Psychometric properties of Indonesian slums dwellers' place attachment.

Social scientists have long considered place attachment to be an important factor in promoting environmentally sustainable behaviours among individuals. Raymond and colleagues have developed a five-factor place attachment measure, comprising place dependence, nature dependence, place attachment, family bonding, and friendship bonding, that encompasses most of the differentiations made and that has been amply tested for validity and reliability. However, the bulk of these confirmatory studies have been conducted in Western societies, neglecting people in the Global South and particularly people living in unstable, environmentally fragile regions such as slum areas. This study aims to fill this omission by testing the psychometric qualities of the five-factor place attachment measure in Indonesian slums using a dataset collected by the Resilient Indonesian Slums Envisioned (RISE) project. The dataset consists of a random sample of 700 respondents, living in slum areas of the cities of Bima, Manado, and Pontianak. We split the dataset into two and run factor analyses in EFA (N = 325) and CFA (N = 375) modes. Most notably, our results suggest a four-factor scale, in which place and nature dependences are merged into a single dimension. This finding seems logical considering that those living in urban slums are likely to have their natural surroundings, such as a river and its banks, as part of their living space. Overall, our study extends the use of place attachment to disaster-prone slum contexts that are often overlooked and, thus, supports the line of research that promotes environmental sustainability among people especially vulnerable to ecological changes.

Current Methods for Identifying Plasma Membrane Proteins as Cancer Biomarkers.

Plasma membrane proteins are a special class of biomolecules present on the cellular membrane. They provide the transport of ions, small molecules, and water in response to internal and external signals, define a cell's immunological identity, and facilitate intra- and intercellular communication. Since they are vital to almost all cellular functions, their mutants, or aberrant expression is linked to many diseases, including cancer, where they are a part of cancer cell-specific molecular signatures and phenotypes. In addition, their surface-exposed domains make them exciting biomarkers for targeting by imaging agents and drugs. This review looks at the challenges in identifying cancer-related cell membrane proteins and the current methodologies that solve most of the challenges. We classified the methodologies as biased, i.e., search cells for the presence of already known membrane proteins. Second, we discuss the unbiased methods that can identify proteins without prior knowledge of what they are. Finally, we discuss the potential impact of membrane proteins on the early detection and treatment of cancer.

Low nanogel stiffness favors nanogel transcytosis across an in vitro blood-brain barrier.

Transport of therapeutics across the blood-brain barrier (BBB) is a fundamental requirement for effective treatment of numerous brain diseases. However, most therapeutics (>500 Da) are unable to permeate through the BBB and do not achieve therapeutic doses. Nanoparticles (NPs) are being investigated to facilitate drug delivery to the brain. Here, we investigate the effect of nanoparticle stiffness on NP transport across an in vitro BBB model. To this end, fluorescently labeled poly(N-isopropylmethacrylamide) (p(NIPMAM)) nanogels' stiffness was varied by the inclusion of 1.5 mol% (NG1.5), 5 mol% (NG5), and 14 mol% (NG14) N,N'-methylenebis(acrylamide) (BIS) cross-linker and nanogel uptake and transcytosis was quantified. The more densely cross-linked p(NIPMAM) nanogels showed the highest level of uptake by polarized brain endothelial cells, whereas the less densely cross-linked nanogels demonstrated the highest transcytotic potential. These findings suggest that nanogel stiffness has opposing effects on nanogel uptake and transcytosis at the BBB.

Fishing against the odds: fishers' motivations to carry on fishing in the wake of the hindering EU Common Fishery Policy-a case study in North Shields, UK.

