5, 6.25, 3.13, 1.56, and 0 ng/mL. The 0 ng/mL calibration

curve point served as the negative control and RIP binding buffer was used as a blank on each plate. The sheep anti-glucocerebrosidase polyclonal antibody in RIP binding buffer with 5% pooled normal human serum was used as a positive control, at concentrations of 600, 200, and 50 ng/mL. Anti-velaglucerase alfa or anti-imiglucerase antibodies were analyzed for their Ig subclass using isotype-specific indirect ECL immunoassays to confirm IgE, IgA, and IgM anti-drug antibodies. The method described was identical for imiglucerase antibodies, substituting imiglucerase for velaglucerase alfa wherever written. Biotinylated velaglucerase alfa was immobilized on streptavidin-coated microwell plates, and used to capture any antibodies present Venetoclax in the samples. Anti-IgE, -IgA, or -IgM antibodies were detected using ruthenium-complex-tagged anti-human

secondary antibodies against the human IgA, IgM, or IgE domains. Since anti-velaglucerase alfa or anti-imiglucerase IgA, IgM, or IgE antibodies were not available to be used as controls, human IgA-, IgM-, and IgE-antibody synthetic hybrids were synthesized by chemically cross-linking purified LDN-193189 purchase human IgA, IgM, or IgE immunoglobulin to the sheep anti-glucocerebrosidase polyclonal antibody previously described. The IgA-, IgM-, and IgE synthetic human–sheep hybrid control antibodies therefore bound to velaglucerase alfa or imiglucerase through the sheep antibody domain, and were detected using ruthenium-complex-tagged anti-human secondary antibodies against the human IgA, IgM, or IgE domains. The method was identical for the preparation of the IgE, IgA, and IgM hybrid antibody controls, substituting IgA or IgM for IgE wherever written. The long spacer

arm cross-linker succinimidyl 6-[3′-2-pyridyldithio-propionamido] hexanoate (LC-SPDP) technique was used as previously described (Gu et al., 2003). LC-SPDP produced disulfide-containing linkages on both the sheep polyclonal and human IgE to yield pyridylthiol-activated proteins. The IgE was then treated with a reducing agent to expose sulfhydryl groups, enabling it to link with the IgG. This human IgE–sheep antibody Adenosine triphosphate hybrid preparation was further characterized by size exclusion chromatography. For the human IgE–GCB antibody hybrid only, the hybrid antibody was further affinity purified by a velaglucerase alfa-coupled Sepharose 4 Fast Flow column in order to separate any unlinked human IgE. Samples as well as positive or negative controls were assayed on each plate. Firstly, 150 μL of 2% blocker buffer B was added to each well and the plate was incubated at room temperature with gentle shaking for 1 h. The wells were then each washed with 300 μL of wash buffer, and 25 μL of diluted biotin-labeled velaglucerase alfa was added to each well, and then the plate incubated further for 1 h at room temperature with gentle mixing.

The discovery of the quantitative trait locus B-cell lymphoma-leukemia

A (BCL11A) on chromosome 2p16 18 and 19 identified this factor as an important regulator of HbF expression. Subsequent studies have shown that BCL11A binds to an intergenic region in the β-globin locus and has a dominant silencing effect on murine embryonic β-type βH1 and εγ-globin, as well as human ε- and ɣ-globin gene expression in β-YAC transgenic mice. 12 and 20 Knockdown of BCL11A in cultured primary human adult erythroid cells also results in a significant upregulation of ɣ-globin gene expression, although the magnitude of this effect is much less than in the β-YAC mouse model.19 The transcription factor SOX6 also mediates embryonic βH1 and εγ-globin gene silencing in the mouse, and it is known to interact with SCH772984 chemical structure BCL11A.21 and 22 Krüppel-like factor 1(KLF1), originally known as erythroid KLF, EKLF was initially shown to be critical Palbociclib for adult β-globin gene transcription,23 and to increase the ability of the β-globin promoter to compete with the ɣ-globin promoter for the enhancer function of the erythroid-specific β-globin locus control region.24 and 25 A more direct role of KLF1 in ɣ-globin gene silencing occurs through its stimulation of BCL11A expression. 26 and 27 The MYB gene has also been implicated in regulating HbF

