Structure and mineralization of the spearing mantis shrimp (Stomatopoda; Lysiosquillina maculata) body and spike cuticles.

Stomatopoda is a crustacean order including sophisticated predators called spearing and smashing mantis shrimps that are separated from the well-studied Eumalacotraca since the Devonian. The spearing mantis shrimp has developed a spiky dactyl capable of impaling fishes or crustaceans in a fraction of second. In this high velocity hunting technique, the spikes undergo an intense mechanical constraint to which their exoskeleton (or cuticle) has to be adapted. To better understand the spike cuticle internal architecture and composition, electron microscopy, X-ray microanalysis and Raman spectroscopy were used on the spikes of 7 individuals (collected in French Polynesia and Indonesia), but also on parts of the body cuticle that have less mechanical stress to bear. In the body cuticle, several specificities linked to the group were found, allowing to determine the basic structure from which the spike cuticle has evolved. Results also highlighted that the body cuticle of mantis shrimps could be a model close to the ancestral arthropod cuticle by the aspect of its biological layers (epi- and procuticle including exo- and endocuticle) as well as by the Ca-carbonate/phosphate mineral content of these layers. In contrast, the spike cuticle exhibits a deeply modified organization in four functional regions overprinted on the biological layers. Each of them has specific fibre arrangement or mineral content (fluorapatite, ACP or phosphate-rich Ca-carbonate) and is thought to assume specific mechanical roles, conferring appropriate properties on the entire spike. These results agree with an evolution of smashing mantis shrimps from primitive stabbing/spearing shrimps, and thus also allowed a better understanding of the structural modifications described in previous studies on the dactyl club of smashing mantis shrimps.

Localization and Bioreactivity of Cysteine-Rich Secretions in the Marine Gastropod Nucella lapillus.

Marine biodiversity has been yielding promising novel bioproducts from venomous animals. Despite the auspices of conotoxins, which originated the paradigmatic painkiller Prialt, the biotechnological potential of gastropod venoms remains to be explored. Marine bioprospecting is expanding towards temperate species like the dogwhelk Nucella lapillus, which is suspected to secrete immobilizing agents through its salivary glands with a relaxing effect on the musculature of its preferential prey, Mytilus sp. This work focused on detecting, localizing, and testing the bioreactivity of cysteine-rich proteins and peptides, whose presence is a signature of animal venoms and poisons. The highest content of thiols was found in crude protein extracts from the digestive gland, which is associated with digestion, followed by the peribuccal mass, where the salivary glands are located. Conversely, the foot and siphon (which the gastropod uses for feeding) are not the main organs involved in toxin secretion. Ex vivo bioassays with Mytilus gill tissue disclosed the differential bioreactivity of crude protein extracts. Secretions from the digestive gland and peribuccal mass caused the most significant molecular damage, with evidence for the induction of apoptosis. These early findings indicate that salivary glands are a promising target for the extraction and characterization of bioactive cysteine-rich proteinaceous toxins from the species.

Persistent polyamorphism in the chiton tooth: From a new biomineral to inks for additive manufacturing.

Engineering structures that bridge between elements with disparate mechanical properties are a significant challenge. Organisms reap synergy by creating complex shapes that are intricately graded. For instance, the wear-resistant cusp of the chiton radula tooth works in concert with progressively softer microarchitectural units as the mollusk grazes on and erodes rock. Herein, we focus on the stylus that connects the ultrahard and stiff tooth head to the flexible radula membrane. Using techniques that are especially suited to probe the rich chemistry of iron at high spatial resolution, in particular synchrotron Mössbauer and X-ray absorption spectroscopy, we find that the upper stylus of Cryptochiton stelleri is in fact a mineralized tissue. Remarkably, the inorganic phase is nano disperse santabarbaraite, an amorphous ferric hydroxyphosphate that has not been observed as a biomineral. The presence of two persistent polyamorphic phases, amorphous ferric phosphate and santabarbaraite, in close proximity, is a unique aspect that demonstrates the level of control over phase transformations in C. stelleri dentition. The stylus is a highly graded material in that its mineral content and mechanical properties vary by a factor of 3 to 8 over distances of a few hundred micrometers, seamlessly bridging between the soft radula and the hard tooth head. The use of amorphous phases that are low in iron and high in water content may be key to increasing the specific strength of the stylus. Finally, we show that we can distill these insights into design criteria for inks for additive manufacturing of highly tunable chitosan-based composites.

