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Patients with atrial septal defects (ASDs) have increased mortality and morbidity. This can only partly be explained by hemodynamic changes caused by the ASD, suggesting additional underlying causes. Patients with an ASD have an increased burden of pathogenic gene variants in ASD-related genes, indicating genetics as an important factor in etiology. Inheritance of genetic variants with high impact can cause ASD in relatives (familial ASD). This study aimed to investigate whether lifelong outcomes were different in patients with familial ASD compared with patients with sporadic ASD. We used health registries and a nationwide cohort of 2,151 patients with ASD to compare the incidences of atrial fibrillation or flutter (together abbreviated as AF), heart failure, and mortality between patients with familial and sporadic ASD using Cox proportional hazard ratio and Fine and Gray analysis. Patients with familial ASD experienced AF and heart failure earlier in life than patients with sporadic ASD, with hazard ratios of 1.6 and 1.7, respectively. Subdistribution hazard ratios showed an increased risk of AF and heart failure in patients with familial ASD compared with patients with sporadic ASDs (2.3 and 3.1, respectively). Our results suggest that genetic variants with high impact may influence the outcomes of patients with ASD. In conclusion, patients with familial ASD have an increased risk and an earlier onset of AF and heart failure compared with patients with sporadic ASD, hence clinical awareness of arrhythmias and heart failure in patients with familial ASD may lead to timely treatment.

Designing a public transport timetable that maximizes passenger service, measured in weighted travel time, is an intricate problem. The weighted travel time depends on the free route choice of passengers. Passenger route choice depends on the timetable. In turn, the timetable that minimizes weighted travel time depends on the route choice of passengers—and therefore requires passenger route choice information. Consequently, a sequential approach where timetables are designed provided pre-fixed passenger assignment to routes may not find the optimal timetable. This paper aims to integrate passenger route choice and timetabling. It addresses the problem of designing maximal passenger service public transport timetables in systems with free route choice within a budget for operating costs. Operating costs are defined by the minimal cost vehicle schedule required to operate the timetable. The proposed methodology integrates a matheuristic for timetabling and vehicle scheduling with a passenger assignment model in an iterative framework, where different forms of integration are evaluated. Focus is on long- to medium-term timetabling, provided an initial timetable. The results for a realistic case study in the Greater Copenhagen area indicate that our approach consistently leads, at no additional cost, to timetables that represent a reduction in passenger weighted travel time in comparison with both an initial timetable and a non-integrated timetabling method that receives a single-passenger assignment as input.

Alexander Disease is a rare leukodystrophy caused by gain-of-function variants in the gene encoding Glial Fibrillary Acidic Protein (GFAP), a major constituent of the intermediate filament of Astrocytes within the central nervous system. Currently, no phenotypic consequence of GFAP haploinsufficiency is known, and recent rodent experiments suggest that antisense oligonucleotide-mediated suppression of GFAP expression can reverse the disease progression in AxD.We investigated a six-generation family with ten individuals presenting with visual impairment, retinal dysplasia and pseudopapilledema. Whole genome sequencing of three affected individuals revealed a rare novel loss-of-function variant in GFAP, which segregated with disease in the family. The variant, c.928dup, results in frameshift and translation into a 422 aa protein (p.Met310Asnfs*113) wild type GFAP is 431-438 aa). Analysis of human embryonic tissues showed strong GFAP expression in retinal neural progenitors in the developing eye at 35-51 days post conception. Experiments using zebrafish models verified that the c.928dup variant does not result in extensive GFAP protein aggregation. Analysis of zebrafish loss-of-function gfap mutants, showed that depletion of GFAP causes vision impairment and retinal dysplasia, characterized by a significant loss of Müller glia cells and photoreceptor cells. Our findings provide novel insight into the function of GFAP and the consequence of GFAP deficiency.

