Experiencing Poverty in an Online Simulation: Effects on Players’ Beliefs, Attitudes and Behaviors about Poverty

Digital simulations are increasingly used to educate about the causes and effects of poverty, and inspire action to alleviate it. Drawing on research about attributions of poverty, subjective well-being, and relative income, this experimental study assesses the effects of an online poverty simulation (entitled Spent) on participants’ beliefs, attitudes, and actions. Results show that, compared with a control group, Spent players donated marginally more money to a charity serving the poor and expressed higher support for policies benefitting the poor, but were less likely to take immediate political action by signing an online petition to support a higher minimum wage. Spent players also expressed greater subjective well-being than the control group, but this was not associated with increased policy support or donations. Spent players who experienced greater presence (perceived realism of the simulation) had higher levels of empathy, which contributed to attributing poverty to structural causes and support for anti-poverty policies. We draw conclusions for theory about the psychological experience of playing online poverty simulations, and for how they could be designed to stimulate charity and support for anti-poverty policies

Do Hostile Media Perceptions Constrain Minipublics? A Study of How Oregon Voters Perceive Citizens' Statements

The deliberative quality of a minipublic often depends on its ability to inform the opinions of a larger public. The Citizens’ Initiative Review (CIR) aims to do so by producing a Citizens’ Statement, which we conceptualize as a deliberative form of mass media. Like any mass media, this Statement can only influence public opinion to the extent that citizens consider it unbiased and credible. Hostile media perceptions often prevent favorable evaluations of media content, but no prior work has considered whether these perceptions could undermine the output of deliberative minipublics. To examine that possibility, we analyze online survey data on Oregon voters’ assessments of two 2014 Citizens’ Statements. Results showed that voters’ evaluations of the Statements were unaffected by hostile media perceptions. Assessments were more favorable when voters had confidence in their knowledge of the CIR’s design, process, and participants. Evaluations also were more favorable for those voters with greater faith in deliberation’s capacity to render considered judgments. We elaborate on these findings in our discussion section and consider their theoretical and practical implications for implementing minipublics and bolstering their deliberative quality

Targeted Transposition of Minicircle DNA Using Single-Chain Antibody Conjugated Cyclodextrin-Modified Poly (Propylene Imine) Nanocarriers

Among non-viral vectors, cationic polymers, such as poly(propylene imine) (PPI), play a prominent role in nucleic acid delivery. However, limitations of polycationic polymer-based DNA delivery systems are (i) insufficient target specificity, (ii) unsatisfactory transgene expression, and (iii) undesired transfer of therapeutic DNA into non-target cells. We developed single-chain antibody fragment (scFv)-directed hybrid polyplexes for targeted gene therapy of prostate stem cell antigen (PSCA)-positive tumors. Besides mono-biotinylated PSCA-specific single-chain antibodies (scFv(AM1-P-BAP)) conjugated to neutravidin, the hybrid polyplexes comprise -cyclodextrinmodified PPI as well as biotin/maltose-modified PPI as carriers for minicircle DNAs encoding for Sleeping Beauty transposase and a transposon encoding the gene of interest. The PSCA-specific hybrid polyplexes efficiently delivered a GFP gene in PSCA-positive tumor cells, whereas control hybrid polyplexes showed low gene transfer efficiency. In an experimental gene therapy approach, targeted transposition of a codon-optimized p53 into p53-deficient HCT116p53 /PSCA cells demonstrated decreased clonogenic survival when compared to mock controls. Noteworthily, p53 transposition in PTEN-deficient H4PSCA glioma cells caused nearly complete loss of clonogenic survival. These results demonstrate the feasibility of combining tumor-targeting hybrid polyplexes and Sleeping Beauty gene transposition, which, due to the modular design, can be extended to other target genes and tumor entities

Reinforcement Learning Control of Six-Phase Permanent Magnet Synchronous Machines

Control of multi-phase machines is a challenging topic due to the high number of controlled variables. Conventional control methods, such as field-oriented control (FOC), address this issue by introducing more control loops. This, however, increases the controller design complexity, while the tuning process can become cumbersome. To tackle the above, this paper proposes a deep deterministic policy gradient algorithm based controller that fulfills all the control objectives in one computational stage. More specifically, the proposed approach aims to learn a suitable current control policy for six-phase permanent magnet synchronous machines to simplify the commissioning of the drive system. In doing so, physical limitations of the drive system can be accounted for, while the compensation of imbalances between the two three-phase subsystems is rendered possible. After validating the training results in a controller-in-the-loop environment, test bench measurements are provided to demonstrate the effectiveness of the proposed controller. As shown, favorable steady-state and dynamic performance is achieved that is comparable to that of FOC. Therefore, as indicated by the presented results, reinforcement learning-based control approaches for multi-phase machines is a promising research area.Peer reviewe

Resistance of HNSCC cell models to pan-FGFR inhibition depends on the EMT phenotype associating with clinical outcome