Quantitative determination of proxalutamide in rat plasma and tissues using liquid chromatography/tandem mass spectrometry.

RATIONALE: Proxalutamide is a novel drug for the treatment of prostate cancer. However, to date, there are almost no reports on the pharmacokinetics of proxalutamide in vivo. This study developed a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method to determine the concentrations of proxalutamide in biological samples for pharmacokinetic studies. METHODS: Chromatographic separation was achieved on a Kromasil 100-5C8 column followed by gradient elution using a Shimadzu HPLC system. MS was performed in positive ion electrospray ionization mode using a SCIEX API 4000 triple quadrupole system. A simple and rapid one-step protein precipitation method was used for sample processing, and a low sample volume of 10 µL was used for processing and analysis. RESULTS: The method was validated to show good selectivity, sensitivity, precision, and accuracy. Good linearity (r2 > 0.99) was observed for rat plasma (range: 2-5000 ng/mL) and rat tissue homogenates (range: 2-2000 ng/mL). The extraction recovery was above 98%, and no significant matrix effect was observed. This method was successfully applied to investigate the pharmacokinetics and tissue distribution of proxalutamide in rats. CONCLUSIONS: A rapid and sensitive LC/MS/MS method was developed and validated to determine the quantity of proxalutamide in rat plasma and tissue homogenates and to further study the pharmacokinetic parameters of proxalutamide in a rat model. The results showed that proxalutamide had good oral bioavailability and wide tissue distribution in vivo.

Unravelling the ultrastructure and mineralogical composition of fireworm stinging bristles.

Amphinomid fireworms are notorious for their stinging dorsal bristles (notochaetae), but it is still unclear whether the irritation they cause is merely mechanical or if the notochaetae contain toxins. Furthermore, although fireworm chaetae have always been described as calcareous, their composition has never been investigated to date and strong debates are ongoing on their internal structure. Unravelling the native ultrastructure and composition of fireworm chaetae is the first crucial step to assess whether the hypothesis of toxin vehiculation could be fully considered. We examined for the first time the chemical and mineralogical composition, the ultrastructure and the external structure of the dorsal and ventral chaetae of the large species Hermodice carunculata. All the measurements were carried out on samples prepared without the use of chemical reagents, except for those targeted to investigate if decalcification altered the ultrastructure of the chaetae. A crystal-chemical strategy, combining chemical, diffraction and thermal analyses clearly showed the occurrence of crystalline calcium carbonate and clusters of phosphatic amorphous material. Scanning electron micrographs and energy dispersive X-ray measurements showed that the dorsal chaetae have an extremely shallow insertion point in the body respect to the ventral chaetae, that could facilitate the release of the notochaetae in the environment. Their proximal part is characterized by canals with a hexagonal pattern rich in Ca and P, followed by a large cavity upwards. The harpoon-shaped ends and the central canals of the notochaetae completely disappeared after exposure to EDTA. The notochaetae are hollow and may be able to vehicle toxins. The absence of the honeycomb pattern in the distal part of the notochaetae and their slenderness probably contribute to their brittleness and high sensitivity to breakage on contact. These observations constitute keystone understandings to shed light on fireworm defensive and offensive capacities and their ecological success.

Toxicokinetics of diisobutyl phthalate and its major metabolite, monoisobutyl phthalate, in rats: UPLC-ESI-MS/MS method development for the simultaneous determination of diisobutyl phthalate and its major metabolite, monoisobutyl phthalate, in rat plasma, urine, feces, and 11 various tissues collected from a toxicokinetic study.

