Temporal genetic structure in a poecilogonous polychaete: the interplay of developmental mode and environmental stochasticity

Background: Temporal variation in the genetic structure of populations can be caused by multiple factors, including natural selection, stochastic environmental variation, migration, or genetic drift. In benthic marine species, the developmental mode of larvae may indicate a possibility for temporal genetic variation: species with dispersive planktonic larvae are expected to be more likely to show temporal genetic variation than species with benthic or brooded non-dispersive larvae, due to differences in larval mortality and dispersal ability. We examined temporal genetic structure in populations of Pygospio elegans, a poecilogonous polychaete with within-species variation in developmental mode. P. elegans produces either planktonic, benthic, or intermediate larvae, varying both among and within populations, providing a within-species test of the generality of a relationship between temporal genetic variation and larval developmental mode. Results: In contrast to our expectations, our microsatellite analyses of P. elegans revealed temporal genetic stability in the UK population with planktonic larvae, whereas there was variation indicative of drift in temporal samples of the populations from the Baltic Sea, which have predominantly benthic and intermediate larvae. We also detected temporal variation in relatedness within these populations. A large temporal shift in genetic structure was detected in a population from the Netherlands, having multiple developmental modes. This shift could have been caused by local extiction due to extreme environmental conditions and (re)colonization by planktonic larvae from neighboring populations. Conclusions: In our study of P. elegans, temporal genetic variation appears to be due to not only larval developmental mode, but also the stochastic environment of adults. Large temporal genetic shifts may be more likely in marine intertidal habitats (e.g. North Sea and Wadden Sea) which are more prone to environmental stochasticity than the sub-tidal Baltic habitats. Sub-tidal and/or brackish (less saline) habitats may support smaller P. elegans populations and these may be more susceptible to the effects of random genetic drift. Moreover, higher frequencies of asexual reproduction and the benthic larval developmental mode in these populations leads to higher relatedness and contributes to drift. Our results indicate that a general relationship between larval developmental mode and temporal genetic variation may not exist

MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke

Cerebral ischemia activates endogenous reparative processes, such as increased proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and migration of neural progenitor cells (NPCs) toward the ischemic area. However, this reparative process is limited because most of the NPCs die shortly after injury or are unable to arrive at the infarct boundary. In this study, we demonstrate for the first time that endogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) protects NSCs against oxygen-glucose-deprivation-induced injury and has a crucial role in regulating NPC migration. In NSC cultures, MANF protein administration did not affect growth of cells but triggered neuronal and glial differentiation, followed by activation of STAT3. In SVZ explants, MANF over expression facilitated cell migration and activated the STAT3 and ERK1/2 pathway. Using a rat model of cortical stroke, intracerebroventricular injections of MANF did not affect cell proliferation in the SVZ, but promoted migration of doublecortin (DCX)(+) cells toward the corpus callosum and infarct boundary on day 14 post-stroke. Long-term infusion of MANF into the per'-infarct zone increased the recruitment of DCX+ cells in the infarct area. In conclusion, our data demonstrate a neuroregenerative activity of MANF that facilitates differentiation and migration of NPCs, thereby increasing recruitment of neuroblasts in stroke cortex.Peer reviewe

Extracellular Vesicles:An Important Biomarker in Recurrent Pregnancy Loss?

Recurrent pregnancy loss (RPL) has an estimated incidence of 1–3% of all couples. The etiology is considered to be multifactorial. Extracellular vesicles (EVs) take part in numerous different physiological processes and their contents show the originating cell and pathophysiological states in different diseases. In pregnancy disorders, changes can be seen in the composition, bioactivity and concentration of placental and non-placental EVs. RPL patients have an increased risk of pregnancy complications. The aim of this prospective study was to examine whether measuring different specific EV markers in plasma before and during pregnancy could be used as predictors of pregnancy loss (PL) in women with RPL. Thirty-one RPL patients were included in this study; 25 had a live birth (LB group) and six had a new PL (PL group). Five blood samples were obtained, one before achieved pregnancy and the others in gestational week 6, 8, 10 and 16. Moreover, some of the patients received intravenous immunoglobulin (IVIG) infusions as part of treatment, and it was also examined whether this treatment influenced the EV levels. Seventeen EV markers specific for the immune system, coagulation, placenta and hypoxia were analyzed in the samples with EV Array, a method able to capture small EVs by using an antibody panel targeting membrane proteins. Comparing the LB and PL groups, one EV marker, CD9, showed a significant increase from before pregnancy to gestational week 6 in the PL group. The changes in the other 16 markers were nonsignificant. One case of late-onset PL showed steeply increasing levels, with sudden decrease after gestational week 10 in nine of 17 markers. Moreover, there was an overall increase of all 17 markers after IVIG treatment in the LB group, which was significant in 15 of the markers. Whether increases in EVs positive for CD9 characterize RPL patients who subsequently miscarry should be investigated in future larger studies

