Developmental effects of endocrine-disrupting chemicals in wildlife and humans.

Large numbers and large quantities of endocrine-disrupting chemicals have been released into the environment since World War II. Many of these chemicals can disturb development of the endocrine system and of the organs that respond to endocrine signals in organisms indirectly exposed during prenatal and/or early postnatal life; effects of exposure during development are permanent and irreversible. The risk to the developing organism can also stem from direct exposure of the offspring after birth or hatching. In addition, transgenerational exposure can result from the exposure of the mother to a chemical at any time throughout her life before producing offspring due to persistence of endocrine-disrupting chemicals in body fat, which is mobilized during egg laying or pregnancy and lactation. Mechanisms underlying the disruption of the development of vital systems, such as the endocrine, reproductive, and immune systems, are discussed with reference to wildlife, laboratory animals, and humans

Host Cell Egress and Invasion Induce Marked Relocations of Glycolytic Enzymes in Toxoplasma gondii Tachyzoites

Apicomplexan parasites are dependent on an F-actin and myosin-based motility system for their invasion into and escape from animal host cells, as well as for their general motility. In Toxoplasma gondii and Plasmodium species, the actin filaments and myosin motor required for this process are located in a narrow space between the parasite plasma membrane and the underlying inner membrane complex, a set of flattened cisternae that covers most the cytoplasmic face of the plasma membrane. Here we show that the energy required for Toxoplasma motility is derived mostly, if not entirely, from glycolysis and lactic acid production. We also demonstrate that the glycolytic enzymes of Toxoplasma tachyzoites undergo a striking relocation from the parasites' cytoplasm to their pellicles upon Toxoplasma egress from host cells. Specifically, it appears that the glycolytic enzymes are translocated to the cytoplasmic face of the inner membrane complex as well as to the space between the plasma membrane and inner membrane complex. The glycolytic enzymes remain pellicle-associated during extended incubations of parasites in the extracellular milieu and do not revert to a cytoplasmic location until well after parasites have completed invasion of new host cells. Translocation of glycolytic enzymes to and from the Toxoplasma pellicle appears to occur in response to changes in extracellular [K+] experienced during egress and invasion, a signal that requires changes of [Ca2+]c in the parasite during egress. Enzyme translocation is, however, not dependent on either F-actin or intact microtubules. Our observations indicate that Toxoplasma gondii is capable of relocating its main source of energy between its cytoplasm and pellicle in response to exit from or entry into host cells. We propose that this ability allows Toxoplasma to optimize ATP delivery to those cellular processes that are most critical for survival outside host cells and those required for growth and replication of intracellular parasites

Trajectories in chronic disease accrual and mortality across the lifespan in Wales, UK (2005–2019), by area deprivation profile: linked electronic health records cohort study on 965,905 individuals

BACKGROUND: Understanding and quantifying the differences in disease development in different socioeconomic groups of people across the lifespan is important for planning healthcare and preventive services. The study aimed to measure chronic disease accrual, and examine the differences in time to individual morbidities, multimorbidity, and mortality between socioeconomic groups in Wales, UK. METHODS: Population-wide electronic linked cohort study, following Welsh residents for up to 20 years (2000–2019). Chronic disease diagnoses were obtained from general practice and hospitalisation records using the CALIBER disease phenotype register. Multi-state models were used to examine trajectories of accrual of 132 diseases and mortality, adjusted for sex, age and area-level deprivation. Restricted mean survival time was calculated to measure time spent free of chronic disease(s) or mortality between socioeconomic groups. FINDINGS: In total, 965,905 individuals aged 5–104 were included, from a possible 2.9 m individuals following a 5-year clearance period, with an average follow-up of 13.2 years (12.7 million person-years). Some 673,189 (69.7%) individuals developed at least one chronic disease or died within the study period. From ages 10 years upwards, the individuals living in the most deprived areas consistently experienced reduced time between health states, demonstrating accelerated transitions to first and subsequent morbidities and death compared to their demographic equivalent living in the least deprived areas. The largest difference were observed in 10 and 20 year old males developing multimorbidity (−0.45 years (99% CI: −0.45, −0.44)) and in 70 year old males dying after developing multimorbidity (−1.98 years (99% CI: −2.01, −1.95)). INTERPRETATION: This study adds to the existing literature on health inequalities by demonstrating that individuals living in more deprived areas consistently experience accelerated time to diagnosis of chronic disease and death across all ages, accounting for competing risks. FUNDING: UK Medical Research Council, Health Data Research UK, and Administrative Data Research Wales

Trajectories in chronic disease accrual and mortality across the lifespan in Wales, UK (2005-2019), by area deprivation profile : linked electronic health records cohort study on 965,905 individuals

