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Usher syndrome (USH) is the most common form of hereditary deaf-blindness in humans. USH is a complex genetic disorder, assigned to three clinical subtypes differing in onset, course and severity, with USH1 being the most severe. Rodent USH1 models do not reflect the ocular phenotype observed in human patients to date; hence, little is known about the pathophysiology of USH1 in the human eye. One of the USH1 genes, USH1C, exhibits extensive alternative splicing and encodes numerous harmonin protein isoforms that function as scaffolds for organizing the USH interactome. RNA-seq analysis of human retinae uncovered harmonin_a1 as the most abundant transcript of USH1C. Bulk RNA-seq analysis and immunoblotting showed abundant expression of harmonin in Müller glia cells (MGCs) and retinal neurons. Furthermore, harmonin was localized in the terminal endfeet and apical microvilli of MGCs, presynaptic region (pedicle) of cones and outer segments (OS) of rods as well as at adhesive junctions between MGCs and photoreceptor cells (PRCs) in the outer limiting membrane (OLM). Our data provide evidence for the interaction of harmonin with OLM molecules in PRCs and MGCs and rhodopsin in PRCs. Subcellular expression and colocalization of harmonin correlate with the clinical phenotype observed in USH1C patients. We also demonstrate that primary cilia defects in USH1C patient-derived fibroblasts could be reverted by the delivery of harmonin_a1 transcript isoform. Our studies thus provide novel insights into PRC cell biology, USH1C pathophysiology and development of gene therapy treatment(s).

Background Patients with vitiligo experience reduced quality of life. Objective To comprehensively describe the available evidence for psychosocial burden in vitiligo. Methods A systematic review of observational studies and clinical trials identified using PubMed, EMBASE, Scopus, and the Cochrane databases was performed through 1 March, 2021, to assess psychosocial comorbidities in vitiligo. Two independent reviewers performed an assessment of articles and extracted data for qualitative synthesis. Results Included studies (N = 168) were published between 1979 and 1 March, 2021; 72.6% were published since 2010. Disorders including or related to depression (41 studies, 0.1–62.3%) and anxiety (20 studies, 1.9–67.9%) were the most commonly reported. The most prevalent psychosocial comorbidities were feelings of stigmatization (eight studies, 17.3–100%), adjustment disorders (12 studies, 4–93.9%), sleep disturbance (seven studies, 4.6–89.0%), relationship difficulties including sexual dysfunction (ten studies, 2.0–81.8%), and avoidance or restriction behavior (12.5–76%). The prevalence of most psychosocial comorbidities was significantly higher vs healthy individuals. Factors associated with a significantly higher burden included female sex, visible or genital lesions, age

The cruise industry is a profitable field for the application of revenue management methods. Existing model formulations for booking limit determination usually assume that the different elements of booking requests are independent. In this work, it is shown that this approach can lead to non-feasible capacity allocations, which consequently are neither optimal nor applicable in practical planning situations. Therefore, a new improved integer linear model formulation is developed here which by explicitly assigning booking requests to cabins derives a feasible and revenue-maximizing capacity allocation. The model and its results are illustrated with a real-world sized case study.

Usher syndrome (USH) is the most common form of hereditary deafness-blindness in humans. USH is a complex genetic disorder, assigned to three clinical subtypes differing in onset, course, and severity, with USH1 being the most severe. Rodent USH1 models do not reflect the ocular phenotype observed in human patients to date; hence, little is known about the pathophysiology of USH1 in the human eye. One of the USH1 genes, USH1C, exhibits extensive alternative splicing and encodes numerous harmonin protein isoforms that function as scaffolds for organizing the USH interactome. RNA-seq analysis of human retinas uncovered harmonin_a1 as the most abundant transcript of USH1C. Bulk RNA-seq analysis and immunoblotting showed abundant expression of harmonin in Müller glia cells (MGCs) and retinal neurons. Furthermore, harmonin was localized in the terminal endfeet and apical microvilli of MGCs, presynaptic region (pedicle) of cones, and outer segments of rods as well as at adhesive junctions of MGCs and photoreceptors in the outer limiting membrane (OLM). Our data provide evidence for the interactions of harmonin with OLM molecules in photoreceptors (PRCs) and MGCs and rhodopsin in PRCs. Subcellular expression and colocalization of harmonin correlate with the clinical phenotype observed in USH1C patients. In addition, primary cilia defects in USH1C patient-derived fibroblasts could be reverted by the delivery of harmonin_a1 transcript isoform. Our data provide novel insights into PRC cell biology, USH1C pathophysiology, and for developing gene therapy treatment.

