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Summary: Nuclear pore complexes (NPCs) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA sequencing was performed in seven individuals from four unrelated consanguineous families with AAAS-negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima, and achalasia. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a triple A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC.

Wet snow events in Hungary can occasionally cause damage to overhead power lines and serious power supply failures. Return period calculation of such high snow mass events was determined upon a 50-year long data series available at 12 meteorological stations. Wet snow masses were estimated with a model of cylindrical accretion around wire of 3.1 cm diameter. Trends in the return periods and ice classes (according to the ISO 12494 standard) were assessed from division of the dataset into two periods (1965–1990 and 1991–2016). Ice classes in the range of R2 to R5 (mass of 0.7–6.1 kg m−1) were identified. The wet snow risk decreased in southern or central Hungary, while an increase was found in the western part of Hungary. Ice classes R6–R8 (up to 40 kg m−1) could occur in mountain areas of Hungary as indicated by numerical simulations in case studies. However, their return period is unknown due to the lack of long observation series. [ABSTRACT FROM AUTHOR]

Nuclear pore complexes (NPCs) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA sequencing was performed in seven individuals from four unrelated consanguineous families with AAAS-negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima, and achalasia. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a triple A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Achalasia‐addisonianism‐alacrima syndrome, frequently referred to as Allgrove syndrome or Triple A syndrome, is a multisystem disorder resulting from homozygous or compound heterozygous pathogenic variants in the gene encoding aladin (AAAS). Aladin is a member of the WD‐repeat family of proteins and is a component of the nuclear pore complex. It is thought to be involved in nuclear import and export of molecules. Here, we describe an individual with a paternally inherited truncating variant and a maternally inherited, novel missense variant in AAAS presenting with alacrima, achalasia, anejaculation, optic atrophy, muscle weakness, dysarthria, and autonomic dysfunction. Methods: Whole‐exome sequencing was performed in the proband, sister, and parents. Variants were confirmed by Sanger sequencing. The localization of aladin to the nuclear pore was assessed in cells expressing the patient variant. Results: Functional testing of the maternally inherited variant, p.(Arg270Pro), demonstrated decreased localization of aladin to the nuclear pore in cells expressing the variant, indicating a deleterious effect. Follow‐up testing in the proband's affected sister revealed that she also inherited the biallelic AAAS variants. Conclusions: Review of the patient's clinical, pathological, and genetic findings resulted in a diagnosis of Triple A syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background Achalasia‐addisonianism‐alacrima syndrome, frequently referred to as Allgrove syndrome or Triple A syndrome, is a multisystem disorder resulting from homozygous or compound heterozygous pathogenic variants in the gene encoding aladin (AAAS). Aladin is a member of the WD‐repeat family of proteins and is a component of the nuclear pore complex. It is thought to be involved in nuclear import and export of molecules. Here, we describe an individual with a paternally inherited truncating variant and a maternally inherited, novel missense variant in AAAS presenting with alacrima, achalasia, anejaculation, optic atrophy, muscle weakness, dysarthria, and autonomic dysfunction. Methods Whole‐exome sequencing was performed in the proband, sister, and parents. Variants were confirmed by Sanger sequencing. The localization of aladin to the nuclear pore was assessed in cells expressing the patient variant. Results Functional testing of the maternally inherited variant, p.(Arg270Pro), demonstrated decreased localization of aladin to the nuclear pore in cells expressing the variant, indicating a deleterious effect. Follow‐up testing in the proband's affected sister revealed that she also inherited the biallelic AAAS variants. Conclusions Review of the patient's clinical, pathological, and genetic findings resulted in a diagnosis of Triple A syndrome.

Abstract Background The elucidation of pathomechanisms leading to the manifestation of rare (genetically caused) neurological diseases including neuromuscular diseases (NMD) represents an important step toward the understanding of the genesis of the respective disease and might help to define starting points for (new) therapeutic intervention concepts. However, these “discovery studies” are often limited by the availability of human biomaterial. Moreover, given that results of next-generation-sequencing approaches frequently result in the identification of ambiguous variants, testing of their pathogenicity is crucial but also depending on patient-derived material. Methods Human skin fibroblasts were used to generate a spectral library using pH8-fractionation of followed by nano LC-MS/MS. Afterwards, Allgrove-patient derived fibroblasts were subjected to a data independent acquisition approach. In addition, proteomic signature of an enriched nuclear protein fraction was studied. Proteomic findings were confirmed by immunofluorescence in a muscle biopsy derived from the same patient and cellular lipid homeostasis in the cause of Allgrove syndrome was analysed by fluorescence (BODIPY-staining) and coherent anti-Stokes Raman scattering (CARS) microscopy. Results To systematically address the question if human skin fibroblasts might serve as valuable biomaterial for (molecular) studies of NMD, we generated a protein library cataloguing 8280 proteins including a variety of such linked to genetic forms of motoneuron diseases, congenital myasthenic syndromes, neuropathies and muscle disorders. In silico-based pathway analyses revealed expression of a diversity of proteins involved in muscle contraction and such decisive for neuronal function and maintenance suggesting the suitability of human skin fibroblasts to study the etiology of NMD. Based on these findings, next we aimed to further demonstrate the suitability of this in vitro model to study NMD by a use case: the proteomic signature of fibroblasts derived from an Allgrove-patient was studied. Dysregulation of paradigmatic proteins could be confirmed in muscle biopsy of the patient and protein-functions could be linked to neurological symptoms known for this disease. Moreover, proteomic investigation of nuclear protein composition allowed the identification of protein-dysregulations according with structural perturbations observed in the muscle biopsy. BODIPY-staining on fibroblasts and CARS microscopy on muscle biopsy suggest altered lipid storage as part of the underlying disease etiology. Conclusions Our combined data reveal that human fibroblasts may serve as an in vitro system to study the molecular etiology of rare neurological diseases exemplified on Allgrove syndrome in an unbiased fashion.

