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http://hdl.handle.net/20.500.11768/96868 Purpose To define proangiogenic angiopoietin 2 (ANG2) expression and role(s) in human and mouse vascularised corneas. Further, to evaluate the effect of ANG2 inhibition on corneal neovascularisation (CNV). Methods CNV was induced in FVB mice by means of intrastromal suture placement. One group of animals was sacrificed 10 days later; corneas were immunostained for ANG2 and compared with (i) mouse non-vascularised corneas and (ii) human vascularised and non-vascularised corneas. A second group of CNV animals was treated systemically with an anti-ANG2 antibody. After 10 days, the corneas were whole-mounted, stained for CD31 and LYVE1 and lymphatic/blood vessels quantified. In another set of experiments, the corneal basal Bowman membrane was either (i) removed or (ii) left in place. After 2 or 10 days the corneas were removed and immunostained for collagen IV, ANG2, CD31, LYVE1, CD11b and MRC1 markers. Results In human beings and mice, ANG2 is expressed only in the epithelium, and, mildly, in the endothelium, of the avascular cornea. Instead, it is expressed in the epithelium, endothelium and stroma of vascularised corneas. Disruption of the Bowman membrane is associated with a significant increase of (i) ANG2 stromal expression and (ii) proangiogenic macrophage infiltration in the corneal stroma. Finally, blocking ANG2 significantly reduced hemangiogenesis, lymphangiogenesis and macrophage infiltration. Conclusions Balancing proper healing and good vision is crucial in the cornea, constantly exposed to potential injuries. In this paper, we suggest the existence of a mechanism regulating the onset of inflammation (and associated CNV) depending on injury severity. ZB 0 Z8 0 ZR 0 ZS 0

Neuropeptides, and specifically Substance P (SP), can crucially contribute to the ocular inflammatory response. SP is an undecapeptide that is secreted from sensory nerve endings and from various immune cells during inflammation. SP modulates ocular inflammation through its binding with the high-affinity neurokinin-1 receptor (NK-1R). This receptor is expressed on nerves, immune cells, and epithelial cells. SP is a key mediator of neurogenic inflammation as it induces increased microvascular permeability, vasodilatation, plasma extravasation, and subsequent tissue edema. In addition, macrophages can release inflammatory mediators such as interleukins, chemokines, and growth factors in response to SP stimulation. Inhibition of SP activity, either through blockade of the neuropeptide release or the use of SP receptor antagonists, ameliorates ocular inflammation, it restores immune privilege and improves a number of clinical endpoints associated with inflammation, such as corneal opacity, ocular perforation, and angiogenesis. This review of the literature will summarize the role of SP in the ocular inflammatory response (with an emphasis on the ocular surface). In addition, it will review the therapeutic effects of SP blockade to control ocular inflammation (i) in animal models and (ii) in highly prevalent human diseases.

HfO2 based high-κ dielectrics are among the most likely candidates to replace SiO2 and the currently favoured oxinitride in the next generation of MOSFETs. High-κ materials allow the use of a thicker gate dielectric, maintaining the gate capacitance at reduced gate leakage. However, they lead to mobility degradation due to among other factors the coupling of carriers to surface soft optical phonons. Comparing the vertical field dependence of the mobility for HfO2 and SiO2, the severe degradation in mobility in the presence of high-κ becomes evident. The introduction of a SiO2 interfacial layer between the channel and the HfO2 mitigates the interaction with the SO phonons, but increases the equivalent oxide thickness (EOT) of the gate dielectric. The material of choice for the first commercial introduction of high-κ gate stacks is Hafnium Silicate (SixHf1-xO2). This alloy stands up better to the processing challenges and as a result suffers less from dielectric fluctuations.

Combining an insight on the quantum transport given by the Wigner function formalism and the classical perturbation theory, an algorithm has been developed that allows the introduction of collisional broadening in semiclassical electron transport Monte Carlo (MC) simulations. In the proposed algorithm, electron energy and momentum are treated as independent variables; the laws of energy and momentum conservation are fulfilled at each scattering event, but the relationship between energy and momentum is not given by the traditional expression, since Bloch states are not eigenstates of the total Hamiltonian. The results obtained for a simple model semiconductor demonstrate that the non-physical instabilities observed in previous attempts to introduce collisional broadening in semiclassical MC simulations have been removed. The algorithm is suitable for application in MC simulations of realistic device models.

HfO 2 -based high- κ dielectrics are among the most likely candidates to replace SiO 2 and the currently favoured oxinitride in the next generation of MOSFETs. High- κ materials allow the use of a thicker gate dielectric, maintaining the gate capacitance with reduced gate leakage. However, they lead to a fundamental mobility degradation due to the coupling of carriers to surface soft (low-energy) optical phonons. Comparing the vertical field dependence of the mobility for HfO 2 and SiO 2 , the severe degradation in mobility in the presence of high- κ becomes evident. The introduction of a SiO 2 interfacial layer between the channel and the HfO 2 mitigates this degradation, by increasing the effective distance between the carriers and the SO phonons, thus decreasing the interaction strength, this does though lead to an increase in the equivalent oxide thickness (EOT) of the gate dielectric. The material of choice for the first commercial introduction of high- κ gate stacks is Hafnium Silicate ( Si x Hf 1 - x O 2 ) . This alloy stands up better to the processing challenges and as a result suffers less from dielectric fluctuations. We show that as the fraction of Hf increases within the alloy, the inversion layer mobility is shown to decrease due to the corresponding decrease in the energy of the surface optical phonons and increase in the dielectric constant of the oxide.