The aim of this study was to explore the toxicokinetics of diisobutyl-phthalate (DiBP) and its major metabolite, monoisobutyl-phthalate (MiBP), by developing a UPLC-ESI-MS/MS method for simultaneously measuring DiBP and MiBP in rat plasma, urine, feces, and 11 different tissues. For the experiment, 0.1% (v/v) aqueous formic acid and acetonitrile mobile phase by gradient elution at a flow rate of 0.3 mL/min, equipped with a KINETEX core-shell C18-column (50 × 2.1 mm, 1.7 µm), was used to completely separate analytes. The mass transitions were m/z 279.1 â†’ 149.0 for DiBP, 221.0 â†’ 77.0 for MiBP, and 283.2 â†’ 153.0 for DiBP-d4 as an internal standard. The developed assay had lower limits of quantification of 0.01 ng/mL for DiBP and 0.1 ng/mL for MiBP at all biological matrices. Toxicokinetics of DiBP were characterized by extensive distribution, short half-life, and high clearance. DiBP was rapidly metabolized to MiBP, with MiBP levels consistently exceeding the DiBP levels. Distribution of MiBP to tissues was considerable. The developed analytical method satisfied international criteria and was successfully applied to toxicokinetic studies after oral and intravenous administration of DiBP to rats. Findings of this study may be useful for evaluating the external exposure and toxic potential of DiBP and its metabolite in risk assessment.

Hierarchically-structured metalloprotein composite coatings biofabricated from co-existing condensed liquid phases.

Complex hierarchical structure governs emergent properties in biopolymeric materials; yet, the material processing involved remains poorly understood. Here, we investigated the multi-scale structure and composition of the mussel byssus cuticle before, during and after formation to gain insight into the processing of this hard, yet extensible metal cross-linked protein composite. Our findings reveal that the granular substructure crucial to the cuticle's function as a wear-resistant coating of an extensible polymer fiber is pre-organized in condensed liquid phase secretory vesicles. These are phase-separated into DOPA-rich proto-granules enveloped in a sulfur-rich proto-matrix which fuses during secretion, forming the sub-structure of the cuticle. Metal ions are added subsequently in a site-specific way, with iron contained in the sulfur-rich matrix and vanadium coordinated by DOPA-catechol in the granule. We posit that this hierarchical structure self-organizes via phase separation of specific amphiphilic proteins within secretory vesicles, resulting in a meso-scale structuring that governs cuticle function.

A reliable and cost-efficient TLC-HPLC method for determining total florfenicol residues in porcine edible tissues.

It is still a challenge to solve the matrix interferences in veterinary drug residue analysis. In this study, we reported a thin layer chromatography (TLC)-high-performance liquid chromatography (HPLC) method for determining total florfenicol (FF) residues, expressed as florfenicol amine (FFA), in porcine edible tissues. The tissue homogenate were acid-hydrolyzed to liberate the bound residues and convert them into FFA. The hydrolysates were washed with ethyl acetate and subsequently extracted with ethyl acetate under alkaline conditions. The supernatants were concentrated through evaporation, defatted with hexane, purified by TLC and analyzed by HPLC at 225 nm. The optimal developing solvent for TLC purification was ethyl acetate-acetone-ammonium hydroxide mixtures (2:8:0.5, v/v/v). The method was fully validated according to decision 2002/657/EC, and could be used for the routine monitoring of FF residues in pig. TLC showed excellent purification efficiency, and was expected to solve the matrix interferences in veterinary drug residue analysis.

Sabellaria alveolata sandcastle worm from the Mediterranean Sea: new insights on tube architecture and biocement.