This article introduces an open‐source software for distributed and decentralized non‐convex optimization named ALADIN‐α. ALADIN‐α is a MATLAB implementation of tailored variants of the Augmented Lagrangian Alternating Direction Inexact Newton (ALADIN) algorithm. It is user interface is convenient for rapid prototyping of non‐convex distributed optimization algorithms. An improved version of the recently proposed bi‐level variant of ALADIN is included enabling decentralized non‐convex optimization with reduced information exchange. A collection of examples from different applications fields including chemical engineering, robotics, and power systems underpins the potential of ALADIN‐α. [ABSTRACT FROM AUTHOR]

Wet snow events in Hungary can occasionally cause damage to overhead power lines and serious power supply failures. Return period calculation of such high snow mass events was determined upon a 50-year long data series available at 12 meteorological stations. Wet snow masses were estimated with a model of cylindrical accretion around wire of 3.1 cm diameter. Trends in the return periods and ice classes (according to the ISO 12494 standard) were assessed from division of the dataset into two periods (1965–1990 and 1991–2016). Ice classes in the range of R2 to R5 (mass of 0.7–6.1 kg m−1) were identified. The wet snow risk decreased in southern or central Hungary, while an increase was found in the western part of Hungary. Ice classes R6–R8 (up to 40 kg m−1) could occur in mountain areas of Hungary as indicated by numerical simulations in case studies. However, their return period is unknown due to the lack of long observation series.

Objective: Experimental evidence suggests that the clinical manifestations of Triple A syndrome result from oxidative stress. Several conditions caused by oxidative stress display retinal involvement. Our objective was to assess the retina and optic nerve involvement in children with Triple A syndrome. Methods: Eleven patients with genetically proven Triple A syndrome followed-up in our centre were approached for study participation. The main outcome was the measurement of the thicknesses of the different retinal layers by Optical Coherence Tomography (OCT). Results: 9 patients with triple A syndrome had OCT measurements. 7 patients were children and 2 were adults; 4 were females and 5 were males. The 7 paediatric patients had at least two OCT measured at a mean interval of 7.9 months after the first one. The average Retinal Nerve Fibre Layer thickness was 74 ± 10 µm in patients compared to the paediatric reference range of 100 ± 2 µm (p<0.05). Conclusions and Relevance: This is the first study to document retinal layer thicknesses in a series of patients with Triple A syndrome. Nearly all retinal thickness and peripapillary RNFL measurements were very significantly inferior to the reference range in Triple A patients, whatever their age. RNFL thinning was more marked at the temporal part of the optic nerve. OCT being non-invasive, it represents a promising tool to assess the severity of neurodegeneration in patients with Triple A syndrome. [ABSTRACT FROM AUTHOR]

This study is focusing on the past and, in particular, the present of the ALADIN-Climate model used at the Hungarian Meteorological Service. The currently applied model version is 5.2 (HMS-ALADIN52). In the recent experiments, the CNRMCM5 global model outputs were downscaled in two steps to 10 km horizontal resolution over Central and Southeast Europe using RCP4.5 and RCP8.5 scenarios. Temperature and precipitation projections are analyzed for 2021-2050 and 2071--2100 with respect to the reference period of 1971--2000 with focus on Hungary. The results are evaluated in comparison to 26 simulations selected from the 12 km horizontal resolution Euro- CORDEX projection ensemble (including two additional versions of ALADIN-Climate: CNRM-ALADIN53 and CNRM-ALADIN63) to get more information about the projection uncertainties over Hungary and to assess the representativeness of HMS-ALADIN52. The HMS-ALADIN52 simulations project a clear warming trend in Central and Southeast Europe, which is more remarkable in case of greater radiative forcing change (RCP8.5). From the 2040s, the Euro-CORDEX simulations start to diverge using different scenarios. The total range of the annual change over Hungary is 1.3--3.3 °C with RCP4.5 and 3.2--5.7 °C with RCP8.5 by the end of the 21st century. HMS-ALADIN52 results are approximately near to the median: 2.9 °C with RCP4.5 and 4 °C with RCP8.5. CNRMALADIN53 shows generally similar results to HMS-ALADIN52, but simulations with CNRM-ALADIN63 indicate higher changes compared to both. In terms of seasonal mean precipitation change, the HMS-ALADIN52 simulations assume an increase between 9% and 33% (less in spring, more in autumn) over Hungary in both periods and with both scenarios. Most of the selected Euro-CORDEX simulations show a precipitation increase, apart from summer, when growth and reduction can be equally expected in 2021--2050, and the drying tendency continues towards the end of the century. Increase projected by HMSALADIN52 is mostly confirmed by CNRM-ALADIN53, while CNRM-ALADIN63 predicts precipitation decrease in summer. Precipitation results do not show a significantly striking difference between the scenarios, likely due to the fact that internal variability and model uncertainty are more relevant sources of uncertainty in precipitation projections over our region. [ABSTRACT FROM AUTHOR]

