(On)begrensde Technologie

Er zijn voorspellingen gedaan, bijvoorbeeld door het World Economic Forum, dat we aan de vooravond van een ‘vierde industriële revolutie’ staan, die draait om het meer verbonden raken van informatie- en productieprocessen. Als dat zo is, zal dat maatschappelijke gevolgen voor Zuid-Holland en daarmee implicaties voor het beleid van de provincie hebben. De onderzoeksvraag van deze studie is dan ook: “Wat is de maatschappelijke [sociale, economische en ruimtelijke] invloed van nieuwe productie- en informatietechnologieën? En, hoe verandert dat de wijze waarop we als provincie aan de opgaven van de toekomst werken?”. Hiertoe hebben we een literatuurstudie over de potentiële maatschappelijke gevolgen van nieuwe technologie verricht en daarna in interactie met stakeholders en de provincie vier scenario’s ontwikkeld

CRISPR/Cas9-induced (CTG⋅CAG)n repeat instability in the myotonic dystrophy type 1 locus: implications for therapeutic genome editing

Myotonic dystrophy type 1 (DM1) is caused by (CTG⋅CAG)n-repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5′ or 3′ unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals, DM1 patients, and a DM1 mouse model could be achieved at high frequency by dual CRISPR/Cas9-cleavage at either side of the (CTG⋅CAG)n sequence. Importantly, removal of the repeat appeared to have no detrimental effects on the expression of genes in the DM1 locus. Moreover, myogenic capacity, nucleocytoplasmic distribution, and abnormal RNP-binding behavior of transcripts from the edited DMPK gene were normalized. Dual sgRNA-guided excision of the (CTG⋅CAG)n tract by CRISPR/Cas9 technology is applicable for developing isogenic cell lines for research and may provide new therapeutic opportunities for patients with DM1

Paraneoplastic pemphigus associated with post-transplant lymphoproliferative disorder after small bowel transplantation

Background PNP is a malignancy-associated autoimmune mucocutaneous syndrome due to autoantibodies against plakins, desmogleins, and other components of the epidermis and basement membrane of epithelial tissues. PNP-causing malignancies comprise mainly lymphoproliferative and hematologic neoplasms. PNP is extremely rare, especially in children. Methods Here, we present the first case of a child who developed PNP on a PTLD after small bowel transplantation because of a severe genetic protein-losing enteropathy. Results The patient in this case report had a severe stomatitis, striate palmoplantar keratoderma, and lichenoid skin lesions. In addition, she had marked esophageal involvement. She had lung pathology due to recurrent pulmonary infections and ventilator injury. Although we found no evidence of BO, she died from severe pneumonia and respiratory failure at the age of 12 years. Conclusion It is exceptional that, despite effective treatment of the PTLD, the girl survived 5 years after her diagnosis of PNP. We hypothesize that the girl survived relatively long after the PNP diagnosis due to strong T-cell suppressive treatments for her small bowel transplantation

Effectiveness of dementia follow-up care by memory clinics or general practitioners: randomised controlled trial

Objective To examine the effectiveness of post-diagnosis dementia treatment and coordination of care by memory clinics compared with general practitioners

Recovery in the myogenic program of congenital myotonic dystrophy myoblasts after excision of the expanded (CTG)n repeat

The congenital form of myotonic dystrophy type 1 (cDM) is caused by the large-scale expansion of a (CTG•CAG)n repeat in DMPK and DM1-AS. The production of toxic transcripts with long trinucleotide tracts from these genes results in impairment of the myogenic differentiation capacity as cDM’s most prominent morpho-phenotypic hallmark. In the current in vitro study, we compared the early differentiation programs of isogenic cDM myoblasts with and without a (CTG)2600 repeat obtained by gene editing. We found that excision of the repeat restored the ability of cDM myoblasts to engage in myogenic fusion, preventing the ensuing myotubes from remaining immature. Although the cDM-typical epigenetic status of the DM1 locus and the expression of genes therein were not altered upon removal of the repeat, analyses at the transcriptome and proteome level revealed that early abnormalities in the temporal expression of differentiation regulators, myogenic progression markers, and alternative splicing patterns before and immediately after the onset of differentiation became normalized. Our observation that molecular and cellular features of cDM are reversible in vitro and can be corrected by repeat-directed genome editing in muscle progenitors, when already committed and poised for myogenic differentiation, is important information for the future development of gene therapy for different forms of myotonic dystrophy type 1 (DM1)