Silicon MOSFETs with high κ gate stacks offer a significant reduction in gate leakage current, but the presence of soft surface optic phonon modes degrades the mobility. A progressively more complex set of models for SO phonon scattering at the Si-HfO2 interface is presented based upon dynamic screening models. Landau damping of the electron-phonon-plasmon coupling is examined by simple approximations. A novel approach to determining the re-normalised phonon spectrum based on Pade approximants is outlined as a route to obtaining practical scattering rate for Monte Carlo simulation.

The cornea receives the densest sensory innervation of the body, which is exclusively from small-fiber nociceptive (pain-sensing) neurons. These are similar to those in the skin of the legs, the standard location for neurodiagnostic skin biopsies used to diagnose small-fiber peripheral polyneuropathies. Many cancer chemotherapy agents cause dose-related, therapy-limiting, sensory-predominant polyneuropathy. Because corneal innervation can be detected non-invasively, it is a potential surrogate biomarker for skin biopsy measurements. Therefore, we compared hindpaw-skin and cornea innervation in mice treated with neurotoxic chemotherapy. Paclitaxel (0, 5, 10, or 20 mg/kg) was administered to C57/Bl6 mice and peri-mortem cornea and skin biopsies were immunolabeled to reveal and permit quantitation of innervation. Both tissues demonstrated dose-dependent, highly correlated (r = 0.66) nerve fiber damage. These findings suggest that the quantification of corneal nerves may provide a useful surrogate marker for skin peripheral innervation.

We present a numerical study of the applicability of the sum rule analysis used, in X-ray absorption spectroscopy (XAS) and resonant inelastic X-ray scattering (RIXS), to evaluate the atomic spin moment of 3d transition metals. Magnetic circular dichroism (MCD) is present both in XAS and RIXS at the L2,3 absorption edges, although the two sum rules presented here assume different experimental setups: in XAS-MCD the magnetic field is parallel to the circularly polarised incident photons, in RIXS-MCD the two are orthogonal (perpendicular geometry). For Mn2+ we explore XAS- and RIXS-MCD by performing atomic model calculation in the single ion limit with inclusion of the appropriate crystal and magnetic fields. The comparison of the XAS-MCD spectra with those measured from a MnFe2O4 sample is used to fix the calculation parameters. The applicability of the XAS- and RIXS-MCD sum rules to Mn2+ is numerically checked within the chosen calculation model.

Background We report the case of monolateral corneal endotheliitis, which occurred following systemic West Nile virus (WNV) infection. Methods A 56-year-old male patient with right eye (RE) endotheliitis, diffuse arthralgias, and diagnosis of previous WNV systemic infection underwent a measurement of best spectacle corrected visual acuity (BSCVA), full ophthalmic examination, biomicroscopy, and in vivo scanning laser confocal microscopy (IVCM), before and after topical immunomodulatory treatment. In addition, a polymerase chain reaction test on aqueous humor was performed to test for WNV RNA sequences. Results Photophobia was reported at presentation. A mild corneal haze was noted at the slit lamp exam. BSCVA in RE was 0.1 LogMar, corneal thickness was 667 micron, and confocal microscopy showed stromal folds. No WNV RNA sequences were detected in the aqueous humor. The cytomegalovirus and herpes virus were not tested as the patient refused additional procedures. One month after topical corticosteroid application in the RE, the patient reported significant improvement in photophobia, BSCVA improved to −0.1 LogMar, and corneal thickness was reduced to 540 microns. In addition, IVCM showed a disappearance of stromal folds. Conclusions A presumptive diagnosis of WNV-associated endotheliitis was formulated. Improvement following topical corticosteroid treatment suggests an immune-based pathophysiology.

PURPOSE To test whether a corneal injury can stimulate inflammation in the trigeminal ganglion (TG), a structure located in the brain. METHODS At 4 and 8 days after alkali burn induced in the right eyes of mice, in vivo magnetic resonance imaging (MRI) of the brain was done before and after ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) contrast to track macrophages. Trigeminal ganglia were stained for Prussian Blue and inflammatory cell markers. Interleukin-1β, TNF-α, and VEGF-A transcripts were quantified on days 1, 4, and 8, and 4 days after corneal topical anti-inflammatory treatment with 0.2% dexamethasone. The expression of Substance P and its receptor NK-1R was also measured in the TG on day 4. RESULTS Corneal alkali burn induced leukocyte infiltration, including T cells, in the right TG at 4 and 8 days. In vivo MRI showed an increased contrast uptake in the right TG, which peaked at day 8. Prussian Blue(+) USPIO(+) macrophages were observed in the right TG and exhibited an M2 phenotype. The M2-macrophage infiltration was preponderant in the TG after damage. The proinflammatory cytokines Substance P and NK-1R were significantly increased in both the TGs. The expression of IL-1β and VEGF-A was significantly reduced in the right TG with dexamethasone treatment. CONCLUSIONS We suggest, for the first time, inflammatory involvement of brain structures following ocular surface damage. Our findings support the hypothesis that the neuropeptide Substance P may be involved in the propagation of inflammation from the cornea to the TG through corneal nerves.

