Scaling of bird wings and feathers for efficient flight.

Aves are an incredibly diverse class of animals, ranging greatly in size and thriving in a wide variety of environments. Here, we explore the scaling trends of bird wings in connection with their flight performance. The tensile strength of avian bone is hypothesized to be a limiting factor in scaling the humerus with mass, which is corroborated by its experimentally determined allometric scaling trend. We provide a mechanics analysis that explains the scaling allometry of the wing humerus length, L H, with body weight W, L H ∝ W 0.44. Lastly, wing feathers are demonstrated to generally scale isometrically with bird mass, with the exception of the spacing between barbules, which falls within the same range for birds of all masses. Our findings provide insight into the "design" of birds and may be translatable to more efficient bird-inspired aircraft structures.

Protein stabilization by RSUME accounts for PTTG pituitary tumor abundance and oncogenicity.

Increased levels of the proto-oncogene pituitary tumor-transforming gene 1 (PTTG) have been repeatedly reported in several human solid tumors, especially in endocrine-related tumors such as pituitary adenomas. Securin PTTG has a critical role in pituitary tumorigenesis. However, the cause of upregulation has not been found yet, despite analyses made at the gene, promoter and mRNA level that show that no mutations, epigenetic modifications or other mechanisms that deregulate its expression may explain its overexpression and action as an oncogene. We describe that high PTTG protein levels are induced by the RWD-containing sumoylation enhancer (RWDD3 or RSUME), a protein originally identified in the same pituitary tumor cell line in which PTTG was also cloned. We demonstrate that PTTG and RSUME have a positive expression correlation in human pituitary adenomas. RSUME increases PTTG protein in pituitary tumor cell lines, prolongs the half-life of PTTG protein and regulates the PTTG induction by estradiol. As a consequence, RSUME enhances PTTG transcription factor and securin activities. PTTG hyperactivity on the cell cycle resulted in recurrent and unequal divisions without cytokinesis, and the consequential appearance of aneuploidies and multinucleated cells in the tumor. RSUME knockdown diminishes securin PTTG and reduces its tumorigenic potential in a xenograft mouse model. Taken together, our findings show that PTTG high protein steady state levels account for PTTG tumor abundance and demonstrate a critical role of RSUME in this process in pituitary tumor cells.

Intrahypophyseal Immune-Endocrine Interactions: Endocrine Integration of the Inflammatory Inputs.

Endotoxin (lipopolysaccharide, LPS) of gram-negative bacteria has been recognized for more than 40 years as a modulator of anterior pituitary hormone production. The action of LPS was thought to be predominantly mediated through LPS-stimulated immune cell-derived cytokines, and is part of the concept of immune-endocrine crosstalk, which regulates bidirectional adaptive processes between the endocrine and immune systems during inflammatory or infectious processes. With the detection of innate immune system components in the normal and tumoral pituitary, including the Toll-like receptor 4, the target of LPS, it has become evident that LPS can directly modify the physiology and pathophysiology of the anterior pituitary. LPS-induced intrapituitary mechanisms involve the stimulation of intrapituitary cytokines, and also directly act on hormone synthesis, growth, and apoptosis of endocrine cells. This review focuses on the effects of LPS on pituitary physiology, its interaction with pro- and anti-inflammatory factors, and the molecular mechanisms involved in these processes.

Hierarchical bioinspired adhesive surfaces-a review.

The extraordinary adherence and climbing agility of geckos on rough surfaces has been attributed to the multiscale hierarchical structures on their feet. Hundreds of thousands of elastic hairs called setae, each of which split into several spatulae, create a large number of contact points that generate substantial adhesion through van der Waals interactions. The hierarchical architecture provides increased structural compliance on surfaces with roughness features ranging from micrometers to millimeters. We review synthetic adhesion surfaces that mimic the naturally occurring hierarchy with an emphasis on microfabrication strategies, material choice and the adhesive performance achieved.

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51.

FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.

RSUME inhibits VHL and regulates its tumor suppressor function.

Somatic mutations or loss of von Hippel-Lindau (pVHL) happen in the majority of VHL disease tumors, which present a constitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. Recently described mechanisms for pVHL modulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determine the molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role of RSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL and negatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF-1 and 2α ubiquitination and degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytoma and hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen-dependent degradation stability reporter assay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHL interaction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in which RSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2α, vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumor progression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function.

Curcumin acts anti-proliferative and pro-apoptotic in human meningiomas.

