A simulation model shows how individual differences affect major life decisions

Individuals are faced with a number of major decisions throughout their lives, including the choice of a suitable education, career, and life partner. Making such ‘major life decisions’ is challenging, as is evidenced by substantial rates of divorce and drop-out from higher education. Although poor major life decisions can lead to considerable costs for both individuals and society, little is known about how people make these decisions. This is because major life decisions are not simple short-term weighings of options – they are strongly intertwined with identity development. Here, we present a simulation model of major life decisions that integrates the short-term perspective of decision science with the long-term perspective of identity theory. We model major life decisions as a process comprising many explorations of available options, resulting in changing commitments, and eventually leading to a decision. Using our model, we run a large-scale in silico experiment, systematically simulating how three key individual characteristics affect the choice process and the quality of the decision: (1) exploration tendency (broad vs in-depth), (2) accuracy in assessing how well options fit, and (3) selectiveness. We identify the types of individuals who are at risk of exhibiting ‘maladaptive’ decision dynamics, including ruminative exploration and rash decision making, and conclude that these features often, but not always, lead to bad decisions. Our simulation results generate concrete predictions that can be empirically tested and may eventually result in individually tailored tools to aid individuals in making major life decisions

Single-conformation spectroscopy of hydrogen bonding networks: Solvation, synthetic foldamers, and neurodegenerative diseases

The hydrogen bond is one of the most important interactions in natural processes ranging from protein folding to chemical reactions. Two complementary methodologies are applied to understanding this important interaction: top-down and bottom-up. Top-down methods use large molecules, such as proteins, revealing secondary structure information. Bottom-up experiments are performed on small molecules, utilizing high-resolution spectroscopy to reveal underlying quantum mechanical effects. The complexity gap is formed between these two experimental regimes; between large and small molecules; between bulk and individual solvent molecules; between classical mechanics calculations and quantum chemical calculations. This dissertation will focus on the application of gas phase, single-conformation ultraviolet (UV) and infrared (IR) spectroscopies to the study of molecules and clusters in the size and solvation complexity gap, with the goal of bridging the gulf between the two experimental approaches. Single-conformation spectroscopy is perfectly suited to study solvation. Solvent molecules, in many instances water, can be frozen onto the solute in a stepwise manner. Here, we solvate a prototypical flexible bichromophore—1,2-diphenoxyethane (DPOE)—by stepwise addition of water molecules. Single-conformation spectroscopy reveals both the structural perturbations associated with water molecule addition and their effect on DPOE’s pair of closely spaced excited electronic states. These experimental studies provide excellent insight into solvent effects on vibronic and excitonic coupling, and can be used to further develop the models used to describe such processes. Similarly, single-conformation spectroscopy can reveal the effects of conformational flexibility on the innate conformational preferences and hydrogen bonding motifs in peptides. Results obtained from a study of a cyclically constrained γ peptide, γACHC, reveal that increased conformational flexibility can be controlled by synthetic chemists in order to direct folding into pre-programmed secondary structures and that these structures are stabilized with intramolecular rather than intermolecular hydrogen bonds. This theme of conformational flexibility is continued in studies of glutamine containing peptides. Glutamine—with its flexible, hydrogen bond forming sidechain—is intimately involved with neurodegenerative diseases such as Huntington’s disease. Single-conformation studies help reveal the delicate interplay between three different types of hydrogen bonds within the molecule: backbone-backbone, sidechain-backbone, and sidechain-sidechain hydrogen bonds. The importance of these competing hydrogen bonds on the conformational preferences will be discussed both locally and within the larger context of disease pathogenesis

A system science perspective on burn-out: development of an expert-based causal loop diagram

IntroductionBurn-out leads to reduced worker well-being, long-term absenteeism, and high costs for employers and society. Determinants at different levels may affect burn-out in an interrelated and dynamic manner. The aim of the present study was to apply a broader systems perspective by exploring and visualizing the complex system of determinants at different levels (living conditions, working conditions, and societal developments) underlying the prevalence of burn-out in the Netherlands.MethodsDuring three group model building (GMB) sessions with in total eight experts on workers’ mental health, a causal loop diagram (CLD) was developed and relevant feedback loops were identified. For the selection of determinants to be included in the CLD a recently published overview of determinants on burn-out at different levels was used. Experts could also add factors that were not listed in the overview.ResultsThe final CLD consists of 20 factors and depicts a central position of working conditions. Societal developments (e.g., access to mental health care, size of the working population, rougher social climate, etc.) were mostly located at the outside of the CLD and barely integrated in feedback loops. Several reinforcing feedback loops resulting in an increase of the prevalence of burn-out were identified in which the factors (very) high workload, imbalance between work and private life, and insufficient recovery time play an important role. Also, several balancing loops were found that visualize the crucial role of functional support from supervisors to prevent burn-out among workers.DiscussionApplying a broader systems perspective, including determinants at different levels, offers new insights into dynamic feedback loops that contribute to the prevalence of burn-out. Supervisors, amongst others, have a considerable impact on the system underlying the high prevalence of burn-out and may therefore contribute to its prevention. Even though societal developments were less integrated in feedback loops, they might be considered drivers of existing feedback loops. The results from this study confirm that determinants at various levels underly the prevalence of burn-out. To be able to address the diversity of determinants underlying a high prevalence of burn-out, a complex system approach can be helpful

Does Being Defended Relate to Decreases in Victimization and Improved Psychosocial Adjustment Among Victims?