Primary microcephaly (MCPH) is characterized by reduced brain size and intellectual disability. The exact pathophysiological mechanism underlying MCPH remains to be elucidated, but dysfunction of neuronal progenitors in the developing neocortex plays a major role. We identified a homozygous missense mutation (p.W155C) in Ribosomal RNA Processing 7 Homolog A, RRP7A, segregating with MCPH in a consanguineous family with 10 affected individuals. RRP7A is highly expressed in neural stem cells in developing human forebrain, and targeted mutation of Rrp7a leads to defects in neurogenesis and proliferation in a mouse stem cell model. RRP7A localizes to centrosomes, cilia and nucleoli, and patient-derived fibroblasts display defects in ribosomal RNA processing, primary cilia resorption, and cell cycle progression. Analysis of zebrafish embryos supported that the patient mutation in RRP7A causes reduced brain size, impaired neurogenesis and cell proliferation, and defective ribosomal RNA processing. These findings provide novel insight into human brain development and MCPH., The RRP7A a gene is involved in ribosome biogenesis. Here the authors report a homozygous missense mutation segregating with primary microcephaly, and show that this occurs via functional defects in both nucleoli and primary cilia disrupting cell proliferation and neurogenesis.

Microcephaly primary hereditary (MCPH) is a congenital disease characterized by nonsyndromic reduction in brain size due to impaired neurogenesis, often associated with a variable degree of intellectual disability (ID). The genetic etiology of MCPH is heterogeneous and comprises more than 20 loci, nearly all following a recessive inheritance pattern. The first causative gene identified, MCPH1 or Microcephalin, encodes a centrosomal protein that modulates chromosome condensation and cell cycle progression. It is also involved in DNA damage response and telomere maintenance in the nucleus. Despite numerous studies on MCPH1 function, MCPH1-affected individuals are rare and the available clinical reports are not sufficient to define the natural history of the disease. Here, we present a novel patient with congenital microcephaly, ID, language delay, short stature, and other minor features such as strabismus. magnetic resonance imaging revealed ventriculomegaly, simplified gyral pattern in the frontal lobes, and a neuronal migration defect. Genetic testing detected a homozygous deletion of exons 1–8 of MCPH1. We compare the patients’ characteristics with a list of features from MCPH1 cases described in the literature, in an effort to provide additional clues for a comprehensive definition of disease presentation and evolution.

The aerodynamics of the twin-box bridge is considered to highlight the reasons for making this type of bridge deck superior to the conventional trapezoidal mono-box for suspension bridges having span lengths longer than 1800 m. The paper proposes a simple theoretical model yielding physical insight into the flutter stability and presents a design example comparing the flutter performance of a 2000 m main span suspension bridge designed with either a mono-box or a twin-box bridge girder. Experience from vortex induced vibration of twin-box bridges is discussed to demonstrate that a twin-box girder can be designed to avoid vortex induced for practical damping levels.

IABSE Task Group 3.1 has the mandate to define reference results for the validation of methodologies and programs used to study both stability and buffeting responses of long-span bridges. These to...

Urban consolidation centers (UCCs) have a key role in many initiatives in urban logistics, yet few of them are successful in the long run. The high costs often prevent attracting a sufficient number of UCC users. In this paper, we study sustainable business models and the supporting role of administrative policies. We perform an agent-based simulation applied to the city of Copenhagen and collect data from a variety of sources to model the agents. Both the data and case setup are validated by means of expert interviews. We test 1,458 schemes that combine several administrative measures and cost settings. Most schemes yield significant environmental benefits; many of them reduce the truck kilometers driven by about 65% and emissions by about 70%. The key challenge is to identify schemes that are also financially sustainable. We show the importance of committing carriers to the UCC as soon as possible, as carriers potentially generate the bulk of the revenue. Subsequent revenues may be generated by offering value-adding services to receivers. Based on the numerical experiments, we pose various propositions that aid in providing favorable conditions for a UCC, improving its chances of long-term success.

This paper presents the ongoing benchmark results of IABSE Task Group 3.1. The task of this working group is to create benchmark results for the validation of methodologies and software programs developed to assess the stability and the buffeting response of long span bridges. Indeed, accurate estimations of structural stability and response to strong winds are critical for the successful design of long-span bridges. While the first results of the benchmark, dealing with a section approach, have been already published, in this paper the ongoing activity and results of the task group are presented. The topic of these results is the numerical response of a full-bridge model under the actions of a multi-correlated wind field both in terms of aeroelastic stability and buffeting response.