levels through both quantitative trait locus studies and functional assays. 18, 28, 29 and 30 A number of other transcription Meloxicam factors have been implicated in embryonic-fetal β-type globin gene silencing. These include transcription factor that binds to the DNA sequence GATA (GATA1) in association with FOG1 and the nucleosome remodeling and deacetylase (NuRD) complex,31, 32, 33 and 34 nuclear factor erythroid 4 (NFE4),35 the TR2/TR4/direct repeat erythroid definitive (DRED) complex,36 and 37 Ikaros in association with the SWI/SNF-related protein complex coregulatory complex.38 As the transcription factors involved in fetal globin gene silencing have been

recently reviewed, the remaining part of this review will focus primarily on epigenetic silencing mechanisms.39 There are only a few examples in which an epigenetic modification of DNA or a chromosomal protein has a direct effect on structure or function.40 An exception is histone acetylation, which does appear to directly alter chromatin structure.11 and 41 In most cases, epigenetic marks serve as a recognition signal for a protein or protein complex, which ultimately carries out the specific associated regulatory function. A useful organizing concept for identifying potential targets for perturbing epigenetic fetal globin gene silencing is that of writers and readers. Writers are the enzymes that deposit or remove an epigenetic mark, whereas readers are the proteins or complexes that interpret those marks and carry out the associated regulatory function.

Our hypothesis is further supported by previous data from our laboratory showing that (PhSe)2-induced

LDH inhibition was attenuated or abolished by NADH (Lugokenski et al., selleck inhibitor 2011). These data indicate that NADH can modulate enzyme conformation preventing the critical thiols from the attack by organochalcogens. Based on the presented results, we suggest that organochalcogen-induced mitochondrial complex I inhibition is linked to their interaction with critical thiol groups present in the active site of the NADH:ubiquinone oxidoreductase (Lin et al., 2002). As mentioned above, the complex I inhibition by organochalcogens was more pronounced than complex II. We suggest that, despite of succinate dehydrogenase (SDH) being described to possess sulfhydryl group essential for catalytic activity, located in the substrate site (Le-Quoc et al., 1981), the organochalcogens-induced mitochondrial complex II inhibition could be due to their interaction with other thiols critical to enzyme activity, than that located in the active site of the SDH (Lin et al., 2002). Our data are further supported by previous data showing that complex II is less prone to inactivation than complex I (Cadenas and Davies, 2000, Orrenius et al., 2007 and Zhang

et al., 1990). Thus, based on the presented results (Fig. 5 and Fig. 7) we suggest that both complexes I and II were directly selleck compound affected by the organochalogens, being the thiols groups the molecular site of action for the organochalcogens. Our hypothesis is further supported by the data showing that organochalcogens induced complex I inhibition was not mediated by ROS formation (Figs. 4A–C). However, as seen in Fig. 6 and Fig. 8, (PhSe)2

has differential Protein kinase N1 effect on complex II in liver and kidney. At the present moment, these results are not completely understood, but they can be related to differences in the molecular composition of mitochondria obtained from different tissues (Benard et al., 2006). Thus, we speculate that the liver and kidney could present different contents and isoforms of complex II enzymes, which resulted in different inhibition by (PhSe)2. Our assumption is based on previous data showing that, at least, two different isoforms of complex II have been reported in the literature (Tomitsuka et al., 2003a, Tomitsuka et al., 2003b and Tomitsuka et al., 2009). In addition to complexes I and II, the activities of the mitochondrial complexes III and IV (both from rat liver and kidney) were practically not targeted by organocompounds. In fact, mitochondrial complex III was minimally inhibited by the treatment with studied compounds, whereas complex IV was nearly unchanged. Thus, organochalcogens possibly did not inhibit mitochondrial complexes III and IV due to steric hindrance of their sulfhydryl groups to the organochalcogens (Lin et al., 2002). Our findings are supported by previous report showing that thiol groups from complex IV are less prone to oxidation than that from complex I (Orrenius et al., 2007).