Two historical Observing System Experiment (OSE) studies using the ALADIN limited area model and its assimilation system are described. The first study, using an OSE scenario that minimizes the impacts of observations through the lateral boundary conditions, demonstrated the importance of each assimilated terrestrial radiosonde, aircraft, and wind profiler) observations on the analyses and short-range forecasts of the ALADIN/HU model and proved evidence, that the role of conventional observations cannot be even partly taken over by satellite measurements without degradation of the forecast quality. The second study demonstrated that the assimilation of radiosonde observations remains indispensable even with a progressively increasing amount of aircraft measurements. [ABSTRACT FROM AUTHOR]

ObjectiveExperimental evidence suggests that the clinical manifestations of Triple A syndrome result from oxidative stress. Several conditions caused by oxidative stress display retinal involvement. Our objective was to assess the retina and optic nerve involvement in children with Triple A syndrome.MethodsEleven patients with genetically proven Triple A syndrome followed-up in our centre were approached for study participation. The main outcome was the measurement of the thicknesses of the different retinal layers by Optical Coherence Tomography (OCT).Results9 patients with triple A syndrome had OCT measurements. 7 patients were children and 2 were adults; 4 were females and 5 were males. The 7 paediatric patients had at least two OCT measured at a mean interval of 7.9 months after the first one. The average Retinal Nerve Fibre Layer thickness was 74 ± 10 µm in patients compared to the paediatric reference range of 100 ± 2 µm (p

Background: The elucidation of pathomechanisms leading to the manifestation of rare (genetically caused) neurological diseases including neuromuscular diseases (NMD) represents an important step toward the understanding of the genesis of the respective disease and might help to define starting points for (new) therapeutic intervention concepts. However, these "discovery studies" are often limited by the availability of human biomaterial. Moreover, given that results of next-generation-sequencing approaches frequently result in the identification of ambiguous variants, testing of their pathogenicity is crucial but also depending on patient-derived material. Methods: Human skin fibroblasts were used to generate a spectral library using pH8-fractionation of followed by nano LC-MS/MS. Afterwards, Allgrove-patient derived fibroblasts were subjected to a data independent acquisition approach. In addition, proteomic signature of an enriched nuclear protein fraction was studied. Proteomic findings were confirmed by immunofluorescence in a muscle biopsy derived from the same patient and cellular lipid homeostasis in the cause of Allgrove syndrome was analysed by fluorescence (BODIPY-staining) and coherent anti-Stokes Raman scattering (CARS) microscopy. Results: To systematically address the question if human skin fibroblasts might serve as valuable biomaterial for (molecular) studies of NMD, we generated a protein library cataloguing 8280 proteins including a variety of such linked to genetic forms of motoneuron diseases, congenital myasthenic syndromes, neuropathies and muscle disorders. In silico-based pathway analyses revealed expression of a diversity of proteins involved in muscle contraction and such decisive for neuronal function and maintenance suggesting the suitability of human skin fibroblasts to study the etiology of NMD. Based on these findings, next we aimed to further demonstrate the suitability of this in vitro model to study NMD by a use case: the proteomic signature of fibroblasts derived from an Allgrove-patient was studied. Dysregulation of paradigmatic proteins could be confirmed in muscle biopsy of the patient and proteinfunctions could be linked to neurological symptoms known for this disease. Moreover, proteomic investigation of nuclear protein composition allowed the identification of protein-dysregulations according with structural perturbations observed in the muscle biopsy. BODIPY-staining on fibroblasts and CARS microscopy on muscle biopsy suggest altered lipid storage as part of the underlying disease etiology. Conclusions: Our combined data reveal that human fibroblasts may serve as an in vitro system to study the molecular etiology of rare neurological diseases exemplified on Allgrove syndrome in an unbiased fashion. [ABSTRACT FROM AUTHOR]

