Tracking Changes in Bioavailable Fe Within High-Nitrate Low-Chlorophyll Oceanic Waters: A First Estimate Using a Heterotrophic Bacterial Bioreporter

It is conventional knowledge that heterotrophic bacteria play a key role in the biogeochemical cycling of oceanic carbon. However, only recently has their role in marine iron ( Fe) biogeochemical cycles been examined. Research during this past decade has demonstrated an inextricable link between Fe chemistry and the biota, as \u3e99% of Fe in marine systems is complexed to organic chelates of unknown but obviously biotic origin. Here we present a novel approach to assess and compare Fe bioavailability in low Fe HNLC waters using a bioluminescent bacterial reporter that quantitatively responds to the concentration of bioavailable Fe by producing light. Originally tested in freshwater environments, this study presents the first characterization of this halotolerant reporter organism in a defined seawater medium and then subsequently in marine surface waters. Laboratory characterizations demonstrate that this reporter displays a dose-dependent response to Fe availability in our defined marine medium. Field tests were performed during the 10-day mesoscale FeCycle experiment ( February 2003) in the Pacific sub-Antarctic high-nitrate low-chlorophyll region. Data from both biogeochemical measures and bioreporter assays are provided which describe how the bioreporter detected changes in Fe bioavailability that occurred during a natural shift in ambient dissolved Fe concentrations (similar to 40 pM). Our data explore the use of heterotrophic bioluminescent reporters as a comparable tool for marine ecosystems and demonstrate the potential utility of this tool in elucidating the relationship between Fe bioavailability and Fe chemistry in complex marine systems

Multi-modality machine learning predicting Parkinson's disease

Personalized medicine promises individualized disease prediction and treatment. The convergence of machine learning (ML) and available multimodal data is key moving forward. We build upon previous work to deliver multimodal predictions of Parkinson's disease (PD) risk and systematically develop a model using GenoML, an automated ML package, to make improved multi-omic predictions of PD, validated in an external cohort. We investigated top features, constructed hypothesis-free disease-relevant networks, and investigated drug-gene interactions. We performed automated ML on multimodal data from the Parkinson's progression marker initiative (PPMI). After selecting the best performing algorithm, all PPMI data was used to tune the selected model. The model was validated in the Parkinson's Disease Biomarker Program (PDBP) dataset. Our initial model showed an area under the curve (AUC) of 89.72% for the diagnosis of PD. The tuned model was then tested for validation on external data (PDBP, AUC 85.03%). Optimizing thresholds for classification increased the diagnosis prediction accuracy and other metrics. Finally, networks were built to identify gene communities specific to PD. Combining data modalities outperforms the single biomarker paradigm. UPSIT and PRS contributed most to the predictive power of the model, but the accuracy of these are supplemented by many smaller effect transcripts and risk SNPs. Our model is best suited to identifying large groups of individuals to monitor within a health registry or biobank to prioritize for further testing. This approach allows complex predictive models to be reproducible and accessible to the community, with the package, code, and results publicly available

Src activation by Chk1 promotes actin patch formation and prevents chromatin bridge breakage in cytokinesis

In cytokinesis with chromatin bridges, cells delay abscission and retain actin patches at the intercellular canal to prevent chromosome breakage. In this study, we show that inhibition of Src, a protein-tyrosine kinase that regulates actin dynamics, or Chk1 kinase correlates with chromatin breakage and impaired formation of actin patches but not with abscission in the presence of chromatin bridges. Chk1 is required for optimal localization and complete activation of Src. Furthermore, Chk1 phosphorylates human Src at serine 51, and phosphorylated Src localizes to actin patches, the cell membrane, or the nucleus. Nonphosphorylatable mutation of S51 to alanine reduces Src catalytic activity and impairs formation of actin patches, whereas expression of a phosphomimicking Src-S51D protein rescues actin patches and prevents chromatin breakage in Chk1-deficient cells. We propose that Chk1 phosphorylates Src-S51 to fully induce Src kinase activity and that phosphorylated Src promotes formation of actin patches and stabilizes chromatin bridges. These results identify proteins that regulate formation of actin patches in cytokinesis

Decreased thermal tolerance under recurrent heat stress conditions explains summer mass mortality of the blue mussel Mytilus edulis