The Atlantic-Mediterranean polychaete Sabellaria alveolata lives in agglutinated tubes adjoined to each other to form discrete reef-like bioconstructions in shallow-water settings characterised by high hydrodynamic energy where sediment particles are constantly resuspended. Tubes are built with sand grains glued by proteinaceous secretions. Analyses of a reef fragment collected near Sampieri (SE Sicily, Sicily Strait) allowed the first detailed description of the tube architecture and biocement of this worms from the Mediterranean. The tube consists of an inner thin organic membrane and three agglutinated layers including: (a) a thin inner layer of flat grains arranged side by side; (b) a thick mid layer with a frame of relatively large sub-rounded grains with cavities partly filled by small grains; and (c) a thin outer layer of large, flat to curved, usually biogenic clasts diverging towards the opening. This particular architecture is distinctive of the family. Morphological and epifluorescence observations revealed that biocement consists of drops at the contact between sub-spherical grains and strips along edges of flat grains. Biocement is a solid foam-like material characterised by high abundance of carbon; the presence of phosphorous and nitrogen confirms its proteinaceous composition. Due to the electrostatic interaction with the proteins, calcium and magnesium are most likely complexed to the cement rather than being trapped in the cells. These elements contribute to the solidification of the glue and stabilisation of the tube structure. However, the organic nature of cement and the high energy of their habitat, make sabellariid reefs dynamic and ephemeral, and the preservation as fossils unlikely, with a confident record only extending back to the Miocene.

Intraspecific Cuticular Chemical Profile Variation in the Social Wasp Mischocyttarus consimilis (Hymenoptera, Vespidae).

Chemical compounds present on the cuticle of social insects are important in communication, as they are used in recognition of nestmates and sexual partners as well as in caste distinction, varying according to several factors, such as genetic and environmental. In this context, some studies have explored the cuticular chemical profile as a tool for assessing intra- and interspecific differences in social insects, although few studies have investigated this in social wasps. This study aimed to assess the differences in cuticular chemical profiles among different geographic samples of the wasp Mischocyttarus consimilis Zikán. Our hypothesis was that environmental factors are decisive to compose the cuticular chemical profiles of colonies of these social wasps and that there are differences regarding the geographic distribution among colonies. We used Fourier Transform Infrared-Photoacoustic Spectroscopy (FTIR-PAS) to assess the chemical profiles of samples. Our results show that despite there are differences between the cuticular chemical composition of the wasps' samples from different populations, there is no significant correlation compared to the spatial distribution of the colonies nor with the environment. Thus, our hypothesis was refuted, and we can infer that in this species neither exogenous nor genetic factors stand out to differentiate the chemical signature of their colonies, but a combination of both.

Construction and Composition of the Squid Pen from Doryteuthis pealeii.

The pen, or gladius, of the squid is an internalized shell. It serves as a site of attachment for important muscle groups and as a protective barrier for the visceral organs. The pen's durability and flexibility are derived from its unique composition of chitin and protein. We report the characterization of the structure, development, and composition of pens from Doryteuthis pealeii. The nanofibrils of the polysaccharide ß-chitin are arranged in an aligned configuration in only specific regions of the pen. Chitin is secreted early in development, enabling us to characterize the changes in pen morphology prior to hatching. The chitin and proteins are assembled in the shell sac surrounded by fluid that has a significantly different ionic composition from squid plasma. Two groups of proteins are associated with the pen: those on its surface and those embedded within the pen. Only 20 proteins are identified as embedded within the pen. Embedded proteins are classified into six groups, including chitin associated, protease, protease inhibitors, intracellular, extracellular matrix, and those that are unknown. The pen proteins share many conserved domains with proteins from other chitinous structures. We conclude that the pen is one of the least complex, load-bearing, chitin-rich structures currently known and is amenable to further studies to elucidate natural construction mechanisms using chitin and protein.

The structure and properties of natural sheep casing and artificial films prepared from natural collagen with various crosslinking treatments.

