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Zusammenfassung Das VGF-Verfahren ist ein moderner Prozess zur Züchtung von Einkristallen, der Grundlage für nahezu alle elektronischen Anwendungen. Die sukzessive Erstarrung der Schmelze zum Einkristall wird dabei durch geeignete Ansteuerung der als Aktoren in der Anlage zur Verfügung stehenden Heizer realisiert. Dieses Regelungsproblem ist Gegenstand des Beitrags, wobei der Schwerpunkt auf einer anschaulichen und einführenden Darstellung der Thematik und weniger den mathematischen Details liegt. Basierend auf einem Modell des Kristallzüchtungsprozesses, das partielle Differentialgleichungen für die Wärmediffusion in Schmelze und Kristall beinhaltet und aufgrund der Übergangsbedingung an der Phasengrenze als zweiphasiges Stefan-Problem bezeichnet wird, werden zwei Entwürfe von Folgereglern vorgestellt. Ein flachheitsbasierter Ansatz nutzt eine endlichdimensionale Approximation des Modells, während eine mittels Backstepping entworfene Zustandsrückführung unendlichdimensional ist. Beide Regler werden in umfangreichen Simulationsstudien validiert und miteinander verglichen.

The hyperbolic distributed-parameter system under consideration comprises a second-order partial differential equation that is bidirectionally coupled with a first-order ordinary differential equation. The system models the transmission at a pneumatic test bench with boundary control and collocated measurement, yet stands in place for several other lossy or loss-free transmission problems. In the paper, an observer-based output feedback tracking controller is designed using the concept of flatness. It is a design based on normal forms, as both the state feedback tracking controller and the state observer are derived using canonical coordinates, which in turn rely on special parametrizations of the system’s solutions. Additionally, a new transformation between the coordinates of the so-called hyperbolic controller and observer canonical form is presented that allows for the implementation of the observer-based controller. Overall, the closed-loop system is exponentially stable. Simulation results illustrate the tracking behavior.

This article deals with the backstepping design of observer-based compensators for parabolic ODE–PDE–ODE systems. The latter consist of $\boldsymbol {n}$ coupled parabolic PDEs with distinct diffusion coefficients and spatially-varying coefficients, that are bidirectionally coupled to ODEs at both boundaries. The actuation and sensing appears through these ODEs resulting in a challenging control problem. For this setup a systematic backstepping approach is proposed, in order to determine a state feedback controller and an observer. In particular, the state feedback loop and the observer error dynamics are mapped into stable ODE–PDE–ODE cascades by making use of a sequence of transformations. With this, the design can be traced back to the solution of kernel equations already found in the literature as well as initial and boundary value problems, that can be solved numerically. Exponential stability of the closed-loop system is verified, wherein the decay rate can be directly specified in the design. The results of the article are illustrated by the output feedback control of an unstable ODE–PDE–ODE system with two coupled parabolic PDEs.

The backstepping design of stabilizing state feedback controllers is addressed for bidirectionally coupled ODE-PDE-ODE systems, that naturally arise for infinite-dimensional systems where actuator or sensor dynamics are taken into account. A common framework for both linear parabolic and hyperbolic partial differential equations with spatially varying coefficients is presented, that solely relies on the strict feedback form of these systems. Without imposing any limitation on the dimension of the ODEs and PDEs involved, a multi-step design algorithm is suggested, that makes use of classical concepts (such as integrator backstepping and output zeroing) known for the control of ODE systems. By that, backstepping is brought back to its ODE origins and a systematic design of backstepping controllers for ODE-PDE-ODE systems is offered, with a unified treatise for parabolic and hyperbolic PDEs.

This paper introduces an approach to trajectory tracking control of linear 2×2 hyperbolic partial differential equations (PDEs) actuated at one boundary and coupled with ordinary differential equations (ODEs) at the other one. Well-known state feedback methods that benefit from so-called backstepping coordinates are limited to the case of boundary conditions consisting of linear time-invariant ODEs. In a first step, the new approach is introduced for this restricted class of linear dynamic boundary conditions. It is shown that tracking control is immediately achieved by a surprisingly simple, yet elegant, modification of a stabilizing state feedback. Then, a direct extension for solving trajectory tracking problems for a class of nonlinear ODEs at the unactuated boundary is discussed. Numerical studies underline the performance of the proposed method.