Meningiomas, the most frequent benign intracranial and intraspinal types of tumors are normally removed by surgery. Complications can occur when the tumor is critically localized and cannot be completely removed or when comorbidities of the mostly elder patients increase the general surgical risk. Thus, alternate medical treatment concepts for the therapy of meningiomas would be desirable. Curcumin, the active ingredient of the spice plant Curcuma longa has shown anti-tumorigenic actions in many different types of tumors and therefore, its effect on growth and apoptosis of meningioma cells was studied in the present paper. In vitro, treatment of the human Ben-Men-1 meningioma cell line and of a series of 21 primary human meningioma cell cultures with curcumin (1-20 µM) strongly reduced the proliferation in all cases in a dose dependent manner. Cell cycle analysis by fluorescence-activated cell sorting showed growth arrest at G2/M phase, which was confirmed by demonstrating the corresponding modulation of proteins involved in G2/M arrest by immunoblotting and/or confocal laser microscopy. High dosages (20, 50 µM) of curcumin induced a significant increase of apoptosis in Ben-Men-1 and primary meningioma cell cultures as demonstrated by morphological changes of cell nuclei, DNA fragmentation, translocation of cell membrane associated phosphatidyl serine and the induction of apoptotic-acting cleaved caspase-3. Our results suggest that the multi-targeting drug curcumin has potent anti-tumorigenic actions in meningioma cells and might therefore be a putative candidate for the pharmacological treatment of meningiomas.

Fabrication of metal nanoparticle arrays by controlled decomposition of polymer particles.

We report a novel fabrication method for ordered arrays of metal nanoparticles that exploits the uniform arrangement of polymer beads deposited as close-packed monolayers. In contrast to colloidal lithography that applies particles as masks, we used thermal decomposition of the metal-covered particles to precisely define metal structures. Large arrays of noble metal (Au, Ag, Pt) nanoparticles were produced in a three-step process on silicon, fused silica and sapphire substrates, demonstrating the generality of this approach. Polystyrene spheres with diameters ranging between 110 nm and 1 µm were convectively assembled into crystalline monolayers, coated with metal and annealed in a resistive furnace or using an ethanol flame. The thermal decomposition of the polymer microspheres converted the metal layer into particles arranged in hexagonal arrays that preserved the order of the original monolayer. Both the particle size and the interparticle distance were adjusted via the thickness of the metal coating and the sphere diameter, respectively.

Curcumin suppresses HIF1A synthesis and VEGFA release in pituitary adenomas.

Curcumin (diferuloylmethane), a polyphenolic compound derived from the spice plant Curcuma longa, displays multiple actions on solid tumours including anti-angiogenic effects. Here we have studied in rodent and human pituitary tumour cells the influence of curcumin on the production of hypoxia inducible factor 1α (HIF1A) and vascular endothelial growth factor A (VEGFA), two key components involved in tumour neovascularisation through angiogenesis. Curcumin dose-dependently inhibited basal VEGFA secretion in corticotroph AtT20 mouse and lactosomatotroph GH3 rat pituitary tumour cells as well as in all human pituitary adenoma cell cultures (n=32) studied. Under hypoxia-mimicking conditions (CoCl(2) treatment) in AtT20 and GH3 cells as well as in all human pituitary adenoma cell cultures (n=8) studied, curcumin strongly suppressed the induction of mRNA synthesis and protein production of HIF1A, the regulated subunit of the hypoxia-induced transcription factor HIF1. Curcumin also blocked hypoxia-induced mRNA synthesis and secretion of VEGFA in GH3 cells and in all human pituitary adenoma cell cultures investigated (n=18). Thus, curcumin may inhibit pituitary adenoma progression not only through previously demonstrated anti-proliferative and pro-apoptotic actions but also by its suppressive effects on pituitary tumour neovascularisation.

Note: An adhesion measurement setup for bioinspired fibrillar surfaces using flat probes.

Current adhesion measurement setups designed for experiments on bioinspired fibrillar surfaces, either commercial or constructed in-house, do not allow adhesion measurements with in situ visualization, high resolution, high force range, and controlled alignment at the same time. In this paper a new adhesion tester is presented, which enables contact experiments with controlled tilt angle (accuracy of ±0.02°). This allows the use of flat probes and thus greatly simplifies the determination of experimental parameters such as pull-off strength or Young's modulus. The deflection of a double-clamped glass beam is measured by laser interferometry with an accuracy of ±60 nm, which yields a precise force measurement over three orders of magnitude force range without changing the glass beam. Contact formation and detachment events can be visualized in situ. The current adhesion tester is designed for force measurements in the range of 1 µN to 1 N and fills the gap between macroscopic tests and atomic force microscopy measurements.

RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells.