BackgroundIn a recent nationwide cohort study, we have discovered that patients living with an atrial septal defect (ASD) have a shorter life expectancy, increased risk of atrial fibrillation, pneumonia, and psychiatric issues compared to the general population. The pathophysiological mechanisms are still unknown. The objective of this study is to investigate if this group of patients is burdened by mutations in genes associated with ASD.MethodsWe included 147 patients with an unrepaired ASD. We curated a list of ASD candidate genes, and patients were analyzed for genetic variants in these genes, using targeted next generation sequencing. We filtered for protein altering variants (PAVs) and protein truncating variants (PTVs) with minor allele frequency (MAF) ResultsWe identified 384 rare (MAFConclusionsPatients with a small, unrepaired ASD were enriched for rare PAVs within 59 ASD candidate disease genes. Our results suggest that recurrence risk of congenital heart defects in offspring may be increased for this group of patients and warrants further investigations.

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes.

In this paper, we study the problem of optimizing the size and mix of a mixed fleet of electric and conventional vehicles owned by firms providing urban freight logistics services. Uncertain customer requests are considered at the strategic planning stage. These requests are revealed before operations commence in each operational period. At the operational level, a new model for vehicle power consumption is suggested. In addition to mechanical power consumption, this model accounts for cabin climate control power, which is dependent on ambient temperature, and auxiliary power, which accounts for energy drawn by external devices. We formulate the problem of stochastic fleet size and mix optimization as a two-stage stochastic program and propose a sample average approximation based heuristic method to solve it. For each operational period, an adaptive large neighborhood search algorithm is used to determine the operational decisions and associated costs. The applicability of the approach is demonstrated through two case studies within urban logistics services.

IABSE Task Group 3.1 has the mandate to define reference results for the validation of methodologies and programs used to study both stability and buffeting responses of long-span bridges. To this ...

Denne artikel omhandler de foreløbige resultater af en showcase i EUFAL (Electric Urban Freight and Logistics) projektet, som har til formål at skabe en udvekslingsplatform i form af et beslutningsstøttesystem for virksomheder, der har et ønske om at integrere elektriske køretøjer i deres flåder af erhvervskøretøjer. Showcasen foregår i samarbejde med en dansk virksomhed (MT Højgaard), der som virksomhedspartner i EUFAL projektet vil teste, om en løsning med elektriske køretøjer kan opfylde en række specifikke krav inden for den kommercielle sektor. Virksomheden har en række håndværkere, der servicerer byggepladser og udfører andre vedligeholdelsesopgaver inden for Københavns Kommune, og som en del af projektet har virksomheden fysisk erstattet nogle af deres konventionelle køretøjer med elektriske køretøjer i en testperiode på et år. Data vil løbende blive indsamlet og behandlet i løbet af foråret og sommeren 2019 og de foreløbige resultater af projektet vil blive præsenteret ved Trafikdage 2019., Proceedings from the Annual Transport Conference at Aalborg University, Vol. 26 No. 1 (2019): Proceedings from the Annual Transport Conference at Aalborg University

BackgroundCongenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease aetiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD.MethodsWe used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach to identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model.ResultsWe identified 1,785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes and 218 of the genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signalling. Replication confirmed increased mutation burden of calcium-signalling genes in CHD patients. Functional investigation of zebrafish orthologues of ITPR1, PLCB2 and ADCY2 verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes.ConclusionsThe study identifies abnormal calcium signalling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.

Smad ubiquitin regulatory factor 1 (SMURF1) is a HECT-type E3 ubiquitin ligase that plays a critical role in vertebrate development by regulating planar cell polarity (PCP) signaling and convergent extension (CE). Here we show that SMURF1 is involved in mammalian heart development. We find that SMURF1 is highly expressed in outflow tract cushion mesenchyme and Smurf1−/− mouse embryos show delayed outflow tract septation. SMURF1 is expressed in smooth muscle cells of the coronary arteries and great vessels. Thickness of the aortic smooth muscle cell layer is reduced in Smurf1−/− mouse embryos. We show that SMURF1 is a negative regulator of cardiomyogenesis and a positive regulator of smooth muscle cell and cardiac fibroblast differentiation, indicating that SMURF1 is important for cell-type specification during heart development. Finally, we provide evidence that SMURF1 localizes at the primary cilium where it may regulate bone morphogenetic protein (BMP) signaling, which controls the initial phase of cardiomyocyte differentiation. In summary, our results demonstrate that SMURF1 is a critical regulator of outflow tract septation and cell-type specification during heart development, and that these effects may in part be mediated via control of cilium-associated BMP signaling.

