Pigmentation, Melanocyte Colonization, and p53 Status in Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common neoplasm in the Caucasian population. Only a fraction of BCC exhibits pigmentation. Lack of melanocyte colonization has been suggested to be due to p53-inactivating mutations in the BCC cells interfering with the p53-proopiomelanocortin pathway and the production of alpha melanocyte-stimulating hormone in the tumor. To evaluate this, we determined tumor pigmentation as well as expression of melan-A and of p53 in 49 BCC tissues by means of immunohistochemistry. As expected, we observed a positive relation between tumor pigmentation and melan-A positive intra-tumoral melanocytes. Melanocyte colonization and, to a lesser extent, p53 overexpression showed intraindividual heterogeneity in larger tumors. p53 overexpression, which is indicative of p53 mutations, was not correlated to melanocyte colonization of BCC. Sequencing of exon 5–8 of the p53 gene in selected BCC cases revealed that colonization by melanocytes and BCC pigmentation is neither ablated by p53 mutations nor generally present in BCCs with wild-type p53

Early encounters of a nascent membrane protein: specificity and timing of contacts inside and outside the ribosome

An unbiased photo–cross-linking approach was used to probe the “molecular path” of a growing nascent Escherichia coli inner membrane protein (IMP) from the peptidyl transferase center to the surface of the ribosome. The nascent chain was initially in proximity to the ribosomal proteins L4 and L22 and subsequently contacted L23, which is indicative of progression through the ribosome via the main ribosomal tunnel. The signal recognition particle (SRP) started to interact with the nascent IMP and to target the ribosome–nascent chain complex to the Sec–YidC complex in the inner membrane when maximally half of the transmembrane domain (TM) was exposed from the ribosomal exit. The combined data suggest a flexible tunnel that may accommodate partially folded nascent proteins and parts of the SRP and SecY. Intraribosomal contacts of the nascent chain were not influenced by the presence of a functional TM in the ribosome

Learning to dislike alcohol: conditioning negative implicit attitudes toward alcohol and its effect on drinking behavior

Rationale: Since implicit attitudes toward alcohol play an important role in drinking behavior, a possible way to obtain a behavioral change is changing these implicit attitudes. Objectives: This study examined whether a change in implicit attitudes and in drinking behavior can be achieved via evaluative conditioning. Methods: Participants were randomly assigned to an experimental condition and a control condition. In the experimental condition, participants were subjected to an evaluative conditioning procedure that consistently pairs alcohol-related cues with negative stimuli. In the control condition, alcohol-related cues were consistently paired with neutral stimuli during the evaluative conditioning phase. Implicit attitudes, explicit attitudes, and drinking behavior were measured before and after the evaluative conditioning phase. Results: Following the evaluative conditioning procedure, participants in the experimental condition showed stronger negative implicit attitudes toward alcohol and consumed less alcohol compared to participants in the control condition. However, this effect was only found when the evaluative conditioning task paired alcohol-related cues with general negative pictures, but not when using pictures of frowning faces. Conclusions: These results demonstrate that evaluative conditioning can effectively change implicit attitudes toward alcohol and also suggest that this procedure can be used to change drinking behavior. Hence, evaluative conditioning may be a useful new intervention tool to combat alcohol misuse

Dutch trends in the use of potentially harmful medication during pregnancy

Aims: Recent population-based data on drug utilization around pregnancy are lacking. This study aims to examine the prevalence of drug exposure in the Netherlands during the preconception, pregnancy and postpartum periods, with special emphasis on trends of potentially harmful medication over the years. Methods: A population-based study was conducted using records from the PHARMO Perinatal Research Network. From 1999 to 2017, the proportion of pregnancies during which women used any medication or potentially harmful medication was assessed, overall and stratified by timing of exposure relative to pregnancy and by the year of delivery. Results: Overall, 357 226 (73%) and 166 484 (34%) of 487 122 selected pregnancies were exposed to any and potentially harmful medication, respectively. Among these 487 122 pregnancies, preconception prevalence for use of potentially harmful medication was 43%, 24% during the first trimester, 19% during the second, 16% during the third, and 45% postpartum. A declining trend was observed for exposure to any medication, from 84% in 1999 to 68% in 2017. No clear changes were observed over time for the proportion of pregnancies exposed to potentially harmful medication. Conclusions: Our study shows that the use of potentially harmful medication was high over the last two decades. Although there was a declining trend over the years in overall medication use, during a steady one-third of pregnancies, women used potentially harmful medication. Our findings highlight the need for an increased sense of urgency among both healthcare providers and women of reproductive age regarding potential risks associated with pharmacological treatment during pregnancy

Subclinical tuberculosis disease - a review and analysis of prevalence surveys to inform definitions, burden, associations and screening methodology

