9 research outputs found
Wat beweegt iemand om vrijmetselaar te worden en te blijven? : een sociaal-wetenschappelijk onderzoek naar de Nederlandse vrijmetselaar
No full text
Het doel van dit onderzoek is om vast te stellen wat iemand beweegt
om vrijmetselaar te worden en dit te blijven. Daarin wordt geprobeerd de
vrijmetselaar die lid is van de Orde zo compleet mogelijk in beeld te
brengen met de focus op zijn persoonlijke, sociale, religieuze en
spirituele identiteit. Daarin worden drie fasen onderscheiden: de
aanloop naar het vrijmetselaar worden, het moment dat hij vrijmetselaar
wordt en de tijd dat hij vrijmetselaar is. Gehoopt wordt dat, op basis
van de onderzoeksresultaten, meer zicht gekregen wordt op de eerder
genoemde ontwikkelingen in het religieuze domein.
Eerst worden hier een aantal thema’s besproken die als uitgangspunt
hebben gediend bij het formuleren van de centrale vraagstelling en de
daaruit afgeleide deelvragen. Achtereenvolgens wordt in deze paragraaf
ingegaan op een aantal thema’s die regelmatig terugkomen in de vragen en
in die zin iets vertellen over de dynamiek en de dilemma’s van de
vrijmetselarij en de vrijmetselaarReligious Studie
Author Correction:A 41,500 year-old decorated ivory pendant from Stajnia Cave (Poland)
No full textCorrection to: Scientific Reports https://doi.org/10.1038/s41598-021-01221-6, published online 25 November 2021The original version of this Article contained errors in the author list where Marjolein D. Bosch was omitted from the author list, and Mikołaj Urbanowski was incorrectly listed as an author of the original Article, and has subsequently been removed.The Author contributions section now reads:“S.T. W.N. and A.N. conceived the project; S.T., W.N., A.P., M.B., S.C., M.D., H.F., A.M., M.D. B., D.P., M.P.R., C.M.R., V.S-M., G.M.S., P.S., M.S., K.S., A.V., F.W., H.W., A.W., M.Z., S.B., A.N., J-J. H., performed research; S.T., A.P., W.N., M.B., M.D.B., S.C., M.D., H.F., A.M., D.P., M.P.R., C.M.R., V.S-M., G.M.S., P.S., M.S., K.S., A.V., F.W., H.W., A.W., M.Z., S.B., A.N., J-J. H. analysed all archaeological data; S.T. and A.P. wrote the paper with the collaboration of all the co-authors.”The original Article and its accompanying Supplementary Information file have been corrected
The optimisation of the energy-related cost function for the Delft Shoulder & Elbow Model
No full textFor inverse-dynamic models cost functions account for the load sharing problem that arises when modelling the musculoskeletal system. This study focuses on the optimisation of the energy-related cost function integrated in the Delft Shoulder & Elbow Model and compares the translation of the obtained representation to results from in vitro measurements. An existing data set containing electromyography (EMG) recordings of elbow flexors (m. biceps brachii, m. brachialis and m. brachioradialis) and extensors (m. triceps brachii and m. anconeus) was used. A grid search was performed over a range of [1, 120] for b¬1 and [1, 60] for b2. The overall explained variance was calculated for each cost function, classifying the particular muscles in flexion and/or extension tasks where activity is expected. For the comparison to in vitro measurements the ratio of contraction dynamics and activation dynamics described by the cost function was determined under varying degree of force production over all muscles used for the analysis. Optimal weight factors were obtained for b1 = 3 and b2 = 50. The contribution of the contraction dynamics compared to the activation dynamics was 60% at 50% of its maximal force generation and 78% at maximal force generation which compares to the in vitro measurements.BMBioMechanical EngineeringMechanical, Maritime and Materials Engineerin