The recently cloned small RWD-domain containing protein RSUME was shown to increase protein levels of hypoxia-inducible factor-1α (HIF-1α). The latter is the oxygen-regulated subunit of HIF-1, the most important transcription factor of the cellular adaptive processes to hypoxic conditions. It is also a major regulator of vascular endothelial growth factor-A (VEGF-A), which is critically involved in the complex process of tumour neovascularisation. In this study, the expression and role of RSUME in pituitary tumours was studied. We found that RSUME mRNA was up-regulated in pituitary adenomas and significantly correlated with HIF-1α mRNA levels. Hypoxia (1% O(2)) or treatment with hypoxia-mimicking CoCl(2) enhanced RSUME and HIF-1α expression, induced translocation of HIF-1α to the nuclei and stimulated VEGF-A production both in pituitary tumour cell lines and primary human pituitary adenoma cell cultures. When RSUME expression was specifically down-regulated by siRNA, the CoCl(2)-induced increase VEGF-A secretion was strongly reduced which was shown to be a consequence of the RSUME knockdown-associated reduction of HIF-1α synthesis. Thus, RSUME plays an important role in initiating pituitary tumour neovascularisation through regulating HIF-1α levels and subsequent VEGF-A production and may therefore be critically involved in pituitary adenoma progression.

Novel medical therapies for pituitary tumors.

Despite considerable progress, there is still no medical treatment available for some kinds of pituitary tumors, in particular hormone inactive adenomas and corticotroph pituitary tumors. Surgical removal or at least debulking of the tumor is the only option to treat these kinds of tumors apart from rarely applied radiotherapy. Moreover, treatment resistance is present in a considerable proportion of patients bearing pituitary tumors, for which medical treatment regimens are already available (prolactinomas, somatotroph adenomas). Thus, novel or improved medical treatment strategies would be desirable. Here, we summarize preclinical and clinical findings about the hormone and growth-suppressive action of various drugs, which will probably lead to novel future medical treatment concepts for pituitary tumors.

In vitro adhesion measurements between skin and micropatterned poly(dimethylsiloxane) surfaces.

Micropatterned adhesive surfaces may have potential in reconstructive surgery. The adhesion performance of mice ear skin to micropatterned poly(dimethylsiloxane) (PDMS) was investigated, under in vitro conditions, and compared to flat substrates. No significant difference in separation force F was observed between flat substrates and micropatterned surfaces with pillar arrays. However, the energy necessary for separation of the substrate from the skin was sensitive to the topography. Furthermore, our results show that the force-displacement curves depended on the wetness of the skin: Highest force values were obtained for fresh skin while the forces decreased as the skin dried out. The results are encouraging for further studies on the potential of patterned PDMS in biomedical applications.

Correlation between critical temperature and strength of small-scale bcc pillars.

Microcompression tests were performed on focused-ion-beam-machined micropillars of several body-centered-cubic metals (W, Mo, Ta, and Nb) at room temperature. The relationship between yield strength and pillar diameter as well as the deformation morphologies were found to correlate with a parameter specific for bcc metals, i.e., the critical temperature T(c). This finding sheds new light on the phenomenon of small-scale plasticity in largely unexplored non-fcc metals.

Curcumin acts as anti-tumorigenic and hormone-suppressive agent in murine and human pituitary tumour cells in vitro and in vivo.

Curcumin (diferuloylmethane) is the active ingredient of the spice plant Curcuma longa and has been shown to act anti-tumorigenic in different types of tumours. Therefore, we have studied its effect in pituitary tumour cell lines and adenomas. Proliferation of lactosomatotroph GH3 and somatotroph MtT/S rat pituitary cells as well as of corticotroph AtT20 mouse pituitary cells was inhibited by curcumin in monolayer cell culture and in colony formation assay in soft agar. Fluorescence-activated cell sorting (FACS) analysis demonstrated curcumin-induced cell cycle arrest at G2/M. Analysis of cell cycle proteins by immunoblotting showed reduction in cyclin D(1), cyclin-dependent kinase 4 and no change in p27(kip). FACS analysis with Annexin V-FITC/7-aminoactinomycin D staining demonstrated curcumin-induced early apoptosis after 3, 6, 12 and 24 h treatment and nearly no necrosis. Induction of DNA fragmentation, reduction of Bcl-2 and enhancement of cleaved caspase-3 further confirmed induction of apoptosis by curcumin. Growth of GH3 tumours in athymic nude mice was suppressed by curcumin in vivo. In endocrine pituitary tumour cell lines, GH, ACTH and prolactin production were inhibited by curcumin. Studies in 25 human pituitary adenoma cell cultures have confirmed the anti-tumorigenic and hormone-suppressive effects of curcumin. Altogether, the results described in this report suggest this natural compound as a good candidate for therapeutic use on pituitary tumours.

