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Background Late-life depression is a serious mental health problem. Behavioral Activation (BA) is an effective, accessible psychotherapeutic treatment for older adults. However, little is known about which symptoms decrease and how associations between depressive symptoms change during BA treatment. Methods Using data from a cluster-randomized trial for older adults with late-life depression, we estimated a partial correlation network and a relative importance network of depressive symptoms before and after 8 weeks of BA treatment in primary care (n = 96). Networks were examined with measures of network structure, con- nectivity, centrality as well as stability. Results The most central symptoms at baseline and post-treatment were anhedonia, fatigue, and feeling depressed. In contrast, sleeping problems had the lowest centrality. The post-treatment network was significantly more interconnected than at baseline. Moreover, all symptoms were significantly more central at post-treatment. Conclusion Our findings highlight the utility of the network approach to better understand symptom networks of depressed older adults before and after BA treatment. Results show that network connectivity and centrality of all symptoms increased after treatment. Future studies should investigate longitudinal idiographic networks to explore symptom dynamics within individuals over time.

BACKGROUND: Guideline-recommended therapies are moderately successful in the treatment of obsessive-compulsive disorder (OCD) and anorexia nervosa (AN), leaving room for improvement. Cognitive inflexibility, a common trait in both disorders, is likely to prevent patients from engaging in treatment and from fully benefiting from existing therapies. Cognitive remediation therapy (CRT) is a practical augmentation intervention aimed at ameliorating this impairing cognitive style prior to disorder-specific therapy.OBJECTIVE: To compare the effectiveness of CRT and a control treatment that was not aimed at enhancing flexibility, named specialized attention therapy (SAT), as add-ons to treatment as usual (TAU).METHODS: In a randomized controlled multicenter clinical trial, 71 adult patients with OCD and 61 with AN were randomized to ten twice-weekly sessions with either CRT or SAT, followed by TAU. Patients were evaluated at baseline, post-CRT/SAT, and after 6 and 12 months, with outcomes being quantified using the Yale-Brown Obsessive Compulsive Scale for OCD and the Eating Disorder Examination Questionnaire for AN.RESULTS: Across study groups, most importantly CRT+TAU was not superior to control treatment (SAT)+TAU in reducing OCD and AN pathology. Contrary to expectations, SAT+TAU may have been more effective than CRT+TAU in patients being treated for OCD.CONCLUSIONS: CRT did not enhance the effect of TAU for OCD and AN more than SAT. Unexpectedly, SAT, the control condition, may have had an augmentation effect on TAU in OCD patients. Although this latter finding may have been due to chance, the effect of SAT delivered as a pretreatment add-on intervention for adults with OCD and AN merits future efforts at replication.

The increased use of nanoparticles (NPs) requires efficient testing of their potential toxic effects. A promising approach is to use reporter cell lines to quickly assess the activation of cellular stress response pathways. This study aimed to use the ToxTracker reporter cell lines to investigate (geno)toxicity of various metal-or metal oxide NPs and draw general conclusions on NP-induced effects, in combination with our previous findings. The NPs tested in this study (n = 18) also included quantum dots (QDs) in different sizes. The results showed a large variation in cytotoxicity of the NPs tested. Furthermore, whereas many induced oxidative stress only few activated reporters related to DNA damage. NPs of manganese (Mn and Mn3O4) induced the most remarkable ToxTracker response with activation of reporters for oxidative stress, DNA damage, protein unfolding and p53-related stress. The QDs (CdTe) were highly toxic showing clearly size-dependent effects and calculations suggest surface area as the most relevant dose metric. Of all NPs investigated in this and previous studies the following induce the DNA damage reporter; CuO, Co, CoO, CdTe QDs, Mn, Mn3O4, V2O5, and welding NPs. We suggest that these NPs are of particular concern when considering genotoxicity induced by metal-and metal oxide NPs., QC 20200420

Most multinational enterprises (MNEs) pursue growth and aim to expand their international portfolios of operating locations. Often, however, they face important limits to growth. This dissertation studies several such limits and aims to restore balance in the international business literature by addressing some of the biases built over time. Firms’ home-country activities may act as a limiting factor in their international expansion trajectory, but have received little attention to date. One of the dissertation chapters reveals that a firm’s domestic footprint, in combination with domestic environmental uncertainties, shapes its cross-cultural expansion strategy, and may limit the complexity it adds to its portfolio. The subsequent chapter indicates that behavioral factors have an important bearing on international portfolio growth decisions, more so than hitherto assumed. It finds that the net growth of an MNE’s country portfolio in the face of cultural and economic diversity within that portfolio hinges on cues as to how well the MNE is performing relative to its o