The UK's fishing industry has contracted considerably since 1972 due to overfishing, increased fuel prices, and implementation of the European Union (EU) Common Fisheries Policy (CFP). Despite this decline affecting the industry at large and the incomes of fishers, some fishers have carried on, or even freshly started or returned to the business. Why have these fishers done so despite the challenges they encounter in the fishing industry? In this article, we investigate why some fishers still choose to fish in the wake of all the EU regulations designed to control overfishing by reducing the size of the industry and discouraging entry by taking measures that affect revenues. Our data are collected through ethnographic research involving participant observation and interviews with fishers in North Shields, England. Based on our findings, we argue that the decision to carry on fishing, or even to return, is predominantly based on so-called intrinsic motivations, rather than on cost-benefit calculations, and stems from three interlinked basic human emotional needs which fishing seems to fulfil: the need to connect (sometimes also defined as the need to relate or belong); the desire for autonomy; and the desire to show competence (and have that competence recognized by relevant others). As such, the findings offer a fresh way to explain fishers' decisions, based on a deliberated choice, to remain or leave the sector, and to understand and interrogate the challenges confronting present-day fishing both on a local level in the UK and also for Europe at large.

The effectiveness of a low-dose esketamine versus an alfentanil adjunct to propofol sedation during endoscopic retrograde cholangiopancreatography: A randomised controlled multicentre trial.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is one of the most complex gastrointestinal endoscopic procedures. Currently, it is still unclear which sedation regimen best facilitates an ERCP. The N-methyl-D-aspartate receptor antagonist esketamine has anaesthetic, analgesic and sympathomimetic properties and is known to cause less cardiorespiratory depression than other sedatives. It could therefore be an ideal adjunct to propofol for deep sedation. OBJECTIVE: To assess the effectiveness of esketamine versus alfentanil as an adjunct to propofol target-controlled infusion (TCI) for deep sedation during ambulant ERCP. DESIGN: A randomised controlled multicentre study. SETTING: Endoscopic intervention suite at an academic and general hospital in the Netherlands. PARTICIPANTS: Adult, American Society of Anesthesiologists Physical Status I to III patients scheduled to undergo ERCP. INTERVENTION: Consecutive patients were randomly assigned to receive sedation for an ERCP with propofol TCI and alfentanil (group A) or with propofol TCI and esketamine (group E). MAIN OUTCOME MEASURES: The primary outcome was effectiveness of the sedation regimen expressed as the total dose of propofol - as a surrogate parameter - necessary to perform ERCP in a satisfactory manner for endoscopist and patients. Secondary outcomes were recovery time, patients' and endoscopists' satisfaction with sedation, side effects (e.g. psychotomimetic effects, nausea and vomiting) and the number of respiratory and cardiovascular adverse events. RESULTS: Data from 162 patients were analysed. The total dose of propofol required was significantly lower in group E (n=83) (8.3 mg kg h) than in group A (n=79) (10.5 mg kg h) (P < 0.001). There were no significant differences in recovery time, patients' and endoscopists' satisfaction, side effects, psychotomimetic effects and the number of sedation-related adverse events. CONCLUSION: Low-dose esketamine reduces the total amount of propofol necessary for sedation during ERCP in American Society of Anesthesiologists I and II patients without affecting recovery time, satisfaction of patients and endoscopists, side effects and respiratory or cardiovascular adverse events, when compared with alfentanil. TRIAL REGISTRATION: The Netherlands Trial Register (NTR5486).

Climbing droplets driven by mechanowetting on transverse waves.

Many applications in modern technology, such as self-cleaning surfaces and digital microfluidics, require control over individual fluid droplets on flat surfaces. Existing techniques may suffer from side effects resulting from high electric fields and high temperatures. Here, we introduce a markedly different method, termed "mechanowetting," that is based on the surface tension-controlled droplet motion on deforming surfaces. The method is demonstrated by transporting droplets using transverse surface waves on horizontal and (vertically) inclined surfaces at transport velocities equal to the wave speed. We fully capture the fundamental mechanism of the mechanowetting force numerically and theoretically and establish its dependence on the fluid properties, surface energy, and wave parameters. Mechanowetting has the potential to lead to a range of new applications that feature droplet control through dynamic surface deformations.

Pillars or Pancakes? Self-Cleaning Surfaces without Coating.