Background It has been recently observed that small fibre neuropathy (SFN) may present as distal symmetrical polyneuropathy and with atypical non-length-dependent pattern. Objective To describe a small series of patients with non-length-dependent SFN, investigating corneal innervation with corneal confocal microscopy (CCM). Methods Evaluation of the corneal nerve fibre density using CCM in six women with non-length-dependent SFN. The patients were characterised by sensory disturbance involving proximal regions of the limbs, face and trunks, and the diagnosis was confirmed by the findings of decreased intraepidermal nerve fibre density on skin biopsy. Results Six women, aged 35–64, had non-length-dependent SFN, related to Crohn disease, impaired glucose tolerance and Sjogren9s syndrome, or idiopathic (three cases). In all patients, CCM demonstrated decreased corneal nerve fibre density (12.5–23.4/mm 2 ; normal, >30.6/mm 2 ). Conclusion Non-length-dependent SFN may represent an intriguing diagnostic problem because of its puzzling presentation and the need for special investigations for its confirmation. In this perspective, CCM may provide a useful, non-invasive tool to complement the diagnostic workup.

The immunopathogenic mechanisms of dry eye disease (DED), one of the most common ophthalmic conditions, is incompletely understood. Data from this prospective, double-masked, randomized trial demonstrate that targeting interleukin 1 (IL-1) by topical application of an IL-1 antagonist is efficacious in significantly reducing DED-related patient symptoms and corneal epitheliopathy.To evaluate the safety and efficacy of treatment with the topical IL-1 receptor antagonist anakinra (Kineret; Amgen Inc) in patients having DED associated with meibomian gland dysfunction.Prospective phase 1/2, randomized, double-masked, vehicle-controlled clinical trial.Seventy-five patients with refractory DED.Participants were randomized to receive treatment with topical anakinra, 2.5% (n = 30), anakinra, 5% (n = 15), or vehicle (1% carboxymethylcellulose) (n = 30) 3 times daily for 12 weeks.Primary outcomes were corneal fluorescein staining (CFS), complete bilateral CFS clearance, dry eye-related symptoms as measured by the Ocular Surface Disease Index, tear film breakup time, and meibomian gland secretion quality.Topical anakinra was well tolerated compared with vehicle, with no reports of serious adverse reactions attributable to the therapy. After 12 weeks of therapy, participants treated with anakinra, 2.5%, achieved a 46% reduction in their mean CFS score (P = .12 compared with vehicle and P.001 compared with baseline); participants treated with anakinra, 5%, achieved a 17% reduction in their mean CFS score (P = .88 compared with vehicle and P = .33 compared with baseline); and patients treated with vehicle achieved a 19% reduction in their mean CFS score (P = .11). Complete bilateral CFS clearance was noted in 8 of 28 patients (29%) treated with anakinra, 2.5%, vs in 2 of 29 patients (7%) treated with vehicle (P = .03). By week 12, treatment with anakinra, 2.5%, and treatment with anakinra, 5%, led to significant reductions in symptoms of 30% and 35%, respectively (P = .02 and P = .01, respectively, compared with vehicle); treatment with vehicle led to a 5% reduction in symptoms.Treatment with topical anakinra, 2.5%, for 12 weeks was safe and significantly reduced symptoms and corneal epitheliopathy in patients with DED. These data suggest that the use of an IL-1 antagonist may have a role as a novel therapeutic option for patients with DED. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00681109.

PURPOSE To evaluate the regulatory cross-talk of the vascular and neural networks in the cornea. METHODS b-FGF micropellets (80 ng) were implanted in the temporal side of the cornea of healthy C57Bl/6 mice. On day 7, blood vessels (hemangiogenesis) and nerves were observed by immunofluorescence staining of corneal flat mounts. The next group of mice underwent either trigeminal stereotactic electrolysis (TSE), or sham operation, to ablate the ophthalmic branch of the trigeminal nerve. Blood vessel growth was detected by immunohistochemistry for PECAM-1 (CD31) following surgery. In another set of mice following TSE or sham operation, corneas were harvested for ELISA (VEGFR3 and pigment epithelium-derived factor [PEDF]) and for quantitative RT-PCR (VEGFR3, PEDF, and CD45). PEDF, VEGFR3, beta-3 tubulin, CD45, CD11b, and F4/80 expression in the cornea were evaluated using immunostaining. RESULTS No nerves were detected in the areas subject to corneal neovascularization, whereas they persisted in the areas that were neovessel-free. Conversely, 7 days after denervation, significant angiogenesis was detected in the cornea, and this was associated with a significant decrease in VEGFR3 (57.5% reduction, P = 0.001) and PEDF protein expression (64% reduction, P < 0.001). Immunostaining also showed reduced expression of VEGFR3 in the corneal epithelial layer. Finally, an inflammatory cell infiltrate, including macrophages, was observed. CONCLUSION Our data suggest that sensory nerves and neovessels inhibit each other in the cornea. When vessel growth is stimulated, nerves disappear and, conversely, denervation induces angiogenesis. This phenomenon, here described in the eye, may have far-reaching implications in understanding angiogenesis.