Background: Focal adhesion signaling involving receptor tyrosine kinases (RTK) and integrins co-controls cancer cell survival and therapy resistance. However, co-dependencies between these receptors and therapeutically exploitable vulnerabilities remain largely elusive in HPV-negative head and neck squamous cell carcinoma (HNSCC). Methods: The cytotoxic and radiochemosensitizing potential of targeting 10 RTK and β1 integrin was determined in up to 20 3D matrix-grown HNSCC cell models followed by drug screening and patient-derived organoid validation. RNA sequencing and protein-based biochemical assays were performed for molecular characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts. Results: Fibroblast growth factor receptor (FGFR 1–4) targeting exhibited the strongest cytotoxic and radiosensitizing effects as monotherapy and combined with β1 integrin inhibition, exceeding the efficacy of the other RTK studied. Pharmacological pan-FGFR inhibition elicited responses ranging from cytotoxicity/radiochemosensitization to resistance/radiation protection. RNA sequence analysis revealed a mesenchymal-to-epithelial transition (MET) in sensitive cell models, whereas resistant cell models exhibited a partial epithelial-to-mesenchymal transition (EMT). Accordingly, inhibition of EMT-associated kinases such as EGFR caused reduced adaptive resistance and enhanced (radio)sensitization to FGFR inhibition cell model- and organoid-dependently. Transferring the EMT-associated transcriptomic profiles to HNSCC patient cohorts not only demonstrated their prognostic value but also provided a conclusive validation of the presence of EGFR-related vulnerabilities that can be strategically exploited for therapeutic interventions. Conclusions: This study demonstrates that pan-FGFR inhibition elicits a beneficial radiochemosensitizing and a detrimental radioprotective potential in HNSCC cell models. Adaptive EMT-associated resistance appears to be of clinical importance, and we provide effective molecular approaches to exploit this therapeutically

Myoglobin‐mediated lipid shuttling increases adrenergic activation of brown and white adipocyte metabolism and is as a marker of thermogenic adipocytes in humans

Background: Recruitment and activation of brown adipose tissue (BAT) results in increased energy expenditure (EE) via thermogenesis and represents an intriguing therapeutic approach to combat obesity and treat associated diseases. Thermogenesis requires an increased and efficient supply of energy substrates and oxygen to the BAT. The hemoprotein myoglobin (MB) is primarily expressed in heart and skeletal muscle fibres, where it facilitates oxygen storage and flux to the mitochondria during exercise. In the last years, further contributions of MB have been assigned to the scavenging of reactive oxygen species (ROS), the regulation of cellular nitric oxide (NO) levels and also lipid binding. There is a substantial expression of MB in BAT, which is induced during brown adipocyte differentiation and BAT activation. This suggests MB as a previously unrecognized player in BAT contributing to thermogenesis. Methods and results: This study analyzed the consequences of MB expression in BAT on mitochondrial function and thermogenesis in vitro and in vivo. Using MB overexpressing, knockdown or knockout adipocytes, we show that expression levels of MB control brown adipocyte mitochondrial respiratory capacity and acute response to adrenergic stimulation, signalling and lipolysis. Overexpression in white adipocytes also increases their metabolic activity. Mutation of lipid interacting residues in MB abolished these beneficial effects of MB. In vivo, whole-body MB knockout resulted in impaired thermoregulation and cold- as well as drug-induced BAT activation in mice. In humans, MB is differentially expressed in subcutaneous (SC) and visceral (VIS) adipose tissue (AT) depots, differentially regulated by the state of obesity and higher expressed in AT samples that exhibit higher thermogenic potential. Conclusions: These data demonstrate for the first time a functional relevance of MBs lipid binding properties and establish MB as an important regulatory element of thermogenic capacity in brown and likely beige adipocytes. Keywords: energy expenditure; hemoprotein; metabolism; obesity; oxphos; uncoupling protein

Meta-analysis of expression and the targeting of cell adhesion associated genes in nine cancer types – A one research lab re-evaluation

Cancer presents as a highly heterogeneous disease with partly overlapping and partly distinct (epi)genetic characteristics. These characteristics determine inherent and acquired resistance, which need to be overcome for improving patient survival. In line with the global efforts in identifying druggable resistance factors, extensive preclinical research of the Cordes lab and others designated the cancer adhesome as a critical and general therapy resistance mechanism with multiple druggable cancer targets. In our study, we addressed pancancer cell adhesion mechanisms by connecting the preclinical datasets generated in the Cordes lab with publicly available transcriptomic and patient survival data. We identified similarly changed differentially expressed genes (scDEGs) in nine cancers and their corresponding cell models relative to normal tissues. Those scDEGs interconnected with 212 molecular targets from Cordes lab datasets generated during two decades of research on adhesome and radiobiology. Intriguingly, integrative analysis of adhesion associated scDEGs, TCGA patient survival and protein-protein network reconstruction revealed a set of overexpressed genes adversely affecting overall cancer patient survival and specifically the survival in radiotherapy-treated cohorts. This pancancer gene set includes key integrins (e.g. ITGA6, ITGB1, ITGB4) and their interconnectors (e.g. SPP1, TGFBI), affirming their critical role in the cancer adhesion resistome. In summary, this meta-analysis demonstrates the importance of the adhesome in general, and integrins together with their interconnectors in particular, as potentially conserved determinants and therapeutic targets in cancer

Experiencing poverty in an online simulation: Effects on players’ beliefs, attitudes and behaviors about poverty

Digital simulations are increasingly used to educate about the causes and effects of poverty, and inspire action to alleviate it. Drawing on research about attributions of poverty, subjective well-being, and relative income, this experimental study assesses the effects of an online poverty simulation (entitled Spent) on participants’ beliefs, attitudes, and actions. Results show that, compared with a control group, Spent players donated marginally more money to a charity serving the poor and expressed higher support for policies benefitting the poor, but were less likely to take immediate political action by signing an online petition to support a higher minimum wage. Spent players also expressed greater subjective well-being than the control group, but this was not associated with increased policy support or donations. Spent players who experienced greater presence (perceived realism of the simulation) had higher levels of empathy, which contributed to attributing poverty to structural causes and support for anti-poverty policies. We draw conclusions for theory about the psychological experience of playing online poverty simulations, and for how they could be designed to stimulate charity and support for anti-poverty policies