The quantification of model structure uncertainty on hydraulic models is very important for flash flood simulations. The choice of an appropriate model structure complexity and assessment of the impacts due to infrastructure failure can have a huge impact on the simulation results. To assess the risk of flash floods, coupled hydraulic models, including 1D-sewer drainage and 2D-surface run-off models are required for urban areas because they include the bidirectional water exchange, which occurs between sewer and overland flow in a city [1]. By including various model components, we create different model structures. For example, modelling the inflow to the city with the 2D surface-runoff or with the delineated 1D model; including the sewer system or use a surrogate as an alternative; modifying the connectivity of manholes and pumps; or representing the drainage system failures during flood events. As the coupling pattern becomes complex, quantifying the model structure uncertainty is essential for the model structure evaluation. If one model component leads to higher model uncertainty, it is reasonable to conclude that the new component has a large impact in our model and therefore needs to be accounted for; if one component has a less impact in the overall uncertainty, then the model structure can be simplified, by removing that model component. In this study, we set up seven different model structures [2] for the German city of Simbach. By comparison with two inflow calculation types (1D-delineated inflow or 2D-catchment), the existence of drainage system and infrastructure failures, the Model Uncertainty Factor (MUF) is calculated to quantify the model structure uncertainties and further trade-off values with Parameter Uncertainty Factor (PUF) [3]. Finally, we can obtain a more efficient hydraulic model with the essential model structure for urban flash flood simulation. 1. Leandro, J., Chen, A. S., Djordjevic, S., and Dragan, S. (2009). "A comparison of 1D/1D and 1D/2D coupled hydraulic models for urban flood simulation." Journal of Hydraulic Engineering-ASCE, 6(1):495-504. 2. Leandro, J., Schumann, A., and Pfister, A. (2016). A step towards considering the spatial heterogeneity of urban, key features in urban hydrology flood modelling. J. Hydrol., Elsevier, 535 (4), 356-365. 3. Van Zelm, R., Huijbregts, M.A.J. (2013). Quantifying the trade-off between parameter and model structure uncertainty in life cycle impact assessment, Environ. Sci. Technol., 47(16), pp. 9274-9280.

Al-rich Ti – Al alloys, as compared to Ti-rich -TiAl-based alloys, offer an additional reduction in density of 20 %, better oxidation resistance and sufficient strength at high temperatures. High temperature creep of a binary Al62Ti28 alloy was studied in compression in the temperature range between 1 173 K and 1 323 K in air. It is shown that the alloy exhibits quite reasonable creep resistance at 1 173 K, especially in view of its low density of around 3.8 g cm– 3. Stress exponents calculated as the slope n = log (strain rate)/ log (stress) = 4 were found to be relatively constant for the temperature and stress regime investigated. This indicates that dislocation climb may be the rate controlling creep mechanism. The values of the activation energies for creep for the as-cast and the annealed Al62Ti38 material coincides well with those found in the literature for interdiffusion of Al in -TiAl.