Resilin is a protein matrix in movable regions of the cuticle conferring resistance to fatigue. The main component of Resilin is Pro-Rresilin that polymerises via covalent di- and tri-tyrosine bounds (DT). Loss of Pro-Resilin is nonlethal and causes a held-down wing phenotype (hdw) in the fruit fly Drosophila melanogaster. To test whether this mild phenotype is recurrent in other insect species, we analysed resilin in the spotted-wing fruit fly Drosophila suzukii. As quantified by DT autofluorescence by microscopy, DT intensities in the trochanter and the wing hinge are higher in D. suzukii than in D. melanogaster, while in the proboscis the DT signal is stronger in D. melanogaster compared to D. suzukii. To study the function of Pro-Resilin in D. suzukii, we generated a mutation in the proresilin gene applying the Crispr/Cas9 technique. D. suzukii pro-resilin mutant flies are flight-less and show a hdw phenotype resembling respective D. melanogaster mutants. DT signal intensity at the wing hinge is reduced but not eliminated in D. suzukii hdw flies. Either residual Pro-Resilin accounts for the remaining DT signal or, as proposed for the hdw phenotype in D. melanogaster, other DT forming proteins might be present in Resilin matrices. Interestingly, DT signal intensity reduction rates in D. suzukii and D. melanogaster are somehow different. Taken together, in general, the function of Pro-Resilin seems to be conserved in the Drosophila genus; small differences in DT quantity, however, allow us to hypothesise that Resilin matrices might be modulated during evolution probably to accommodate the species-specific lifestyle.

Zusammenfassung Der systematische Zugang zum Backstepping-Entwurf von Zustandsrückführungen für gekoppelte ODE-PDE-ODE-Systeme, die sich zumeist für verteilt-parametrische Prozesse unter Berücksichtigung der Dynamik von Aktoren und Sensoren ergeben, erlaubt nicht nur die sukzessive und vereinfachte Herleitung von bereits bekannten Backstepping-Reglern sondern ermöglicht auch deren Entwurf für bisher nicht betrachtete Systemklassen. Der Zugang nutzt dabei die diesen Systemen inhärente strenge Rückkopplungsform aus. Wie beim klassischen Integrator-Backstepping wird das ODE-PDE-ODE-System schrittweise durch virtuelle Zustandsrückführungen stabilisiert und der Zustand in Fehlerkoordinaten überführt. Der vorgeschlagene, modulare Entwurf ist dabei im Wesentlichen unabhängig davon, ob der verteilt-parametrische Teil des Systems parabolisch oder hyperbolisch ist.

This contribution is concerned with the motion planning for underactuated Euler-Bernoulli beams. The design of the feedforward control is based on a differential parametrization of the beam, where all system variables are expressed in terms of a free time function and its infinitely many derivatives. In the paper, we derive an advantageous representation of the set of all formal differential parametrizations of the beam. Based on this representation, we identify a well-known parametrization, for the first time without the use of operational calculus. This parametrization is a flat one, as the corresponding series representations of the system variables converge. Furthermore, we discuss a formal differential parametrization where the free time function allows a physical interpretation as the bending moment at the unactuated boundary. Even though the corresponding series do not converge, a numerical simulation using a least term summation illustrates the usefulness of this formal differential parametrization for the motion planning.

Introduction: Phosphate homeostasis is regulated by a complex network involving the parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and calcitriol acting on several organs including the kidney, intestine, bone, and parathyroid gland. Previously, we showed that activation of the Janus kinase 1 (Jak1)-signal transducer and activator of transcription 3 (Stat3) signaling pathway leads to altered mineral metabolism with higher FGF23 levels, lower PTH, and higher calcitriol levels. Here, we investigated if there are sex differences in the role of Jak1/Stat3 signaling pathway on phosphate metabolism and if this pathway is sensitive to extracellular phosphate alterations. Methods: We used a mouse model (Jak1S645P+/−) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans and analyzed the impact of sex on mineral metabolism parameters. Furthermore, we challenged Jak1S645P+/− male and female mice with a high (1.2% w/w) and low (0.1% w/w) phosphate diet and a diet with phosphate with organic origin with lower bioavailability. Results: Female mice, as male mice, showed higher intact FGF23 levels but no phosphaturia, and higher calcitriol and lower PTH levels in plasma. A phosphate challenge did not alter the effect of Jak1/Stat3 activation on phosphate metabolism for both genders. However, under a low phosphate diet or a diet with lower phosphate availability, the animals showed a tendency to develop hypophosphatemia. Moreover, male and female mice showed similar phosphate metabolism parameters. The only exception was higher PTH levels in male mice than those in females. Discussion/Conclusion: Sex and extracellular phosphate levels do not affect the impact of Jak1/Stat3 activation on phosphate metabolism.