Abstract Background Membrane-associated progesterone receptors are restricted to the endoplasmic reticulum and are shown to regulate the activity of cytochrome P450 enzymes which are involved in steroidogenesis or drug detoxification. PGRMC1 and PGRMC2 belong to the membrane-associated progesterone receptor family and are of interest due to their suspected role during cell cycle. PGRMC1 and PGRMC2 are thought to bind to each other; thereby suppressing entry into mitosis. We could previously report that PGRMC2 interacts with the nucleoporin ALADIN which when mutated results in the autosomal recessive disorder triple A syndrome. ALADIN is a novel regulator of mitotic controller Aurora kinase A and depletion of this nucleoporin leads to microtubule instability. Results In the current study, we present that proliferation is decreased when ALADIN, PGRMC1 or PGRMC2 are over-expressed. Furthermore, we find that depletion of ALADIN results in mislocalization of Aurora kinase A and PGRMC1 in metaphase cells. Additionally, PGRMC2 is over-expressed in triple A patient fibroblasts. Conclusion Our results emphasize the possibility that loss of the regulatory association between ALADIN and PGRMC2 gives rise to a depletion of PGRMC1 at kinetochore fibers. This observation may explain part of the symptoms seen in triple A syndrome patients.

This paper deals with the temperature projections of two regonal climate models, actually three scenarios by 2100: the A2 scenario of the EBU-POM model and the RCP4.5 and RCP8.5 scenarios, the latest projections of the ALADIN model. Kolašin was chosen, because the altitude of the place is the average height of the northern region of Montenegro (about 1000 m). A total of 22 temperature parameters for the period 2011- 2100 were analyzed. The upward trend of projected seasonal and annual (TY, TYx, and TYn) mean, mean maximum, and mean minimum temperatures by 2100 is very significant. According to the RCP4.5 and RCP8.5 scenarios, in 2011-2100, the trend of projected mean winter (TW) temperatures will be from 0.2 to 0.37 °C per decade, and the trend of projected mean summer (TSu) temperatures will be from 0.24 to 0.54 °C per decade. Compared to the base period (1981-2010), the average annual temperature in 2071-2100 is expected to be higher than 2.2 (RCP4.5) to 3.6 °C (A2 and RCP8.5). Also, by the end of the 21st century, a significant increase in the number of summer and tropical days (SD and TD) together with a decrease in the number of frost and ice days (FD and ID) are expected. During the instrumental period, a temperature higher than 37 °C was not recorded. According to projections, in the late 21st century, in summer, maximum temperatures of 40 °C are possible, even in the milder variant (RCP4.5) scenario. According to projections of the used models, Kolašin and the northern region of Montenegro expect a warmer future with more frequent extreme temperatures in a positive direction. [ABSTRACT FROM AUTHOR]

The physical and virtual connectivity of systems via flows of energy, material, information, etc., steadily increases. This paper deals with systems of sub-systems that are connected by networks of shared resources that have to be balanced. For the optimal operation of the overall system, the couplings between the sub-systems must be taken into account, and the overall optimum will usually deviate from the local optima of the sub-systems. However, for reasons, such as problem size, confidentiality, resilience to breakdowns, or generally when dealing with autonomous systems, monolithic optimization is often infeasible. In this contribution, iterative distributed optimization methods based on dual decomposition where the values of the objective functions of the different sub-systems do not have to be shared are investigated. We consider connected dynamic systems that share resources. This situation arises for continuous processes in transient conditions between different steady states and in inherently discontinuous processes, such as batch production processes. This problem is challenging since small changes during the iterations towards the satisfaction of the overarching constraints can lead to significant changes in the arc structures of the optimal solutions for the sub-systems. Moreover, meeting endpoint constraints at free final times complicates the problem. We propose a solution strategy for coupled semi-batch processes and compare different numerical approaches, the sub-gradient method, ADMM, and ALADIN, and show that convexification of the sub-systems around feasible points increases the speed of convergence while using second-order information does not necessarily do so. Since sharing of resources has an influence on whether trajectory dependent terminal constraints can be satisfied, we propose a heuristic for the computation of free final times of the sub-systems that allows the dynamic sub-processes to meet the constraints. For the example of several semi-batch reactors which are coupled via a bound on the total feed flow rate, we demonstrate that the distributed methods converge to (local) optima and highlight the strengths and the weaknesses of the different distributed optimization methods. [ABSTRACT FROM AUTHOR]

In recent years, there has been a noticeable uneven distribution of rainfall in Central Europe during the main vegetation season of most field crops. The rising air temperatures also increase the evapotranspiration demands of the environment and increase the frequency and length of heatwaves, which is a stress factor for plants. Using the GIS procedures, we identified the areas of significant abiotic risks occurring during the critical growth stages of spring barley (high air temperatures at the time of tillering and lack of soil moisture from the beginning of flowering to yellow ripening) with potential impact on grain yield in the Czech Republic. Unique datasets, including i) meteorological data, ii) phenological data, iii) pedological data, iv) land-use data, and v) geographic data, have been integrated and analysed using the sophisticated ArcGIS software environment. The method used in this study is universally applicable and allows comparisons at the local, regional, and supra-regional levels. The identification of risk areas will allow for a) finding tolerant varieties from problematic areas, b) locating the use of these varieties in risk areas and c) recommending and implementing adequate farming practices to reduce the impact of risk abiotic stressors on spring barley under current climate conditions. This will allow accurate estimation of weather impacts on spring barley grain yield in a particular year and precise application of countermeasures leading to reduced negative impacts on yield and the quality of spring barley production. Using the data and methods presented, we identified areas that correspond in good accordance to areas with spring barley yield deficits in dry years. [ABSTRACT FROM AUTHOR]