Collagen crosslinking (CXL) has been proposed as a treatment for infectious keratitis. Given the insurgence of antibiotic-resistant microorganisms and frequent toxicity of topical medications, CXL may be a potential treatment for corneal infections. However, corneal infection is itself a possible complication of this treatment. We describe a case of severe corneal thinning and melting in a woman who had a CXL procedure as a treatment for herpetic keratitis. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Background Goldenhar Syndrome is characterized by malformations of multiple anatomical districts. Between these, bulbar dermoids are common and represent a significant clinical problem as they can affect both ocular function and aesthetic comfort. Histologic characterization of dermoids has been extensively performed; however, no reports exist describing in vivo confocal microscopy (IVCM) of these lesions. We aimed to (i) describe the in vivo confocal morphology of limbal dermoids in Goldenhar syndrome and (ii) compare these findings with standard light microscopy. Case presentation A 15-year-old Caucasian female affected by Goldenhar Syndrome showed a left, infero-temporal, limbal neoformation, with extension to the left orbital region. Prior to surgical removal, IVCM was performed with the Heidelberg Retina Tomograph II, Cornea Module, using the “section” modality. The IVCM sections showed structures resembling corneal epithelium and vascular structures. Surgical removal of the lesion was decided as it caused poor eyelid closure. After surgical removal, sectioning and standard optical microscopy were performed. The comparison between IVCM imaging and standard microscopy sections were highly correlated in the detection of the pilar and vascular structures. Conclusions This study showed that IVCM may be a useful technique to study limbal dermoids, given its ability to detect typical microscopic features and its comparability to optical microscopy, which is the current standard.

In mesoscopic systems the Wigner function picture is used for studying electron quantum transport. In this work we present theoretical results on the effect of contact proximity in nanometric devices. If the correlation of the electron wavefunction vanishes inside the contact regions, the transport properties inside the device are affected. We have verified this influence analytically. The main effect is the dependence of the tunnel current through potential barriers on the distance between the contacts. Using three different simulation schemes we have observed modifications in the electron density and conductance for simple devices depending on the distance between the contacts.

Corneolimbal epithelial stem/progenitor cells are a small subpopulation of oligopotent cells located primarily in the basal epithelial layer of the limbus. They produce undifferentiated progeny with limited proliferative potential that migrate centripetally from the periphery of the cornea to replace cells desquamating during normal life.1–7 Corneal limbal stem cells reside primarily in the palisades of Vogt in a niche which maintains their “stemness” by producing a unique anatomic and functional milieu.8,9 Although the exact anatomic location of the niche is thought to be the limbus in humans, it has recently been proposed that epithelial stem/progenitor cells of equal potency are distributed throughout the entire ocular surface in other mammals.10 Detection of corneal epithelial stem cells is the object of controversy between many groups, as there is still no universal consensus over which marker(s) should be used. Side population (SP) cell detection is a commonly used method to quantify these cells. Stem cells express the SP phenotype based on the ability to efflux the DNA-binding dye Hoechst 33342.11–13 SP cells have also been identified in the hematopoietic compartments of different species, and have been isolated from various other adult tissues.12,13 These findings suggest that the SP phenotype represents a common feature of adult tissue-specific stem cells, and the same method has been used to isolate stem cells from human, rabbit, rat, and mouse limbi.14–17 The cornea is the most densely innervated tissue in the body, being 400 times more sensitive than the skin.18 Corneal nerves, in addition to their well known sensory function, help maintain the integrity of the ocular surface by releasing epitheliotrophic substances that promote corneal surface health.19 The limbus, where stem cells reside, is densely innervated; however, the role of these nerves is poorly understood.20 It has been suggested that various nerve-secreted factors and neuropeptides such as nerve growth factor (NGF), substance P, acetylcholine, and brain-derived neurotrophic factor (BDNF) could influence corneal stem cells, and play a role in maintaining epithelial integrity, and promote epithelial proliferation.19 It has also been shown that human corneal stem cells express TrkA which is a high affinity receptor for NGF.21–23 Moreover, corneal limbal stem cells grown in the presence of both epidermal growth factor (EGF) and nerve-secreted factors show the highest rate of colony expansion in vitro compared with EGF alone.24 However, the influence of corneal denervation on epithelial stem/progenitor cells has not yet been studied in vivo. The purpose of the present study was to elucidate the relationship between corneal stem/progenitor cells and trigeminal nerves in vivo using a mouse model of denervated cornea. Herein, we hypothesize that corneal stem/progenitor cell survival and/or function is dependent on intact corneal innervation. Our data demonstrate that sensory nerve deprivation of cornea affects stem cell homeostasis and lead to a significant decrease in both the frequency and the function of corneolimbal stem/progenitor cells.