The sustainability of local government finances in England, Germany and the Netherlands: the impact of intergovernmental regulatory regimes
No full textDe Widt investigates how local government financial sustainability is influenced by the regulatory framework in which local governments operate. Applying a comparative constitutional approach, the chapter analyzes the regulatory regimes on local finances in England, Germany, and the Netherlands. The regimes are investigated by concentrating on the impact of fiscal rules, and the monitoring structures in place to impose their implementation. Special attention is paid to the institutional arrangements that apply to non-compliant local authorities. The author demonstrates that growing local financial stress is partly met by regulators with a relaxation of fiscal rules, carrying considerable risks for the sustainability of local and intergovernmental finances. The chapter concludes with policy recommendations on how to improve the robustness of the regulatory regimes that govern local finances
On the clarification of the dating of the Radziwill map of the Grand Duchy of Lithuania from 1613
No full textW artykule przedstawiono analizę dotychczasowych badań stanów mapy Wielkiego Księstwa Litewskiego opublikowanej przez Willema Blaeu’a w roku 1613. Do niedawna uważano, że istnieje tylko pięć stanów tej mapy. Cztery, które związane są z wydaniami atlasu, zostały opracowane przez Fryderyka Wiedera (1929). Uważano również, że dwie mapy ścienne Litwy (w Bibliotece Uniwersytetu w Uppsali i Bibliotece Księżnej Anny Amalii w Weimarze) to te same stany mapy, jednak Gunther Schilder (1989) udowodnił, że mapa w Uppsali należy do późniejszego stanu. Analiza dużej liczby egzemplarzy mapy Litwy doprowadziła autora artykułu do opisu jeszcze dwóch stanów mapy. Dodatkowo wskazano istnienie jeszcze trzeciego egzemplarza mapy ściennej (obecnie zaginionego). Autor sugeruje wprowadzenie dodatkowej gradacji map według zidentyfikowanych stabilnych defektów, co pozwala na ich dokładniejsze datowanie.The article contains an analysis of the previous research on the states of the map of the Grand Duchy of Lithuania, the so-called “Radziwill map”, published in 1613 in Amsterdam and included in Willem Blaeu’s atlases from 1631. Until recently, it was thought that there were only five states of this map. The four states that are associated with the editions of Blaeu’s atlas were described by Friedrich Wieder in 1929. It was also believed that the two wall maps of Lithuania, in the Uppsala University Library and the Duchess Anna Amalia Library in Weimar, were the same map, but Günter Schilder (1989) described in detail the differences between these maps and proved that the map in Uppsala belongs to a later state. The author of this article provides exhaustive evidence that the Uppsala copy of the map was printed between 1635 and 1638. According to the author, the Amsterdam edition of the map of Lithuania was first printed in the autumn of 1613 at the latest. Based on an analysis of wall maps published in Amsterdam between 1608 and 1618 and the suggestions by Paul Reklaitis, the author proves the indisputable existence of another copy of the wall map of the Grand Duchy of Lithuania from 1613 (now lost). The author identified two new states of the 1613 map of Lithuania. In the first, a dot appears after the word Severiensis on the inscription Ducatus Severiensis Pars (ca. 1643–1645), and