Funding: This work was supported by Health Data Research UK (HDRUK) Measuring and Understanding Multimorbidity using Routine Data in the UK (MUrMuRUK, HDR-9006; CFC0110). Health Data Research UK (HDR-9006) is funded by: UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, the National Institute for Health Research (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. This work also was co-funded by the Medical Research Council (MRC) and the National Institute for Health Research (NIHR) through grant number MR/S027750/1. The work was supported by the ADR Wales programme of work, part of the Economic and Social Research Council (part of UK Research and Innovation) funded ADR UK (grant ES/S007393/1).Background  Understanding and quantifying the differences in disease development in different socioeconomic groups of people across the lifespan is important for planning healthcare and preventive services. The study aimed to measure chronic disease accrual, and examine the differences in time to individual morbidities, multimorbidity, and mortality between socioeconomic groups in Wales, UK. Methods  Population-wide electronic linked cohort study, following Welsh residents for up to 20 years (2000-2019). Chronic disease diagnoses were obtained from general practice and hospitalisation records using the CALIBER disease phenotype register. Multi-state models were used to examine trajectories of accrual of 132 diseases and mortality, adjusted for sex, age and area-level deprivation. Restricted mean survival time was calculated to measure time spent free of chronic disease(s) or mortality between socioeconomic groups. Findings  In total, 965,905 individuals aged 5-104 were included, from a possible 2·9m individuals following a 5-year clearance period, with an average follow-up of 13·2 years (12·7 million person-years). Some 673,189 (69·7 %) individuals developed at least one chronic disease or died within the study period. From ages 10 years upwards, the individuals living in the most deprived areas consistently experienced reduced time between health states, demonstrating accelerated transitions to first and subsequent morbidities and death compared to their demographic equivalent living in the least deprived areas. The largest difference were observed in 10 and 20 year old males developing multimorbidity (-0·45 years (99%CI:-0·45,-0·44)) and in 70 year old males dying after developing multimorbidity (-1·98 years (99%CI:-2·01,-1·95)). Interpretation  This study adds to the existing literature on health inequalities by demonstrating that individuals living in more deprived areas consistently experience accelerated time to diagnosis of chronic disease and death across all ages, accounting for competing risks.Publisher PDFPeer reviewe

Pollutants Increase Song Complexity and the Volume of the Brain Area HVC in a Songbird

Environmental pollutants which alter endocrine function are now known to decrease vertebrate reproductive success. There is considerable evidence for endocrine disruption from aquatic ecosystems, but knowledge is lacking with regard to the interface between terrestrial and aquatic ecosystems. Here, we show for the first time that birds foraging on invertebrates contaminated with environmental pollutants, show marked changes in both brain and behaviour. We found that male European starlings (Sturnus vulgaris) exposed to environmentally relevant levels of synthetic and natural estrogen mimics developed longer and more complex songs compared to control males, a sexually selected trait important in attracting females for reproduction. Moreover, females preferred the song of males which had higher pollutant exposure, despite the fact that experimentally dosed males showed reduced immune function. We also show that the key brain area controlling male song complexity (HVC) is significantly enlarged in the contaminated birds. This is the first evidence that environmental pollutants not only affect, but paradoxically enhance a signal of male quality such as song. Our data suggest that female starlings would bias their choice towards exposed males, with possible consequences at the population level. As the starling is a migratory species, our results suggest that transglobal effects of pollutants on terrestrial vertebrate physiology and reproduction could occur in birds

Phylogenetic Analysis of the Neks Reveals Early Diversification of Ciliary-Cell Cycle Kinases

NIMA-related kinases (Neks) have been studied in diverse eukaryotes, including the fungus Aspergillus and the ciliate Tetrahymena. In the former, a single Nek plays an essential role in cell cycle regulation; in the latter, which has more than 30 Neks in its genome, multiple Neks regulate ciliary length. Mammalian genomes encode an intermediate number of Neks, several of which are reported to play roles in cell cycle regulation and/or localize to centrosomes. Previously, we reported that organisms with cilia typically have more Neks than organisms without cilia, but were unable to establish the evolutionary history of the gene family

Is health research undertaken where the burden of disease is greatest? Observational study of geographical inequalities in recruitment to research in England 2013–2018

Background: Research is fundamental to high-quality care, but concerns have been raised about whether health research is conducted in the populations most affected by high disease prevalence. Geographical distribution of research activity is important for many reasons. Recruitment is a major barrier to research delivery, and undertaking recruitment in areas of high prevalence could be more efficient. Regional variability exists in risk factors and outcomes, so research done in healthier populations may not generalise. Much applied health research evaluates interventions, and their impact may vary by context (including geography). Finally, fairness dictates that publically funded research should be accessible to all, so that benefits of participating can be fairly distributed. We explored whether recruitment of patients to health research is aligned with disease prevalence in England. Methods: We measured disease prevalence using the Quality and Outcomes Framework in England (total long-term conditions, mental health and diabetes). We measured research activity using data from the NIHR Clinical Research Network. We presented descriptive data on geographical variation in recruitment rates. We explored associations between the recruitment rate and disease prevalence rate. We calculated the share of patient recruitment that would need to be redistributed to align recruitment with prevalence. We assessed whether associations between recruitment rate and disease prevalence varied between conditions, and over time. Results: There was significant geographical variation in recruitment rates. When areas were ranked by disease prevalence, recruitment was not aligned with prevalence, with disproportionately low recruitment in areas with higher prevalence of total long-term and mental health conditions. At the level of 15 local networks, analyses suggested that around 12% of current recruitment activity would need to be redistributed to align with disease prevalence. Overall, alignment showed little change over time, but there was variation in the trends over time in individual conditions. Conclusions: Geographical variations in recruitment do not reflect the suitability of the population for research. Indicators should be developed to assess the fit between research and need, and to allow assessment of interventions among funders, researchers and patients to encourage closer alignment between research activity and burden