Background Phosphate intake has increased in the last decades due to a higher consumption of processed foods. This higher intake is detrimental for patients with chronic kidney disease, increasing mortality and cardiovascular disease risk and accelerating kidney dysfunction. Whether a chronic high phosphate diet is also detrimental for the healthy population is still under debate. Methods We fed healthy mature adult mice over a period of 1 year with either a high (1.2% w/w) or a standard (0.6% w/w) phosphate diet, and investigated the impact of a high phosphate diet on mineral homeostasis, kidney function and bone health. Results The high phosphate diet increased plasma phosphate, parathyroid hormone (PTH) and calcitriol levels, with no change in fibroblast growth factor 23 levels. Urinary phosphate, calcium and ammonium excretion were increased. Measured glomerular filtration rate was apparently unaffected, while blood urea was lower and urea clearance was higher in animals fed the high phosphate diet. No change was observed in plasma creatinine levels. Blood and urinary pH were more acidic paralleled by higher bone resorption observed in animals fed a high phosphate diet. Total and cortical bone mineral density was lower in animals fed a high phosphate diet and this effect is independent of the higher PTH levels observed. Conclusions A chronic high phosphate intake did not cause major renal alterations, but affected negatively bone health, increasing bone resorption and decreasing bone mineral density.

The stability of extracellular matrices is in general ensured by cross-linking of its components. Previously, we had shown that the integrity of the layered Drosophila cuticle relies on the presence of a covalent cuticular dityrosine network. Production and composition of this structure remained unstudied. In this work, we present our analyses of the schlaff (slf) gene coding for a putative C-type lectin that is needed for the adhesion between the horizontal cuticle layers. The Slf protein mainly localizes between the two layers called epicuticle and procuticle that separate from each other when the function of Slf is reduced or eliminated paralleling the phenotype of a cuticle with reduced extracellular dityrosine. Localisation of the dityrosinylated protein Resilin to the epicuticle-procuticle interface suggests that the dityrosine network mediates the adhesion of the epicuticle to the procuticle. Ultimately, compromised Slf function is associated with massive water loss. In summary, we propose that Slf is implied in the stabilisation of a dityrosine layer especially between the epicuticle and the procuticle that in turn constitutes an outward barrier against uncontrolled water flow.

Mineral homeostasis is regulated by a complex network involving endocrine actions by calcitriol, parathyroid hormone (PTH), and FGF23 on several organs including kidney, intestine, and bone. Alterations of mineral homeostasis are found in chronic kidney disease and other systemic disorders. The interplay between the immune system and the skeletal system is not fully understood, but cytokines play a major role in modulating calcitriol production and function. One of the main cellular signaling pathways mediating cytokine function is the Janus kinase (JAK)--signal transducer and activator of transcription (STAT) pathway. Here, we used a mouse model (Jak1S645P+/- ) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans, and shows altered mineral metabolism, with higher fibroblast growth factor 23 (FGF23) levels, lower PTH levels, and higher calcitriol levels. The higher calcitriol levels are probably due to extrarenal calcitriol production. Furthermore, systemic Jak1/Stat3 activation led to growth impairment and skeletal alterations. The growth plate in long bones showed decreased chondrocyte proliferation rates and reduced height of terminal chondrocytes. Furthermore, we demonstrate that Jak1 is also involved in bone remodeling early in life. Jak1S645P+/- animals have decreased bone and cortical volume, imbalanced bone remodeling, reduced MAP kinase signaling, and local inflammation. In conclusion, Jak1 plays a major role in bone health probably both, directly and systemically by regulating mineral homeostasis. Understanding the role of this signaling pathway will contribute to a better knowledge in bone growth and in mineral physiology, and to the development of selective Jak inhibitors as osteoprotective agents.