in the second the name of the town Der Memel is added (ca. 1645 and later). Hence, we are now aware of seven states of the map of the Grand Duchy of Lithuania published in Amsterdam in 1613. This article presents three defects (stable defects) in the copper plate of this map. The author suggests introducing an additional gradation of the maps according to the identified stable defects which permit more accurate dating. The article includes illustrations that demonstrate the differences between all the states in [email protected] S., 1965, Mapa Wielkiego Księstwa Litewskiego Tomasza Makowskiego z 1613 r. tzw. „radziwiłłowska”, jako źródło do dziejów Litwy i Białorusi, „Studia Źródłoznawcze”, 10, s. 33–67.Alexandrowicz S., 2012, Rozwój kartografii Wielkiego Księstwa Litewskiego od XV do połowy XVIII wieku, Warszawa.Aurivillius P.F., 1814, Catalogus librorum impressorum Bibliothecae Regiae Academiae Upsaliensis, vol. 2, s. 144.Birkenmajer L., 1913, Wiadomość o mapie geograficznej Litwy Tomasza Makowskiego (z r. 1613), uważanej za zaginioną, „Sprawozdania z Czynności i Posiedzeń Akademii Umiejętności w Krakowie”, t. 18, nr 4, s. 24–25.Broecke M.P.R., Krogt P.C.J., Meurer P., 1998, Abraham Ortelius and the first atlas: essays commemorating the quadricentennial of his death, 1598–1998, Wydawnictwo HES.Broecke M.P.R., 2011, Ortelius Atlas Maps. An Illustrated Guide. Second Revised Edition. Wydawnictwo HES.Catalogus universalis pro nundinis Francofurtensibus autumnalibus de Anno 1613: Hoc est: Designatio omnium librorum, qui hisce..., 1613, Leipzig: Lamberg.Catalogus librorum, et tabularum, geographicarum & hydrographicarum nec non sphaerarum, & c. Ioannis Blaeu, 1646, s. 13–14.Catalogus librorum, omnium facultate & variarum linguarum, qui in officina Ioannis Blaeu, venales reperiuntur, 1659.Catalogus librorum, et tabularum geographicarum & hydrographicarum, nec non globorum, ac sphaerarum armillarium, quos exudebat Joannes Blaeu, 1661.Gliožaitis A., 2017, Lietuvos didžiosios kunigaikštystės žemėlapis ir jo variantai, Gairės.Janocki J.D., 1779, Janociana sive clarorum atque illustrium Poloniae auctorum mecenatumque memoriae miscellae. Vol. II, Varsaviae et Lipsiae.Koeman C., 2000, Atlantes Neerlandici, vol. 2, The Folio Atlases Published by Willem Jansz. Blaeu and Joan Blaeu, 2000, s. 502–504.Koeman C., Schilder G., Krogt P., Egmond M., 2007, The History of Cartography, Vol. III: Cartography in the European Renaissance. Commercial Cartography and Map Production in the Low Countries, 1500–ca. 1672.
Chicago.Paprotny Z., 2000, Termin „stan mapy” w piśmiennictwie kartograficznym: przykład map Jonasa Scultetusa, „Polish Cartographical Review. Suplement w języku polskim”, t. 5, nr 1, s. 27–41.Reklaitis P., 1964, Lietuvos senoji Kartografija, „Tautos praetis”, vol. 2, kn. 1(5), Chicago.Rėklaitis P., 1972a, Die Stadtansichten Alt–Litauens in der Graphik des 16. bis 19, s. 26.Rėklaitis P., 1972b, Du Vilniaus vaizdo tipai XVI–XIX amžių grafikoje, “Lietuvių Katalikų Mokslo Akademija. Suvažiavimo darbai VII”, Roma.Schilder G., 1990, Monumenta Cartographica Neerlandica, vol. 4, s. 75–77.Schilder G., 2013, Monumenta Cartographica Neerlandica, vol. 9, Hessel Gerritsz., Master engraver and Map maker, who ‘ruled’ the sea, s. 195–218.Wieder F.C., 1929, Monumenta Cartographica: reproductions of unique and rare maps, plans and views in the actual size of the originals, accompanied by cartographical monographs, vol. 3, s. 69, nos. 34–37.14917
Jatropha curcas biodiesel production in Kenya: economics and potential value chain development for smallholder farmers.