TDAG51 is an ERK signaling target that opposes ERK-mediated HME16C mammary epithelial cell transformation

<p>Abstract</p> <p>Introduction</p> <p>Signaling downstream of Ras is mediated by three major pathways, Raf/ERK, phosphatidylinositol 3 kinase (PI3K), and Ral guanine nucleotide exchange factor (RalGEF). Ras signal transduction pathways play an important role in breast cancer progression, as evidenced by the frequent over-expression of the Ras-activating epidermal growth factor receptors EGFR and ErbB2. Here we investigated which signal transduction pathways downstream of Ras contribute to EGFR-dependent transformation of telomerase-immortalized mammary epithelial cells HME16C. Furthermore, we examined whether a highly transcriptionally regulated ERK pathway target, PHLDA1 (TDAG51), suggested to be a tumor suppressor in breast cancer and melanoma, might modulate the transformation process.</p> <p>Methods</p> <p>Cellular transformation of human mammary epithelial cells by downstream Ras signal transduction pathways was examined using anchorage-independent growth assays in the presence and absence of EGFR inhibition. TDAG51 protein expression was down-regulated by interfering small hairpin RNA (shRNA), and the effects on cell proliferation and death were examined in Ras pathway-transformed breast epithelial cells.</p> <p>Results</p> <p>Activation of both the ERK and PI3K signaling pathways was sufficient to induce cellular transformation, which was accompanied by up-regulation of EGFR ligands, suggesting autocrine EGFR stimulation during the transformation process. Only activation of the ERK pathway was sufficient to transform cells in the presence of EGFR inhibition and was sufficient for tumorigenesis in xenografts. Up-regulation of the PHLDA1 gene product, TDAG51, was found to correlate with persistent ERK activation and anchorage-independent growth in the absence or presence of EGFR inhibition. Knockdown of this putative breast cancer tumor-suppressor gene resulted in increased ERK pathway activation and enhanced matrix-detached cellular proliferation of Ras/Raf transformed cells.</p> <p>Conclusion</p> <p>Our results suggest that multiple Ras signal transduction pathways contribute to mammary epithelial cell transformation, but that the ERK signaling pathway may be a crucial component downstream of EGFR activation during tumorigenesis. Furthermore, persistent activation of ERK signaling up-regulates TDAG51. This event serves as a negative regulator of both Erk activation as well as matrix-detached cellular proliferation and suggests that TDAG51 opposes ERK-mediated transformation in breast epithelial cells.</p

Discovery of a Distinct Superfamily of Kunitz-Type Toxin (KTT) from Tarantulas

BACKGROUND: Kuntiz-type toxins (KTTs) have been found in the venom of animals such as snake, cone snail and sea anemone. The main ancestral function of Kunitz-type proteins was the inhibition of a diverse array of serine proteases, while toxic activities (such as ion-channel blocking) were developed under a variety of Darwinian selection pressures. How new functions were grafted onto an old protein scaffold and what effect Darwinian selection pressures had on KTT evolution remains a puzzle. PRINCIPAL FINDINGS: Here we report the presence of a new superfamily of ktts in spiders (TARANTULAS: Ornithoctonus huwena and Ornithoctonus hainana), which share low sequence similarity to known KTTs and is clustered in a distinct clade in the phylogenetic tree of KTT evolution. The representative molecule of spider KTTs, HWTX-XI, purified from the venom of O. huwena, is a bi-functional protein which is a very potent trypsin inhibitor (about 30-fold more strong than BPTI) as well as a weak Kv1.1 potassium channel blocker. Structural analysis of HWTX-XI in 3-D by NMR together with comparative function analysis of 18 expressed mutants of this toxin revealed two separate sites, corresponding to these two activities, located on the two ends of the cone-shape molecule of HWTX-XI. Comparison of non-synonymous/synonymous mutation ratios (omega) for each site in spider and snake KTTs, as well as PBTI like body Kunitz proteins revealed high Darwinian selection pressure on the binding sites for Kv channels and serine proteases in snake, while only on the proteases in spider and none detected in body proteins, suggesting different rates and patterns of evolution among them. The results also revealed a series of key events in the history of spider KTT evolution, including the formation of a novel KTT family (named sub-Kuntiz-type toxins) derived from the ancestral native KTTs with the loss of the second disulfide bridge accompanied by several dramatic sequence modifications. CONCLUSIONS/SIGNIFICANCE: These finding illustrate that the two activity sites of Kunitz-type toxins are functionally and evolutionally independent and provide new insights into effects of Darwinian selection pressures on KTT evolution, and mechanisms by which new functions can be grafted onto old protein scaffolds