Objective: To study genotype–phenotype spectrum of triple A syndrome (TAS). Methods: Retrospective chart analysis of Indian TAS patients (cohort 1, n = 8) and review of genotyped TAS cases reported in world literature (cohort 2, n = 133, 68 publications). Results: Median age at presentation was 4.75 years (range: 4–10) and 5 years (range: 1–42) for cohorts 1 and 2, respectively. Alacrima, adrenal insufficiency (AI), achalasia and neurological dysfunction (ND) were seen in 8/8, 8/8, 7/8 and 4/8 patients in cohort 1, and in 99, 91, 93 and 79% patients in cohort 2, respectively. In both cohorts, alacrima was present since birth while AI and achalasia manifested before ND. Mineralocorticoid deficiency (MC) was uncommon (absent in cohort 1, 12.5% in cohort 2). In cohort 1, splice-site mutation in exon 1 (p.G14Vfs*45) was commonest, followed by a deletion in exon 8 (p.S255Vfs*36). Out of 65 mutations in cohort 2, 14 were recurrent and five exhibited regional clustering. AI was more prevalent, more often a presenting feature, and was diagnosed at younger age in T group (those with truncating mutations) as compared to NT (non-truncating mutations) group. ND was more prevalent, more common a presenting feature, with later age at onset in NT as compared to T group. Conclusion: Clinical profile of our patients is similar to that of patients worldwide. Alacrima is the earliest and most consistent finding. MC deficiency is uncommon. Some recurrent mutations show regional clustering. p.G14Vfs*45 and p.S255Vfs*36 account for majority of AAAS mutations in our cohort. Phenotype of T group differs from that of NT group and merits future research.

A new index for climate change assessment has been introduced. It is a ratio between the number of cases from a future period and the cases of a control experiment (reference period) falling within a predefined interval of the reference period. By "case" we mean the value of a meteorological element that meets certain conditions. Additionally, its conservation is a necessary condition for reducing the risk of losing a reliable signal of the modeled variability of future climate when applying bias correction methods (BCM's). The spatial distribution of this index is presented by using two regional climate models, ALADIN and RegCM4, over an area including the Balkan and Apennine Peninsulas. The assessment is performed for the average monthly temperature and precipitation. Both models have similar indices in broad areas. In winter, spring, and summer this refers to temperature and in spring and summer to rainfall. [ABSTRACT FROM AUTHOR]

Distributed or multi-area optimal power flow (OPF) in alternating current (AC) grids is currently a subject undergoing intense study to cope with computational burdens in large-scale grids and to maintain self-control of a regional system operator. However, future power grids will most likely be hybrid grids consisting of the conventional AC transmission system combined with high voltage direct current (DC) technology. Thus, we reformulate the full AC–DC OPF problem such that it becomes separable and, therefore, accessible to distributed algorithms. Then, we show in detail two different approaches on the decomposition of a hybrid AC–DC grid. Finally, we implement an improved alternating direction of multipliers method (ADMM) as well as the most recently proposed augmented Lagrangian based alternating direction inexact Newton (ALADIN) method. Simulation results show that optimality gaps below 0.01% are reached with both decomposition approaches and algorithms for two different test systems (5-bus and 66-bus). Furthermore, convergence rates and wall clock times are reduced by around one order of magnitude from ADMM to ALADIN. [ABSTRACT FROM AUTHOR]

The occurrence of drought during flowering (usually from the end of May to the beginning of June) is the most hazardous timing in terms of the possible negative impact of agricultural drought on winter wheat, which is the most cultivated crop in the Czech Republic (about 800000 ha). Lack of water, often accompanied by high temperatures, negatively affects the number of grains in the wheat ear and the tissue development of the developing grain, with consequent impacts on yield and quality of product. With the use of a) long-term time series of agrometeorological data (1961–2010), b) long-term phenological time series of winter wheat (1981–2010), and c) soil conditions data (available water capacity of soils of the Czech Republic) for the arable soil, the ratio of actual evapotranspiration and potential evapotranspiration for the period of 1961–2010, used as an indicator of agricultural drought (lack of water) for wheat, was calculated. The innovative aspect of this categorization of the territory of the Czech Republic according to the risk of occurrence of agricultural drought for winter wheat is considering drought from the aspect of the plant, i.e., evaluation based on the actual consumption of water by the vegetation. This is a very sophisticated procedure. Frequently, water content in soils data, presented as an output of some models, do not fully indicate the possible negative impacts on yield generation because the plants themselves are typically not considered. The method used in this study is universally applicable and allows comparisons of regions at the local, regional, and supra-regional levels. For estimation of the development of agronomic drought in the future, the basic water balances in the growing seasons of 1961–2010 and 2071–2100 were compared using a climate scenario. The forecast indicates a significant deterioration of agricultural drought in the region with probable direct impacts on agricultural production. [ABSTRACT FROM AUTHOR]