Purified CD4+ (~ 97%) and CD8+ T (~ 98%) cells were isolated from the PBMCs using anti-CD4 and anti-CD8 mAbs conjugated MACS beads. PBMCs (5 × 106 cells/ml) or purified CD4+ and CD8+ T cells (1 × 106 cells/ml) in RPMI 1640 supplemented with 10% FCS were stimulated this website with

either 5 μg/ml PHA, co-stimulated with plate bound 5 μg/ml anti-CD3 (OKT3 mAb) and 2.5 μg/ml anti-CD28 in the absence or presence of caspase inhibitors for various time periods in an atmosphere of 5% CO2 in air at 37 °C. Proliferating T cells were derived by activating purified CD4+ and CD8+ T cells with PHA for 24 h and then reseeded in media supplemented with rIL-2 (25 Units/ml). The activated T cells were cultured for 7 days prior to use. The human leukemic

T cell line, Jurkat, clone E6-1 (ATCC) were maintained in logarithmic phase of growth in RPMI 1640 supplemented with 10% FCS and 2 mM L-Glutamine in an atmosphere of 5% CO2 in air at 37 °C. To induce apoptosis, Jurkat T cells (1 × 106 cells/ml) or activated T cells (1 × 106 cells/ml) in complete medium were stimulated with recombinant Flag-tagged FasL (100 ng/ml) followed by cross-linking with anti-Flag (1 μg/ml) for 16 h. Apoptotic cells were determined using mTOR inhibitor UV microscopy, annexin V staining and TMRE labelling of mitochondria as previously described (Jayaraman, 2005 and Johnson et al., 2000). Cell viability was determined by suspending treated cells in 500 μl ice-cold PBS with 10 μl of 20 μg/ml propidium iodide (PI) and the uptake of PI was analysis using flow cytometry. T cell proliferation following mitogen Tacrolimus (FK506) stimulation was determined using [3H]-thymidine incorporation. In brief, PBMCs or purified T cells were seeded at 1 × 106 cells/ml

in 96 well plates and stimulated with either PHA (5 μg/ml) or co-stimulated with anti-CD3 mAb (5 μg/ml) and anti-CD28 mAb (2.5 μg/ml) in the presence or absence of caspase inhibitors. The cells were cultured for 72 h with the last 16 h pulsed with [3H]-labelled methyl-thymidine (0.037 MBq) prior to harvest onto glass fibre filter mats using a Tomtec automated multi-well harvester (Perkin Elmer Life Sciences, Boston USA). Wallac Betaplate scintillation reagent (Perkin Elmer Life Sciences) was added to the glass fibre filter mats and the radioactivity was determined on a 1450 Microbeta liquid scintillation counter (Perkin Elmer Life Sciences, Boston USA). T lymphocyte division following mitogen stimulation was determined using CFSE labelling of the cells (Lyons and Parish, 1994). In brief, PBMCs were suspended in PBS at a density of 5 × 107/ml and incubated with 5 μM CFSE at 37 °C for 10 minutes. Following incubation with CFSE the labelled PBMCs were washed twice in RPMI to remove excess CFSE. The CFSE labelled cells were treated with mitogens as previously described in the presence or absence of caspase inhibitors.

In the microarray analysis, combination therapy had reduced expression of genes in the integrin-mediated cell adhesion pathway and signaling of HGF receptor pathway compared to bevacizumab monotherapy. These data may indicate the mechanisms underlying the anti-invasive effects of cilengitide on glioma. We showed that bevacizumab and cilengitide reduced tumor vascularity by changing the diameter and density of tumor vessels Ipilimumab manufacturer in the in vivo glioma

models. von Baumgarten et al. reported that bevacizumab decreased vascular density and normalized the vascular permeability of glioma [27]. Conversely, cilengitide was shown to shrink the diameter of tumor vessels in angiogenesis-dependent invasive glioma models [13]. Moreover, we investigated the ultra-microstructure of tumor vessels and proved that bevacizumab reduced the distance between endothelial DAPT cells and tumor cells with a broken basal lamina at the blood-brain barrier in the border of the tumor. We also focused on the ECM of gliomas, which

is considered to play as a critical regulator of angiogenesis and invasiveness [28]. In the center area of U87ΔEGFR tumors following bevacizumab treatment and combination therapy of bevacizumab and cilengitide, ECMs were thickened remarkably at perivascular space with respectively different characteristics. Fibronectin, vitronectin, laminin, tenascin, and different types of collagen promote invasion of glioma [29] and [30]; in contrast, glycosylated chondroitin