The structure and properties of natural sheep casing and collagen films with various crosslinking treatments have been investigated in detail to develop satisfied artificial casings prepared from collagen. The sheep casing consists of large number of thick collagen fibers oriented at ±45° from longitudinal direction with high-density interwoven network structure. The structural feature of sheep casing gave the special mouthfeel of 'cracking bite' of sausages. Whereas, layered structure filled with fine collagen fibrils and large gaps in collagen film results in poor mechanical properties and higher swelling ratio in water. Furthermore, a degree of denaturation of collagen during extraction process also lead to poor mechanical properties. After glutaraldehyde (GTA) and dehydrothermal (DHT) treatments, the formation of crosslinking improved mechanical properties of collagen films significantly and the tensile strength and tensile modulus increased more than three times compared with those of untreated collagen film in wet before and after boiling. The swelling ratio of treated collagen films also decreased dramatically. No obvious effects on denaturation of collagen film after GTA treatment, but the degree of denaturation of DHT treated collagen film increased slightly.

Quantitative MALDI Imaging of Spatial Distributions and Dynamic Changes of Tetrandrine in Multiple Organs of Rats.

Detailed spatio-temporal information on drug distribution in organs is of paramount importance to assess drug clinically-relevant properties and potential side-effects. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) as a label-free and sensitive imaging modality provides an additional means of accurately visualizing drug and its metabolites distributions in tissue sections. However, technical limitations, complex physiochemical environment of surface and low abundance of target drugs make quantitative MALDI imaging of drug and its metabolites quite challenging. Methods: In this study, an internal standard correction strategy was applied for quantitative MALDI imaging of tetrandrine in multiple organs of rats including lung, liver, kidney, spleen, and heart. The feasibility and reliability of the developed quantitative MSI method were validated by conventional liquid chromatography-tandem MS (LC-MS/MS) analysis, and the two methods showed a significant correlation. Results: The quantitative MALDI imaging method met the requirements of specificity, sensitivity and linearity. Tissue-specific spatio-temporal distribution patterns of tetrandrine in different organs were revealed after intravenous administration in the rat. Moreover, demethylated metabolite was detected in liver tissues. Conclusions: The current work illustrates that quantitative MALDI imaging provides an alternative means of accurately addressing the problem of drug and its metabolites distribution in tissues, complementary to traditional LC-MS/MS of tissue homogenates and whole-body autoradiography (WBA). Quantitative spatio-chemical information obtained here can improve our understanding of pharmacokinetics (PK), pharmacodynamics (PD), and potential transient toxicities of tetrandrine in organs, and possibly direct further optimization of drug properties to reduce drug-induced organ toxicity.

Structural and Mass Spectrometric Imaging Analyses of Adhered Tunic and Adhesive Projections of Solitary Ascidians.

Most ascidian species settle on underwater substrates during a short free-swimming tadpole larval period. During this process, "rapid adhesion" occurs on adhesive papillae located at the anterior region of the cephalenteron. Settled and transformed ascidians subsequently expand the attachment area by "slow adhesion" with ampullae. In the present study, we attempted to identify the ultrastructures related to the adhesion process and adhesive materials in the ascidian tunic and to elucidate the biological function of vanadium in adhesion. We focused on an adhesive organ named the adhesive projection, which is newly generated by the adhered tunic to enlarge the bonding area between ascidian and substrate. Based on its structure and the presence of vanadiumcontaining blood cells, the adhesive projection was considered to be a large tunic vessel. At the adhered tunic, eosinophilic regions and migrated tunic cells were observed, but metal deposition was not detected. We speculate that the eosinophilic materials were components of the adhesive glue, and these are likey produced in epithelial cells, tunic cells, or both. Furthermore, using imaging mass spectrometry, we identified eight tunic-specific molecules as glue candidates.

Organochlorine pesticides and polychlorinated biphenyls in the Bering flounder (Hippoglossoides robustus) from the Sea of Okhotsk.