Fibroblast growth factor 23 (FGF23) is a main regulator of mineral homeostasis. Low and high circulating FGF23 levels are associated with bone, renal, cardiovascular diseases, and increased mortality. Understanding the factors and signaling pathways affecting FGF23 levels is crucial for the management of these diseases and their complications. Here, we show that activation of the Jak1/Stat3 signaling pathway leads to inflammation in liver and to an increase in hepatic FGF23 synthesis, a key hormone in mineral metabolism. This increased synthesis leads to massive C-terminal FGF23 circulating levels, the inactive C-terminal fragment, and increased intact FGF23 levels, the active form, resulting in imbalanced production and cleavage. Liver inflammation does not lead to activation of the calcineurin-NFAT pathway, and no signs of systemic inflammation could be observed. Despite the increase of active intact FGF23, excessive C-terminal FGF23 levels block the phosphaturic activity of FGF23. Therefore, kidney function and renal αKlotho expression are normal and no activation of the MAPK pathway was detected. In addition, activation of the Jak1/Stat3 signaling pathway leads to high calcitriol levels and low parathyroid hormone production. Thus, JAK1 is a central regulator of mineral homeostasis. Moreover, this study also shows that in order to assess the impact of high FGF23 levels on disease and kidney function, the source and the balance in FGF23 production and cleavage are critical.

Graphical abstract, Highlights • Contact to Dithiothreitol (DTT), a widely used antioxidant, is lethal to the fruit fly Drosophila melanogaster. • At low concentrations, DTT contact induces the expression of some apoptosis genes. • In parallel, DTT triggers the expression of a cuticle barrier gene. • Expression of some genes involved in detoxification is intensified with increasing DTT concentrations. • Toxicity of DTT to the exnvironment should be tested., The thiol-containing compound Dithiothreitol (DTT) has been shown to be toxic to cultured cells by inducing the generation of reactive oxygen species that ultimately cause cell death. However, its effects on multicellular organisms and the environment have not been investigated yet in detail. In this work, we tested the toxicity of DTT to the model insect Drosophila melanogaster. We show that DTT is lethal to D. melanogaster by topical application but not through feeding. DTT treatment triggers the transcription of the canonical apoptosis regulators grim, hid and rpr at low amounts. The amplitude of this induction declines with elevating DTT amounts. By live microscopy, we observe apoptotic cells especially in the gut of DTT treated flies. In parallel, low DTT amounts also activate the expression of the cuticle barrier component gene snsl. This indicates that a physical defence response is launched upon DTT contact. This combined measure is seemingly successful in preventing fly death. The expression of a number of known detoxification genes including cyp6a2, cyp6a8, cyp12d1 and GstD2 is also enhanced through DTT contact. The degree of upregulation of these genes is proportional to the applied DTT amounts. Despite this effort, flies exposed to high amounts of DTT eventually die. Together, D. melanogaster is able to sense DTT toxicity and adjust the defence response successfully at least at low concentrations. This is the first time to analyse the molecular consequences of DTT exposure in a multicellular organism. Our work provides a new model to discuss the physiological response of animals against thiol toxins and to resurvey the effect of redox agents on the environment.

Prevention of desiccation is a constant challenge for terrestrial organisms. Land insects have an extracellular coat, the cuticle, that plays a major role in protection against exaggerated water loss. Here, we report that the ABC transporter Oskyddad (Osy)—a human ABCA12 paralog—contributes to the waterproof barrier function of the cuticle in the fruit fly Drosophila melanogaster. We show that the reduction or elimination of Osy function provokes rapid desiccation. Osy is also involved in defining the inward barrier against xenobiotics penetration. Consistently, the amounts of cuticular hydrocarbons that are involved in cuticle impermeability decrease markedly when Osy activity is reduced. GFP-tagged Osy localises to membrane nano-protrusions within the cuticle, likely pore canals. This suggests that Osy is mediating the transport of cuticular hydrocarbons (CHC) through the pore canals to the cuticle surface. The envelope, which is the outermost cuticle layer constituting the main barrier, is unaffected in osy mutant larvae. This contrasts with the function of Snu, another ABC transporter needed for the construction of the cuticular inward and outward barriers, that nevertheless is implicated in CHC deposition. Hence, Osy and Snu have overlapping and independent roles to establish cuticular resistance against transpiration and xenobiotic penetration. The osy deficient phenotype parallels the phenotype of Harlequin ichthyosis caused by mutations in the human abca12 gene. Thus, it seems that the cellular and molecular mechanisms of lipid barrier assembly in the skin are conserved during evolution., Author summary As in humans, lipids on the surface of the skin of insects protect the organism against excessive water loss and penetration of potentially harmful substances. During evolution, a greasy surface was indeed an essential trait for adaptation to life outside a watery environment. Here, we show that the membrane-gate transporter Oskyddad (Osy) is needed for the deposition of barrier lipids on the integument surface in the fruit fly Drosophila melanogaster through extracellular nano-tubes, called pore canals. In principle, the involvement of Osy parallels the scenario in humans, where the membrane-gate transporter ABCA12 is implicated in the construction of the lipid-based stratum corneum of the skin. In both cases, mutations in the genes coding for the respective transporter cause rapid water-loss and are lethal soon after birth. We conclude that the interaction between the organism and the environment obviously implies an analogous mechanism of barrier formation and function in vertebrates and invertebrates.