sulfate proteoglycans consisting ECMs inhibit invasion in glioma [31]. These different mechanisms might be necessary for the regulation of tumor angiogenesis Resveratrol and invasion; however, the detailed mechanisms have not been elucidated and they need to be clarified in the future. This study showed that anti-VEGF therapy induced glioma invasion despite its intense antiangiogenic effect; however, the combination of bevacizumab with the αvβ3 and αvβ5 integrin inhibitor cilengitide exerted a significant anti-invasive effect. We revealed that combination therapy suppressed the integrin-mediated cell adhesion pathway as an underlying mechanism of its anti-invasive effect. We thank M. Furutani, M. Arao, and N. Uemori for their technical assistance. The following medical students also contributed to the animal experiments: K. Fukumoto and N. Hayashi. Cilengitide was generously provided by Merck KGaA and the Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health. Bevacizumab was generously provided by Genentech/Roche/Chugai Pharmaceutical Co. “
“Lung cancer is the most common cancer in the world, and non–small cell lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer. Platinum-based chemotherapy is the standard first-line care for NSCLC [1] and [2].

Additionally, false positives (i.e. non-carcinogens detected as mutagens) do occur GSK126 in vitro in the Ames test. There are a small number of compounds that are Ames positive mutagens due to their bacterium-specific metabolism e.g. sodium azide and some nitro-group containing compounds (Prival, 1983). The strains of Salmonella typhimurium used in the Ames test contain different mutations in various histidine synthesis genes ( Table 1). The mutations carried by the specific strains prevent the bacteria from growing in media without histidine. However, if the test chemical mutates the defective mutation

back to functional status (revert initial mutation), the bacteria will acquire the ability to grow in histidine-free media and form colonies. These colonies are thus known as revertants ( Ames et al., 1975). All strains except TA102 are missing the uvrB DNA repair gene, thus removing the main error-free DNA excision repair pathway, compared to wild-type cells. This will amplify the mutations as DNA repair, in the absence of excision repair, occurs by error-prone

pathways. TA102 bacteria strain maintains the excision repair system to be able to detect DNA cross-linking agents such as mitomycin C. Otherwise compounds with DNA cross-link mechanism of action will not be detected, as unrepaired cross-links are lethal to the cell. In addition, all strains have the mutation known as deep rough or rfa genotype. This is an alteration of the phenotype, where the polysaccharide capsule surrounding the cell is no longer www.selleckchem.com/products/atezolizumab.html present. Therefore, larger compounds are able to enter through the cell membrane reaching the bacterial DNA. Various strains possess the plasmid pKM101 which contains the operon muc. Enzymes encoded by this operon allow the damaged DNA to continue its synthesis. The effect of Ribose-5-phosphate isomerase this operon is to amplify the translation of DNA damage to mutations. The plasmid also contains a gene coding for resistance to the antibiotic ampicillin. This ampicillin-resistant property

permits the selection of mutants containing the plasmid. Alternatively, some Escherichia coli strains can be used to screen for mutagens. These strains have base change mutations in one of the tryptophan synthesis operon genes (trpE) instead of the histidine operon genes. Strains with and without the uvrA mutation are available as are strains with and without the plasmid pKM101. E. coli WP2 strains are equivalent to TA102 in terms of types of mutagen detected (including oxidative mutagens). However, if a cross-linking effect is to be detected, then the E. coli strain must have an intact excision repair system. The rfa mutation is not required as E. coli cells are naturally permeable to larger molecules. Each strain of bacteria used in the Ames test detects a different spectrum of mutagens.

An alternative perspective holds that the meanings Venetoclax nmr of abstract words are heavily dependent on the linguistic context in which they are being used (in line with the idea that knowledge of abstract words is tied strongly to language use). Initial evidence for this proposal was presented by Schwanenflugel and colleagues (Schwanenflugel et al., 1988 and Schwanenflugel

and Shoben, 1983), who noted that when participants were presented with an abstract word, they found it hard to generate a plausible context in which it could be used. More recently, Hoffman, Lambon Ralph, and Rogers (2013) conducted a quantitative analysis of the contextual usage of a large set of words, using a measure of contextual variability called semantic diversity. They found that abstract words tended to appear in a broader variety of contexts than did concrete words. We have argued that the greater semantic diversity of abstract words means that they place greater demands on executive semantic

control processes that provide top-down regulation of knowledge ( Hoffman et al., 2010 and Hoffman et al., 2011). Semantic control processes interact with semantic representations to ensure that the information accessed at any given moment is appropriate to the current task and context ( Badre and Wagner, 2002, Linsitinib manufacturer Jefferies, 2013, Jefferies and Lambon Ralph, 2006 and Thompson-Schill et al., 1997). Because abstract words can occur in many different contexts, with different semantic information potentially required in each, top-down control of knowledge retrieval is thought to be particularly critical for successful comprehension of these words. In summary, there are two perspectives on the nature of differences between concrete and abstract words, one proposing differences in the types and quantity of semantic knowledge involved in each and one proposing