The cornea is the most innervated tissue in the entire human body (400 times more than skin).1 It receives dense sensory innervation from the trigeminal ganglion and, in some species, modest autonomic innervation. The trigeminal nerve divides into three main branches, one of which, the ophthalmic branch, provides corneal innervation. The organization of corneal nerves, from the depth to the surface of the cornea, is made up of penetrating stromal nerve bundles, subepithelial plexus, sub-basal nerve plexus, and intraepithelial nerve terminals.2 More than a dozen different neurotransmitters and neuropeptides, whose functions are still incompletely understood, are secreted by corneal nerves.3 Corneal nerves are lost because of many pathologic conditions, such as ocular infection, topical anesthetic abuse, surgery, diabetes, stroke, and dry eye syndrome,1,4–6 which affect millions of people annually. When corneal nerves are severely reduced, neurotrophic keratopathy (NK), a poorly treatable disease, develops. This includes the development of persistent epithelial defects and potentially stromal ulceration that may progress to perforation. However, the exact mechanisms and interactions between trigeminal nerves and corneal cells, including stem cells, epithelial cells, and keratocytes, remain unclear. It is known that nerve-secreted peptides influence corneal cell proliferation in vitro,7 and corneal epithelial cell mitosis has been shown to be altered in denervated rats.8,9 Apoptosis and cell proliferation play key roles in ocular wound healing.10 Reduced cell proliferation and thinning have been described in the denervated skin11; however, it is not known whether enhanced apoptosis or simply reduced cell proliferation is associated with NK. In addition, apoptosis and proliferation have not been studied simultaneously in this condition. This has significant clinical implications because it is a well-known fact that NK patients have delayed healing and often experience persistent epithelial defects12 and that even minor injuries can seriously threaten ocular integrity. To address these shortcomings in our current understanding of these important pathophysiologic mechanisms, we have developed, for the first time, a mouse model by removing corneal nerves reproducibly using electrolysis of the ophthalmic branch of the trigeminal nerve with a stereotactic approach, trigeminal stereotactic electrolysis (TSE). This procedure aims to destroy only the fibers providing corneal innervation, leaving the rest of the trigeminus undamaged. Other denervation models have been proposed in monkeys,13 rabbits,14–16 and rats.17,18 NK induction with a hot metal probe through the roof of the mouth has been described in mice; however, no report of death or success rate has been provided, and no stereotactic technique was used.19 When the same procedure was performed on rats, the authors reported a success rate of 60%, and animals could be kept alive for only 3 to 6 days, which precludes long-term follow-up.9 Our method represents an advancement of one of the most effective denervation procedures.20 In addition, this technique applies to the mouse, which is the most widespread experimental mammal used, and is available with the full array of research tools. The procedure was followed by the development of progressive degeneration of the corneal tissue, confirmed clinically by biomicroscopy, functionally by examination of the blink reflex, and histologically by the loss of corneal nerves and the degeneration of corneal tissues. Finally, we show histologic evidence of a simultaneous increase in corneal cell apoptosis and a reduction in basal epithelial cell proliferation.

The effective potential originated by the nonplanar geometry of a two-dimensional electron gas (2DEG) modifies its coherent transport properties. To date no direct evidence of such purely geometric potential has been revealed. Here we expose its effects by computing the transmission characteristics of a semiconductor cylindrical 2DEG forming a Y junction. For some cylinder radii, we find that the activation thresholds of the transmission channels in the two drain leads are exchanged, with this effect being robust against the geometrical details of the three-terminal junction.

We study the electronic states of core multi-shell semiconductor nanowires, including the effect of strong magnetic fields. We show that the multi-shell overgrowth of a free-standing nanowire, together with the prismatic symmetry of the substrate, may induce quantum confinement of carriers in a set of quasi-1D quantum channels corresponding to the nanowire edges. Localization and inter-channel tunnel coupling are controlled by the curvature at the edges and the diameter of the underlying nanowire. We also show that a magnetic field may induce either Aharonov-Bohm oscillations of the energy levels in the axial configuration, or a dimensional transition of the quantum states from quasi-1D to Landau levels for fields normal to the axis. Explicit predictions are given for nanostructures based on GaAs, InAs, and InGaN with different symmetries., Comment: 13 pages, 4 figures, To be published in Nano Letters

We study the electronic states of hexagonal core multishell semiconductor nanowires, including the effect of magnetic fields. We find that the two dimensional electron states formed at the interface between different layers are mostly localized at the six edges of the hexagonal prism, and behave as a set of quasi-1D quantum channels. They can be manipulated by magnetic fields either parallel or perpendicular to the wire axis. These results can be rationalized in terms of Aharonov-Bohm oscillations or Landau level formation. We also show that inter-channel coupling and magnetic behavior is influenced by the geometric details of the nanowires.

We compute the single-particle states of a two-dimensional electron gas confined to the surface of a cylinder immersed in a magnetic field. The envelope-function equation has been solved exactly for both an homogeneous and a periodically modulated magnetic field perpendicular to the cylinder axis. The nature and energy dispersion of the quantum states reflects the interplay between different lengthscales, namely, the cylinder diameter, the magnetic length, and, possibly, the wavelength of the field modulation. We show that a transverse homogeneous magnetic field drives carrier states from a quasi-2D (cylindrical) regime to a quasi-1D regime where carriers form channels along the cylinder surface. Furthermore, a magnetic field which is periodically modulated along the cylinder axis may confine the carriers to tunnel-coupled stripes, rings or dots on the cylinder surface, depending on the ratio between the the field periodicity and the cylinder radius. Results in different regimes are traced to either incipient Landau levels formation or Aharonov-Bohm behaviour., 23 pages, 14 figures

We derive the Schrödinger equation for a spinless charged particle constrained to move on a curved surface in the presence of an electric and magnetic field. The particle is confined on the surface using a thin-layer procedure, which gives rise to the well-known geometric potential. The electric and magnetic fields are included via the four potential. We find that there is no coupling between the fields and the surface curvature and that, with a proper choice of the gauge, the surface and transverse dynamics are exactly separable. Finally, we derive an analytic form of the Hamiltonian for spherical, cylindrical, and toroidal surfaces.