Long transfer times often add unnecessary inconvenience to journeys in public transport systems. Synchronizing relevant arrival and departure times through small timetable modifications could reduce excess transfer times, but may also directly affect the operational costs, as the timetable defines the set of feasible vehicle schedules. Therefore better results in terms of passenger service, operational costs, or both, could be obtained by solving these problems simultaneously. This paper addresses the tactical level of the integrated timetabling and vehicle scheduling problem as a bi-objective mixed integer programming problem that minimizes transfer costs and operational costs. Given an initial non-cyclical timetable, and time-dependent service times and passenger demand, the weighted sum of transfer time cost and operational costs is minimized by allowing modifications to the timetable that respect a set of headway constraints. Timetable modifications consist of shifts in departure time and addition of dwell time at intermediate stops with transfer opportunities. A matheuristic is proposed that iteratively solves the mathematical formulation of the integrated timetabling and vehicle scheduling problem allowing timetable modifications for a subset of timetabled trips only, while solving the full vehicle scheduling problem. We compare different selection strategies for defining the sub-problems. Results for a realistic case study of the Greater Copenhagen area indicate that the matheuristic is able to find better feasible solutions faster than a commercial solver and that allowing the addition of dwell time creates a larger potential for reducing transfer costs.

Battery electric buses are seen as a well-suited technology for the electrification of road-based public transport. However, the transition process from conventional diesel to electric buses faces major hurdles caused by range limitations and required charging times of battery buses. This work addresses these constraints and provides a methodology for the cost-optimized planning of depot charging battery bus fleets and their corresponding charging infrastructure. The defined problem covers the scheduling of battery buses, the fleet composition, and the optimization of charging infrastructure in a joint process. Vehicle schedule adjustments are monetized and evaluated together with the investment and operational costs of the bus system. The resulting total cost of ownership enables a comparison of technical alternatives on a system level, which makes this approach especially promising for feasibility studies comprising a wide range of technical concepts. Two scenarios of European cities are analyzed and discussed in a case study, revealing that the cost structure is influenced significantly by the considered bus type and its technical specifications. For example, the total energy consumption of the considered lightweight bus is up to 32% lower than the total consumption of the high range bus, although the deadheading mileage increases. However, the total costs of ownership for operating both bus types are relatively close, due to the increased fleet size and driver expenses required for the lightweight bus system. The case study furthermore reveals that a mixed fleet of different bus types could be advantageous depending on the operational characteristics of the bus route.

Aims: Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis.Methods and results: We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes.Conclusion: Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.

CDK5RAP2 gene encodes a centrosomal protein, highly expressed in fetal brain and essentially indispensable for its normal development, as biallelic mutations in it lead to primary microcephaly (MCPH). Despite being known as MCPH linked gene for more than a decade, the phenotypic spectrum of CDK5RAP2 mutations is still under explored as only eleven families have been reported worldwide. Here, we analyzed a consanguineous Pakistani MCPH family, characterized by moderate to severe intellectual disability, speech impairment, moderately short stature and sparse eyebrows. Whole exome sequencing of the proband identified a 2bp duplication in exon 34 of CDK5RAP2 that causes frame-shift, leading to a premature stop codon. The resultant transcript is resistant to nonsense mediated decay, suggesting that the mutation leads to a truncated protein lacking C-terminal domains; CDK5R1, and Cnn motif 2 (CM2), required for its localization to centrosome and Golgi Apparatus. Clinical variability observed in the family highlights the importance of further detailed clinical description of patients with CDK5RAP2 mutations.

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways., Author summary Congenital heart disease (CHD) is the most common congenital anomaly and represents a major global health burden. Multiple studies have identified a key genetic component contributing to the aetiology of CHD. However, despite the advances in the field of CHD within the last three decades, the genetic causes underlying CHD are still not fully understood. Herein we have assembled a large patient CHD cohort and performed a data-driven meta-analysis of genomic variants in CHD. This analysis has allowed us to strengthen the disease association of known CHD genes, as well as identifying novel haploinsufficient CHD candidate genes.

This paper is part of a series of publications aimed at the divulgation of the results of the 3-step benchmark proposed by the IABSE Task Group 3.1 to define reference results for the validation of the software that simulate the aeroelastic stability and the response to the turbulent wind of super-long span bridges. Step 1 is a numerical comparison of different numerical models both a sectional model (Step 1.1) and a full bridge (Step 1.2) are studied. Step 2 will be the comparison of predicted results and experimental tests in wind tunnel. Step 3 will be a comparison against full scale measurements.The results of Step 1.1 related to the response of a sectional model were presented to the last IABSE Symposium in Nantes 2018. In this paper, the results of Step 1.2 related to the response long-span full bridge are presented in this paper both in terms of aeroelastic stability and buffeting response, comparing the results coming from several TG members.