School bullying is a clear violation of children’s rights to a safe education and is a major concern among school professionals and parents. Many antibullying interventions focus on enhancing peer defending of victims to combat bullying and to promote victims’ psychosocial functioning. However, longitudinal studies on the effects of being defended on (a) diminishing victimization and (b) enhancing victims’ psychosocial adjustment are lacking, and the role of the broader peer context has been largely unexplored. Therefore, this study examined whether being defended decreases victimization and improves victims’ psychosocial adjustment, and whether defending peer norms moderate these effects. Data were derived from a nationwide Dutch study on the effectiveness of antibullying interventions, with N = 5,415 students (Mage = 9.93; 48.3% girls) from 238 classrooms (54.2% control classrooms) in 68 elementary schools. Findings indicate that victims with at least one defender at the start of the school year (Time 1) experienced higher feelings of belonging at the end of the school year (Time 2) compared with nondefended victims, but experienced lower feelings of belonging compared with nonvictims. Defended victims did not differ from nondefended victims in self-esteem, depressive symptoms, and severity of victimization at Time 2. Nonvictims were significantly better adjusted than defended and nondefended victims regarding these outcomes. Descriptive and popularity norms for defending did not moderate the links between being defended and victims’ adjustment and severity of victimization at Time 2. Thus, being defended only partly relieves victims’ plight, irrespective of how normative defending behaviors are in classrooms. </p

Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism

The sterol-regulatory element binding proteins (SREBP) are central transcriptional regulators of lipid metabolism. Using haploid genetic screens we identify the SREBPRegulating Gene (SPRING/C12ORF49) as a determinant of the SREBP pathway. SPRING is a glycosylated Golgi-resident membrane protein and its ablation in Hap1 cells, Hepa1-6 hepatoma cells, and primary murine hepatocytes reduces SREBP signaling. In mice, Spring deletion is embryonic lethal yet silencing of hepatic Spring expression also attenuates the SREBP response. Mechanistically, attenuated SREBP signaling in SPRING(KO) cells results from reduced SREBP cleavage-activating protein (SCAP) and its mislocalization to the Golgi irrespective of the cellular sterol status. Consistent with limited functional SCAP in SPRING(KO) cells, reintroducing SCAP restores SREBP-dependent signaling and function. Moreover, in line with the role of SREBP in tumor growth, a wide range of tumor cell lines display dependency on SPRING expression. In conclusion, we identify SPRING as a previously unrecognized modulator of SREBP signaling

Poor outcome in hypoxic endometrial carcinoma is related to vascular density

Background Identification of endometrial carcinoma (EC) patients at high risk of recurrence is lacking. In this study, the prognostic role of hypoxia and angiogenesis was investigated in EC patients. Methods Tumour slides from EC patients were stained by immunofluorescence for carbonic anhydrase IX (CAIX) as hypoxic marker and CD34 for assessment of microvessel density (MVD). CAIX expression was determined in epithelial tumour cells, with a cut-off of 1%. MVD was assessed according to the Weidner method. Correlations with disease-specific survival (DSS), disease-free survival (DFS) and distant disease-free survival (DDFS) were calculated using Kaplan–Meier curves and Cox regression analysis. Results Sixty-three (16.4%) of 385 ECs showed positive CAIX expression with high vascular density. These ECs had a reduced DSS compared to tumours with either hypoxia or high vascular density (log-rank p = 0.002). Multivariable analysis showed that hypoxic tumours with high vascular density had a reduced DSS (hazard ratio [HR] 3.71, p = 0.002), DDFS (HR 2.68, p = 0.009) and a trend for reduced DFS (HR 1.87, p = 0.054). Conclusions This study has shown that adverse outcome in hypoxic ECs is seen in the presence of high vascular density, suggesting an important role of angiogenesis in the metastatic process of hypoxic EC. Differential adjuvant treatment might be indicated for these patients.publishedVersio

Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing

Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, and flexible platform for AML diagnostics. We developed HAMLET (Human AML Expedited Transcriptomics) as bioinformatics pipeline for simultaneous detection of fusion genes, small variants, tandem duplications, and gene expression with all information assembled in an annotated, user-friendly output file. Whole transcriptome RNA sequencing was performed on 100 AML cases and HAMLET results were validated by reference assays and targeted resequencing. The data showed that HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and tandem duplications in FLT3 and KMT2A were detected by a novel algorithm based on soft-clipped reads with 100% sensitivity and 97.1% specificity. In conclusion, HAMLET has the potential to provide accurate comprehensive diagnostic information relevant for AML classification, risk assessment and targeted therapy on a single technology platform