Most climate models do not explicitly model urban areas and at best describe them as rock covers. Nonetheless, the very high resolutions reached now by the regional climate models may justify and require a more realistic parameterization of surface exchanges between urban canopy and atmosphere. To quantify the potential impact of urbanization on the regional climate, and evaluate the benefits of a detailed urban canopy model compared with a simpler approach, a sensitivity study was carried out over France at a 12-km horizontal resolution with the ALADIN-Climate regional model for 1980-2009 time period. Different descriptions of land use and urban modeling were compared, corresponding to an explicit modeling of cities with the urban canopy model TEB, a conventional and simpler approach representing urban areas as rocks, and a vegetated experiment for which cities are replaced by natural covers. A general evaluation of ALADIN-Climate was first done, that showed an overestimation of the incoming solar radiation but satisfying results in terms of precipitation and near-surface temperatures. The sensitivity analysis then highlighted that urban areas had a significant impact on modeled near-surface temperature. A further analysis on a few large French cities indicated that over the 30 years of simulation they all induced a warming effect both at daytime and nighttime with values up to + 1.5 °C for the city of Paris. The urban model also led to a regional warming extending beyond the urban areas boundaries. Finally, the comparison to temperature observations available for Paris area highlighted that the detailed urban canopy model improved the modeling of the urban heat island compared with a simpler approach. [ABSTRACT FROM AUTHOR]

It has been shown that the nucleoporin ALADIN plays a significant role in the redox homeostasis of the cell, but its function in steroidogenesis contributing to adrenal atrophy in triple A syndrome remains largely unknown. In an attempt to identify new interaction partners of ALADIN, co-immunoprecipitation followed by proteome analysis was conducted in different expression models using the human adrenocortical tumour cell line NCI-H295R. Our results suggest an interaction of ALADIN with the microsomal protein PGRMC2. PGRMC2 is shown to be activity regulator of CYP P450 enzymes and, therefore, to be a possible target for adrenal dysregulation in triple A syndrome. We show that there is a sexual dimorphism regarding the expression of Pgrmc2 in adrenals and gonads of wild-type (WT) and Aaas knock-out (KO) mice. Female Aaas KO mice are sterile due to delayed oocyte maturation and meiotic spindle assembly. A participation in meiotic spindle assembly confirms the recently investigated involvement of ALADIN in mitosis and emphasises an interaction with PGRMC2 which is a regulator of the cell cycle. By identification of a novel interaction partner of ALADIN, we provide novel aspects for future research of the function of ALADIN during cell cycle and for new insights into the pathogenesis of triple A syndrome.

Flash floods are common in small Mediterranean watersheds and the alerts provided by real-time monitoring systems provide too short anticipation times to warn the population. In this context, there is a strong need to develop flood forecasting systems in particular for developing countries such as Morocco where floods have severe socio-economic impacts. In this study, the AROME (Application of Research to Operations at Mesoscale), ALADIN (Aire Limited Dynamic Adaptation International Development) and WRF (Weather Research and Forecasting) meteorological models are evaluated to forecast flood events in the Rheraya and Ourika basin located in the High-Atlas Mountains of Morocco. The model evaluation is performed by comparing for a set of flood events the observed and simulated probabilities of exceedances for different precipitation thresholds. In addition, two different flood forecasting approaches are compared: the first one relies on the coupling of meteorological forecasts with a hydrological model and the second one is a based on a linear relationship between event rainfall, antecedent soil moisture and runoff. Three different soil moisture products (in-situ measurements, European Space Agency’s Climate Change Initiative ESA-CCI remote sensing data and ERA5 reanalysis) are compared to estimate the initial soil moisture conditions before flood events for both methods. Results showed that the WRF and AROME models better simulate precipitation amounts compared to ALADIN, indicating the added value of convection-permitting models. The regression-based flood forecasting method outperforms the hydrological model-based approach, and the maximum discharge is better reproduced when using the WRF forecasts in combination with ERA5. These results provide insights to implement robust flood forecasting approaches in the context of data scarcity that could be valuable for developing countries such as Morocco and other North African countries.

