Building Up Demand-Oriented Charging Infrastructure for Electric Vehicles in Germany

Mobility offerings have never been as abundant and varied as the present. While users welcome new and innovative mobility options, this current paradigm shift presents a challenge for authorities that plan, organize, and operate such services. In particular, integrating new mobility services into existing infrastructure systems can generate problems of acceptance, co-operability, and compatibility. This problem is especially relevant for electric vehicles. Limited range and battery capacity of battery electric vehicles make them dependent on charging infrastructure, which in turn hinders their acceptance. In light of the German government’s goal of one million electric vehicles by 2020, establishing a demand-oriented charging infrastructure is of crucial importance. However, numerous questions remain unanswered regarding the quantity, type, and location of electric vehicle charging stations in Germany. This article presents the findings of the project “LADEN2020: Concept to build up a demand-oriented charging infrastructure in Germany between today and 2020.” The research project develops a systematically comprehensible and consistent strategy for electric vehicle charging infrastructure in Germany. The paper presents the methodological framework to estimate the charging demand for daily and long-distance travel, which is unique and innovative as similar comprehensive and consistent analytical tools do not exist to date

Synthesis, Crystallographic Characterization and Reactivity of a Phosphinine-B(C6F5)3 Lewis Pair

A phosphinine-borane adduct of a Me3Si-functionalized phosphinine and the Lewis acid B(C6F5)3 has been synthesized and characterized crystallographically for the first time. The reaction strongly depends on the nature of the substituents in the α-position of the phosphorus heterocycle. In contrast, the reaction of B2H6 with various substituted phosphinines leads to an equilibrium between the starting materials and the phosphinine–borane adducts that is determined by the Lewis basicity of the phosphinine. The novel phosphinine borane adduct (6-B(C6F5)3) shows rapid and facile insertion and [4+2] cycloaddition reactivity towards phenylacetylene. A hitherto unknown dihydro-1-phosphabarrelene is formed with styrene. The reaction with an ester provides a new, facile and selective route to 1-R-phosphininium salts. These salts then undergo a [4+2] cycloaddition in the presence of Me3Si−C≡CH and styrene to cleanly form unprecedented derivatives of 1-R-phosphabarrelenium salts

From Understanding Genetic Drift to a Smart-Restart Parameter-less Compact Genetic Algorithm

One of the key difficulties in using estimation-of-distribution algorithms is choosing the population size(s) appropriately: Too small values lead to genetic drift, which can cause enormous difficulties. In the regime with no genetic drift, however, often the runtime is roughly proportional to the population size, which renders large population sizes inefficient. Based on a recent quantitative analysis which population sizes lead to genetic drift, we propose a parameter-less version of the compact genetic algorithm that automatically finds a suitable population size without spending too much time in situations unfavorable due to genetic drift. We prove a mathematical runtime guarantee for this algorithm and conduct an extensive experimental analysis on four classic benchmark problems both without and with additive centered Gaussian posterior noise. The former shows that under a natural assumption, our algorithm has a performance very similar to the one obtainable from the best problem-specific population size. The latter confirms that missing the right population size in the original cGA can be detrimental and that previous theory-based suggestions for the population size can be far away from the right values; it also shows that our algorithm as well as a previously proposed parameter-less variant of the cGA based on parallel runs avoid such pitfalls. Comparing the two parameter-less approaches, ours profits from its ability to abort runs which are likely to be stuck in a genetic drift situation.Comment: 4 figures. Extended version of a paper appearing at GECCO 202

Borane Adducts of Aromatic Phosphorus Heterocycles: Synthesis, Crystallographic Characterization and Reactivity of a Phosphinine‐B(C 6 F 5 ) 3 Lewis Pair

