Multidimensional Construction Planning and Agile Organized Project Execution?The 5D-PROMPT Method

Although tremendous technological and strategic advances have been developed and implemented in the construction sector in recent years, there is substantial room for improvement in the areas of productivity growth, project performance, and schedule reliability. Thus, the present paper seeks to discover why the currently applied scheduling tools and the latest agile-based project organization approaches have not yet achieved their full potential. A missing interlinkage between the project?s design, cost, and time aspects within the project design phase and its sparse utilization throughout project execution were indicated as the driving contributors responsible for the slow progress in development. To fundamentally change this situation, an extensive and coherent project organization solution is proposed. The key process of this solution utilizes a 5D Building Information Model comprising tight concatenations between the individual model objects and the corresponding construction cost and time effort values. The key dates of a waterfall-based construction process simulation, set during the project planning phase, provide particular information to create a structure for agile organized project execution. The implementation of information feedback loops allows target/actual comparisons and contributes to continual improvements in future planning. A comparative case study was conducted with auspicious results on improvements in the overall project performance, and schedule and cost reliabilityThis research was supported by Heinrich Schmid GmbH&Co.KG regarding the cooperative conduction of two construction projects used for the case-study; RIB Software SE, who provided the BIM software platform iTWO Baseline and the site management software OnSite, and Contelos GmbH for the provision of the 3D Building Information Model

Genomic epidemiology of clinical ESBL-producing Enterobacteriaceae in a German hospital suggests infections are primarily community- and regionally-acquired

Clinical Enterobacteriaceae isolates that produce extended-spectrum β-lactamases (ESBLs) have been increasingly reported at a global scale. However, comprehensive data on the molecular epidemiology of ESBL-producing strains are limited and few studies have been conducted in non-outbreak situations. We used whole-genome sequencing to describe the population structure of 294 ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates that were recovered from a German community hospital throughout a 1 year sampling period in a non-outbreak situation. We found a high proportion of E. coli isolates (61.5 %) belonged to the globally disseminated extraintestinal pathogenic ST131, whereas a wider diversity of STs was observed among K. pneumoniae isolates. The E. coli ST131 population in this study was shaped by multiple introductions of strains as demonstrated by contextual genomic analysis including ST131 strains from other geographical sources. While no recent common ancestor of the isolates of the current study and other international isolates was found, our clinical isolates clustered with those previously recovered in the region. Furthermore, we found that the isolation of ESBL-producing clinical strains in hospitalized patients could only rarely be associated with likely patient-to-patient transmission, indicating primarily a community and regional acquisition of strains. Further genomic analyses of clinical, carriage and environmental isolates is needed to uncover hidden transmissions and thus discover the most common sources of ESBL-producing pathogen infections in our hospitals

Phenotypic and molecular insights into CASK-related disorders in males

Background: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. Methods: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. Results: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. Conclusions: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups

Allergens induce enhanced bronchoconstriction and leukotriene production in C5 deficient mice

BACKGROUND: Previous genetic analysis has shown that a deletion in the complement component 5 gene-coding region renders mice more susceptible to allergen-induced airway hyperresponsiveness (AHR) due to reduced IL-12 production. We investigated the role of complement in a murine model of asthma-like pulmonary inflammation. METHODS: In order to evaluate the role of complement B10 mice either sufficient or deficient in C5 were studied. Both groups of mice immunized and challenged with a house dust extract (HDE) containing high levels of cockroach allergens. Airways hyper-reactivity was determined with whole-body plesthysmography. Bronchoalveolar lavage (BAL) was performed to determine pulmonary cellular recruitment and measure inflammatory mediators. Lung homogenates were assayed for mediators and plasma levels of IgE determined. Pulmonary histology was also evaluated. RESULTS: C5-deficient mice showed enhanced AHR to methylcholine challenge, 474% and 91% increase above baseline Penh in C5-deficient and C5-sufficient mice respectively, p < 0.001. IL-12 levels in the lung homogenate (LH) were only slightly reduced and BAL IL-12 was comparable in C5-sufficient and C5-deficient mice. However, C5-deficient mice had significantly higher cysteinyl-leukotriene levels in the BAL fluid, 1913 +/- 246 pg/ml in C5d and 756 +/- 232 pg/ml in C5-sufficient, p = 0.003. CONCLUSION: These data demonstrate that C5-deficient mice show enhanced AHR due to increased production of cysteinyl-leukotrienes

Anaphylatoxin C3a receptors in asthma

The complement system forms the central core of innate immunity but also mediates a variety of inflammatory responses. Anaphylatoxin C3a, which is generated as a byproduct of complement activation, has long been known to activate mast cells, basophils and eosinophils and to cause smooth muscle contraction. However, the role of C3a in the pathogenesis of allergic asthma remains unclear. In this review, we examine the role of C3a in promoting asthma. Following allergen challenge, C3a is generated in the lung of subjects with asthma but not healthy subjects. Furthermore, deficiency in C3a generation or in G protein coupled receptor for C3a abrogates allergen-induced responses in murine models of pulmonary inflammation and airway hyperresponsiveness. In addition, inhibition of complement activation or administration of small molecule inhibitors of C3a receptor after sensitization but before allergen challenge inhibits airway responses. At a cellular level, C3a stimulates robust mast cell degranulation that is greatly enhanced following cell-cell contact with airway smooth muscle (ASM) cells. Therefore, C3a likely plays an important role in asthma primarily by regulating mast cell-ASM cell interaction

Complement and the Alternative Pathway Play an Important Role in LPS/D-GalN-Induced Fulminant Hepatic Failure

Fulminant hepatic failure (FHF) is a clinically severe type of liver injury with an extremely high mortality rate. Although the pathological mechanisms of FHF are not well understood, evidence suggests that the complement system is involved in the pathogenesis of a variety of liver disorders. In the present study, to investigate the role of complement in FHF, we examined groups of mice following intraperitoneal injection of LPS/D-GalN: wild-type C57BL/6 mice, wild-type mice treated with a C3aR antagonist, C5aR monoclonal antibody (C5aRmAb) or CR2-Factor H (CR2-fH, an inhibitor of the alternative pathway), and C3 deficient mice (C3−/− mice). The animals were euthanized and samples analyzed at specific times after LPS/D-GalN injection. The results show that intraperitoneal administration of LPS/D-GalN activated the complement pathway, as evidenced by the hepatic deposition of C3 and C5b-9 and elevated serum levels of the complement activation product C3a, the level of which was associated with the severity of the liver damage. C3a receptor (C3aR) and C5a receptor (C5aR) expression was also upregulated. Compared with wild-type mice, C3−/− mice survived significantly longer and displayed reduced liver inflammation and attenuated pathological damage following LPS/D-GalN injection. Similar levels of protection were seen in mice treated with C3aR antagonist,C5aRmAb or CR2-fH. These data indicate an important role for the C3a and C5a generated by the alternative pathway in LPS/D-GalN-induced FHF. The data further suggest that complement inhibition may be an effective strategy for the adjunctive treatment of fulminant hepatic failure

Studien zu Protein-Protein-Interaktionen der kleinen GTPase RRAS, dem Adaptorprotein RIAM und dem Zytoskelettprotein TALIN

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