No full textA targeted likelihood estimation comparing cefepime and piperacillin/tazobactam in critically ill patients with community-acquired pneumonia (CAP)
No full textCefepime and piperacillin/tazobactam are antimicrobials recommended by IDSA/ATS guidelines for the empirical management of patients admitted to the intensive care unit (ICU) with community-acquired pneumonia (CAP). Concerns have been raised about which should be used in clinical practice. This study aims to compare the effect of cefepime and piperacillin/tazobactam in critically ill CAP patients through a targeted maximum likelihood estimation (TMLE). A total of 2026 ICU-admitted patients with CAP were included. Among them, (47%) presented respiratory failure, and (27%) developed septic shock. A total of (68%) received cefepime and (32%) piperacillin/tazobactam-based treatment. After running the TMLE, we found that cefepime and piperacillin/tazobactam-based treatments have comparable 28-day, hospital, and ICU mortality. Additionally, age, PTT, serum potassium and temperature were associated with preferring cefepime over piperacillin/tazobactam (OR 1.14 95% CI [1.01¿1.27], p = 0.03), (OR 1.14 95% CI [1.03¿1.26], p = 0.009), (OR 1.1 95% CI [1.01¿1.22], p = 0.039) and (OR 1.13 95% CI [1.03¿1.24], p = 0.014)]. Our study found a similar mortality rate among ICU-admitted CAP patients treated with cefepime and piperacillin/tazobactam. Clinicians may consider factors such as availability and safety profiles when making treatment decisions. © The Author(s) 2024
Ambient observations of dimers from terpene oxidation in the gas phase : Implications for new particle formation and growth
No full textWe present ambient observations of dimeric monoterpene oxidation products (C16-20HyO6-9) in gas and particle phases in the boreal forest in Finland in spring 2013 and 2014, detected with a chemical ionization mass spectrometer with a filter inlet for gases and aerosols employing acetate and iodide as reagent ions. These are among the first online dual-phase observations of such dimers in the atmosphere. Estimated saturation concentrations of 10(-15) to 10(-6)mu gm(-3) (based on observed thermal desorptions and group-contribution methods) and measured gas-phase concentrations of 10(-3) to 10(-2)mu gm(-3) (similar to 10(6)-10(7)moleculescm(-3)) corroborate a gas-phase formation mechanism. Regular new particle formation (NPF) events allowed insights into the potential role dimers may play for atmospheric NPF and growth. The observationally constrained Model for Acid-Base chemistry in NAnoparticle Growth indicates a contribution of similar to 5% to early stage particle growth from the similar to 60 gaseous dimer compounds. Plain Language Summary Atmospheric aerosol particles influence climate and air quality. We present new insights into how emissions of volatile organic compounds from trees are transformed in the atmosphere to contribute to the formation and growth of aerosol particles. We detected for the first time over a forest, a group of organic molecules, known to grow particles, in the gas phase at levels far higher than expected. Previous measurements had only measured them in the particles. This finding provides guidance on how models of aerosol formation and growth should describe their appearance and fate in the atmosphere.Peer reviewe
Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis,”NatureMedicine,
No full textFocal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte b 3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte b 3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-b 3 integrin interaction through antibodies and small molecules targeting either uPAR or b 3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS. A R T I C L E S NATURE MEDICINE VOLUME 17 | NUMBER 8 | AUGUST 2011 953 It can be elevated in some malignant neoplasms (for example, ovarian cancer 21 ) as well as in HIV infection In conclusion, our study suggests circulating suPAR as a previously undescribed cause for both primary and recurrent FSGS. RESULTS suPAR is increased in serum of subjects with FSGS We found that suPAR serum concentrations are significantly elevated in people with FSGS when compared to healthy subjects We then stratified the FSGS cases into three different subpopulations: primary FSGS, recurrent FSGS in the allograft and FSGS without recurrence after transplantation. We found the highest suPAR concentrations in pretransplantation blood from subjects with FSGS who later developed recurrent FSGS after transplantation We also compared suPAR serum concentrations in transplanted FSGS patients 1 year after transplantation and found significantly higher suPAR serum concentrations in