Surfaces that stay clean when immersed in water are important for an enormous range of applications from ships and buildings to marine, medical, and other equipment. Up until now the main strategy for designing self-cleaning surfaces has been to combine hydrophilic/hydrophobic coatings with a high aspect ratio structuring (typically micron scale pillars) to trap a (semi)static water/air layer for drag and adhesion reduction. However, such coating and structuring can distort optical properties and get damaged in harsh environments, and contamination, i.e., particles, oil droplets, and biofouling, can get trapped and aggregate in the structure. Here we present a radically different strategy for self-cleaning surface design: We show that a surface can be made self-cleaning by structuring with a pattern of very low aspect ratio pillars ("pancakes"). Now the water is not trapped. It can flow freely around the pancakes thus creating a dynamic water layer. We have applied the new pancake design to sapphire windows and made the first surfaces that are self-cleaning through structuring alone without the application of any coating. An offshore installation has now been running continuously with structured windows for more than one year. The previous uptime for unstructured windows was 7 days.

A filter-free blood-brain barrier model to quantitatively study transendothelial delivery of nanoparticles by fluorescence spectroscopy.

The delivery of therapeutics to the brain is greatly hampered by the blood-brain barrier (BBB). The use of nanoparticles that can cross the BBB via the process of receptor-mediated transcytosis at blood-brain barrier endothelial cells seems a promising strategy to transport therapeutics into the brain. To screen for suitable nanocarriers, and to study the process of transcytosis, a cultured polarized monolayer of brain microvascular endothelial cells on an extracellular matrix-coated porous membrane filter is widely used as an in vitro BBB model. However, due to the adhesion of numerous types of nanoparticles to the membrane filter and within the filter pores, such a model is unsuitable for the quantification of transendothelial delivery of nanoparticles. Hence, there is a pressing need for a filter-free in vitro BBB model. Ideally, the model is inexpensive and easy to use, in order to allow for its wide use in nanomedicine and biology laboratories around the world. Here, we developed a filter-free in vitro BBB model that consists of a collagen gel covered with a monolayer of brain microvascular endothelial (hCMEC/D3) cells. The paracellular leakage of differently sized dextrans and the transcellular transport of LDL were measured to demonstrate the validity of the filter-free model. Finally, the transendothelial delivery of fluorescently-labelled PEG-P(CL-g-TMC) polymersomes that were functionalized with GM1-targeting peptides was assessed by fluorescence spectroscopy measurement of the luminal, cellular, and abluminal parts of the filter-free BBB model. Our data confirm the effectiveness of the G23 peptide to mediate transport of polymersomes across the BBB and the suitability of this filter-free in vitro model for quantification of nanoparticle transcytosis.

Sedation with propofol during ERCP: is the combination with esketamine more effective and safer than with alfentanil? Study protocol for a randomized controlled trial.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a gastrointestinal procedure that requires a relatively motionless patient during the intervention. Deep sedation by intravenous propofol combined with an opioid has recently become the preferred sedation technique. However, when high doses of propofol are used, side effects, namely respiratory depression, may occur. Esketamine has hypnotic, analgesic, and sympathomimetic effects. Our assumption is that a combination of propofol with esketamine reduces the dosage of individual drugs, thereby minimizing sedation side effects while keeping the same satisfaction level of patients and endoscopists. METHODS/DESIGN: The study will be performed as a randomized controlled multicenter trial. Patients undergoing ERCP, ≥ 18 years old, with American Society of Anesthesiologists (ASA) classification I-III will be randomized after written informed consent to group K (propofol/esketamine) or to group A (propofol/alfentanil). The primary outcome, reflecting effectiveness of sedation, is the total dose of propofol. Secondary outcome parameters are patients' and endoscopists' satisfaction with the procedure and the number of sedation-related pulmonary and cardiovascular events. Data on sedation-related events are collected by recording of oxygen saturation (SpO2), respiratory rate (RR), end-tidal CO2 (etCO2), heart rate (HR), arrhythmias (electrocardiogram (ECG)), and non-invasive blood pressure (NIBP) measurements. Satisfaction parameters are collected by means of questionnaires before and after the procedure and on the following day. DISCUSSION: Esketamine is known for its effective anesthetic and analgesic effects maintaining spontaneous breathing and airway reflexes. Due to an increase in sympathetic tone, hypotension and cardiac depression is less common. Unfortunately esketamine is also known for its psychotomimetic effects. We aim to demonstrate that the combination of esketamine with propofol for sedation in patients subjected to ERCP interventions is nevertheless superior to a combination of propofol with an opioid. TRIAL REGISTRATION: Nederland's Trial Register, NTR5486 . Registered on 17 September 2015.