Mutations in the AAAS gene coding for the nuclear pore complex protein ALADIN lead to the autosomal recessive disorder triple A syndrome. Triple A patients present with a characteristic phenotype including alacrima, achalasia and adrenal insufficiency. Patient fibroblasts show increased levels of oxidative stress, and several in vitro studies have demonstrated that the nucleoporin ALADIN is involved in both the cellular oxidative stress response and adrenal steroidogenesis. It is known that ALADIN knock-out mice lack a phenotype resembling human triple A syndrome. The objective of this study was to determine whether the application of chronic oxidative stress by ingestion of paraquat would generate a triple A-like phenotype in ALADIN null mice. Adult male mice were fed either a paraquat (0.25 g/kg diet) or control diet for 11 days. After application of chronic oxidative stress, ALADIN knock-out mice presented with an unexpected compensated glutathione metabolism, but lacked a phenotype resembling human triple A syndrome. We did not observe increased levels of oxidative stress and alterations in adrenal steroidogenesis in mice depleted for ALADIN. This study stresses the species-specific role of the nucleoporin ALADIN, which in mice involves a novel compensatory mechanism for regulating the cellular glutathione redox response.

The precise knowledge of the beginning and the end of the growing season is necessary for the calculation of climatic indicators with evident effect on grapevine production. The aim of this study is to develop suitable methods on the basis of thermal conditions that can be used for calculation of the beginning, the end, and the length of the growing season for every single year. The two most accurate methods ('5mid' and 'int') are selected using the root-mean-square error compared to the reference growing season values based on averaging the daily mean temperature for several decades. In case of the '5mid' method, the beginning (or the end) is the middle day of the first (or last) 5-day period with temperature not less than 10 °C. In case of the 'int' method, the beginning (or the end) of the growing season is the day after March 15 (or September 15), when the smoothed series of daily temperature using the monthly average temperatures of March and April (or September and October) exceeds 10 °C (or falls below 10 °C). As a next step, several climatic indicators (e.g., Huglin index and hydrothermal coefficient) are calculated for Hungary for three time periods (1961-1990, 2021-2050, and 2071-2100*) using the '5mid' and 'int' methods. For this purpose, the bias-corrected daily mean, minimum, and maximum temperature and daily precipitation outputs of three different regional climate models (RegCM, ALADIN, and PRECIS) are used. Extreme temperature and precipitation indices are also evaluated as they determine the risk of grapevine production. The spatial distributions of the indicators are presented on maps. We compare the indicators for the past and for the future using one-way completely randomized robust ANOVA (analysis of variance). Results suggest that changes of temperature conditions in the 21st century will favor the production of red grapevine and late-ripening cultivars. Furthermore, drought seasons will be longer and extreme high summer temperatures will become more frequent, which are clearly considered as high risk factors in grapevine production. Besides the negative effects, the risk of winter frost damage is expected to decrease, which is evidently a favorable change in terms of grapevine production. [ABSTRACT FROM AUTHOR]

In case of a temporal undefined failure of the active cooling system of a spent fuel pool (SFP), the water inside the pool heats up depending on the decay heat of the stored spent fuel. In the worst case, this leads to a boil-off scenario with a water level decrease and, after appropriate time, to a progressive uncovery of the fuel assemblies (FA). The cooling of the uncovered structures is limited by the steam production in the lower still wetted part of the FA, radiative heat transfer, radial heat conduction and convection inside the FA and interaction with ambient air depending on the storage conditions. As a result, the removal of decay heat can be endangered and, by reaching certain cladding temperatures, the integrity of the cladding tubes can be compromised. The detailed heat and mass transfer mechanisms of the boil-off scenario are not yet sufficiently investigated – especially experimentally. Therefore, reliable conclusions about the development of the cladding temperatures cannot be made. Against this background, the SINABEL project was launched in 2013 at TU Dresden for an improved understanding of the heat transport processes inside a SFP under accident conditions. Studies are performed both experimentally on the test facility ALADIN and theoretically by using computational fluid dynamics (CFD) calculations and integral codes for severe accidents. The test facility simulates a generic boiling water reactor (BWR) FA on almost original scale with regard to the boundary and ambient conditions within a SFP. Through an appropriate unique net of instrumentation, the distribution and development of radial and axial cladding temperatures and the development of the water level can be investigated in detail. Experiments were carried out for various decay heats respectively rod powers and changing storage distances. The thermal hydraulics of the heat-up and the boil-off phase with the occurrence of subcooled boiling in the beginning followed by geysering-like instabilities are described in the present paper. The higher the heat load, the faster the heat-up and, as boiling temperature is reached, the lowering of the water level. The maximum limit of the water level and the influence by the radial heat conduction, convection and radiative heat transfer is shown and explained. The experimental data and thermohydraulic findings provide the basis for the phenomenological understanding of this accident scenario and are used for the validation and improvement of numerical simulations. [ABSTRACT FROM AUTHOR]

Nowadays, hydrological forecasts are based on wide range of meteorological inputs, including observations and forecasts. In this paper four main areas are covered. First of all, milestones covering last four decades from usage of a simple statistical method to regional limited area modeling are summarized. Then an overview of the main activities of the European Flood Awareness System (EFAS) is given. Usage of ensemble forecasts for providing uncertainty is getting larger and larger attention for hydrological applications too. Benefits of a locally developed new tool, the ensemble calibration method based on reforecast model climate is given in the third part. Finally, local developments on regional hydrostatic and non-hydrostatic models are shown. It is shown that a high resolution limited area non-hydrostatic model can predict summer heavy precipitation more accurately. [ABSTRACT FROM AUTHOR]