In this note we represent a classical bankruptcy problem as a standard flow problem on a simple network and implement some known division rules from the bankruptcy literature via suitable cost functions in the related minimum cost flow problem.

We compute carrier states on a cylindrical 2DEG under the influence of a magnetic field perpendicular to the tube axis. The field and the topology of the cylindrical surface have been included in the Schrodinger equation, that has been solved exactly. The results show that carrier states can be driven from a 2D regime, to a quasi-ID regime by transverse magnetic field. In the case of a spatially modulated magnetic field, the carriers can localise to quasi-OD states. (c) 2007 Elsevier B.V. All rights reserved.

The development of the devastating neurodegenerative condition, Alzheimer's disease, is strongly associated with amyloid-β (Aβ) deposition, neuronal apoptosis, and cell loss. Here, we provide evidence that implicates these same mechanisms in the retinal disease glaucoma, a major cause of irreversible blindness worldwide, previously associated simply with the effects of intraocular pressure. We show that Aβ colocalizes with apoptotic retinal ganglion cells (RGC) in experimental glaucoma and induces significant RGC apoptosis in vivo in a dose- and time-dependent manner. We demonstrate that targeting different components of the Aβ formation and aggregation pathway can effectively reduce glaucomatous RGC apoptosis in vivo , and finally, that combining treatments (triple therapy) is more effective than monotherapy. Our work suggests that targeting the Aβ pathway provides a therapeutic avenue in glaucoma management. Furthermore, our work demonstrates that the combination of agents affecting multiple stages in the Aβ pathway may be the most effective strategy in Aβ-related diseases.

In the past years a strong attention has been focused on the optical and transport properties of semiconductor hetero-structures owing to the possibility of tailoring material parameters such as the electron effective mass and the band gap, by changing the structure parameters. Recent experimental results on InxGa1−xAs structures cannot be explained in the framework of standard theoretical and simulative approaches for the description of carrier transport in quantum wells. In order to get a better insight on the effect of the surface roughness on the conductance, we have considered meandering quantum wires and have computed their coherent transport characteristics. We find that, at low energies, the transmission coefficient is strongly dependent on the SR parameters. The dependence of conductance upon length of the device is also analyzed.

Publisher Summary This chapter explains the concepts behind the invention, programming, and behavior of the LEGO Turing Machine. The Turing Machine is a very primitive sort of computer; the simplest possible machine that could perform computation, and an ancestor of any modern computer. It can be considered as a grandparent of RCX. The first and main part of the original Turing Machine consists of a tape of infinite length, divided into cells. Each cell has just enough space for a single symbol to be written. A head reads and writes on the tape, and can move one cell at a time, moving to either the left or to the right. The device itself is always in one of a finite number of states. These states determine what action the machine should perform via a special programming feature called a state transition table (or action table). The state transition table tells the Turing Machine what to do when it is in a certain state and encounters a specific symbol. Finally, the chapter illustrates the programming of LEGO Turing Machine using NQC.

We present theoretical results on electron dynamics inside nanometric systems, where the coherence of the electron ensemble is maintained in a very short region. The contacts are supposed to spoil such a coherence, therefore the interference processes between the carrier wavefunction and the internal potential profile can be affected by the proximity of the contacts. The problem has been analysed by using the Wigner-function formalism. For very short devices, transport properties, such as tunnelling through potential barriers, are significantly influenced by the distance between the contacts. (c) 2006 Elsevier B.V. All rights reserved.

A fully quantum theory of phonon-limited electron transport in semiconductors is applied to a homogeneous steady-state situation to investigate the difference between quantum results and the results of a semiclassical theory. The Wigner function is used for the quantum approach, and Monte Carlo simulations are performed in both semiclassical and quantum theories. In the considered case, hot-electron transport in a simple silicon model at 77 K, very little difference has been found since collisional broadening changes the possible final states of the electronic transitions without altering in a significant way the total scattering rate and therefore the momentum relaxation efficiency of phonon scattering.

Resonant inelastic x-ray scattering (RIXS) and resonant photoemission spectroscopy (RPES) can be used to selectively measure the ground-state properties of atoms in solid materials. For the two types of experiment we compare the sum rules developed in the past years to extract quantitative information from the measured spectra. We show that if the measurements are not sensitive to the emitted photon polarization state (in RIXS) or to the photoelectron spin orientation (in RPES), the two experiments exhibit the same angular dependence of the spectral intensities but differ in some numerical coefficients in the sum rules. In particular we give explicit expressions for the RIXS sum rules in the so-called perpendicular geometry for all the cases of practical interest. These rules can serve, in combination with the well-known x-ray magnetic circular dichroism sum rules in absorption, to evaluate the quadrupole and octupole moments of the scattering atoms.