patients that developed recurrent FSGS than in FSGS patients who received kidney transplants and then had normal renal function A R T I C L E S 954 VOLUME 17 | NUMBER 8 | AUGUST 2011 NATURE MEDICINE As multiple forms of suPAR have been attributed to domain cleavage or alternative splicing Concentrations of the ligand of uPAR, urokinase (uPA), are often elevated in certain types of cancers that also present with elevated suPAR concentrations in various body fluids 27 . Thus, we measured serum uPA concentrations in the groups within our glomerular disease cohort. Notably, and unlike suPAR, we found no difference in the serum uPA concentrations among the groups ( We hypothesized that suPAR could activate 3 integrin in a similar manner to membrane-bound uPAR in podocytes 18 . The activity of 3 integrin is typically measured using the activation epitope-recognizing antibodies such as the 3 integrin-specific antibody AP5 (refs. 29,30). We used human differentiated podocytes 31 and incubated them either with FSGS serum that contains high concentrations of suPAR or with recombinant suPAR, in the absence or presence of a blocking antibody to uPAR or with the 3 integrin small molecule-inhibitor cycloRGDfV A R T I C L E S NATURE MEDICINE VOLUME 17 | NUMBER 8 | AUGUST 2011 955 adhesions are known to be the location of 3 integrin 32 . We also found that this effect could be blocked by a blocking antibody specific to uPAR or by cycloRGDfV To show that circulating suPAR affects the transplanted kidney by activating podocyte 3 integrin, we used double immunofluorescent staining with synaptopodin, a podocyte marker 33 , to analyze aftertransplantation graft biopsies for the presence of AP5 signal in podocytes. We found that 3 integrin activity is low in graft podocytes before reperfusion, whereas it is markedly increased 2 h after reperfusion in recurrent FSGS, but not in nonrecurrent FSGS suPAR and b 3 integrin activity during plasmapheresis To further define the relationship between suPAR and podocyte 3 integrin activity, we did fluorescence-activated cell sorting (FACS) analysis for 3 integrin activity in cultured human podocytes g h e f Figure 3 suPAR serum concentrations and podocyte 3 integrin activity determine treatment response to plasmapheresis in recurrent FSGS. (a) Human podocytes incubated with different pooled serum samples and assayed for 3 integrin activity. MFI, mean fluorescence intensity. *P < 0.05 for nonrecurrent FSGS versus normal subjects, ***P < 0.001 for recurrent versus nonrecurrent FSGS or versus healthy subjects. The respective suPAR concentration of the pooled sera is marked in red. NS, normal (healthy) subject; NR, nonrecurrent FSGS; REC, recurrent FSGS (representative of three experiments). (b) Pharmacological modulation of 3 integrin activity in podocytes. **P < 0.01 for cylcoRGDfv co-treated cells versus recurrent FSGS serum alone; ***P < 0.001 for uPAR-specific mAb co-treated cells versus recurrent FSGS serum alone. (c) suPAR in serum from subjects with recurrent FSGS (n = 4) before and after a course of plasmapheresis. **P < 0.01. (d) Effect of plasmapheresis on 3 integrin activity in podocytes incubated with recurrent FSGS serum (n = 6), collected before and after serial treatment with plasmapheresis. ***P < 0.001. (e-h) Clinical cases of recurrent FSGS. Top graphs show serum suPAR, urine protein/creatinine ratio (g/g) and individual plasmapheresis treatment as indicated by arrows and plotted over time (d) from before (−1) to after transplantation. Bottom graphs and images show podocyte 3 integrin activity measured by FACS (left) and immunofluorescence (right) as a result of incubation with pretransplantation serum, or with the after-transplantation serum collected after repetitive plasmapheresis treatments. As a reference, the mean concentration of AP5 from a is marked as a dashed line. (e,f) Patients who obtained full remission after pheresis. (g,h) Patients who did not achieve remission after pheresis. Scale bars, 30 m. Whiskers in plots of AP5 activity and serum suPAR show minimum to maximum. A R T I C L E S 956 VOLUME 17 | NUMBER 8 | AUGUST 2011 NATURE MEDICINE incubated with serum from healthy subjects (n = 5) or with pretransplantation serum from subjects with nonrecurrent (n = 10) and recurrent FSGS (n = 15). We found that incubation with recurrent FSGS pretransplantation serum significantly elevated 3 integrin activity compared to serum from subjects with nonrecurrent FSGS or from healthy subjects Mouse models showing that suPAR causes proteinuria and FSGS To determine whether suPAR is a cause or a consequence of FSGS, we established three different mouse models: (i) uPAR-knockout (Plaur −/− ) mice injected with