The evaluation of several climatological background-error covariance matrix (defined as the B matrix) estimation methods was performed using the ALADIN limited-area modeling data-assimilation system at a 4 km horizontal grid spacing. The B matrices compared were derived using the standard National Meteorological Center (NMC) and ensemble-based estimation methods. To test the influence of lateral boundary condition (LBC) perturbations on the characteristics of ensemble-based B matrix, two ensemble prediction systems were established: one used unperturbed lateral boundary conditions (ENS) and another used perturbed lateral boundary conditions (ENSLBC). The characteristics of the three B matrices were compared through a diagnostic comparison, while the influence of the different B matrices on the analysis and quality of the forecast were evaluated for the ENSLBC and NMC matrices. The results showed that the lateral boundary condition perturbations affected all the control variables, while the smallest influence was found for the specific humidity. The diagnostic comparison showed that the ensemble-based estimation method shifted the correlations toward the smaller spatial scales, while the LBC perturbations gave rise to larger spatial scales. The influence on the analysis showed a smaller spatial correlation for the ensemble B matrix compared to that of the NMC, with the most pronounced differences for the specific humidity. The verification of the forecast showed modest improvement for the experiment with the ensemble B matrix. Among the methods tested, the results suggest that the ensemble-based data-assimilation method is the favorable approach for background-error covariance calculation in high-resolution limited-area data assimilation systems.

Acercarnos a un respirador anestésico (o bien, a una estación de trabajo para los más finos) es acercarnos a una maquinaria relativamente reciente. Y a pesar de que los actuales modelos se presentan con diseños futuristas, mostrando variedad de pantallas y lucecitas, acercándolos más a la consola de un vehículo Tesla que a un dispositivo para ventilar pacientes, la verdad es que la tecnología de un respirador descansa más sobre aspectos mecánicos que sobre aspectos puramente electrónicos. Y junto al respirador está, casi siempre, el vaporizador. El vaporizador anestésico se ha convertido en un elemento fundamental dentro de la obra de ingeniería que es un respirador y representa, en sí mismo, la labor de un anestesiólogo en quirófano. Hay que admirar también cómo su funcionamiento tiene mucho de física y poco de electrónica siendo el propósito de este escrito mostrar algo más sobre la evolución y el funcionamiento de estos aparatos que nos acompañan en nuestra vida profesional. ABSTRACT Anaesthetic vaporizer Approaching an anaesthetic respirator (or a workstation for the finer ones) is to approach a relatively new machine: the current models are presented with futuristic designs, showing a variety of screens and little lights, and look more like a Tesla vehicle console than a patient ventilation device. The truth is that the technology of a respirator rests more on mechanical aspects than on electronic aspects. And next to the respirator is almost always the vaporizer. The anesthetic vaporizer has become a fundamental element in the design of a respirator and represents the work of an anesthesiologist in the operating room. The purpose of this paper is to show something more about the evolution and functioning of these devices. An engineering design that accompanies our professional life.

Triple A (Allgrove) syndrome, an autosomal recessive disease is characterized by achalasia, alacrimia and ACTH-resistant adrenal failure with progressive neurological syndrome including central, peripheral and autonomic nervous system impairment, and mild mental retardation. The triple A syndrome gene, designated AAAS, localized on chromosome 12q 13 encodes for a 546 amino acid protein called ALADIN (Alacrimia-Achlasia-Adrenal Insufficiency and Neurologic disorder). This report relates to two sisters, aged 8 and 12 years, who had vomiting, muscle weakness, alacrimia, excessive fatigue and dysphagia. Abdominal sonography, esophago-gastroduodenoscopy, barium swallow, esophageal manometry, CT scan abdomen and brain, biochemical profiles, as well as neurologic and ophthalmic evaluations were consistent with Allgrove's syndrome. Management consisted of pneumatic balloon dilatation for achalasia and initiation of cortisone therapy with successful resolution of dysphagia and other symptoms. [ABSTRACT FROM AUTHOR]

Kinetic energy spectra from the mesoscale numerical weather prediction (NWP) model ALADIN with horizontal resolution 4.4 km are split into divergent and rotational components which are then compared at horizontal scales below 300 km and various vertical levels. It is shown that about 50% of kinetic energy in the free troposphere in ALADIN is divergent energy. The percentage increases towards 70% near the surface and in the upper troposphere towards 100 hPa. The maximal percentage of divergent energy is found at stratospheric levels around 100 hPa and at scales below 100 km which are not represented by the global models. At all levels, the divergent energy spectra are characterised by shallower slopes than the rotational energy spectra, and the difference increases as horizontal scales become larger. A very similar vertical distribution of divergent energy is obtained by using the standard ALADIN approach for the computation of spectra based on the extension zone and by applying detrending approach commonly used in mesoscale NWP community.