While it is known that a substantial proportion of individuals with tuberculosis disease (TB) present subclinically, usually defined as bacteriologically-confirmed but negative on symptom screening, considerable knowledge gaps remain. Our aim was to review data from TB prevalence population surveys and generate a consistent definition and framework for subclinical TB, thus enabling an estimate of the proportion of TB that is subclinical, explore associations with overall burden and programme indicators, and performance of screening strategies. We extracted data from all publicly available prevalence surveys conducted since 1990. Between 36.1-79.7% (median 50.4%) of prevalent bacteriologically-confirmed TB was subclinical. No association was found between prevalence of subclinical and all bacteriologically confirmed TB, patient diagnostic rate or country-level HIV prevalence (p-values, 0.32, 0.4, 0.34, respectively). Chest X-ray detected 89% (range 73-98%) of bacteriologically-confirmed TB disease, highlighting the potential of optimizing current TB case-finding policies

YidC and SecY mediate membrane insertion of a type I transmembrane domain

YidC has been identified recently as an evolutionary conserved factor that is involved in the integration of inner membrane proteins (IMPs) in Escherichia coli. The discovery of YidC has inspired the reevaluation of membrane protein assembly pathways in E. coli. In this study, we have analyzed the role of YidC in membrane integration of a widely used model IMP, leader peptidase (Lep). Site-directed photocross-linking experiments demonstrate that both YidC and SecY contact nascent Lep very early during biogenesis, at only 50-amino acid nascent chain length. At this length the first transmembrane domain (TM), which acquires a type I topology, is not even fully exposed outside the ribosome. The pattern of interactions appears dependent on the position of the cross-linking probe in the nascent chain. Upon elongation, nascent Lep remains close to YidC and comes into contact with lipids as well. Our results suggest a role for YidC in both the reception and lipid partitioning of type I TMs

Natural vs anthropogenic streams in Europe: History, ecology and implications for restoration, river-rewilding and riverine ecosystem services

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordIn Europe and North America the prevailing model of “natural” lowland streams is incised-meandering channels with silt-clay floodplains, and this is the typical template for stream restoration. Using both published and new unpublished geological and historical data from Europe we critically review this model, show how it is inappropriate for the European context, and examine the implications for carbon sequestration and Riverine Ecosystem Services (RES) including river rewilding. This paper brings together for the first time, all the pertinent strands of evidence we now have on the long-term trajectories of floodplain system from sediment-based dating to sedaDNA. Floodplain chronostratigraphy shows that early Holocene streams were predominantly multi-channel (anabranching) systems, often choked with vegetation and relatively rarely single-channel actively meandering systems. Floodplains were either non-existent or limited to adjacent organic-filled palaeochannels, spring/valley mires and flushes. This applied to many, if not most, small to medium rivers but also major sections of the larger rivers such as the Thames, Seine, Rhône, Lower Rhine, Vistula and Danube. As shown by radiocarbon and optically stimulated luminescence (OSL) dating during the mid-late Holocene c. 4–2 ka BP, overbank silt-clay deposition transformed European floodplains, covering former wetlands and silting-up secondary channels. This was followed by direct intervention in the Medieval period incorporating weir and mill-based systems – part of a deep engagement with rivers and floodplains which is even reflected in river and floodplain settlement place names. The final transformation was the “industrialisation of channels” through hard-engineering – part of the Anthropocene great acceleration. The primary causative factor in transforming pristine floodplains was accelerated soil erosion caused by deforestation and arable farming, but with effective sediment delivery also reflecting climatic fluctuations. Later floodplain modifications built on these transformed floodplain topographies. So, unlike North America where channel-floodplain transformation was rapid, the transformation of European streams occurred over a much longer time-period with considerable spatial diversity regarding timing and kind of modification. This has had implications for the evolution of RES including reduced carbon sequestration over the past millennia. Due to the multi-faceted combination of catchment controls, ecological change and cultural legacy, it is impractical, if not impossible, to identify an originally natural condition and thus restore European rivers to their pre-transformation state (naturalisation). Nevertheless, attempts to restore to historical (pre-industrial) states allowing for natural floodplain processes can have both ecological and carbon offset benefits, as well as additional abiotic benefits such as flood attenuation and water quality improvements. This includes rewilding using beaver reintroduction which has overall positive benefits on river corridor ecology. New developments, particularly biomolecular methods offer the potential of unifying modern ecological monitoring with the reconstruction of past ecosystems and their trajectories. The sustainable restoration of rivers and floodplains designed to maximise desirable RES and natural capital must be predicated on the awareness that Anthropocene rivers are still largely imprisoned in the banks of their history and this requires acceptance of an increased complexity for the achievement and maintenance of desirable restoration goals.OSL dating from the Severn-Wye Basin was undertaken at the Geochronology Laboratories, University of Gloucestershire under grants from the EU Leader+ Programme (administered by English Heritage) and the Leverhulme Flood and Flow Project (RPG-2016-004)

Educational Theories and Learning Analytics : From Data to Knowledge

Under embargo until 17.01.21.acceptedVersio