In the present work, nanostructured (Fe–18Cr–8Ni–2W) austenitic base and oxide dispersion strengthened (ODS) alloy powders were produced through mechanical alloying and these nano powders were consolidated by vacuum hot pressing. The results showed that initially bcc solid solution formed in both the alloys and this transformed to fcc with continued milling. The bcc solid solution formation and the subsequent transformation to fcc were significantly faster in the ODS alloys when compared to the base alloy. In the ODS alloy, a grain size of ~25 nm is achieved within 5 h of milling. Study of variation of microhardness of mechanically alloyed powder particles with grain size showed linear Hall–Petch kind of behavior. Following vacuum hot pressing of mechanically alloyed powders, nearly fully dense (>99% of theoretical density) compacts were obtained with a grain size of ~80 nm. The bulk hardness of base and ODS alloys are ~530 and ~900 HV, respectively. These are significantly higher than the values reported in the literature so far. The enhanced strength the ODS alloy is due to increased dislocation density and presence of fine dispersoids along with the nanocrystalline grains.

The microstructure and mechanical properties of ultrafine-grained ferritic alloys containing nanoclusters (NCs) are investigated. The NCs (diameter ∼3 nm) as well as the grain size (∼200 nm) remain stable at 1000 oC. Substantial Hall–Petch strengthening occurs at room temperature. Surprisingly, the creep rate at 800 oC is up to a factor of 108 slower than that predicted for diffusional creep. Possible reasons are the high NC coverage as well as Cr and W enrichment at the grain boundaries, and inhibition of self-diffusion.

Mo–1.5 at.% Si alloys with additions of either Y2O3 or Zr were manufactured by mechanical alloying. The Y2O3 particles reduced the grain size and increased the room temperature strength, but did not alleviate the brittleness of previously investigated Mo–1.5 at.% Si without Y2O3. Additions of Zr, on the other hand, resulted not only in a fine grain size and an extremely high bend strength (∼2 GPa), but also in limited bend ductility at room temperature. Zr additions are seen to be beneficial for three reasons. First, Zr reduces the grain size. Second, Zr getters detrimental oxygen by forming ZrO2 particles (which in turn help to pin the grain boundaries). Third, in situ Auger analysis shows that Zr reduces the concentration of Si segregated at the grain boundaries. This is thought to enhance the grain boundary cohesive strength and thus leads to the observed ductility.

High-temperature creep of a binary Al 60 Ti 40 (at.%) alloy in the as-cast state and after annealing at 1223 K for 200 h which produced nearly lamellar γ-TiAl + r-Al 2 Ti microstructure was studied utilizing creep compression tests in a temperature range between 1173 and 1323 K in air. The material was manufactured by centrifugal casting. Microstructural characterization was carried out employing light-optical scanning (SEM) and transmission electron microscopy (TEM) as well as X-ray diffraction (XRD) analyses. It is shown that the alloy exhibits reasonable creep resistance at 1173 K, especially in relation to its low density of around 3.8 g/cm 3 . Stress exponents calculated as n = Δlog (strain rate)/Δlog (stress) = 4 were found to be relatively constant for the temperature and stress regime investigated. This indicates that dislocation climb may be the rate controlling creep mechanism. The assessment of creep tests conducted at identical stress levels and varying temperatures yielded activation energies for creep of around Q = 457 kJ/mol in the as-cast condition. This value is significantly higher than those found in literature for interdiffusion of Al or Ti in γ-TiAl. It is concluded that the difference is a due to the instability of the microstructure of the as-cast multi-phase alloy.

Mo–Si alloys containing up to 1 wt.% Si were fabricated by powder-metallurgical processing and their lattice parameters, elastic constants, densities, grain sizes, strengths, ductilities, and fracture toughness values were measured. The yield strength was insensitive to the grain size, i.e., a Hall–Petch relationship was not observed. Generally, Si additions caused pronounced solid solution strengthening. However, for small Si concentrations (≤0.1 wt.%) solid solution softening was observed at room temperature and below. With increasing Si concentration, the room temperature ductility and fracture toughness dropped precipitously. This is attributed to the increase in strength and a transition from transgranular to intergranular fracture.