This paper examines the most important approaches that could be applied for the introduction of circular economy strategies for the banana production process in the region of Piura (Peru). Based on this, a framework for an optimized economic cycle that is able to conserve resources and minimize the capital investments of farmers, while simultaneously increasing their production, can be created. Challenges and potential solutions are discussed for the production stages.

This paper considers the backstepping design of observer-based compensators for general linear heterodirectional hyperbolic ODE–PDE–ODE systems, where the ODEs are coupled to the PDEs at both boundaries and the input appears in an ODE. A state feedback controller is designed by mapping the closed-loop system into a stable ODE–PDE–ODE cascade. This is achieved by representing the ODE at the actuated boundary in Byrnes–Isidori normal form. The resulting state feedback is implemented by an observer for a collocated measurement of the PDE state, for which a systematic backstepping approach is presented. The exponential stability of the closed-loop system is verified in the ∞-norm. It is shown that all design equations can be traced back to kernel equations known from the literature, to simple Volterra integral equations of the second kind and to explicitly solvable boundary value problems. This leads to a systematic approach for the boundary stabilization of the considered class of ODE–PDE–ODE systems by output feedback control. The results of the paper are illustrated by a numerical example.

Lipids in extracellular matrices (ECM) contribute to barrier function and stability of epithelial tissues such as the pulmonary alveoli and the skin. In insects, skin waterproofness depends on the outermost layer of the extracellular cuticle termed envelope that contains cuticulin, an unidentified water-repellent complex molecule composed of proteins, lipids and catecholamines. Based on live-imaging analyses of fruit fly larvae, we find that initially envelope units are assembled within putative vesicles harbouring the ABC transporter Snu and the extracellular protein Snsl. In a second step, the content of these vesicles is distributed to cuticular lipid-transporting nanotubes named pore canals and to the cuticle surface in dependence of Snu function. Consistently, the surface of snu and snsl mutant larvae is depleted from lipids and cuticulin. By consequence, these animals suffer uncontrolled water loss and penetration of xenobiotics. Our data allude to a two-step model of envelope i.e. barrier formation. The proposed mechanism in principle parallels the events occurring during differentiation of the lipid-based ECM by keratinocytes in the vertebrate skin suggesting establishment of analogous mechanisms of skin barrier formation in vertebrates and invertebrates.

This paper considers the flatness-based tracking control design for a pneumatic system, where a tank and a proportional valve are connected via a long transmission line of approximately 20 m. Motivated by this test bench set-up and the aim to implement fast pressure changes in the tank, three distributed-parameter models of different complexity and physical accuracy are presented, involving linear and quasi-linear hyperbolic partial differential equations. A flatness-based state feedback control is derived based on a linear distributed-parameter model of the pneumatic system. In combination with flatness-based feedforward controllers, designed for two of the three models, tracking controllers are obtained. Based on a simulation model of the test bench, verified to match the measurement data almost perfectly, the controllers are shown to execute fast pressure changes in the tank very accurately.

Solid-oxide fuel cells (SOFCs) represent a group of electrochemical conversion devices that utilise hydrogen rich fuels and are characterised by their high efficiency of energy conversion. For optimal exploitation of SOFCs, accurate and online state-of-health (SoH) assessment is of utmost importance. SoH assessment is usually performed through the frequency domain analysis by characterising the changes of the Nyqvist curves, a process also known as electrochemical impedance spectroscopy. Such an approach is time consuming and suffers from low accuracy particularly at low frequencies. Methodologies for time-domain identification of fractional-order systems offer a way of resolving these issues. Using an algebraic approach to identification, the complete fractional-order transfer function is identified from a series of several step responses. The SoH can be estimated from the identified parameters of the fractional-order transfer function either in a form of a Nyqvist curve or by directly linking particular parameter values to electrochemical processes. The proposed approach was validated on a 300 W SOFC using pure hydrogen fuel.