A novel model for predicting railway-induced vibrations nuisance and structure-borne noise in nearby dwellings exposed to railway-traffic is described in this paper. The model is based on partitioning the transmission path from the railway to a building into different steps through the track system, ground, foundation and building – each characterised by a probabilistic approach towards adding frequency response functions obtained by statistical analysis of measurements obtained at various locations passed by the most common train types. The model output consists of an estimate of the acceleration level at a particular building floor, an estimate of the associated error and an estimate of the structure-borne noise level. The main new feature of the proposed approach in relation to existing empirical formulations is the probabilistic framework undertaken to estimate model errors as a function of the quality of the measured data and of the mathematical formulation developed to predict railway-induced vibration and noise levels. The paper first describes the general model formulation considered. Details of the measurement campaigns along with the associated data analyses for model development are then described. Finally, the mathematical formulation for calculating the model output is presented, and a comparison between model-based predictions and measurements is carried out to assess the performance of the model.

Objective Atrial septal defect (ASD) is the second most common congenital heart defect (CHD) and is observed in families as an autosomal dominant trait as well as in nonfamilial CHD. Mutations in the NKX2-5 gene, located on chromosome 5, are associated with ASD, often combined with conduction disturbances, cardiomyopathies, complex CHD, and sudden cardiac death as well. Here, we show that NKX2-5 mutations primarily occur in ASD patients with conduction disturbances and heritable ASD. Furthermore, these families are at increased risk of sudden cardiac death. Results We screened 39 probands with familial CHD for mutations in NKX2-5 and discovered a novel mutation in one family (2.5%) with ASD and atrioventricular block. A review of the literature revealed 59 different NKX2-5 mutations in 202 patients. Mutations were significantly more common in familial cases compared to nonfamilial cases (P = 7.1 × 10−9). The majority of patients (74%) had ASD with conduction disturbance. Nineteen patients (15%) of 120 with familial ASD and conduction disturbance died from sudden cardiac death of which nine (8%) were confirmed mutation carriers, and 10 were possible carriers. Conclusions NKX2-5 mutations mainly occur in familial CHD, the signature phenotype is ASD with conduction disturbances and mutation carriers are at increased risk of sudden cardiac death. We suggest that familial ASD patients should be screened for NKX2-5 mutations and, if they are mutation carriers, implantation of an implantable cardioverter-defibrillator should be considered in these patients.

Disasters such as fires, earthquakes, and floods cause severe casualties and enormous economic losses. One effective method to reduce these losses is to construct a disaster relief network to deliver disaster supplies as quickly as possible. This method requires solutions to the following problems. 1) Given the established distribution centers, which center(s) should be open after a disaster? 2) Given a set of vehicles, how should these vehicles be assigned to each open distribution center? 3) How can the vehicles be routed from the open distribution center(s) to demand points as efficiently as possible? 4) How many supplies can be delivered to each demand point on the condition that the relief allocation plan is made a priority before the actual demands are realized? This study proposes a model for risk-averse optimization of disaster relief facility location and vehicle routing under stochastic demand that solves the four problems simultaneously. The novel contribution of this study is its presentation of a new model that includes conditional value at risk with regret (CVaR-R)—defined as the expected regret of worst-case scenarios—as a risk measure that considers both the reliability and unreliability aspects of demand variability in the disaster relief facility location and vehicle routing problem. Two objectives are proposed: the CVaR-R of the waiting time and the CVaR-R of the system cost. Due to the nonlinear capacity constraints for vehicles and distribution centers, the proposed problem is formulated as a bi-objective mixed-integer nonlinear programming model and is solved with a hybrid genetic algorithm that integrates a genetic algorithm to determine the satisfactory solution for each demand scenario and a non-dominated sorting genetic algorithm II (NSGA-II) to obtain the non-dominated Pareto solution that considers all demand scenarios. Moreover, the Nash bargaining solution is introduced to capture the decision-maker’s interests of the two objectives. Numerical examples demonstrate the trade-off between the waiting time and system cost and the effects of various parameters, including the confidence level and distance parameter, on the solution. It is found that the Pareto solutions are distributed unevenly on the Pareto frontier due to the difference in the number of the distribution centers opened. The Pareto frontier and Nash bargaining solution change along with the confidence level and distance parameter, respectively.