ATP Changes the Fluorescence Lifetime of Cyan Fluorescent Protein via an Interaction with His148

Recently, we described that ATP induces changes in YFP/CFP fluorescence intensities of Fluorescence Resonance Energy Transfer (FRET) sensors based on CFP-YFP. To get insight into this phenomenon, we employed fluorescence lifetime spectroscopy to analyze the influence of ATP on these fluorescent proteins in more detail. Using different donor and acceptor pairs we found that ATP only affected the CFP-YFP based versions. Subsequent analysis of purified monomers of the used proteins showed that ATP has a direct effect on the fluorescence lifetime properties of CFP. Since the fluorescence lifetime analysis of CFP is rather complicated by the existence of different lifetimes, we tested a variant of CFP, i.e. Cerulean, as a monomer and in our FRET constructs. Surprisingly, this CFP variant shows no ATP concentration dependent changes in the fluorescence lifetime. The most important difference between CFP and Cerulean is a histidine residue at position 148. Indeed, changing this histidine in CFP into an aspartic acid results in identical fluorescence properties as observed for the Cerulean fluorescent based FRET sensor. We therefore conclude that the changes in fluorescence lifetime of CFP are affected specifically by possible electrostatic interactions of the negative charge of ATP with the positively charged histidine at position 148. Clearly, further physicochemical characterization is needed to explain the sensitivity of CFP fluorescence properties to changes in environmental (i.e. ATP concentrations) conditions

Effects of maternal and paternal smoking on attentional control in children with and without ADHD

Maternal smoking during pregnancy is a risk factor for attention-deficit/hyperactivity disorder (ADHD), but data on its adverse effects on cognitive functioning are sparse and inconsistent. Since the effect of maternal smoking during pregnancy may be due to correlated genetic risk factors rather than being a pure environmental effect, we examined the effect of prenatal exposure to smoking on attentional control, taking into account the effects of both maternal and paternal smoking, and examined whether these effects were genetically mediated by parental genotypes. We further examined whether the effect of prenatal exposure to smoking on attentional control interacted with genotypes of the child. Participants were 79 children with ADHD, ascertained for the International Multi-centre ADHD Gene project (IMAGE), and 105 normal controls. Attentional control was assessed by a visual continuous performance task. Three genetic risk factors for ADHD (DRD4 7-repeat allele of the exon 3 variable number of tandem repeats (VNTR), DAT1 10/10 genotype of the VNTR located in the 3′ untranslated region, and the DAT1 6/6 genotype of the intron 8 VNTR) were included in the analyses. Paternal smoking had a negative effect on attentional control in children with ADHD and this effect appeared to be mediated by genetic risk factors. The prenatal smoking effect did not interact with genotypes of the child. Maternal smoking had no main effect on attentional control, which may be due to lower smoking rates. This study suggests that the effects of paternal smoking on attentional control in children with ADHD should be considered a proxy for ADHD and/or smoking risk genes. Future studies should examine if the results can be generalized to other cognitive domains

Are motor inhibition and cognitive flexibility dead ends in ADHD?

Contains fulltext : 53518.pdf (publisher's version ) (Closed access)Executive dysfunction has been postulated as the core deficit in ADHD, although many deficits in lower order cognitive processes have also been identified. By obtaining an appropriate baseline of lower order cognitive functioning light may be shed on as to whether executive deficits result from problems in lower order and/or higher order cognitive processes. We examined motor inhibition and cognitive flexibility in relation to a baseline measure in 816 children from ADHD and control families. Multiple children in a family were tested in order to examine the familiality of the measures. No evidence was found for deficits in motor inhibition or cognitive flexibility in children with ADHD or their nonaffected siblings: Compared to their baseline speed and accuracy of responding, children with ADHD and their (non)affected siblings were not disproportionally slower or inaccurate when demands for motor inhibition or cognitive flexibility were added to the task. However, children with ADHD and their (non)affected siblings were overall less accurate than controls, which could not be attributed to differences in response speed. This suggests that inaccuracy of responding is characteristic of children having (a familial risk for) ADHD. Motor inhibition and cognitive flexibility as operationalized with mean reaction time were found to be familial. It is concluded that poorer performance on executive tasks in children with ADHD and their (non)affected siblings may result from deficiencies in lower order cognitive processes and not (only) from higher order cognitive processes/executive functions

Speed, Variability, and Timing of Motor Output in ADHD: Which Measures are Useful for Endophenotypic Research?