In this work the Wigner function approach to quantum transport developed for the single electron case is extended to a more complicated system for n indistingushable particles. In particular we study how the Monte Carlo tecnique and the Wigner paths method can be applyed to a single particle Wigner function defined for a system of n interacting particles. The numerical results are obtained for the case of a system of two particles under different conditions: two noninteracting fermions, two noninteracting bosons, two non interacting distinguishable particles and two interacting fermions.

The Wigner function formalism is used for studying electron quantum transport in mesoscopic systems. In this work we show that, if the correlation of the electron wave function vanishes outside the region of interest (for example inside the contacts), then transport is affected inside the device. This property is verified analytically. Results show that, for very short devices, tunneling is actually influenced by the distance between the contacts. Modification in the electron density and conductivity have been numerically observed.

orneal nerves are known to con-tribute significantly to ocularsurface integrity. A normal cornealinnervation is required for a normaltear secretion and flow. In fact, dryeye disease is defined as a disorder ofthe lacrimal functional unit, an inte-grated system comprising the sensoryand motor nerves (DEWS 2007). Cor-neal nerve depletion reduces tearsecretion by decreasing reflex-inducedlacrimal secretion and by reducing theblink rate. Moreover, corneal nervessecrete up to 17 different mediatorssuch as nerve growth factor and oth-ers, which have profound effects oncorneal surface homoeostasis (Mu¨lleret al. 2003).Damage to the sensory nerves in theocular surface, particularly the cornea,is common in a number of conditions,including refractive surgery, keratopl-asty and even normal ageing (He et al.2010). Corneal nerve damage oftenoccurs in concomitance with inflam-mation elicited by surgery or drugs;hence, it is difficult to precisely dissectthe role of corneal nerves in dry eye.We recently developed a murinemodel of corneal denervation (TSE,Trigeminal Stereotactic Electrolysis)where we selectively ablate the oph-thalmic branch of the trigeminal nerve(Ferrari et al. 2011). We used thismodel to test whether and to whichextent selective sensory nerve ablationcould induce dry eye in terms of (i)tear secretion and (ii) corneal fluores-cein staining.Eight eyes of eight C57BL⁄6 micewere used. Animals were examinedbefore and 7 days after TSE. Theeffectiveness of the procedure wasconfirmed by the absence of blinkreflex (Ferrari et al. 2011). At the endof the procedure, a complete tars-orrhaphy was performed to minimizethe effect of absent blink reflex. Theanimals were examined using a biomi-croscope, and tear production wasquantified with phenol red thread test.Finally, the corneas were stained withfluorescein and scored according tothe National Eye Institute GradingSystem.Before TSE was performed, biomi-croscopy revealed a normal cornea.Corneal fluorescein staining was nega-tive before TSE (score, 0) and phenoltest was 2.59 ± 0.44 mm (mean ±SD). Corneal reflex was tested with acotton thread and found to be presentin all the eyes. Following TSE, corneafluorescein staining score was10.39 ± 2.20 (mean ± SD), phenoltest decreased to 0.52 ± 0.36 mm(mean ± SD) and corneal reflex wasabsent in all the eyes (Fig. 1). AfterTSE, we found significant differencesin both the fluorescein score (p

Publisher Summary The most known characteristic creation of Logo is the Turtle; it is a symbolic turtle that moves across the computer screen according to the instruction it receives. With simple instructions like “forward 10” the turtle moves straight ten units, and with “right 90” it turns clockwise to 90 degrees. The statements “pen-up” and “pen-down” specify whether the turtle leaves a track behind it, thus producing drawings or rather just moving to a different location. The language includes many other commands, but these are enough to understand the principles of the Turtle Graphics that made Logo so famous. The idea behind building the turtle is about building a small robotic platform that is able to go forward and backward, turn in place, and lower and raise a pen. Despite this apparent simplicity, if one wants a turtle that works as expected, the task has many stringent requirements that must be adhered to. For instance, the robot must go absolutely straight, the pen must be exactly in the pivoting point of the robot, because it must stay in the same place on the floor while the robot turns, and one needs a tracking system to measure both the traveled distances and angles.

The ability to find a way through a maze is considered a good test of intelligence, and has been used with mice and other animals to measure their capacities. This chapter briefly provides an overview of solving a maze. In addition, it explains what knowledge and skills are necessary to find the way out. Analysis is important to implement maze solving: one requires a strategy and it has to be detailed enough to be translated into program instructions for a robot. Finding one's way in a labyrinth is a special case of navigation and requires some abilities, with the addition of some memory to remember. There are several techniques discussed to find a way, such as using the left side–right side strategy. This technique solves an incredibly large class of mazes, its rule being quite simple to remember and apply. It states that, when applicable, if one follows the left wall and turns left whenever possible, one will find the exit. To be more precise, if following the right wall then one should use the same route or follow the left wall from the exit to the entrance.

Publisher Summary This chapter illustrates some ways to build arms, hands, clamps, pliers, and other tools to grab and handle objects. One of the basic measurements of movement explored in this chapter is the degree of freedom (DOF), or the number of directions in which an object (like a robotic arm) has a range of motion. Every independent movement represents a degree of freedom (DOF), something that can happen without affecting and being affected by other movements in the same device. The DOF concept helps in understanding the terms of numbers why simple hands diverged so widely from the flexibility a human hand has. This chapter explains that finding the object is the hardest part of the job, but there are cases where one can use a random search pattern, or where the object sits on the robot's path, as in the line following example.