A phosphinine-borane adduct of a Me3Si-functionalized phosphinine and the Lewis acid B(C6F5)3 has been synthesized and characterized crystallographically for the first time. The reaction strongly depends on the nature of the substituents in the α-position of the phosphorus heterocycle. In contrast, the reaction of B2H6 with various substituted phosphinines leads to an equilibrium between the starting materials and the phosphinine–borane adducts that is determined by the Lewis basicity of the phosphinine. The novel phosphinine borane adduct (6-B(C6F5)3) shows rapid and facile insertion and [4+2] cycloaddition reactivity towards phenylacetylene. A hitherto unknown dihydro-1-phosphabarrelene is formed with styrene. The reaction with an ester provides a new, facile and selective route to 1-R-phosphininium salts. These salts then undergo a [4+2] cycloaddition in the presence of Me3Si−C≡CH and styrene to cleanly form unprecedented derivatives of 1-R-phosphabarrelenium salts

Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients

Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD

At a glance:the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years

Niemann-Pick type C1 disease (NPC1 [OMIM 257220]) is a rare and severe autosomal recessive disorder, characterized by a multitude of neurovisceral clinical manifestations and a fatal outcome with no effective treatment to date. Aiming to gain insights into the genetic aspects of the disease, clinical, genetic, and biomarker PPCS data from 602 patients referred from 47 countries and diagnosed with NPC1 in our laboratory were analyzed. Patients’ clinical data were dissected using Human Phenotype Ontology (HPO) terms, and genotype–phenotype analysis was performed. The median age at diagnosis was 10.6 years (range 0–64.5 years), with 287 unique pathogenic/likely pathogenic (P/LP) variants identified, expanding NPC1 allelic heterogeneity. Importantly, 73 P/LP variants were previously unpublished. The most frequent variants detected were: c.3019C &gt; G, p.(P1007A), c.3104C &gt; T, p.(A1035V), and c.2861C &gt; T, p.(S954L). Loss of function (LoF) variants were significantly associated with earlier age at diagnosis, highly increased biomarker levels, and a visceral phenotype (abnormal abdomen and liver morphology). On the other hand, the variants p.(P1007A) and p.(S954L) were significantly associated with later age at diagnosis (p &lt; 0.001) and mildly elevated biomarker levels (p ≤ 0.002), consistent with the juvenile/adult form of NPC1. In addition, p.(I1061T), p.(S954L), and p.(A1035V) were associated with abnormality of eye movements (vertical supranuclear gaze palsy, p ≤ 0.05). We describe the largest and most heterogenous cohort of NPC1 patients published to date. Our results suggest that besides its utility in variant classification, the biomarker PPCS might serve to indicate disease severity/progression. In addition, we establish new genotype–phenotype relationships for “frequent” NPC1 variants.</p

Genetic and Evolutionary Analyses of the Human Bone Morphogenetic Protein Receptor 2 (BMPR2) in the Pathophysiology of Obesity

Human bone morphogenetic protein receptor 2 (BMPR2) is essential for BMP signalling and may be involved in the regulation of adipogenesis. The BMPR2 locus has been suggested as target of recent selection in human populations. We hypothesized that BMPR2 might have a role in the pathophysiology of obesity.Evolutionary analyses (dN/dS, Fst, iHS) were conducted in vertebrates and human populations. BMPR2 mRNA expression was measured in 190 paired samples of visceral and subcutaneous adipose tissue. The gene was sequenced in 48 DNA samples. Nine representative single nucleotide polymorphisms (SNPs) were genotyped for subsequent association studies on quantitative traits related to obesity in 1830 German Caucasians. An independent cohort of 925 Sorbs was used for replication. Finally, relation of genotypes to mRNA in fat was examined.The evolutionary analyses indicated signatures of selection on the BMPR2 locus. BMPR2 mRNA expression was significantly increased both in visceral and subcutaneous adipose tissue of 37 overweight (BMI>25 and <30 kg/m²) and 80 obese (BMI>30 kg/m²) compared with 44 lean subjects (BMI< 25 kg/m²) (P<0.001). In a case-control study including lean and obese subjects, two intronic SNPs (rs6717924, rs13426118) were associated with obesity (adjusted P<0.05). Combined analyses including the initial cohort and the Sorbs confirmed a consistent effect for rs6717924 (combined P = 0.01) on obesity. Moreover, rs6717924 was associated with higher BMPR2 mRNA expression in visceral adipose tissue.Combined BMPR2 genotype-phenotype-mRNA expression data as well as evolutionary aspects suggest a role of BMPR2 in the pathophysiology of obesity

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.Peer reviewe