Attention-Deficit/Hyperactivity Disorder (ADHD) shares a genetic basis with motor coordination problems and probably motor timing problems. In line with this, comparable problems in motor timing should be observed in first degree relatives and might, therefore, form a suitable endophenotypic candidate. This hypothesis was investigated in 238 ADHD-families (545 children) and 147 control-families (271 children). A motor timing task was administered, in which children had to produce a 1,000 ms interval. In addition to this task, two basic motor tasks were administered to examine speed and variability of motor output, when no timing component was required. Results indicated that variability in motor timing is a useful endophenotypic candidate: It was clearly associated with ADHD, it was also present in non-affected siblings, and it correlated within families. Accuracy (under- versus over-production) in motor timing appeared less useful: Even though accuracy was associated with ADHD (probands and affected siblings had a tendency to under-produce the 1,000 ms interval compared to controls), non-affected siblings did not differ from controls and sibling correlations were only marginally significant. Slow and variable motor output without timing component also appears present in ADHD, but not in non-affected siblings, suggesting these deficits not to be related to a familial vulnerability for ADHD. Deficits in motor timing could not be explained by deficits already present in basic motor output without a timing component. This suggests abnormalities in motor timing were predominantly related to deficient motor timing processes and not to general deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD

Sell-side analysts' use and communication of intellectual capital information

Structural economic changes in many countries, together with unprecedented developments in the business environment, have significantly affected the value creation processes of firms and the way business is conducted. The traditional financial reporting model is inadequate as a consequence of these developments, and intellectual capital (IC) information has gained importance for investment decision making. Empirical capital markets research demonstrates the value-relevance and predictive ability of certain types of IC information. The use of IC information by capital market participants is a topic that has begun to gain attention from contemporary researchers, but for which scant empirical evidence exists. Much of the research in this area relies on the literature about the use of non-financial information (NFI), which is inadequate in its examination of certain types of IC information. Therefore, the main aim of this thesis is to examine the use and communication of IC information by sell-side analysts. Sell-side analysts are of particular interest because they are capital market intermediaries and sophisticated processors of corporate information. The reports they produce provide an opportunity to examine their use and communication of IC information. The specific objectives of this thesis are to examine: the extent and types of IC information used by sell-side analysts in initiating coverage reports produced by them; how IC information is used and communicated in these reports; and factors that may influence the use of IC information by sell-side analysts. In order to address these research objectives a content analysis of IC references in 64 initiating coverage reports written on an equivalent number of S&P/ASX 200/300 companies is performed. The content analysis identifies and measures IC references by topic, evidence (discursive, monetary, numerical, or visual), news-tenor (positive, neutral or negative) and time orientation (forward-looking, past-oriented or non-time-specific). The findings indicate that Australian sell-side analysts appreciate the importance of IC in firm valuation, and thus are not ambivalent about the use of IC information in general. However, the findings suggest that their communication of IC information is inconsistent and unsystematic, and inadequate in relation to certain types of IC. This highlights the need for undertaking work at a policy level to educate and train sell-side analysts to deal with IC information, and the development of better models and guidelines for analysing and communicating IC information. On how IC information is used, this thesis finds that sell-side analysts have varying uses of IC information. It was found that IC is predominantly communicated discursively, positively, and in a past-oriented manner; and in doing so IC is used as a tool to further the sell-side analysts’ agenda for the company analysed. Further, the results highlight that the type of investment recommendation in analyst reports impacts on the evidence, news tenor, and time-orientation of IC communicated. These findings alert future researchers to the wider role played by IC beyond its use in forecasts and valuations. Also, the findings indicate inter-sectoral differences in the use of IC information in analyst reports, highlighting the need to improve IC reporting practices of firms by including additional information on industry-specific IC value drivers. Further, it was found that sell-side analysts emphasise IC information in analyst reports for companies from high IC-intensive sectors compared to those from low IC-intensive sectors. Similarly, it was found that analyst reports on risky companies contain significantly more IC information than analyst reports on less risky companies. Contrary to expectations, the extent of IC information is not found to vary with firm size and firm profitability. Also, the results support that the extent of certain types of IC information differs between types of analysts’ investment recommendations. More generally, the findings of this thesis suggest that the corporate reporting process could be improved by including additional types of IC information and providing this information more effectively in a manner that enables users to visualise the interrelationships between resources (both tangible and intangible) and outcomes. This study calls for standards or guidelines for intellectual capital reporting (ICR) in Australia and the expansion of the role of auditing and assurance services to enhance reliability of firm provided IC information in a bid to improve the use of IC information in company analysis by sell-side analysts