Elasticity prevents fatigue of tissues that are extensively and repeatedly deformed. Resilin is a resilient and elastic extracellular protein matrix in joints and hinges of insects. For its mechanical properties, Resilin is extensively analysed and applied in biomaterial and biomedical sciences. However, there is only indirect evidence for Resilin distribution and function in an insect. Commonly, the presence of dityrosines that covalently link Resilin protein monomers (Pro-Resilin), which are responsible for its mechanical properties and fluoresce upon UV excitation, has been considered to reflect Resilin incidence.Using a GFP-tagged Resilin version, we directly identify Resilin in pliable regions of the Drosophila body, some of which were not described before. Interestingly, the amounts of dityrosines are not proportional to the amounts of Resilin in different areas of the fly body, arguing that the mechanical properties of Resilin matrices vary according to their need. For a functional analysis of Resilin matrices, applying the RNA interference and Crispr/Cas9 techniques, we generated flies with reduced or eliminated Resilin function, respectively. We find that these flies are flightless but capable of locomotion and viable suggesting that other proteins may partially compensate for Resilin function. Indeed, localizations of the potentially elastic protein Cpr56F and Resilin occasionally coincide.Thus, Resilin-matrices are composite in the way that varying amounts of different elastic proteins and dityrosinylation define material properties. Understanding the biology of Resilin will have an impact on Resilin-based biomaterial and biomedical sciences.

In this paper the boundary control of linear 2 × 2 hyperbolic systems with spatially-varying coefficients and dynamic boundary conditions is considered. This leads to the stabilization problem for a bidirectionally coupled PDE-ODE system. For its solution a two-step backstepping approach is developed, that yields the usual kernel equations and additional decoupling equations of simple form. The latter can be traced back to a Volterra integral equation of the second kind, which is directly solvable with a successive approximation. The results of the paper are illustrated for a heavy rope with load.

Identification of fractional-order systems is considered from an algebraic point of view. The approach presented allows for a simultaneous estimation of model parameters and fractional (or integer) orders from input and output data. It is exact in that no approximations are required. Using the Laplace transform, algebraic manipulations are performed on the operational representation of the system. The unknown parameters and fractional orders are calculated solely from convolutions of known signals. A generalized Voigt model describing a viscoelastic material and a diffusion-wave equation representing a fractional partial differential equation are used to illustrate the approach.

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincided with expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.

Prevention of desiccation is a constant challenge for terrestrial organisms. Land insects have an extracellular coat, the cuticle, that plays a major role in protection against exaggerated water loss. Here, we report that the ABC transporter Torr - a human ABCA12 paralog - contributes to the waterproof barrier function of the cuticle in the fruit fly Drosophila melanogaster. We show that the reduction or elimination of Torr function provokes rapid desiccation. Torr is also involved in defining the inward barrier against xenobiotics penetration. Consistently, the amounts of cuticular hydrocarbons that are involved in cuticle impermeability decrease markedly when Torr activity is reduced. GFP-tagged Torr localises to membrane nano-protrusions within the cuticle, likely pore canals. This suggests that Torr is mediating the transport of cuticular hydrocarbons (CHC) through the pore canals to the cuticle surface. The envelope, which is the outermost cuticle layer constituting the main barrier, is unaffected in torr mutant larvae. This contrasts with the function of Snu, another ABC transporter needed for the construction of the cuticular inward and outward barriers, that nevertheless is implicated in CHC deposition. Hence, Torr and Snu have overlapping and independent roles to establish cuticular resistance against transpiration and xenobiotic penetration. The torr deficient phenotype parallels the phenotype of Harlequin ichthyosis caused by mutations in the human abca12 gene. Thus, it seems that the cellular and molecular mechanisms of lipid barrier assembly in the skin are conserved in vertebrates in invertebrates.Author SummaryAs in humans, lipids on the surface of the skin of insects protect the organism against excessive water loss and penetration of potentially harmful substances. During evolution, a greasy surface was indeed an essential trait for adaptation to life outside a watery environment. Here, we show that the membrane-gate transporter Torr is needed for the deposition of barrier lipids on the skin surface in the fruit fly Drosophila melanogaster through extracellular nano-tubes, called pore canals. In principle, the involvement of Torr parallels the scenario in humans, where the membrane-gate transporter ABCA12 is implicated in the construction of the lipid-based stratum corneum of the skin. In both cases, mutations in the genes coding for the respective transporter cause rapid water-loss and are lethal soon after birth. We conclude that the interaction between the organism and the environment obviously implies an analogous mechanism of barrier formation and function in vertebrates and invertebrates.