Family studies have established that the heritability of blood pressure is significant and genome-wide association studies (GWAS) have identified numerous susceptibility loci, including one within the non-coding part of Rho GTPase-activating protein 42 gene (ARHGAP42) on chromosome 11q22.1. Arhgap42-deficient mice have significantly elevated blood pressure, but the phenotypic effects of human variants in the coding part of the gene are unknown. In a Danish cohort of carriers with apparently balanced chromosomal rearrangements, we identified a family where a reciprocal translocation t(11;18)(q22.1;q12.2) segregated with hypertension and obesity. Clinical re-examination revealed that four carriers (age 50–77 years) have had hypertension for several years along with an increased body mass index (34–43 kg/m(2)). A younger carrier (age 23 years) had normal blood pressure and body mass index. Mapping of the chromosomal breakpoints with mate-pair and Sanger sequencing revealed truncation of ARHGAP42. A decreased expression level of ARHGAP42 mRNA in the blood was found in the translocation carriers relative to controls and allele-specific expression analysis showed monoallelic expression in the translocation carriers, confirming that the truncated allele of ARHGAP42 was not expressed. These findings support that haploinsufficiency of ARHGAP42 leads to an age-dependent hypertension. The other breakpoint truncated a regulatory domain of the CUGBP Elav-like family member 4 (CELF4) gene on chromosome 18q12.2 that harbours several GWAS signals for obesity. We thereby provide additional support for an obesity locus in the CELF4 domain.

PDGFRα signals from cilia to control development and tumorigenesis. Schmid et al. now show that intraflagellar transport protein 20 (IFT20) interacts with and stabilizes the E3 ubiquitin ligases c-Cbl and Cbl-b to promote feedback inhibition of PDGFRα signaling at the primary cilium., Primary cilia have pivotal roles as organizers of many different signaling pathways, including platelet-derived growth factor receptor α (PDGFRα) signaling, which, when aberrantly regulated, is associated with developmental disorders, tumorigenesis, and cancer. PDGFRα is up-regulated during ciliogenesis, and ciliary localization of the receptor is required for its appropriate ligand-mediated activation by PDGF-AA. However, the mechanisms regulating sorting of PDGFRα and feedback inhibition of PDGFRα signaling at the cilium are unknown. Here, we provide evidence that intraflagellar transport protein 20 (IFT20) interacts with E3 ubiquitin ligases c-Cbl and Cbl-b and is required for Cbl-mediated ubiquitination and internalization of PDGFRα for feedback inhibition of receptor signaling. In wild-type cells treated with PDGF-AA, c-Cbl becomes enriched in the cilium, and the receptor is subsequently ubiquitinated and internalized. In contrast, in IFT20-depleted cells, PDGFRα localizes aberrantly to the plasma membrane and is overactivated after ligand stimulation because of destabilization and degradation of c-Cbl and Cbl-b.

Most university biobanks begin like other university research projects, that is, with an idea conceived by an individual researcher in pursuit of his/her own research interests, publications, funding, and career. Some biobanks, however, come to have scientific value that goes beyond the projects that were initially responsible for the collection of the samples and data they contain. Such value may derive from among other things the uniqueness of the samples in terms of their sheer volume, the quality of the samples, the ability to link the samples with information retrieved in disease registries, or the fact that the samples represent very rare diseases. This article focuses on biobanks of this kind, and the special obligations that publicly funded universities have to ensure the sustainability of biobanks with continued scientific value. We argue that universities should adopt policies to deal with the various, diverse issues which may arise during the lifecycle of a biobank. The policies should be flexible, accommodate the freedoms of individual researchers, and reflect the multifaceted nature of biobanks. Yet they should be specific enough to provide guidance and robust enough to safeguard legal norms and ethical values. The article sets out concrete recommendations which universities should consider and act upon.