Amygdaloid pERK1/2 in corticotropin-releasing hormone overexpressing mice under basal and acute stress conditions.

Corticotropin-releasing hormone (CRH) coordinates neuroendocrine and behavioral adaptations to stress. Acute CRH administration in vivo activates extracellular signal-regulated kinase 1/2 (ERK1/2) in limbic brain areas, acting through the CRH receptor type 1 (CRH-R1). In the present study, we used CRH-COE-Cam mice that overexpress CRH in limbic-restricted areas, to analyze the effect of chronic CRH overexpression on ERK1/2 activation. By immunohistochemistry and confocal microscopy analysis we found that pERK1/2 levels in the basolateral amygdala (BLA) were similar in control and CRH overexpressing mice under basal conditions. Acute stress caused comparably increased levels of corticosterone in both control (CRH-COEcon-Cam) and CRH overexpressing (CRH-COEhom-Cam) animals. CRH-COEhom-Cam mice after stress showed reduced pERK1/2 immunoreactivity in the BLA compared to CRH-COEhom-Cam animals under basal conditions. Radioligand binding and in situ hybridization revealed higher density of CRH-R1 in the amygdala of CRH-COEhom mice under basal conditions compared to control littermates. A significant reduction of the receptor levels was observed in this area after acute stress, suggesting that stress may trigger CRH-R1 internalization/downregulation in these CRH overexpressing mice. Chronic CRH overexpression leads to reduced ERK1/2 activation in response to acute stress in the BLA.

Capillary forces between chemically different substrates.

Motivated by experimental results, we present numerical and analytical calculations of the capillary force exerted by a capillary bridge spanning the gap between two parallel flat plates of asymmetric wettability. Depending on whether the sum of the two contact angles is smaller or larger than 180 degrees, the capillary force is either attractive or repulsive at small separations D between the plates. In either cases the magnitude of the force diverges as D approaches zero. The leading order of this divergence is captured by an analytical expression deduced from the geometry of the meniscus of a flat capillary bridge. The results for substrates with different wettability reveal an interesting behavior: with the sum of the contact angles fixed, the magnitude of the capillary force and the rupture separation decreases as the asymmetry in contact angles is increased. In addition, we present the rupture separation, i.e., the maximal extension of a capillary bridge, as a function of the contact angles. Our results provide an extensive picture of surface wettability effects on capillary adhesion.

Enhancement of capillary forces by multiple liquid bridges.

Capillary forces can significantly contribute to the adhesion of biological and artificial micro- and nanoscale objects. In this paper, we study numerically the effect of meniscus size on the force between two homogeneous flat plates for different contact angles. The force distance curves show excellent quantitative agreement with previous investigations. The results for n menisci of equal total liquid volume reveal interesting scaling properties and an unexpected maximum force for moderately hydrophilic surfaces (i.e., contact angles around 70 degrees ). Further, we calculate the minimum solid-liquid area for multiple bridges, the cohesive stress (i.e., force per area) between the plates, and the work required to separate them. The results are presented in two-dimensional maps, which may be useful in the understanding of biological attachment structures and in the design of artificial contact systems.

The effect of shape on the adhesion of fibrillar surfaces.

Experimental data have demonstrated that mushroom-shaped fibrils adhere much better to smooth substrates than punch-shaped fibrils. We present a model that suggests that detachment processes for such fibrils are controlled by defects in the contact area that are confined to its outer edge. Stress analysis of the adhered fibril, carried out for both punch and mushroom shapes with and without friction, suggests that defects near the edge of the adhesion area are much more damaging to the pull-off strength in the case of the punch than for the mushroom. The simulations show that the punch has a higher driving force for extension of small edge defects compared with the mushroom adhesion. The ratio of the pull-off force for the mushroom to that of the punch can be predicted from these simulations to be much greater than 20 in the friction-free case, similar to the experimental value. In the case of sticking friction, a ratio of 14 can be deduced. Our analysis also offers a possible explanation for the evolution of asymmetric mushroom shapes (spatulae) in the adhesion organ of geckos.

Effect of contact angle hysteresis on the measurement of capillary forces.

We conduct experimental investigations of macroscopic capillary forces between two flat rigid substrates characterized by their advancing and receding contact angles with water. Our results exhibit excellent agreement with theoretical predictions obtained by the numerical solution of the capillary equation. On the basis of this comparison, we use the measurements of the capillary force to investigate the phenomenon of contact angle hysteresis. We present examples of force measurements for surfaces that display low, moderate, and high contact angle hysteresis and compare results for a larger variety of substrates. Finally, we show that for the case of water, the role of viscosity is insignificant within the range of force and velocity measured in the present work.