Previously, we showed that inhibition of the activity of fatty acid desaturases (Desat) perturbs signalling of the developmental timing hormone ecdysone in the fruit fly Drosophila melanogaster. To understand the impact of this effect on cuticle differentiation, a process regulated by ecdysone, we analysed the cuticle of D. melanogaster larvae fed with the Desat inhibitor CA10556. In these larvae, the expression of most of the key cuticle genes is normal or slightly elevated at day one of CA10556 feeding. As an exception, expression of twdlM coding for a yet uncharacterised cuticle protein is completely suppressed. The cuticle of these larvae appears to be normal at the morphological level. However, these animals are sensitive to desiccation, a trait that according to our data, among others, may be associated with reduced TwdlM amounts. At day two of CA10556 feeding, expression of most of the cuticle genes tested including twdlM is suppressed. Expression of cpr47Eb coding for a chitin-binding protein is, by contrast, highly elevated suggesting that Cpr47Eb participates at a specific compensation program. Overall, the cuticle of these larvae is thinner than the cuticle of control larvae. Taken together, lipid desaturation is necessary for a coordinated deployment of a normal cuticle differentiation program.

The stability of extracellular matrices is in general ensured by cross-linking of its components. Previously, we had shown that the integrity of the layeredDrosophilacuticle relies on the presence of a covalent cuticular dityrosine network. Production and composition of this structure remained unstudied. In this work, we present our analyses of theschlaff(slf) gene coding for a C-type lectin that is needed for the adhesion between the horizontal cuticle layers. The Slf protein mainly localizes between the two layers called epicuticle and procuticle that separate from each other when the function of Slf is reduced or eliminated paralleling the phenotype of a cuticle with reduced extracellular dityrosine. Localisation of the dityrosinylated protein Resilin to the epicuticle-procuticle interface suggests that the dityrosine network mediates the adhesion of the epicuticle to the procuticle. Ultimately, compromised Slf function is associated with massive water loss. In summary, we propose that Slf is implied in the stabilisation of a dityrosine layer especially between the epicuticle and the procuticle that in turn constitutes an outward barrier against uncontrolled water flow.Summary statementExtracellular matrices adopt a stereotypic organisation for function during development. The lectin Schlaff assists adhesion reactions to ensure compactness of the epidermal cuticle in Drosophila.

This paper presents a tracking controller for a long pneumatic transmission line modeled by a bidirectionally coupled system of partial differential equations (PDEs) and ordinary differential equations (ODEs). The feedforward part of the controller is designed by applying a flatness-based approach for hyperbolic PDEs to a second-order quasilinear model of the pneumatic system. The stabilizing feedback is derived by the application of a recently developed backstepping approach for coupled PDE-ODE systems to a different, more simple, linear model of the line. In simulations, the tracking controller is used to asymptotically stabilize a complex quasilinear third-order distributed parameter model of the pneumatic transmission line along a desired trajectory. This complex model has previously been shown to accurately reproduce the behavior of the pneumatic test bench considered.

Lipids in extracellular matrices (ECM) contribute to barrier function and stability of epithelial tissues such as the pulmonary alveoli and the skin. In insects, skin waterproofness depends on the outermost layer of the extracellular cuticle termed envelope that contains cuticulin, an unidentified water-repellent complex molecule composed of proteins, lipids and catecholamines. Based on live-imaging analyses of fruit fly larvae, we find that initially envelope units are assembled within vesicles harbouring the ABC transporter Snu and the extracellular protein Snsl. In a second step, the content of these vesicles is distributed to cuticular lipid-transporting nanotubes named pore canals and to the cuticle surface in dependence of Snu function. Consistently, the surface ofsnuandsnslmutant larvae is depleted from lipids and cuticulin. By consequence, these animals suffer uncontrolled water loss and penetration of xenobiotics. Our data allude to a two-step model of envelope i.e. barrier formation. The proposed mechanism in principle parallels the events occurring during differentiation of the lipid-based ECM by keratinocytes in the vertebrate skin suggesting establishment of analogous mechanisms of skin barrier formation in vertebrates and invertebrates.