Stratification strength and light climate explain variation in chlorophyll a at the continental scale in a European multilake survey in a heatwave summer

To determine the drivers of phytoplankton biomass, we collected standardized morphometric, physical, and biological data in 230 lakes across the Mediterranean, Continental, and Boreal climatic zones of the European continent. Multilinear regression models tested on this snapshot of mostly eutrophic lakes (median total phosphorus [TP] = 0.06 and total nitrogen [TN] = 0.7 mg L−1), and its subsets (2 depth types and 3 climatic zones), show that light climate and stratification strength were the most significant explanatory variables for chlorophyll a (Chl a) variance. TN was a significant predictor for phytoplankton biomass for shallow and continental lakes, while TP never appeared as an explanatory variable, suggesting that under high TP, light, which partially controls stratification strength, becomes limiting for phytoplankton development. Mediterranean lakes were the warmest yet most weakly stratified and had significantly less Chl a than Boreal lakes, where the temperature anomaly from the long-term average, during a summer heatwave was the highest (+4°C) and showed a significant, exponential relationship with stratification strength. This European survey represents a summer snapshot of phytoplankton biomass and its drivers, and lends support that light and stratification metrics, which are both affected by climate change, are better predictors for phytoplankton biomass in nutrient-rich lakes than nutrient concentrations and surface temperature.Additional co-authors: Jolanda Verspagen, Maria van Herk, Maria G. Antoniou, Nikoletta Tsiarta, Valerie McCarthy, Victor C. Perello, Danielle Machado-Vieira, Alinne Gurjao de Oliveira, Dubravka Špoljaric Maronic, Filip Stevic, Tanja Žuna Pfeiffer, Itana Bokan Vucelic, Petar Žutinic, Marija Gligora Udovic, Anđelka Plenkovic-Moraj, Ludek Blaha, Rodan Geriš, Markéta Frankova, Kirsten Seestern Christoffersen, Trine Perlt Warming, Tõnu Feldmann, Alo Laas, Kristel Panksep, Lea Tuvikene, Kersti Kangro, Judita Koreiviene, Jurate Karosiene, Jurate Kasperoviciene, Ksenija Savadova-Ratkus, Irma Vitonyte, Kerstin Häggqvist, Pauliina Salmi, Lauri Arvola, Karl Rothhaupt, Christos Avagianos, Triantafyllos Kaloudis, Spyros Gkelis, Manthos Panou, Theodoros Triantis, Sevasti-Kiriaki Zervou, Anastasia Hiskia, Ulrike Obertegger, Adriano Boscaini, Giovanna Flaim, Nico Salmaso, Leonardo Cerasino, Sigrid Haande, Birger Skjelbred, Magdalena Grabowska, Maciej Karpowicz, Damian Chmura, Lidia Nawrocka, Justyna Kobos, Hanna Mazur-Marzec, Pablo Alcaraz-Parraga, Elżbieta Wilk-Wozniak, Wojciech Krzton, Edward Walusiak, Ilona Gagala-Borowska, Joana Mankiewicz-Boczek, Magdalena Toporowska, Barbara Pawlik-Skowronska, Michał Niedzwiecki, Wojciech Pęczuła, Agnieszka Napiorkowska-Krzebietke, Julita Dunalska, Justyna Sienska, Daniel Szymanski, Marek Kruk, Agnieszka Budzynska, Ryszard Goldyn, Anna Kozak, Joanna Rosinska, Elżbieta Szeląg-Wasielewska, Piotr Domek, Natalia Jakubowska-Krepska, Kinga Kwasizur, Beata Messyasz, Aleksandra Pełechata, Mariusz Pełechaty, Mikolaj Kokocinski, Beata Madrecka-Witkowska, Iwona Kostrzewska-Szlakowska, Magdalena Frąk, Agnieszka Bankowska-Sobczak, Michał Wasilewicz, Agnieszka Ochocka, Agnieszka Pasztaleniec, Iwona Jasser, Ana M. Antao-Geraldes, Manel Leira, Vitor Vasconcelos, Joao Morais, Micaela Vale, Pedro M. Raposeiro, Vítor Gonçalves, Boris Aleksovski, Svetislav Krstic, Hana Nemova, Iveta Drastichova, Lucia Chomova, Spela Remec-Rekar, Tina Elersek, Lars-Anders Hansson, Pablo Urrutia-Cordero, Andrea G. Bravo, Moritz Buck, William Colom-Montero, Kristiina Mustonen, Don Pierson, Yang Yang, Christine Edwards, Hannah Cromie, Jordi Delgado-Martín, David García, Jose Luís Cereijo, Joan Gomà, Mari Carmen Trapote, Teresa Vegas-Vilarrúbia, Biel Obrador, Ana García-Murcia, Monserrat Real, Elvira Romans, Jordi Noguero-Ribes, David Parreño Duque, Elísabeth Fernandez-Moran, Barbara Úbeda, José Angel Galvez, Núria Catalan, Carmen Pérez-Martínez, Eloísa Ramos-Rodríguez, Carmen Cillero-Castro, Enrique Moreno-Ostos, José María Blanco, Valeriano Rodríguez, Jorge Juan Montes-Pérez, Roberto L. Palomino, Estela Rodríguez-Pérez, Armand Hernandez, Rafael Carballeira, Antonio Camacho, Antonio Picazo, Carlos Rochera, Anna C. Santamans, Carmen Ferriol, Susana Romo, Juan Miguel Soria, Arda Özen, Tünay Karan, Nilsun Demir, Meryem Beklioglu, Nur Filiz, Eti Levi, Ugur Iskin, Gizem Bezirci, Ülkü Nihan Tavsanoglu, Kemal Çelik, Koray Ozhan, Nusret Karakaya, Mehmet Ali Turan Koçer, Mete Yilmaz, Faruk Maras¸lıoglu, Özden Fakioglu, Elif Neyran Soylu, Meral Apaydın Yagcı, Sakir Çınar, Kadir Çapkın, Abdulkadir Yagcı, Mehmet Cesur, Fuat Bilgin, Cafer Bulut, Rahmi Uysal, Köker Latife, Reyhan Akçaalan, Meriç Albay, Mehmet Tahir Alp, Korhan Özkan, Tugba Ongun Sevindik, Hatice Tunca, Burçin Önem, Hans Paerl, Cayelan C. Carey, Bastiaan W. Ibeling

