozoa which do not contain chlorophyll (such as consumers of unpigmented bacteria and other heterotrophs) can also be recorded. Staining IFCB (IFCB-S) revealed higher abundances of grazers than the original IFCB, as well as some cell types not previously detected. Feeding habits of certain morphotypes could be inferred from their fluorescence properties: grazers with stain fluorescence but without chlorophyll cannot be mixotrophs, but could be either starving or feeding on heterotrophs. Comparisons between cell counts for IFCB-S and manual light microscopy of Lugol’s stained samples showed consistently similar or higher counts from IFCB-S. We show how automated classification through the extraction of image features and application of a machine-learning algorithm can be used to evaluate the large high-resolution data sets collected by IFCBs; the results reveal varying seasonal patterns in abundance among groups of protists.This research was supported in part by NSF (grants OCE-1130140, OCE-1434440), NASA (grants NNX11AF07G and NNX13AC98G), the Gordon and Betty Moore Foundation (grants 934 and 2649), and the Woods Hole Oceanographic Institution’s Innovative Technology Program

Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy

p97 is a “segregase” that plays a key role in numerous ubiquitin (Ub)-dependent pathways such as ER-associated degradation. It has been hypothesized that p97 extracts proteins from membranes or macromolecular complexes to enable their proteasomal degradation; however, the complex nature of p97 substrates has made it difficult to directly observe the fundamental basis for this activity. To address this issue, we developed a soluble p97 substrate—Ub-GFP modified with K48-linked ubiquitin chains—for in vitro p97 activity assays. We demonstrate that WT p97 can unfold proteins and that this activity is dependent on the p97 adaptor NPLOC4-UFD1L, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation. Furthermore, we show that a p97 mutant that causes inclusion body myopathy, Paget’s disease of bone, and frontotemporal dementia in humans unfolds substrate faster, suggesting that excess activity may underlie pathogenesis. This work overcomes a significant barrier in the study of p97 and will allow the future dissection of p97 mechanism at a level of detail previously unattainable

Mesoscale variability in intact and ghost colonies of Phaeocystis antarctica in the Ross Sea : distribution and abundance

© The Author(s), 2016. This is the author's version of the work and is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Marine Systems 166 (2017): 97-107, doi:10.1016/j.jmarsys.2016.05.007.Phaeocystis, a genus with a cosmopolitan distribution and a polymorphic life cycle, was observed during summer in the Ross Sea, Antarctica, where large blooms of this haptophyte regularly occur. The mesoscale vertical and horizontal distributions of colonies of P. antarctica were assessed using a towed Video Plankton Recorder (VPR). The mean size of colonies was 1.20 mm, and mean abundances within the three VPR surveys were 4.86, 1.96, and 11.5 mL-1. In addition to the typical spherical, transparent colonies, the VPR quantified an optically dissimilar form of colony that had a distinctive translucent appearance. It also measured the abundance of collapsed colonies, similar to those observed previously from cultures and mesocosms, which we called “ghost colonies”. The translucent colonial form had a different distribution than the more common colonial form, and at times was more abundant. Relative to intact colonies, the ghost colonies occurred less frequently, with mean abundances in the three surveys being 0.01, 0.08, and 0.0004 mL-1. Ghost colonies generally were found below the euphotic zone, where they often were in greater abundance than intact colonies. However, the relationship of ghost colonies to intact P. antarctica colonies was not direct or consistent, suggesting that the formation of ghost colonies from living colonies and their appearance within the water column were not tightly coupled. Given their relative scarcity and low carbon content, it is unlikely that ghost colonies contribute substantially to vertical flux; however, it is possible that we did not sample periods of major flux events, and as a result minimized the importance of ghost colonies to vertical flux. They do, however, represent a poorly documented feature of polar haptophyte life cycles.This research was supported by grants from the National Science Foundation (ANT-0944254 and ANT-0944165). HMS and EEP acknowledge support of the Gordon and Betty Moore Foundation (Grant #2649) for image informatics development.2018-06-0

Deeper habitats and cooler temperatures moderate a climate-driven seagrass disease