recombinant suPAR, (ii) hybrid-transplant mice modeling endogenous suPAR release and (iii) genetically engineered wild-type mice that drive expression of a suPAR plasmid in the skin, leading to increased serum suPAR concentrations. First, we examined whether exogenous circulating suPAR could deposit into kidneys and cause albuminuria. We used Plaur −/− mice and injected escalating doses of recombinant mouse suPAR protein intravenously into Plaur −/− mice. We found that low-dose injection at 2 and 10 g did not cause albuminuria, which is consistent with the physiological low concentrations of suPAR we observed in the blood of healthy subjects A R T I C L E S NATURE MEDICINE VOLUME 17 | NUMBER 8 | AUGUST 2011 957 that this deposition was associated with an increase in 3 integrin activity in podocytes, as shown by increased AP5 labeling that, again, is suPAR dose dependent Third, to explore whether prolonged elevation of suPAR in the serum of mice causes a progressive glomerulopathy, we engineered wild-type mice that drive expression of suPAR in the skin. We generated a mouse plasmid (sPlaur WT ) based on a known coding sequence for secreted suPAR 26 that contains the D I and D II domains. We delivered this plasmid into mice by in vivo electroporation into the skin. As a control, we generated a 3 integrin binding-deficient suPAR mutant, sPlaur E134A . This mutant has a point mutation (E134A) in the D II domain We next studied the ultrastructure of podocytes after 4 weeks and noted prominent foot process effacement consistent with glomerular disease; however, we only observed this in mice that expressed suPAR capable of binding 3 integrin A R T I C L E S 958 VOLUME 17 | NUMBER 8 | AUGUST 2011 NATURE MEDICINE To further study the disease-causing effects of suPAR, we also carried out experiments that blocked suPAR action. We administered an uPAR-specific monoclonal antibody to mice expressing sPlaur WT and found protection of proteinuria whereas proteinuria was high when using an IgG isotype control DISCUSSION The present study identifies suPAR as a circulating, causative FSGS factor that is elevated in the serum of approximately two-thirds of primary FSGS patients. suPAR-mediated activation of 3 integrin on podocyte foot processes is the mechanism of injury caused by high suPAR blood concentrations. Since the first clinical description of nephrotic syndrome recurrence after kidney transplantation The amount of podocyte 3 integrin activity that is driven by circulating systemic suPAR depends on the amount of individual serum suPAR and, possibly, also on suPAR post-translational modifications (such as glycosylation status). In addition, podocyte 3 integrin activity can also be driven by augmented podocyte uPAR expression, which is sufficient to initiate podocyte foot process effacement and proteinuria 18 . Podocyte 3 integrin activity seems to be independent of total serum uPA concentrations; this is in contrast to the suPARuPA associations in some forms of cancer Several modes of interference can protect from suPAR-mediated podocyte injury: (i) blockade of suPAR using a blocking antibody specific to suPAR; (ii) protecting 3 integrin from increased activation by cycloRGDfV or 3 integrin-specific antibody 18 ; (iii) blocking suPAR-3 integrin interaction by modulating the suPAR-3 integrin binding site (E134A) and (iv) removing suPAR by plasmapheresis to levels that decrease podocyte 3 integrin activity. Using assays that measure all suPAR forms, we noted that ~70% of subjects with primary FSGS presented with significantly elevated concentrations of serum suPAR before transplantation when compared to other primary glomerulopathies. In addition, we found that total suPAR concentrations remained significantly elevated after kidney transplantation in people who have developed recurrent FSGS compared to those with proper renal function. On the basis of these clinical observations, we created mouse models that could explore the cause or effect nature of suPAR and demonstrate the kidney pathogenicity of elevated systemic suPAR. Notably, we found different forms of suPAR that correspond to different domain fragments in the serum of subjects with FSGS, with molecular weights ranging from 22 to 45 kDa. This is close to the molecular range (30 to 50 kDa) of the factor predicted by others Our study provides the rationale for a more measurable prediction of FSGS risk in subjects with FSGS before and after transplantation. Approximately 70% of subjects with FSGS have elevated concentrations of suPAR compared to other glomerular diseases such as membranous nephropathy, MCD or preeclampsia. This further separates FSGS from other glomerulopathies involving phospholipase A2 