The purpose of this study is to establish the presence of POPs in the Bering flounder (Hippoglossoides robustus) from the Sea of Okhotsk (North-West Pacific). Concentration of OCPs (α-HCH, ß-HCH, γ-HCH, o,p'-DDT, p,p'-DDT, o,p'-DDD, p,p'-DDD, o,p'-DDE and p,p'-DDE) and PCBs (28, 52, 155, 101, 118, 143, 153, 138, 180, 207) in samples were measured by GC-MS and GC-ECD. The mean OCP concentrations in flounder from East and South areas of the Sea of Okhotsk were 99.8 ±â€¯125.4 and 53.6 ±â€¯40.5 ng/g lipid, respectively; PCB congeners - 112 ±â€¯94.2 and 88.8 ±â€¯50.8 ng/g lipid, respectively. POPs in fish tissue decreased in the order: PCBs > HCHs > DDTs. Our results indicate that consumers will have no health risk due to fish consumption from Sea of Okhotsk. OCP and PCB levels in the Sea of Okhotsk may be considered as background level for the North Pacific.

Experimental degradation of helicoidal photonic nanostructures in scarab beetles (Coleoptera: Scarabaeidae): implications for the identification of circularly polarizing cuticle in the fossil record.

Scarab beetles (Coleoptera: Scarabaeidae) can exhibit striking colours produced by pigments and/or nanostructures. The latter include helicoidal (Bouligand) structures that can generate circularly polarized light. These have a cryptic evolutionary history in part because fossil examples are unknown. This suggests either a real biological signal, i.e. that Bouligand structures did not evolve until recently, or a taphonomic signal, i.e. that conditions during the fossilization process were not conducive to their preservation. We address this issue by experimentally degrading circularly polarizing cuticle of modern scarab beetles to test the relative roles of decay, maturation and taxonomy in controlling preservation. The results reveal that Bouligand structures have the potential to survive fossilization, but preservation is controlled by taxonomy and the diagenetic history of specimens. Further, cuticle of specific genus (Chrysina) is particularly decay-prone in alkaline conditions; this may relate to the presence of certain compounds, e.g. uric acid, in the cuticle of these taxa.

Hypoxia weakens mussel attachment by interrupting DOPA cross-linking during adhesive plaque curing.

Marine mussels (Mytilus spp.) attach to a wide variety of surfaces underwater using a network of byssal threads, each tipped with a protein-based adhesive plaque that uses the surrounding seawater environment as a curing agent. Plaques undergo environmental post-processing, requiring a basic seawater pH be maintained for up to 8 days for the adhesive to strengthen completely. Given the sensitivity of plaques to local pH conditions long after deposition, we investigated the effect of other aspects of the seawater environment that are known to vary in nearshore habitats on plaque curing. The effect of seawater temperature, salinity and dissolved oxygen concentration were investigated using tensile testing, atomic force microscopy and amino acid compositional analysis. High temperature (30°C) and hyposalinity (1 PSU) had no effect on adhesion strength, while incubation in hypoxia (0.9 mg l-1) caused plaques to have a mottled coloration and prematurely peel from substrates, leading to a 51% decrease in adhesion strength. AFM imaging of the plaque cuticle found that plaques cured in hypoxia had regions of lower stiffness throughout, indicative of reductions in DOPA cross-linking between adhesive proteins. A better understanding of the dynamics of plaque curing could aid in the design of better synthetic adhesives, particularly in medicine where adhesion must take place within wet body cavities.

Anthocyanin Tissue Bioavailability in Animals: Possible Implications for Human Health. A Systematic Review.

Anthocyanins (ACNs) are promising health-enhancing phenolic compounds. We focus on ACN animal tissue bioavailability to provide an evidentiary link between tissue ACNs and their associated health properties. We performed a systematic review of electronic libraries; 279 results were retrieved, and 13 publications met inclusion criteria. Extracted information included animal model employed, administration route, doses, analysis method, and ACN concentration values in tissues. Total ACN concentrations were detected in mice kidney (2.17 × 105 pmol/g), liver (1.73 × 105 pmol/g), heart (3.6 × 103 pmol/g), and lung (1.16 × 105 pmol/g); and in pig brain (6.08 × 103 pmol/g). ACNs showed a predominance of parent ACNs in long-term experiments versus an ACN metabolite predominance in short-term experiments. ACNs detected in animal tissues, such as cyanidin-3-glucoside, suggest it may have an important role in human health. This information could be useful to determine proper ACN-intake biomarkers in biological samples in futures studies.