Entry of PIP3-containing polyplexes into MDCK epithelial cells by local apical-basal polarity reversal.

The polarized architecture of epithelium presents a barrier to therapeutic drug/gene carriers, which is mainly due to a limited (apical) internalization of the carrier systems. The bacterium Pseudomonas aeruginosa invades epithelial cells by inducing production of apical phosphatidylinositol-3, 4, 5-triphosphate (PIP3), which results in the recruitment of basolateral receptors to the apical membrane. Since basolateral receptors are known receptors for gene delivery vectors, apical PIP3 may improve the internalization of such vectors into epithelial cells. PIP3 and nucleic acids were complexed by the cationic polymer polyethylenimine (PEI), forming PEI/PIP3 polyplexes. PEI/PIP3 polyplexes showed enhanced internalization compared to PEI polyplexes in polarized MDCK cells, while basolateral receptors were found to redistribute and colocalize with PEI/PIP3 polyplexes at the apical membrane. Following their uptake via endocytosis, PEI/PIP3 polyplexes showed efficient endosomal escape. The effectiveness of the PIP3-containing delivery system to generate a physiological effect was demonstrated by an essentially complete knock down of GFP expression in 30% of GFP-expressing MDCK cells following anti-GFP siRNA delivery. Here, we demonstrate that polyplexes can be successfully modified to mimic epithelial entry mechanisms used by Pseudomonas aeruginosa. These findings encourage the development of pathogen-inspired drug delivery systems to improve drug/gene delivery into and across tissue barriers.

Anticancer effects of 15d-prostaglandin-J2 in wild-type and doxorubicin-resistant ovarian cancer cells: novel actions on SIRT1 and HDAC.

15-Deoxy-delta-12,14-prostaglandin-J(2) (15d-PGJ(2)), an arachidonic metabolite and a natural PPARγ agonist, is known to induce apoptosis in tumor cells. In this study, we investigated new therapeutic potentials of 15d-PGJ(2) by determining its anticancer effects in wild-type and doxorubicin-resistant ovarian carcinoma cells. Despite high expression of resistance-inducing genes like MDR1, Bcl2 and Bcl-xl, 15d-PGJ(2) strongly induced apoptosis in doxorubicin-resistant (A2780/AD) cells similar to the wild-type (A2780). This was found to be related to caspase-3/7- and NF-κB pathways but not to its PPARγ agonistic activity. 15d-PGJ(2) also was able to reduce the doxorubicin resistance of A2780/AD cells at low doses as confirmed by the inhibition of gene expression of MDR1 (p-glycoprotein) and SIRT1 (a drug senescence gene). We also investigated effects of 15d-PGJ(2) on cell migration and transformation using a wound-healing assay and morphological analyses, respectively. We found that 15d-PGJ(2) inhibited migration most likely due to NF-κB inhibition and induced transformation of the round-shape A2780/AD cells into elongated epithelial cells due to HDAC1 inhibition. Using a 15d-PGJ(2) analog, we found the mechanism of action of these new activities of 15d-PGJ(2) on SIRT1 and HDAC1 gene expressions and enzyme activities. In conclusion, the present study demonstrates that 15d-PGJ(2) has a high therapeutic potential to kill drug-resistant tumor cells and, the newly described inhibitory effects of this cyclo-oxygenase product on SIRT1 and HDAC will provide new opportunities for cancer therapeutics.