The IABSE Task Group 10 (super-long span bridge aerodynamics) has the mandate to create a standard procedure for validation of methodology and software programs applied for stability and buffeting response analyses of super-long span bridges. Precise estimations of structural stability and response to strong winds are critical for the successful design of long-span bridges.Task Group 10 covers several important problems related to its mandate including: review and verification of methods developed and adopted by researchers and bridge designers; the definition of guidelines and sample tests for verification and calibration of analytical procedures; identification of fundamental problems of the computation methods; relevant input and output data.Since the beginning of its work, this working group has developed a 3-step benchmark, with multiple sub-steps of fundamental problems to resolve. The first step of this benchmark has been a numerical comparison of the results obtained using different models adopted across the workgroup members. Using the same inputs: flutter stability and the buffeting response of both a deck sectional model and a full bridge are studied. Step 2 will be the comparison of predicted results and experimental tests in wind tunnels, and Step 3 will be of validation against full scale measurements. In this paper, the results of Step 1 will be presented, highlighting critical issues and differences found during the comparison of results. The response of a 3-degrees of freedom bridge deck will be presented both in terms of aeroelastic stability and buffeting response. The results presented are intended to be a reference for the validation of methodologies and software programs that solve for wind response of bridges.

A stochastic method of generating a synthetic turbulent flow field is combined with a 2D mesh-free vortex method to simulate the effect of an oncoming turbulent flow on a bridge deck cross-section within the atmospheric boundary layer. The mesh-free vortex method is found to be capable of preserving the a priori specified statistics as well as anisotropic characteristics of the synthesised turbulent flow field. From the simulation, the aerodynamic admittance is estimated and the instantaneous effect of a time varying angle of attack is briefly investigated. The obtained aerodynamic admittance of four aerodynamically different bridge sections is compared to available wind tunnel data, showing good agreement between the two.

Most of the operational problems in container terminals are strongly interconnected. In this paper, we study the integrated Berth Allocation and Quay Crane Assignment Problem in seaport container terminals. We will extend the current state-of-the-art by proposing novel set partitioning models. To improve the performance of the set partitioning formulations, a number of variable reduction techniques are proposed. Furthermore, we analyze the effects of different discretization schemes and the impact of using a time-variant/invariant quay crane allocation policy. Computational experiments show that the proposed models significantly improve the benchmark solutions of the current state-of-art optimal approaches.

Focal chondral lesions of the knee are commonly occurring. A lot is known about their frequency, size and localisation in arthroscopic series, but less about the symptoms they elicit and little about how the arthroscopic findings and symptoms correlate. The purposes of the present study included to investigate the relationship between articular cartilage lesion factors and patient factors, and to compare the symptoms and function of cartilage lesion patients to those of patients with a deficient ACL.A prospective registration was conducted of preoperative data including Lysholm knee score and perioperative findings in 1,000 consecutive patients undergoing an arthroscopic procedure of the knee-including microfracture of articular cartilage defects and ACL reconstructions.Chondral or osteochondral lesions were found in 57 % of the arthroscopies. The mean Lysholm score in this subgroup was 55. The mean Lysholm score was significantly lower in women (50, SD 19) compared to men (59, SD 18, p 0.001). Among the chondral lesion factors, only kissing (vs. non-kissing) lesions and multiple (vs. single) lesions influenced symptoms and function to a more than negligible degree. Microfracture in one or two articular cartilage defects was performed in 187 patients. The microfracture group had a significant lower mean Lysholm score (54, SD 18) than a group of patients (N = 71) undergoing ACL reconstruction group (67, SD 17, p 0.001).The study confirms that articular cartilage lesions are both common and cumbersome. Women seem to have more problems than men, whereas chondral lesion factors-such as localisation and size-seem to influence symptoms and function to a small degree. These aspects should be addressed when designing outcome studies, and should also be of interest to the orthopaedic surgeon-in the day-by-day clinical work. When treating these patients, our prime focus need to be on knee function rather than the cartilage defect as the relationship between the latter and the former is unclear.Case-control study, Level III.

A novel splice site mutation in CEP135 is associated with primary microcephaly in a Pakistani family

The present paper outlines the salient aerodynamic features in present and future bridge design. The theoretical and experimental tools available to the designer are addressed. These include wind screens, specially designed cables and towers, and aerodynamic appendages such as guide vanes. Various systems used to control oscillation are also discussed. These include: a) "passive" control systems such as damping systems and the deployment of eccentric mass; and b) active control systems such as computer controlled servo hydraulic actuators. A specific active control system designed to be applied to very long span bridges, where either flutter or static divergence stability is difficult to attain, is described. The concept is based on application of actively governed control surfaces installed in front and behind the leading/trailing edges of an aerodynamically smooth girder. For the covering abstract of the conference see IRRD 857429.