Pharmacokinetics and biodistribution of polymeric micelles containing miRNA and small-molecule drug in orthotopic pancreatic tumor-bearing mice.

Rationale: Successful treatment of pancreatic cancer remains a challenge due to desmoplasia and prevalence of KRAS mutation. While hedgehog (Hh) ligand levels are upregulated in pancreatic cancer cells and contribute to desmoplasia, there is significant downregulation of tumor suppressor let-7b, which targets mutant KRAS, C-MYC and several other genes involved in pancreatic cancer progression, invasion, and metastasis. We recently explored combination therapy of GDC-0449 (Hh inhibitor) and let-7b mimic using poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol-graft-tetraethylenepentamine) (PEG-b-PCC-g-DC-g-TEPA) micelles in pancreatic tumor mouse model. Here, our objective was to determine the biodistribution (BD), pharmacokinetics (PK), therapeutic efficacy and toxicity of this micellar formulation. Methods: We determined the PK of micelles encapsulating Cy5.5-let-7b and GDC-0449 following intravenous injection in orthotopic pancreatic tumor-bearing NSG mice at doses of 2 mg/kg and 10 mg/kg, respectively. Mice were scanned for fluorescence by IVIS to determine the biodistribution of Cy5.5-let-7b at the whole-body level, and its concentration in plasma and major organs was determined by measuring fluorescence using a fluorimeter and by real-time RT-PCR. GDC-0449 concentration was determined by LC/MS/MS. Therapeutic efficacy and toxicity of the micellar formulation of let-7b and GDC-0449 was also determined after two weeks of treatment. Results: The use of a micellar formulation markedly prolonged the elimination half-life (t1/2, e) of Cy5.5-let-7b in plasma from 0.49 ± 0.19 h to 2.65 ± 0.46 h and increased the area-under-the-curve (AUC 0-∞ ) by 7-fold, while t1/2,e and AUC 0-∞ of GDC-0449 were increased by 1.78-fold and 3.2-fold, respectively. The micelles significantly decreased the clearance of both encapsulated let-7b mimic and GDC-0449 compared to the emulsion formulation. Compared to the emulsion counterpart, the micellar formulation elevated the delivery of Cy5.5-let-7b and GDC-0449 to the orthotopic pancreatic tumor tissue by 7.8- and 4.2-fold, respectively. Furthermore, there was a significant reduction in tumor volume and negligible systemic toxicity as evident by hematological parameters and histological evaluation. Conclusion: PEG-b-PCC-g-DC-g-TEPA micelles carrying GDC-0449 and let-7b mimic have great potential to improve drug delivery for pancreatic cancer treatment.

Are stable isotope ratios and oscillations consistent in all baleen plates along the filtering apparatus? Validation of an increasingly used methodology.

RATIONALE: Baleen plates are anatomical structures composed of inert tissue that hang from the upper jaw in mysticetes. Baleen plates may differ in size and in coloration between different segments of the filtering row or between sides of the mouth. Concern has been raised that variation in baleen plate characteristics may reflect dissimilar structural composition and growth rates liable to affect stable isotope ratios and their oscillation patterns. METHODS: We measured stable carbon (δ13 C values) and nitrogen (δ15 N values) isotope ratios at intervals of 1 cm along the longitudinal axis of six baleen plates collected from different positions along the mouth of a fin whale. All samples were analysed using a continuous flow isotope ratio mass spectrometer. Generalized additive models were fitted to the data from each baleen plate and the results of the models were compared visually. RESULTS: A total of 206 samples were analysed. Visually, all baleen plates presented nearly identical oscillations, independent of the position or the coloration of the baleen plate. However, the variation in δ13 C and δ15 N values occurring between the different baleen plates was higher in the segments of oscillations exhibiting steeper slopes. CONCLUSIONS: Differences in size between plates in an individual are due to differential erosion rates according to their position in the mouth. Therefore, the position of sampling along the baleen plate row should not be a reason for concern when conducting stable isotope studies.