Objective To provide a review of the etiology, epidemiology, clinical features, diagnostic findings, and treatment options for multiple sclerosis (MS). Data sources A PubMed search of English language articles using a combination of words: elderly; multiple sclerosis*, late onset multiple sclerosis*, etiology; screening; diagnosis; or treatment to identify original studies, guidelines, and reviews on multiple sclerosis and late-onset multiple sclerosis, published 2002 to 2013. Primary sources were then used to search for additional relevant material. Study selection and data extraction Original studies, clinical reviews, references, and guidelines were obtained and evaluated for their clinical relevance. Data synthesis The literature included guidelines and considerations for the etiology, diagnosis, screening, and management of MS. Conclusion MS is a chronic autoimmune disease characterized by inflammation, demyelination, and local axonal injury. It typically presents between ages 20 and 40 and largely affects women. However, 2% to 10% of individuals are diagnosed after 50 years of age. Diagnosis is based on presentation of clinical symptoms and the McDonald criteria for diagnosing MS. Management focuses on suppression of the immune system and prevention of relapses.

Al-rich Ti-Al alloys attracted some attention during the past years due to the possibility of their application as light-weight, high-performance materials at elevated temperatures. The effect of the addition of Nb to Al-rich Ti-Al alloys has been studied for Ti36 Al62 Nb2 by a combined approach of transmission electron microscopy (TEM) techniques for unraveling the structure and composition at the nanoscale. Structural analyses on as-cast ternary alloys revealed the presence of h-TiAl2-, Ti3Al5- and γ-TiAl-type phases. After heat treatment, phase transformations like the replacement of the metastable h-TiAl2-type by the stable r-TiAl2-type were identified. Additionally, changes of the microstructural features like the formation of interfaces with different orientation relationships are apparent. The orientation and interfacial relationships involved are compared to those of binary Ti-Al alloys rich in Al.

In the present paper, microstructural characterization and compression creep properties of nanostructured ferritic oxide dispersion strengthened alloys (Fe–12Cr–2W–0.5Y 2 O 3 (in wt.%)) synthesized by mechanical alloying and vacuum hot pressing are presented. In particular, the effect of starting yttria particle size (20 nm and 45 μm before mechanical alloying) on microstructure and creep properties was investigated. Study of compression creep properties (at 800 °C and 900 °C) revealed that the ODS alloy with finer dispersoids showed higher creep resistance. Grain growth was not very significant following creep testing at 800 °C (from ∼300 nm in hot pressed condition to ∼550 nm following creep at 800 °C). Analysis of stress exponents indicates that dislocation creep is the dominant deformation mechanism at 800 °C and 900 °C.

In the present paper, we present the microstructure and mechanical properties of cryorolled and annealed Cu-5 wt.% Zn and Cu-5 wt.% Al alloys. Ultrafine grained microstructures with very fine annealing twins are obtained after cryrolling and annealing at 250 �C for 15 min. The study of Young's modulus (E) variation with temperature revealed that E is lower (about ?15%) in the as-rolled condition and it increases to the isotropic value after recrystallisation. This variation is attributed to the crystallographic texture that develops during rolling and recrystallisation. The Cu-Al alloy exhibited much higher strength (600 MPa) with similar strain to fracture (0.26) in comparison to Cu-Zn alloy (355 MPa). The higher strength of Cu-Al alloy is explained in terms of the higher contribution to solid solution strengthening of Al. � 2007 Elsevier B.V. All rights reserved.

This paper explores to what extent secondary policy issues are infuenced by electoral incentives. We develop a two dimensional political agency model in which a politician decides on both a frontline policy issue and a secondary policy issue. The model predicts when the incumbent should manipulate the secondary policy to attract voters. We test our model by using panel data on environmental policy choices in the U.S. states. In contrast to the popular view that secondary policies are largely determined by lobbying, we find strong effects of electoral incentives.