differential involvement of semantic control processes in each as a result of contextual variability. These two perspectives have often been treated as competing Adenosine triphosphate hypotheses (e.g., Binder, Westbury, McKiernan, Possing, & Medler, 2005). In this study, we evaluated a different possibility: namely that both perspectives are correct but that they apply to different neural regions within the semantic network. Semantic control is most strongly associated with the left inferior frontal gyrus (IFG) (Badre and Wagner, 2007 and Thompson-Schill et al., 1997). This region shows increases in activation when participants select among semantic competitors (Badre et al., 2005 and Thompson-Schill et al., 1997) and when semantic ambiguity must be resolved (Bedny et al., 2008, Rodd et al., 2005 and Zempleni et al., 2007).

Subsequently, the maximal treadmill exercise test was repeated to evaluate aerobic performance. The non-aerobically trained groups (Control and OVA) were not submitted to the AE protocol and were instead adapted to the treadmill for 3 days per week (8% inclination, 0.3 km/h, 5 min per session) until the last treadmill exercise test. Forty-eight hours after the last session of training and OVA or saline inhalation, all animals were anesthetized with sodium thiopental (170 mg/kg, i.p.), tracheostomized, and mechanically ventilated (60 breaths/min; 6 ml/kg of tidal volume)

with a mechanical ventilator for small animals Selleckchem Alectinib (Harvard, Rodent Ventilator Model 683, MA, USA) (Prado et al., 2005). Next, a sample of exhaled air was collected in a Mylar bag at the expiratory output valve for 5 min (Mehta et al., 1998 and Ramos et al., 2010). ENO was Entinostat supplier measured by chemiluminescences using a rapidly responding analyzer (NOA 280; Sievers Instruments, CO, USA). The equipment was calibrated before each measurement with a certified 47 parts per billion (ppb) NO source (White Martins, SP, BRA). To avoid environmental contamination, a zero NO filter (Sievers Instruments) was attached to the inspiratory input. The results were expressed as parts of ENO per billion. After ENO collection, a 3-cm incision was

made in the abdomen, and blood from the inferior cava vein was collected (5 ml). The animals were then exsanguinated by cutting the abdominal aorta. A positive end-expiratory pressure of 5 cmH2O with 4% paraformaldehyde

was applied through the cannulated trachea; the anterior chest wall was removed; and the lungs were removed en bloc and immediately immersed in 4% paraformaldehyde for 24 h. Next, sections were processed with paraffin embedding, and 5-μm slices were obtained and stained with click here hematoxylin and eosin for routine histological analysis and with Luna for eosinophil detection. Immunohistochemistry was also performed with anti-IL-4 (1:300), anti-IL-13 (1:150), anti-IL-2 (1:150), anti-IFN-γ (1:150), anti-IL-10 (1:50) and anti-IL-1ra (1:120) antibodies (Santa Cruz Biotechnology, Santa Cruz, CA, USA) using the biotin–streptavidin–peroxidase method ( Vieira et al., 2007 and Silva et al., 2010). The peribronchial density of eosinophils, lymphocytes, and cells positive for IL-4, IL-13, IFN-γ, IL-2, IL-10 and IL-1ra was assessed by conventional morphometry using an ocular microscope with an integrating eyepiece with 100-point and 50 lines (point-counting technique) with a known area (10,000 μm2) at 1000× magnification. Counting was performed in five non-cartilaginous airways per animal at 1000× magnification (Vieira et al., 2007). The results are expressed as cells per square millimeter.