PIRCHE-II Is Related to Graft Failure after Kidney Transplantation

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor–recipient couples that were transplanted between 1995 and 2005. For these donors–recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04–1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10–1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival

Eigenvalue asymptotics for weighted Laplace equations on rough Riemannian manifolds with boundary

Our topological setting is a smooth compact manifold of dimension two or higher with smooth boundary. Although this underlying topological structure is smooth, the Riemannian metric tensor is only assumed to be bounded and measurable. This is known as a rough Riemannian manifold. For a large class of boundary conditions we demonstrate a Weyl law for the asymptotics of the eigenvalues of the Laplacian associated to a rough metric. Moreover, we obtain eigenvalue asymptotics for weighted Laplace equations associated to a rough metric. Of particular novelty is that the weight function is not assumed to be of fixed sign, and thus the eigenvalues may be both positive and negative. Key ingredients in the proofs were demonstrated by Birman and Solomjak nearly fifty years ago in their seminal work on eigenvalue asymptotics. In addition to determining the eigenvalue asymptotics in the rough Riemannian manifold setting for weighted Laplace equations, we also wish to promote their achievements which may have further applications to modern problems

Ellipro scores of donor epitope specific HLA antibodies are not associated with kidney graft survival

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants.</p

T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation

CD4(+) T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4(+) memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4(+) memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4(+) memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4(+) memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation

Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan–Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p &lt; 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1–5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84–3.25) in deceased donation, and 2.22 (1.25–3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.</p

Temperature Effects Explain Continental Scale Distribution of Cyanobacterial Toxins

Insight into how environmental change determines the production and distribution of cyanobacterial toxins is necessary for risk assessment. Management guidelines currently focus on hepatotoxins (microcystins). Increasing attention is given to other classes, such as neurotoxins (e.g., anatoxin-a) and cytotoxins (e.g., cylindrospermopsin) due to their potency. Most studies examine the relationship between individual toxin variants and environmental factors, such as nutrients, temperature and light. In summer 2015, we collected samples across Europe to investigate the effect of nutrient and temperature gradients on the variability of toxin production at a continental scale. Direct and indirect effects of temperature were the main drivers of the spatial distribution in the toxins produced by the cyanobacterial community, the toxin concentrations and toxin quota. Generalized linear models showed that a Toxin Diversity Index (TDI) increased with latitude, while it decreased with water stability. Increases in TDI were explained through a significant increase in toxin variants such as MC-YR, anatoxin and cylindrospermopsin, accompanied by a decreasing presence of MC-LR. While global warming continues, the direct and indirect effects of increased lake temperatures will drive changes in the distribution of cyanobacterial toxins in Europe, potentially promoting selection of a few highly toxic species or strains.Peer reviewe

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Ellipro scores of donor epitope specific HLA antibodies are not associated with kidney graft survival

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants

Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level