Eelgrass creates critical coastal habitats worldwide and fulfills essential ecosystem functions as a foundation seagrass. Climate warming and disease threaten eelgrass, causing mass mortalities and cascading ecological impacts. Subtidal meadows are deeper than intertidal and may also provide refuge from the temperature-sensitive seagrass wasting disease. From cross-boundary surveys of 5761 eelgrass leaves from Alaska to Washington and assisted with a machine-language algorithm, we measured outbreak conditions. Across summers 2017 and 2018, disease prevalence was 16% lower for subtidal than intertidal leaves; in both tidal zones, disease risk was lower for plants in cooler conditions. Even in subtidal meadows, which are more environmentally stable and sheltered from temperature and other stressors common for intertidal eelgrass, we observed high disease levels, with half of the sites exceeding 50% prevalence. Models predicted reduced disease prevalence and severity under cooler conditions, confirming a strong interaction between disease and temperature. At both tidal zones, prevalence was lower in more dense eelgrass meadows, suggesting disease is suppressed in healthy, higher density meadows. These results underscore the value of subtidal eelgrass and meadows in cooler locations as refugia, indicate that cooling can suppress disease, and have implications for eelgrass conservation and management under future climate change scenarios

Canvass: a crowd-sourced, natural-product screening library for exploring biological space

NCATS thanks Dingyin Tao for assistance with compound characterization. This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). R.B.A. acknowledges support from NSF (CHE-1665145) and NIH (GM126221). M.K.B. acknowledges support from NIH (5R01GM110131). N.Z.B. thanks support from NIGMS, NIH (R01GM114061). J.K.C. acknowledges support from NSF (CHE-1665331). J.C. acknowledges support from the Fogarty International Center, NIH (TW009872). P.A.C. acknowledges support from the National Cancer Institute (NCI), NIH (R01 CA158275), and the NIH/National Institute of Aging (P01 AG012411). N.K.G. acknowledges support from NSF (CHE-1464898). B.C.G. thanks the support of NSF (RUI: 213569), the Camille and Henry Dreyfus Foundation, and the Arnold and Mabel Beckman Foundation. C.C.H. thanks the start-up funds from the Scripps Institution of Oceanography for support. J.N.J. acknowledges support from NIH (GM 063557, GM 084333). A.D.K. thanks the support from NCI, NIH (P01CA125066). D.G.I.K. acknowledges support from the National Center for Complementary and Integrative Health (1 R01 AT008088) and the Fogarty International Center, NIH (U01 TW00313), and gratefully acknowledges courtesies extended by the Government of Madagascar (Ministere des Eaux et Forets). O.K. thanks NIH (R01GM071779) for financial support. T.J.M. acknowledges support from NIH (GM116952). S.M. acknowledges support from NIH (DA045884-01, DA046487-01, AA026949-01), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (W81XWH-17-1-0256), and NCI, NIH, through a Cancer Center Support Grant (P30 CA008748). K.N.M. thanks the California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board for support. B.T.M. thanks Michael Mullowney for his contribution in the isolation, elucidation, and submission of the compounds in this work. P.N. acknowledges support from NIH (R01 GM111476). L.E.O. acknowledges support from NIH (R01-HL25854, R01-GM30859, R0-1-NS-12389). L.E.B., J.K.S., and J.A.P. thank the NIH (R35 GM-118173, R24 GM-111625) for research support. F.R. thanks the American Lebanese Syrian Associated Charities (ALSAC) for financial support. I.S. thanks the University of Oklahoma Startup funds for support. J.T.S. acknowledges support from ACS PRF (53767-ND1) and NSF (CHE-1414298), and thanks Drs. Kellan N. Lamb and Michael J. Di Maso for their synthetic contribution. B.S. acknowledges support from NIH (CA78747, CA106150, GM114353, GM115575). W.S. acknowledges support from NIGMS, NIH (R15GM116032, P30 GM103450), and thanks the University of Arkansas for startup funds and the Arkansas Biosciences Institute (ABI) for seed money. C.R.J.S. acknowledges support from NIH (R01GM121656). D.S.T. thanks the support of NIH (T32 CA062948-Gudas) and PhRMA Foundation to A.L.V., NIH (P41 GM076267) to D.S.T., and CCSG NIH (P30 CA008748) to C.B. Thompson. R.E.T. acknowledges support from NIGMS, NIH (GM129465). R.J.T. thanks the American Cancer Society (RSG-12-253-01-CDD) and NSF (CHE1361173) for support. D.A.V. thanks the Camille and Henry Dreyfus Foundation, the National Science Foundation (CHE-0353662, CHE-1005253, and CHE-1725142), the Beckman Foundation, the Sherman Fairchild Foundation, the John Stauffer Charitable Trust, and the Christian Scholars Foundation for support. J.W. acknowledges support from the American Cancer Society through the Research Scholar Grant (RSG-13-011-01-CDD). W.M.W.acknowledges support from NIGMS, NIH (GM119426), and NSF (CHE1755698). A.Z. acknowledges support from NSF (CHE-1463819). (Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH); CHE-1665145 - NSF; CHE-1665331 - NSF; CHE-1464898 - NSF; RUI: 213569 - NSF; CHE-1414298 - NSF; CHE1361173 - NSF; CHE1755698 - NSF; CHE-1463819 - NSF; GM126221 - NIH; 5R01GM110131 - NIH; GM 063557 - NIH; GM 084333 - NIH; R01GM071779 - NIH; GM116952 - NIH; DA045884-01 - NIH; DA046487-01 - NIH; AA026949-01 - NIH; R01 GM111476 - NIH; R01-HL25854 - NIH; R01-GM30859 - NIH; R0-1-NS-12389 - NIH; R35 GM-118173 - NIH; R24 GM-111625 - NIH; CA78747 - NIH; CA106150 - NIH; GM114353 - NIH; GM115575 - NIH; R01GM121656 - NIH; T32 CA062948-Gudas - NIH; P41 GM076267 - NIH; R01GM114061 - NIGMS, NIH; R15GM116032 - NIGMS, NIH; P30 GM103450 - NIGMS, NIH; GM129465 - NIGMS, NIH; GM119426 - NIGMS, NIH; TW009872 - Fogarty International Center, NIH; U01 TW00313 - Fogarty International Center, NIH; R01 CA158275 - National Cancer Institute (NCI), NIH; P01 AG012411 - NIH/National Institute of Aging; Camille and Henry Dreyfus Foundation; Arnold and Mabel Beckman Foundation; Scripps Institution of Oceanography; P01CA125066 - NCI, NIH; 1 R01 AT008088 - National Center for Complementary and Integrative Health; W81XWH-17-1-0256 - Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program; P30 CA008748 - NCI, NIH, through a Cancer Center Support Grant; California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board; American Lebanese Syrian Associated Charities (ALSAC); University of Oklahoma Startup funds; 53767-ND1 - ACS PRF; PhRMA Foundation; P30 CA008748 - CCSG NIH; RSG-12-253-01-CDD - American Cancer Society; RSG-13-011-01-CDD - American Cancer Society; CHE-0353662 - National Science Foundation; CHE-1005253 - National Science Foundation; CHE-1725142 - National Science Foundation; Beckman Foundation; Sherman Fairchild Foundation; John Stauffer Charitable Trust; Christian Scholars Foundation)Published versionSupporting documentatio