Humans hunted seals and sea lions since at least the Terminal Pleistocene, but early records of pinniped hunting are scarce, with dramatic increases at some locations beginning around 1500 years ago ( Braje et al., 2011a, Braje et al., 2011b and Erlandson et al., 2013). One of the more interesting trends in

pinniped demographics during the Holocene compared to today is the changing abundance of Guadalupe fur seals and elephant seals ( Fig. 2c; Rick et al., 2009a and Rick et al., 2011). For much of the Holocene, Guadalupe fur seals are the most abundant taxa found in archeological sites, suggesting they were frequently encountered when hunting and scavenging. In contrast, elephant seals are rarely found in archeological sites, with just a handful of bones found in island (or mainland) sites. Both of these species were hunted to near selleck inhibitor extinction during the 18th–19th century global fur and oil trade. Following federal protection in the 1970s, populations have grown exponentially and

there are now more than 50,000 elephant seals in Alta California waters. Guadalupe fur seals, however, are very rare north of PF-06463922 clinical trial Mexico, with only a few observations during the last decade ( Rick et al., 2009a). These dramatic differences in abundance between Holocene seal and sea lion populations and those of today suggest that recovered pinniped populations are not ‘natural’ and are largely an artifact of management and conservation (see Braje et al., 2011a, Braje et al., 2011b and Erlandson et al., 2013). Seal and sea lion conservation can lead to debate between conservationists focused on the management of marine mammal populations and commercial fisheries concerned about shellfish and fish stocks that are common prey of pinnipeds and sea otters. Such conflicts have also begun in Hawaii with debate over monk seal conservation and the effects on Hawaiian fisheries and recreation. Finally, the extensive growth of some pinniped

populations in California demonstrates the conflicts between natural and cultural resource management, with pinnipeds hauling Exoribonuclease out on, disturbing, and destroying non-renewable archeological sites located on the shoreline of the Channel Islands and elsewhere (see Braje et al., 2011a and Braje et al., 2011b). The records of finfish and seabirds are just beginning to be explored in detail, but Braje et al. (2012) recently documented size changes in rockfish (Sebastes spp.), including estimates that many prehistoric specimens were larger than modern fishes. Chendytes lawi, an extinct flightless duck, appears to have been slowly pushed to extinction on the Channel Islands and mainland by human predation and other variables over several millennia ( Jones et al., 2008 and Rick et al., 2012a). Along with human hunting, the extinction of C.

The Chilia III lobe begun developing at the open coast sometimes around 1700 AD (Mikhailova and Levashova, 2001). Although still primitive, the earliest realistically detailed map of the Danube delta region dating from 1771 (Fig. 2a; Panin and Overmars, 2012) provides important information about the earliest growth phase of the lobe. Its wave-dominated

deflected morphology (sensu Bhattacharya and Giosan, 2003) is evident. Two thalwegs at the mouth separated by a submerged middle-ground bar are oriented southward in the direction of the dominant longshore drift. Updrift of the mouth, the offshore-recurving shape of the contemporary Jebrieni beach Gefitinib chemical structure plain ridges clearly indicates that the submarine deltaic deposition was already significant. Only a few islets were emergent on the

updrift side of the submarine channel, but a shallow submerged depositional platform appears to have developed on its downdrift side ( Fig. 2a). Subsequently, as recorded in numerous maps and charts since 1830 ( Fig. 4a), the Chilia III lobe evolved as a typical river-dominated delta in a frictional regime, which has led to repeated bifurcations LY294002 via formation of middle-ground bars ( Giosan et al., 2005). The influence of the longshore drift, expressed as a southward deflection of main distributary of Old Stambul, remained noticeable until the end of the 19th century as documented by a survey in 1871 (Fig. 4a). The isometric shape of the lobe acquired after that time resulted from the infilling of the shallow bay left between the deflected part delta plain and the mainland (Fig. 4a). Throughout the history of Chilia III growth, deltaic progradation was favored at northern Oceacov mouth, which advanced into the dominant direction of the waves, and the southern Old Stambul distributary mouth, which grew in the direction longshore drift. Slower progradation

is evident along the central coast (Fig. 4a) fed by eastward directed distributaries that had to contend with the strong longshore drift removing sediments GPX6 southward (Giosan et al., 2005). The decrease in new fluvial sediment delivered per unit shoreline as the lobe grew larger and advanced into deeper water resulted in progressively slower growth of the entire lobe in the 20th century (Fig. 4a). By 1940, clear signs of erosion were apparent, and a general erosional trend continues until today leading to a wave-dominated morphology characterized by barrier islands and spit development (Fig. 4b and c). Our reconstruction of the Chilia lobe evolution supports the idea that the rapid Danube delta growth in the late Holocene (Giosan et al., 2012) led to its radical reorganization via flow redistribution across the delta. Initially the southernmost St. George branch was reactivated around 2000 years BP and constructed the bulk of its wave-dominated open coast lobe (Fig. 1) in the last 1000–1500 years (Giosan et al., 2006 and Giosan et al.