In this paper we explore to what extent secondary policy issues are influenced by electoral incentives. We develop a political agency model in which a politician decides on both a frontline policy issue, such as the level of public spending, and a secondary policy issue, such as environmental policy. The model shows under which conditions the incumbent finds it worthwhile to manipulate the secondary policy to attract additional votes to his platform. We test the predictions of the model using state-level panel data on Gubernatorial environmental policy choices over the years 1960-2000. In contrast to the popular view that choices on secondary policy instruments are largely determined by lobbying, we find strong effects of electoral incentives on environmental policy.

Trade disputes over national product standards are a growing source of tension in the international trading system. The usual pattern is that a country introduces a new product standard for all sales of a good in its local market, which is justified as necessary for consumer or environmental protection. Importers into the local market, however, challenge the standard as a ''disguised barrier to trade'' or ''green protectionism''. The paper develops a two country political economy model to explain such disputes. It is shown how the political process can lead to a ''political failure'' which takes the form of either too many or too few product standards and disagreement between politicians in different countries over the optimal policy. In a second step the model is used to evaluate whether two common proposals to settle or avoid such disputes, mutual recognition of standards and harmonization, can improve the political process.

Extended abstract of a paper presented at MC 2007, 33rd DGE Conference in Saarbrücken, Germany, September 2 – September 7, 2007

Nanocrystalline Fe-12Cr-2W (wt.%) and oxide dispersion strengthened (ODS) Fe-12Cr-2W-0.25 Y2O3 (wt. %) alloy powders were produced through mechanical alloying in a high energy planetary ball mill. Microhardness studies on individual milled powder particles revealed a clear increase of hardness for the Yttria containing alloy, thus, proving the ODS effect to be operative in the powders. Consolidation was carried out in a uniaxial hot press at 900°C with a pressure of 200 MPa. TEM and XRD analyses consistently revealed the nanocrystalline grain size before (12 to 30 nm) and after consolidation (120 nm), respectively. Compression creep studies in a temperature range between 800 and 1000°C revealed that diffusional creep is obviously suppressed in these materials. However, the creep resistance of the ODS ferritic steel is only marginally higher than its base alloy and both alloys are by far less creep resistant than that of a ferritic steel of comparable baseline composition strengthened by complex and exceptionally thermally stable Ti-Y-O nanoclusters [1]. Both differences can be rationalized by the instability of the microstructure leading to significant particle and grain growth after creep testing.

Compared to Ti-rich γ-TiAl-based alloys Al-rich Ti-Al alloys offer an additional reduction of in density and a better oxidation resistance which are both due to the increased Al content. Polycrystalline material was manufactured by centrifugal casting. Microstructural characterization was carried out employing light-optical, scanning and transmission electron microscopy and XRD analyses. The high temperature creep of two binary alloys, namely Al60Ti40 and Al62Ti38 was comparatively assessed with compression tests at constant true stress in a temperature range between 1173 and 1323 K in air. The alloys were tested in the cast condition (containing various amounts of the metastable phases Al5Ti3 and h-Al2Ti) and after annealing at 1223 K for 200 h which produced (thermodynamically stable) lamellar γ-TiAl + r-Al2Ti microstructures. In general, already the as-cast alloys exhibit a reasonable creep resistance at 1173 K. Compared with Al60Ti40, both, the as-cast and the annealed Al62Ti38 alloy exhibit better creep resistance up to 1323 K which can be rationalized by the reduced lamella spacing. The assessment of creep tests conducted at identical stress levels and varying temperatures yielded apparent activation energies for creep of Q = 430 kJ/mol for the annealed Al60Ti40 alloy and of Q = 383 kJ/mol for the annealed Al62Ti38 material. The latter coincides well with that of Al diffusion in γ-TiAl, whereas the former can be rationalized by the instability of the microstructure containing metastable phases.