Synergistic induction of profibrotic PAI-1 by TGF-ß and radiation depends on p53.

Radiation-induced fibrosis is a severe side effect of radiotherapy. TGF-ß and radiation synergistically induce expression of the profibrotic PAI-1 gene and this cooperation potentially involves p53. Here, we demonstrate that p53 is both indispensable and sufficient for the radiation effect inducing synergistic activation of PAI-1 by radiation and TGF-ß.

A novel approach to deliver anticancer drugs to key cell types in tumors using a PDGF receptor-binding cyclic peptide containing carrier.

Tumor stromal cells have been recently recognized to contribute to tumor growth. Therefore, we hypothesized that delivery of anticancer drugs to these cells in addition to the tumor cells might treat cancer more effectively. Stromal cells abundantly expressed Platelet-Derived Growth Factor Receptor-beta (PDGFR-beta) in different human tumors as shown with immunohistochemistry. To achieve targeting through PDGFR-beta, we developed a carrier by modifying albumin with a PDGFR-beta recognizing cyclic peptide (pPB-HSA). pPB-HSA specifically bound to PDGFR-beta-expressing 3T3 fibroblasts, C26 and A2780 cancer cells in vitro. Subsequently, doxorubicin was conjugated to pPB-HSA through an acid-sensitive hydrazone linkage. In vitro, Dox-HSA-pPB was taken up by fibroblasts and tumor cells and a short exposure of the conjugate induced cell death in these cells. In vivo, the conjugate rapidly accumulated into PDGFR-beta expressing cells in C26 tumors. Treatment with Dox-HSA-pPB significantly reduced the C26 tumor growth in mice while free doxorubicin treated mice had lower response to the therapy. Furthermore, in contrast to free doxorubicin the conjugate did not induce loss in body weight. In conclusion, the present study reveals a novel approach to target key cell types in tumors through PDGFR-beta, which can be applied to enhance the therapeutic efficacy of anticancer drugs.

Conformational studies of peptides representing a segment of TM7 from H+-VO-ATPase in SDS micelles.

The conformation of a transmembrane peptide, sMTM7, encompassing the cytoplasmic hemi-channel domain of the seventh transmembrane section of subunit a from V-ATPase from Saccharomyces cerevisiae solubilized in SDS solutions was studied by circular dichroism (CD) spectroscopy and fluorescence spectroscopy of the single tryptophan residue of this peptide. The results show that the peptide adopts an alpha-helical conformation or aggregated beta-sheet depending on the peptide-to-SDS ratio used. The results are compared with published data about a longer version of the peptide (i.e., MTM7). It is concluded that the bulky, positively charged arginine residue located in the center of both peptides has a destabilizing effect on the helical conformation of the SDS-solubilized peptides, leading to beta-sheet formation and subsequent aggregation.

Segment TM7 from the cytoplasmic hemi-channel from VO-H+-V-ATPase includes a flexible region that has a potential role in proton translocation.

A 900-MHz NMR study is reported of peptide sMTM7 that mimics the cytoplasmic proton hemi-channel domain of the seventh transmembrane segment (TM7) from subunit a of H(+)-V-ATPase from Saccharomyces cerevisiae. The peptide encompasses the amino acid residues known to actively participate in proton translocation. In addition, peptide sMTM7 contains the amino acid residues that upon mutation cause V-ATPase to become resistant against the inhibitor bafilomycin. 2D TOCSY and NOESY (1)H-(1)H NMR spectra are obtained of sMTM7 dissolved in d(6)-DMSO and are used to calculate the three-dimensional structure of the peptide. The NMR-based structures and corresponding dynamical features of peptide sMTM7 show that sMTM7 is composed of two alpha-helical regions. These regions are separated by a flexible hinge of two residues. The hinge acts as a ball-and-joint socket and both helical segments move independently with respect to one another. This movement in TM7 is suggested to cause the opening and closing of the cytoplasmic proton hemi-channel and enables proton translocation.

A monotonic archive for pareto-coevolution.