Extreme events such as heat waves have increased in frequency and duration over the last decades. Under future climate scenarios, these discrete climatic events are expected to become even more recurrent and severe. Heat waves are particularly important on rocky intertidal shores, one of the most thermally variable and stressful habitats on the planet. Intertidal mussels, such as the blue mussel Mytilus edulis, are ecosystem engineers of global ecological and economic importance, that occasionally suffer mass mortalities. This study investigates the potential causes and consequences of a mass mortality event of M. edulis that occurred along the French coast of the eastern English Channel in summer 2018. We used an integrative, climatological and ecophysiological methodology based on three complementary approaches. We first showed that the observed mass mortality (representing 49 to 59% of the annual commercial value of local recreational and professional fisheries combined) occurred under relatively moderate heat wave conditions. This result indicates that M. edulis body temperature is controlled by non-climatic heat sources instead of climatic heat sources, as previously reported for intertidal gastropods. Using biomimetic loggers (i.e. 'robomussels'), we identified four periods of 5 to 6 consecutive days when M. edulis body temperatures consistently reached more than 30 °C, and occasionally more than 35 °C and even more than 40 °C. We subsequently reproduced these body temperature patterns in the laboratory to infer M. edulis thermal tolerance under conditions of repeated heat stress. We found that thermal tolerance consistently decreased with the number of successive daily exposures. These results are discussed in the context of an era of global change where heat events are expected to increase in intensity and frequency, especially in the eastern English Channel where the low frequency of commercially exploitable mussels already questions both their ecological and commercial sustainability.Funding Agency French Ministere de l'Enseignement Superieur et de la Recherche Region Hauts-de-France European Funds for Regional Economical Development Pierre Hubert Curien PESSOA Felloswhip Fundacao para a Ciencia e Tecnologia (FCT-MEC, Portugal) IF/01413/2014/CP1217/CT0004 National Research Foundation - South Africa 64801 South African Research Chairs Initiative (SARChI) of the Department of Science and Technology National Research Foundation - South Africainfo:eu-repo/semantics/publishedVersio

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

From Duty to Right: The Role of Public Education in the Transition to Aging Societies

This paper argues that the introduction of compulsory schooling in early industrialization promoted the growth process that eventually led to a vicious cycle of population aging and negative pressure on education policy. In the early phases of industrialization, public education was undesirable for the young poor who relied on child labor. Compulsory schooling therefore discouraged childbirth, while the accompanying industrialization stimulated their demand for education. The subsequent rise in the share of the old population, however, limited government resources for education, placing heavier financial burdens on the young. This induced further fertility decline and population aging, and the resulting cycle may have delayed the growth of advanced economies in the last few decades

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Climate change eutrophication risk mapping for England - Phase 1. Project outputs report

Purpose of this report: This report has been produced for the purpose of describing the methods and results of modelling work undertaken for the Environment Agency, to indicate the possible effects of climate change and future potential improvements in wastewater treatment on concentrations of phosphorus at selected river monitoring sites in England. This work represents the first phase of a wider project to predict how climate change might increase the risk of eutrophication of surface waters. Methods: The methodology for predicting phosphorus concentrations in rivers is based around the use of the CEH Load Apportionment Model (LAM). This model apportions observed phosphorus loads between diffuse and point source inputs, as a function of flow. Models were developed for 115 WFD waterbodies based on recent measurements of phosphorus concentration and flow. These models were then used with Future Flows Hydrology datasets, which provide projections of future river flows including the effects of climate change, to indicate how phosphorus concentrations in watercourses might be impacted by climate change. Additional model scenario predictions predict the impact on in-stream phosphorus concentrations of potential improvements in sewage effluent quality. Results: The key outputs of the project are a series of spreadsheets and maps (provided as GIS layers). The spreadsheets provide a means of visualising and analysing the outputs of the Load Apportionment Model and predict future WFD status at each of 115 river monitoring sites across England. The maps provide a means of visualising the same results spatially. Climate change is predicted to cause generally small increases in annual average phosphorus concentrations in rivers but associated WFD status is unlikely to change significantly as a result of the flow changes alone. Improvements in wastewater treatment have the potential to cause reductions in phosphorus concentrations which are greater in magnitude than the increases due to climate change. Changes in summer month and low flow period phosphorus concentrations are of more direct relevance to eutrophication risks than annual averages and show greater rates of increase as low flows are projected to decline

Climate change and eutrophication risk in English rivers

This report presents the results of a study that is a first step towards a better understanding of eutrophication risk from climate change in rivers across England. It examines how future changes in river flow may alter the dilution of phosphorus (as phosphate), because phosphorus is considered a primary driver of eutrophication