Zircon as a tracer of plumbing processes in an active magmatic system: insights from mingled magmas of the 2010 dome collapse, Montserrat, Lesser Antilles Arc, Caribbean

This project has received funding from the European Union's Hori-zon 2020 research and innovation programme under the Marie Skodowska-Curie grant agreement No. 749611 (JHS) . We also ac-knowledge funding from the Natural Environment Research Council Isotope Geoscience Facilities Steering Committee, grant IP-1746-1117 (JB) . The work has been financially supported by the Spanish grant CGL 2017-84469-P (JHS) . Funding for open access charge: Universidad de Granada/CBUA. Alexander Varychev at the University of Heidelberg, Germany, and Jeremy Rushton at the British Geological Survey, U.K., are thanked for help with analytical work. Jose Luis Macias is thanked for editorial handling. We are obliged to two anonymous reviewers for the time and effort they took to help us improve the clarity and rigour of our interpretations. 19Soufriere Hills Volcano, Montserrat, erupted from 1995 to 2010, with activity including dome growth, destructive pyroclastic density currents and Vulcanian explosions. Monitoring data, such as gas emissions, show the system is still in a state of unrest. The recent eruptions provide an opportunity to study, in real time, a complex subduction-related subvolcanic transaustal melt-mush reservoir, its magma fluxes, and the timing of crystal and melt storage prior to eruptive paroxysms. How and when mush destabilisation occurs prior to volcanic eruptions continues to be a question of intense debate. Evidence of mafic magma intrusion, a potential eruptive trigger, is preserved in enclaves with quenched and diffuse margins that are mingled with crystal-rich andesite. Here, in this first study of Soufriere Hills Volcano zircon, we report zircon ages and compositions for mafic-intermediate enclaves and host andesites from the most recent dome collapse in 2010 to place temporal constraints on magma reservoir processes. Zircon U-238-Th-230 ages disequilibrium crystallisation ages ranging between c. 2-250 ka constrain the longevity of the magmatic plumbing system. Uniform Hf isotopes, epsilon Hf 11.3 +/- 12 to 14.6 +/- 1.5, indicate invariant compositions that are typical for island arc magma sources. Zircon trace element concentrations and Ti-in-zircon crystallisation temperatures indicate crystallisation in isolated, small-volume, lenses with variable fractions of melt of heterogeneous compositions. We suggest amalgamation of assorted crystal cargoes from these lenses occurred prior to eruption during mush destabilisation triggered by mafic magma recharge. Zircon textures, on the other hand, shed light on recent centimetre-scale magma mingling immediately prior to eruption. Euhedral-subhedral zircon is preferentially preserved in or near quenched contacts of the least-evolved enclave and host andesite. By contrast, reheating of the andesite by the mafic magma recharge in the presence of zircon-undersaturated melts promoted zircon resorption. This led to the formation of subhedral-anhedral corroded zircon that is typical in the host andesite mush. Zircon thus reveals processes ranging from 100,000s of years of andesite storage to short-term partial destruction in response to transient heating and magma mixing events.European Commission 749611Natural Environment Research Council Isotope Geoscience Facilities Steering Committee IP-1746-1117Spanish Government CGL 2017-84469-PUniversidad de Granada/CBU

Perceived Stress Levels, Chemotherapy, Radiation Treatment and Tumor Characteristics Are Associated with a Persistent Increased Frequency of Somatic Chromosomal Instability in Women Diagnosed with Breast Cancer: A One Year Longitudinal Study