Long span suspension bridges are flexible structures which are highly sensitive to the action of the wind, hence aerodynamic performance often becomes a governing factor in the design process. The magnitude of the East Bridge, a 3 span suspension bridge of span lengths 535 m - 1624 m - 535 m, has warranted an aerodynamic design process which involves state-of-the-art model testing and analytical procedures. The present paper focuses on the use of wind tunnel test results in the design of the East Bridge. Particular attention is given to the strategy adopted for wind tunnel testing, and to selected results obtained. Considerations for the bridge in service cover aerodynamic stability, dynamic wind loads and vortex shedding response of the girder. For the erection phase aerodynamic stability of the girder is treated in some detail. Comparisons between model tests and analytical predictions are given and results are evaluated against current codes of practice. Finally, consideration is given to future wind tunnel testing and the extension and application of analytical procedures utilized in connection with the aerodynamic design process. (A) For the covering abstract of the conference see IRRD 857429.

Summary: The centrosome is the main microtubule-organizing center in animal cells and comprises a mother and daughter centriole surrounded by pericentriolar material. During formation of primary cilia, the mother centriole transforms into a basal body that templates the ciliary axoneme. Ciliogenesis depends on mother centriole-specific distal appendages, whereas the role of subdistal appendages in ciliary function is unclear. Here, we identify CEP128 as a centriole subdistal appendage protein required for regulating ciliary signaling. Loss of CEP128 did not grossly affect centrosomal or ciliary structure but caused impaired transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) signaling in zebrafish and at the primary cilium in cultured mammalian cells. This phenotype is likely the result of defective vesicle trafficking at the cilium as ciliary localization of RAB11 was impaired upon loss of CEP128, and quantitative phosphoproteomics revealed that CEP128 loss affects TGF-β1-induced phosphorylation of multiple proteins that regulate cilium-associated vesicle trafficking. : Mönnich et al. show that CEP128 localizes to the subdistal appendages of the mother centriole and basal body of the primary cilium. CEP128 regulates vesicular trafficking and targeting of RAB11 to the primary cilium. CEP128 loss leads to impaired TGF-β/BMP signaling, which, in zebrafish, is associated with defective organ development. Keywords: primary cilium, basal body, centriole, subdistal appendage, centrosome, transforming growth factor β, TGF-β, bone morphogenetic protein, BMP, zebrafish, phosphoproteomics, CEP128

STUDY DESIGN: Mutation analysis of a candidate disease gene in a cohort of patients with moderate to severe Adolescent idiopathic scoliosis (AIS).OBJECTIVE: To investigate if damaging mutations in the planar cell polarity gene VANGL1 could be identified in AIS patients.SUMMARY OF BACKGROUND DATA: AIS is a spinal deformity which occurs in 1-3% of the population. The cause of AIS is often unknown, but genetic factors are important in the etiology. Rare variants in genes encoding regulators of WNT/planar cell polarity (PCP) signaling were recently identified in AIS patients.METHODS: We analyzed the coding region of the VANGL1 gene for mutations using Sanger sequencing in 157 unrelated patients with moderate to severe AIS. The frequency of mutations in the patient cohort was compared with their frequency in a large cohort of controls. Functional effect of mutations were predicted in silico and analyzed in vitro by transfection of normal and mutant recombinant VANGL1 protein in Madin-Darby Canine Kidney (MDCK) cells. Cellular localization of recombinant proteins was analyzed by immunofluorescence microscopy analysis.RESULTS: In the patient cohort we identified two rare missense mutations in VANGL1, encoding a receptor involved in WNT/PCP signalling. The mutations, p.I136N and p.F440 V are very rare in the normal population. Both mutations are predicted to be damaging, and to affect evolutionary conserved amino acid residues of VANGL1. Functional analysis in MDCK cells showed that the mutations abolished the normal translocation of VANGL1 to the cell membrane.CONCLUSION: Our data support that mutations in genes involved in WNT/PCP signalling may be associated with AIS, but replication in other patient cohorts and further analysis of the role of WNT/PCP signalling in AIS is needed.LEVEL OF EVIDENCE: 4.