Publisher Summary This chapter discusses some projects that could be considered “classic,” because almost everybody with a MINDSTORMS kit tries them sooner or later. With exploring the room, the task is to build a robot with the basic ability to move around, detect obstacles, and change its route accordingly. If a room has a flight of stairs going down, one can equip the robot with a kind of detector to sense the edge and avoid a bad fall. There is a theme that pervades this chapter concerns the care one should put into the particulars: building a robot that works roughly as expected, compared to looking for optimal performance are two very different approaches. The concept behind the design of a robot is an important element in regard to its functioning; this chapter explains how shifting from the differential drive to the steering drive can have an impressive effect on the resulting efficiency.

Publisher Summary This chapter provides a brief discussion of various electronic games, such as pinball machine, Simon-says games, and other electronic games. The pinball machine is probably the only survivor in the gaming arcade's evolution to electronics. To build a pinball machine, an incredible amount of parts are used: most of the parts are plain 2 x n bricks. The surface of the pinball is built with bricks turned on their side. This technique allows achieving a smooth surface without using tiles, and makes it easy to insert sensors, axle pegs, and anything else that needs a vertical mount over the surface. Programming a pinball is not very complicated. When the game starts, the score is reset to zero, and the ball counts to the initial number. Furthermore, the Simon says game is inspired by Milton Bradley's commercial product Simon, which has had great success among families. It is not an arcade game, but is still very challenging and devised for players to compete against themselves or others. The purpose of the game is to copy the sequence performed by the machine. It starts with just one light, then the sequence of lights becomes longer and longer as the game proceeds. Every time the user successfully reproduces the series, the machine plays it again, adding one more light to the end of the sequence.

Publisher Summary This chapter focuses on designing and constructing a LEGO robot and mainly focuses on two projects that are of a mouse and turtle. Mouse is a simple project, which uses one motor and two touch sensors, and it's easy to replicate using only the parts contained in the Robotic Invention System. The turtle, on the contrary, is a bit more sophisticated and requires a few additional parts. The LEGO turtle project is ambitious than the mouse project. The most relevant parts in turtles are the legs. In contrast to mouse, the turtle robot walks on feet and uses leg geometry. The turtle does not only employ its legs to support its weight, but it helps itself along with the rest of the body. In describing the mouse, the goal was to limit its size. This led to use a variant of the steering drive configuration, which, at the price of reduced control regarding direction, works with a single motor. Another goal was to make the robot very fast, which resulted in the use of wheels instead of true legs. The turtle project started with a different premise: the robot could be slow or had to be slow, thus a legged configuration was quite appropriate.

Publisher Summary Pneumatics is the discipline that describes gas flows and how to use its properties to transmit energy or convert the same into force and motion. Most pneumatic applications use that gaseous mixture most widely available—air—and the LEGO world is no exception. Pneumatics is a great tool for robotics, and is especially useful when mechanisms need linear motion or an elastic behavior. It is also very useful as a way to store energy for subsequent uses. The most important property of pneumatics is that they have neither specific shape nor volume, because they expand and fill all available space within a container. This means that the quantity of gas inside a tank does not solely depend on the tank's volume. The greater the quantity of gas in a given volume, the higher is its pressure. The fact that gases are so easy to compress is what makes pneumatics different from hydraulics (the science of liquid flow). Essentially, liquids are uncompressible. When an individual compresses a gas into a tank, increasing its pressure, he is storing energy. Pressure can be interpreted also as a density of energy, that is, the quantity of energy per unit volume. This leads to a very interesting application of pneumatics: one can use tanks to accumulate energy, which can then be later released when needed.

Publisher Summary This chapter deals with competitions where the rival robots fight face-to-face in a spectacular way. The technical aspects of building a successful Sumo robot are important, the design requires much more than simply putting together a few mechanical solutions: it requires a strategy. The process starts before building a robot. It begins by examining the rules carefully, understanding what one can and cannot do, and deciding a line of action. Also, one must try to imagine what the opponents strategy can be, plan the robot to be able to resist their attacks, and then take advantage of their weak points. The making of a strong Sumo robot requires much more than just brute force. When optimizing the pushing power of a robot, the first thing required is an objective way to measure it. Without measuring the force, the improvements one make are subjective and as a result are very inaccurate. While building and programming a robot, one should make reliability the first priority.

Publisher Summary This chapter briefly discusses the gears and discovers the powerful qualities they offer, transforming one force into another almost magically. A single gear wheel alone is not very useful, unless there is a different usage from what it was conceived for. One of the finest properties of gears is that this conversion is symmetrical: one can convert torque into velocity or vice versa. And the math required to manage and understand the process is as simple as doing division. Gears are not the only way to transfer power the present that pulley–belt systems, as well as chains, serve the same purpose and helps in connecting distant systems. Belts provide an intrinsic torque-limiting function, and do well in high-speed low-torque situations. Chains, on the other hand, don't limit torque but do increase friction, so they are more suitable for transferring power at slow speeds.