While advances in therapeutic approaches have resulted in improved survival rates for women diagnosed with breast cancer, subsets of these survivors develop persistent psychoneurological symptoms (fatigue, depression/anxiety, cognitive dysfunction) that compromise their quality of life. The biological basis for these persistent symptoms is unclear, but could reflect the acquisition of soma-wide chromosomal instability following the multiple biological/psychological exposures associated with the diagnosis/treatment of breast cancer. An essential first step toward testing this hypothesis is to determine if these cancer-related exposures are indeed associated with somatic chromosomal instability frequencies. Towards this end, we longitudinally studied 71 women (ages 23-71) with early-stage breast cancer and quantified their somatic chromosomal instability levels using a cytokinesis-blocked micronuclear/cytome assay at 4 timepoints: before chemotherapy (baseline); four weeks after chemotherapy initiation; six months after chemotherapy (at which time some women received radiotherapy); and one year following chemotherapy initiation. Overall, a significant change in instability frequencies was observed over time, with this change differing based on whether the women received radiotherapy (p=0.0052). Also, significantly higher instability values were observed one year after treatment initiation compared to baseline for the women who received: sequential taxotere/doxorubicin/cyclophosphamide (pp=0.014). Significant predictive associations for acquired micronuclear/cytome abnormality frequencies were also observed for race (p=0.0052), tumor type [luminal B tumors] (p=0.0053), and perceived stress levels (p=0.0129). The impact of perceived stress on micronuclear/cytome frequencies was detected across all visits, with the highest levels of stress being reported at baseline (p =0.0024). These findings suggest that the cancer-related exposome has an impact on both healthy somatic cells and tumor cells, and may lead to persistent chromosomal instability. In addition, stress was a significant predictor of chromosomal instability; thus, interventions that aim to reduce stress may reduce acquired soma-wide chromosomal instability for cancer survivors

Molecular profile of the rat peri-infarct region four days after stroke: Study with MANF

The peri-infarct region after ischemic stroke is the anatomical location for many of the endogenous recovery processes, and the molecular events in the peri-infarct region remain poorly characterized. In this study, we examine the molecular profile of the peri-infarct region on post-stroke day four, time when reparative processes are ongoing. We used a multiomics approach, involving RNA sequencing, and mass spectrometry-based proteomics and metabolomics to characterize molecular changes in the peri-infarct region. We also took advantage of our previously developed method to express transgenes in the peri-infarct region where self-complementary adeno-associated virus (AAV) vectors were injected into the brain parenchyma on post-stroke day 2. We have previously used this method to show that mesencephalic astrocyte-derived neurotrophic factor (MANF) enhances functional recovery from stroke and recruits phagocytic cells to the peri-infarct region. Here, we first analyzed the effects of stroke to the peri-infarct region on post-stroke day 4 in comparison to sham-operated animals, finding that stroke induced changes in 3345 transcripts, 341 proteins, and 88 metabolites. We found that after stroke genes related to inflammation, proliferation, apoptosis, and regeneration were upregulated, whereas genes encoding neuroactive ligand receptors and calcium-binding proteins were downregulated. In proteomics, we detected upregulation of proteins related to protein synthesis and downregulation of neuronal proteins. Metabolomic studies indicated that in after stroke tissue there is increase in saccharides, sugar phosphates, ceramides and free fatty acids and decrease of adenine, hypoxantine, adenosine and guanosine. We then compared the effects of post-stroke delivery AAV1-MANF delivery to AAV1-eGFP (enhanced green fluorescent protein). MANF administration increased the expression of 77 genes, most of which were related to immune response. In proteomics, MANF administration reduced S100A8 and S100A9 protein levels. In metabolomics, no significant differences between MANF and eGFP treatment were detected, but relative to sham surgery group, most of the changes in lipids were significant in the AAV-eGFP group only. This work describes the molecular profile of the peri-infarct region during recovery from ischemic stroke, and establishes a resource for further stroke studies. These results provide further support for parenchymal MANF as a modulator of phagocytic function.Peer reviewe

Comparative Hepatic and Intestinal Metabolism and Pharmacodynamics of Statins

The study aimed to comprehensively investigate the in vitro metabolism of statins. The metabolism of clinically relevant concentrations of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and their metabolites were investigated using human liver microsomes (HLMs), human intestine microsomes (HIMs), liver cytosol, and recombinant cytochrome P450 enzymes. We also determined the inhibitory effects of statin acids on their pharmacological target, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. In HLMs, statin lactones were metabolized to a much higher extent than their acid forms. Atorvastatin lactone and simvastatin (lactone) showed extensive metabolism [intrinsic clearance (CLint) values of 3700 and 7400 mu l/min per milligram], whereas the metabolism of the lactones of 2-hydroxyatorvastatin, 4-hydroxyatorvastatin, and pitavastatin was slower (CLint 20-840 mu l/min per milligram). The acids had CLint values in the range SIGNIFICANCE STATEMENT The present comparison of the in vitro metabolic and pharmacodynamic properties of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin and their metabolites using unified methodology provides a strong basis for further application. Together with in vitro drug transporter and clinical data, the present findings are applicable for use in comparative systems pharmacology modeling to predict the pharmacokinetics and pharmacological effects of statins at different dosages.Peer reviewe