Enhancing social cohesion adds to a decrease in mortality and crime rates, while also increasing the stability of fragile groups, the wellbeing of elderly people and economic growth. Municipal policies around culture, like cultural heritage and tourism, can be used in a way that has an increasing effect on social cohesion. Cultural policy experts of sixteen municipalities and people from two market organizations within the province of Utrecht were studied and interviewed about their strategies to enhance social cohesion through heritage locations and their touristic profile. The main question: In municipalities located in the province of Utrecht, do policies on cultural heritage and tourism have an effect on social cohesion and if so, how, according to the policymakers and other relevant civil servants? Policy experts did not know about these strategies or did not utilize them, due to capacity constraints and a lack of knowledge on the subject. However, another player seemed to be taking over the role of enhancing the cohesion of the municipal inhabitants: the library. Along with cultural centers, the libraries are modernizing and are becoming hubs for all social groups. Through volunteers and encounters of all social groups, the libraries and/or cultural centers manage to add to the social cohesion within municipalities. It is advised to keep up with this trend, while also educating policy experts on strategies to enhance social cohesion through cultural policies by bundling knowledge and collaborating with umbrella and specialized organizations. The libraries and cultural centers alone should not be responsible for the social cohesion of municipalities.

QC 20180917

A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomicmethods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.

Emerging-market multinational enterprises (EMNEs) play an increasingly important role as investors in developing economies. When certain conditions are met, their foreign investment can contribute to host-country progress towards the Sustainable Development Goals (SDGs). Moreover, foreign investment by EMNEs could also bring positive development effects for the home economies from which they internationalize. However, some concern exists about the possibility that gains will not be equitably shared or that potential will be not realized in one or the other. This article aims to shed light on the conditions that will allow both the home country of an EMNE and the host country receiving its investment to make progress towards the SDGs. Five areas for policy action are presented, together with a research agenda. It is argued that the most promising measures encourage foreign investment to be long-term, stimulate linkages between EMNEs' home-country partners and host-economy firms, incentivize home-and host-country firms to take on new roles within global value chains, capitalize on institutional upgrading potential and tie certain conditions to the right to access natural resources. Both home and host countries could then potentially benefit from EMNEs' outward investment and make progress on goals related to poverty alleviation (SDG 1), economic growth and the creation of decent work (SDG 8), infrastructure development (SDG 9) and institutional upgrading (SDG 16).

Contains fulltext : 76117.pdf (publisher's version ) (Open Access), Vasopressin binding to the V2 receptor in renal principal cells leads to activation of protein kinase A, phosphorylation of aquaporin 2 (AQP2) at Ser256, and the translocation of AQP2 to the apical membrane, resulting in concentration of the urine. In contrast, phorbol ester-induced activation of protein kinase C pathway leads to ubiquitination of AQP2 at Lys270 and its internalization to multivesicular bodies, where it is targeted for lysosomal degradation or stored for recycling. Because little is known about the regulation of AQP2 trafficking, we used the carboxy-terminal tail of constitutively nonphosphorylated AQP2 (S256A) as a bait for interacting proteins in a yeast two-hybrid assay. We isolated lysosomal trafficking regulator-interacting protein 5 (LIP5) and found that LIP5 interacted with the proximal carboxy-terminal tail (L230-D243) of AQP2 in vitro but not with AQP3 or AQP4, which are also expressed in principal cells. Immunohistochemistry revealed that LIP5 co-localized with AQP2 in principal cells. LIP5 binding occurred independent of the state of Ser256 phosphorylation or Lys270 ubiquitination. LIP5 has been shown to facilitate degradation of the EGF receptor; here, LIP5 seemed to bind this receptor. Knockdown of LIP5 in mouse renal cells (mpkCCD) reduced the phorbol ester-induced degradation of AQP2 approximately two-fold. In summary, LIP5 binds cargo proteins and, considering the role of LIP5 in protein sorting to multivesicular bodies, plays a role in the degradation of AQP2, possibly by reducing the formation of late endosomes.