receptorspecific antibodies in membranous nephropathy 39 and factors such as angiopoietin-like 40 or c-mip in MCD 41 . Because suPAR is detectable both in healthy human subjects and normal mice, physiological suPAR concentrations or physiological suPAR domain combinations do not seem to be harmful. It is also important to note that there might be species differences with respect to the pathogenic strength of various suPAR domain combinations. Future studies with new and more A R T I C L E S NATURE MEDICINE VOLUME 17 | NUMBER 8 | AUGUST 2011 959 specific suPAR domain-specific antibodies should clarify this question and focus more on the role of suPAR glycosylation in FSGS. Another interesting question is why a few FSGS patients without elevated suPAR still develop FSGS as well as recurrent FSGS. An obvious answer would be that suPAR can act in concert with podocyte uPAR 18 and this might drive FSGS even in the absence of high suPAR concentrations. Another reason might be that native FSGS is caused by a mutation in a podocyte gene 6 . Also, the current ELISA assay for serum suPAR is likely to measure all suPAR domains, and thus it might be possible that FSGS subjects with low total suPAR do have a higher portion of pathological suPAR fragments that current tests cannot readily detect. Once new reagents are developed, even more subjects with FSGS might test positive for pathological suPAR, thereby further increasing the clinical prediction of the test. Alternatively, there is the possibility of the presence of yet-to-be-identified additional permeability factor candidates 17 or the absence of protective podocyte factors Podocyte 3 integrin expression and activation responses must also be evaluated further. Future studies will have to focus more on the expression of the 3 integrin-encoding gene (ITGB3) in the graft In conclusion, we show that suPAR is a circulating factor that can cause FSGS before and after transplantation. Our studies will allow better risk stratification of patients with FSGS by measuring serum and urine concentrations of suPAR, and they will provide the conceptual framework for refined treatment options that remove or neutralize suPAR to a level insufficient to activate podocyte 3 integrin. Regardless of the source of the stimulant (podocyte or systemic), a pathological activation of podocyte 3 integrin is emerging as a key event for the initiation of proteinuric glomerular disease; it is likely to be important in some forms of secondary FSGS, such as diabetic nephropathy 18 , as well. Accordingly, pharmacological modulation of excessive podocyte 3 integrin activation is a promising target for achieving protection from renal disease. METHODS Methods and any associated references are available in the online version of the paper at http://www.nature.com/naturemedicine/. Note: Supplementary information is available on the Nature Medicine website. ACKNOWLEDGMENTS We thank N. Sidenius (Foundation FIRC Institute of Molecular Oncology, Italy) for help with the suPAR assay in mouse samples. We are grateful to L.H. Beck, Jr. and D. Salant (Boston University Medical Center) for providing the membranous nephropathy patient cohort. We thank S. Hsiesh for help with sample collection. We thank G. Høyer-Hansen (the Finsen Laboratory, Denmark) for additional suPAR assays and discussions. The authors are grateful to P.J. Goldschmidt for helpful scientific discussions regarding the manuscript and to M.J. Tracy for critical reading of the manuscript. This work was supported in part by the US National Institutes of Health (grants DK073495 and DK089394 to J.R., DK-82636 to A.F., DK070011 to G.B.), the Halpin Foundation-American Society of Nephrology Research Grant (to C.W.), a grant from the American Diabetes Association (7-09-JF-23 to A.F.), and a grant from the Diabetes Research Institute Foundation (to A.F.). The authors also wish to acknowledge the generous support of the Katz Family Fund. AUTHOR CONTRIBUTIONS J.R. conceived the study. J.R. and C.W. designed the experiments, coordinated the study, analyzed the data and wrote the manuscript. C.W., S.E.H., J.L., D.M., Q.Z., B.N., P.D., V.G. performed the experiments. A.F., N.G., G.B., J.S., S.A.K., H.-K.Y., M.Saleem, A.C., E.S., A.T., M.Salifu, M.M.S., F.S., C.M., V.S., M.Z., D.R., M.P.R., P.R., J.R. contributed to clinical samples and clinical information. M.P.R. and P.R. provided pathology service. COMPETING FINANCIAL INTERESTS The authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturemedicine/. Published online at http://www.nature.com/naturemedicine/. Reprints and permissions information is available online at http://www.nature.com/ reprints/index.html. A R T I C L E S NATURE MEDICIN