Coevolution has already produced promising results, but its dynamic evaluation can lead to a variety of problems that prevent most algorithms from progressing monotonically. An important open question therefore is how progress towards a chosen solution concept can be achieved. A general solution concept for coevolution is obtained by viewing opponents or tests as objectives. In this setup known as Pareto-coevolution, the desired solution is the Pareto-optimal set. We present an archive that guarantees monotonicity for this solution concept. The algorithm is called the Incremental Pareto-Coevolution Archive (IPCA), and is based on Evolutionary Multi-Objective Optimization (EMOO). By virtue of its monotonicity, IPCA avoids regress even when combined with a highly explorative generator. This capacity is demonstrated on a challenging test problem requiring both exploration and reliability. IPCA maintains a highly specific selection of tests, but the size of the test archive nonetheless grows unboundedly. We therefore furthermore investigate how archive sizes may be limited while still providing approximate reliability. The LAyered Pareto-Coevolution Archive (LAPCA) maintains a limited number of layers of candidate solutions and tests, and thereby permits a trade-off between archive size and reliability. The algorithm is compared in experiments, and found to be more efficient than IPCA. The work demonstrates how the approximation of a monotonic algorithm can lead to algorithms that are sufficiently reliable in practice while offering better efficiency.

Reconstruction of a functional human gene network, with an application for prioritizing positional candidate genes.

Most common genetic disorders have a complex inheritance and may result from variants in many genes, each contributing only weak effects to the disease. Pinpointing these disease genes within the myriad of susceptibility loci identified in linkage studies is difficult because these loci may contain hundreds of genes. However, in any disorder, most of the disease genes will be involved in only a few different molecular pathways. If we know something about the relationships between the genes, we can assess whether some genes (which may reside in different loci) functionally interact with each other, indicating a joint basis for the disease etiology. There are various repositories of information on pathway relationships. To consolidate this information, we developed a functional human gene network that integrates information on genes and the functional relationships between genes, based on data from the Kyoto Encyclopedia of Genes and Genomes, the Biomolecular Interaction Network Database, Reactome, the Human Protein Reference Database, the Gene Ontology database, predicted protein-protein interactions, human yeast two-hybrid interactions, and microarray co-expressions. We applied this network to interrelate positional candidate genes from different disease loci and then tested 96 heritable disorders for which the Online Mendelian Inheritance in Man database reported at least three disease genes. Artificial susceptibility loci, each containing 100 genes, were constructed around each disease gene, and we used the network to rank these genes on the basis of their functional interactions. By following up the top five genes per artificial locus, we were able to detect at least one known disease gene in 54% of the loci studied, representing a 2.8-fold increase over random selection. This suggests that our method can significantly reduce the cost and effort of pinpointing true disease genes in analyses of disorders for which numerous loci have been reported but for which most of the genes are unknown.

Ideal evaluation from coevolution.

In many problems of interest, performance can be evaluated using tests, such as examples in concept learning, test points in function approximation, and opponents in game-playing. Evaluation on all tests is often infeasible. Identification of an accurate evaluation or fitness function is a difficult problem in itself, and approximations are likely to introduce human biases into the search process. Coevolution evolves the set of tests used for evaluation, but has so far often led to inaccurate evaluation. We show that for any set of learners, a Complete Evaluation Set can be determined that provides ideal evaluation as specified by Evolutionary Multi-Objective Optimization. This provides a principled approach to evaluation in coevolution, and thereby brings automatic ideal evaluation within reach. The Complete Evaluation Set is of manageable size, and progress towards it can be accurately measured. Based on this observation, an algorithm named DELPHI is developed. The algorithm is tested on problems likely to permit progress on only a subset of the underlying objectives. Where all comparison methods result in overspecialization, the proposed method and a variant achieve sustained progress in all underlying objectives. These findings demonstrate that ideal evaluation may be approximated by practical algorithms, and that accurate evaluation for test-based problems is possible even when the underlying objectives of a problem are unknown.