Contains fulltext : 50652.pdf (publisher's version ) (Closed access), To regulate mammalian water homeostasis, arginine-vasopressin (AVP) induces phosphorylation and thereby redistribution of renal aquaporin-2 (AQP2) water channels from vesicles to the apical membrane. Vice versa, AVP (or forskolin) removal and hormones activating PKC cause AQP2 internalization, but the mechanism is unknown. Here, we show that a fraction of AQP2 is modified with two to three ubiquitin moieties in vitro and in vivo. Mutagenesis revealed that AQP2 is ubiquitinated with one K63-linked chain at K270 only. In Madin-Darby canine kidney cells, AQP2 ubiquitination occurs preferentially when present in the apical membrane, is transiently increased with forskolin removal or PKC activation, and precedes its internalization. Internalization kinetics assays with wild type (wt) and ubiquitination-deficient (K270R) AQP2 revealed that ubiquitination enhances AQP2 endocytosis. Electron microscopy showed that a translational fusion of AQP2 with ubiquitin (AQP2-Ub) localized particularly to internal vesicles of multivesicular bodies (MVBs), whereas AQP2-K270R largely localized to the apical membrane, early endosomes, and the limiting membrane of MVBs. Consistent with this distribution pattern, lysosomal degradation was extensive for AQP2-Ub, low for AQP2-K270R, and intermediate for wt-AQP2. Our data show that short-chain ubiquitination is involved in the regulated endocytosis, MVB sorting, and degradation of AQP2 and may be the mechanism used by AVP removal and PKC-activating hormones to reduce renal water reabsorption. Moreover, because several other channels are also (short-chain) ubiquitinated, our data suggest that ubiquitination may be a general mediator for the regulated endocytosis and degradation of channels in higher eukaryotes.

Contains fulltext : 49704.pdf (publisher's version ) (Closed access), Polarisation of cells is crucial for vectorial transport of ions and solutes. In literature, however, proteins specifically targeted to the apical or basolateral membrane are often studied in non-polarised cells. To investigate whether these data can be extrapolated to expression in polarised cells, we studied several membrane-specific proteins. In polarised MDCK cells, the Aquaporin-2 water channel resides in intracellular vesicles and apical membrane, while the vasopressin-type 2 receptor, anion-exchanger 1 (AE1) protein and E-Cadherin mainly localise to the basolateral membrane. In non-polarised MDCK cells, however, Aquaporin-2 localises, besides plasma membrane, mainly in the Golgi complex, while the others show a dispersed staining throughout the cell. Moreover, while AQP2 mutants in dominant nephrogenic diabetes insipidus are missorted to different organelles in polarised cells, they all predominantly localise to the Golgi complex in non-polarised MDCK cells. Additionally, the maturation of V2R, and likely its missorting, is affected in transiently-transfected compared to stably-transfected cells. In conclusion, we show that the use of stably-transfected polarised cells is crucial in interpreting the processing and the localisation of membrane targeted proteins.

Contains fulltext : 58382.pdf (Publisher’s version ) (Open Access), Aquaporin-2 (AQP2) is a pore-forming protein that is required for regulated reabsorption of water from urine. Mutations in AQP2 lead to nephrogenic diabetes insipidus, a disorder in which functional AQP2 is not expressed on the apical cell surface of kidney collecting duct principal cells. The mechanisms and pathways directing AQP2 from the endoplasmic reticulum to the Golgi complex and beyond have not been defined. We found that approximately 25% of newly synthesized AQP2 is glycosylated. Nonglycosylated and complex-glycosylated wild-type AQP2 are stable proteins with a half-life of 6-12 h and are both detectable on the cell surface. We show that AQP2 forms tetramers in the endoplasmic reticulum during or very early after synthesis and reaches the Golgi complex in 1-1.5 h. We also report that glycosylation is neither essential for tetramerization nor for transport from the endoplasmic reticulum to the Golgi complex. Instead, the N-linked glycan is important for exit from the Golgi complex and sorting of AQP2 to the plasma membrane. These results are important for understanding the molecular mechanisms responsible for the intracellular retention of AQP2 in nephrogenic diabetes insipidus.

A population-based case-control study of the association between head trauma and Alzheimer's disease was conducted in the Netherlands from 1980 to 1987. The study comprised 198 patients with clinically diagnosed early onset Alzheimer's disease and 198 age- and sex-matched population controls. Adjusted for sex, age, family history of dementia, and education, the odds ratio of a history of head trauma with loss of consciousness was 1.6 (95% confidence interval (CI) 0.8-3.4). The odds ratio for men was 2.5 (95% CI 0.9-7.0), and that for women was 0.9 (95% CI 0.3-2.8). The increase in odds ratio was limited to head trauma that occurred within the period of 10 years prior to the onset of dementia (odds ratio = 10.0; 95% CI 1.0-96.8). There was no evidence of effect modification by family history of dementia as measured on a multiplicative scale. However, the power to show interaction may have been low in this study. The authors' findings are compatible with the view that head trauma may be implicated in Alzheimer's disease, with a short lag time between the head trauma and the first symptoms of disease. The association needs to be confirmed in a prospective follow-up study to fully exclude the possibility of recall bias.