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Investigating the effect of independent blinded digital image assessment on the STOP GAP trial

Background Blinding is the process of keeping treatment assignment hidden and is used to minimise the possibility of bias. Trials at high risk of bias have been shown to report larger treatment effects than low risk studies. In dermatology, one popular method of blinding is to have independent outcome assessors who are unaware of treatment allocation assessing the end point using digital photographs. However, this can be complex, expensive and time-consuming. The objective of this study was to compare the effect of blinded and unblinded outcome assessment on the results of the STOP GAP trial. Methods The STOP GAP trial compared prednisolone to ciclosporin in treating pyoderma gangrenosum. Participants’ lesions were measured at baseline and 6 weeks to calculate the primary outcome, speed of healing. Independent blinded assessors obtained measurements from digital photographs using specialist software. In addition, unblinded treating clinicians estimated lesion area by measuring length and width. The primary outcome was determined using blinded measurements where available, otherwise unblinded measurements were used (method referred to as trial measurements). In this study, agreement between the trial and unblinded measurements was determined using the intraclass correlation coefficient (ICC). The STOP GAP primary analysis was repeated using unblinded measurements only. We introduced differential and non-differential error in unblinded measurements and investigated the effect on the STOP GAP primary analysis. Results 86 (80%) of the 108 patients were assessed using digital images. Agreement between trial and unblinded measurements was excellent (ICC=0.92 at baseline; 0.83 at 6 weeks). There was no evidence that the results of the trial primary analysis differed according to how the primary outcome was assessed (p-value for homogeneity = 1.00). Conclusions Blinded digital image assessment in STOP GAP did not meaningfully alter trial conclusions compared with unblinded assessment. However, as the process brought added accuracy and credibility to the trial it was considered worthwhile. These findings question the usefulness of digital image assessment in a trial with an objective outcome and where bias is not expected to be excessive. Further research should investigate if there are alternative, less complex ways of incorporating blinding in clinical trials

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors