Contribution of cyclin G2 to the cell cycle inhibitory effects of cancer therapeutics

Zimmermann M. Contribution of cyclin G2 to the cell cycle inhibitory effects of cancer therapeutics. Bielefeld: Universitätsbibliothek Bielefeld; 2012.Cancers develop as the result of uncontrolled proliferation, growth and metastasis of aberrantly differentiated cells. CycG2 is an unconventional cyclin homolog linked to inhibition of cellular proliferation and promotion of cell differentiation. Expression of the CycG2 gene, CCNG2, is repressed in variety of human cancers. Reduced CCNG2 transcript levels are found in more aggressive, poor-prognosis breast cancer (BC) subtypes, compared to normally differentiated breast tissues, and are elevated in tumor cells responding to cancer therapies. This thesis addresses the question of CycG2’s contribution to the cell cycle inhibitory responses of tumor cells to chemotherapeutics and growth inhibitory drugs; namely, DNA damaging topoisomerase II poisons, estrogen signaling inhibitors, mTOR signaling inhibitors and drugs that induce endoplasmic reticulum stress (ERS). Evaluation of previous findings suggested that CycG2 could be a DNA damage response (DDR) protein that participates in DNA damage checkpoint regulation. This thesis further defines the involvement of CycG2 in the DDR signaling pathway. Ectopic expression of CycG2 promotes phosphorylation of the DDR checkpoint kinase Chk2 on an activational target site. Furthermore, induction of DNA double strand breaks (DSBs) through treatment with the chemotherapeutic doxorubicin (Dox) induces CycG2 expression that correlates with the induced cell cycle arrest and the activation of DDR proteins. Transient and stable shRNA mediated knockdown (KD) of CycG2 attenuates the G2/M checkpoint arrest response of multiple cell lines caused by the Dox-induced DNA damage. Furthermore, KD of CycG2 blunts the DDR-triggered reduction in Cdc25B levels, inhibitory-phosphorylation of Cdc2 and accumulation of CycB1, which are important processes for a potent G2/M checkpoint arrest. Thus, CycG2 may participate in the enforcement and maintenance of G2/M checkpoints by limiting the Cdc25B-mediated promotion of CycB1/Cdc2 activity. The role CycG2 plays in the anti-proliferative responses of BC cells to estrogen (E2)-signaling deprivation was analyzed in a second study. CycG2 expression is elevated in E2-deprived cells, but reduced in E2-stimulated cells. CycG2 KD diminishes the cell cycle arrest response following inhibition of E2 signaling. In addition, these clones showed elevated levels of the growth promoting cyclin, CycD1,and elevated activation of the growth factor signaling cascade, mitogen activated protein kinase (MAPK), pathway. These results indicate that loss of CycG2 expression may promote the development of BC tumor cell resistance to E2 antagonizing therapeutics by stimulating the activation of the MAPK pathway. Importantly, results presented here show that CycG2 can associate with the cyclin dependent kinase (CDK) 10, which was recently implicated as an upstream repressor of MAPK signaling. Thus suggesting that the resistance of BC cells to the inhibition of E2 signaling that is acquired following CycG2 KD could result from loss of CycG2-mediated stimulation of CDK10 activity. CycG2 expression is upregulated following inhibition of the growth promoting kinase mTOR and the induction of ERS. KD of CycG2 expression in multiple cell lines induces CycD1 expression and attenuates cell cycle arrest responses to treatments with rapamycin, metformin and thapsigargin. These results suggest that CycG2 expression restricts proliferation of cells responding to mTOR inhibition (rapamycin and metformin) and ERS-induction (thapsigargin). The data further indicate that rapamycin-induced CycG2 expression is not dependent on FOXO TF expression. In contrast, the potent upregulation of CycG2 expression triggered by thapsigargin is likely the consequence of the FOXO TF activity at the CCNG2 promoter

Reorientation mechanisms of block copolymer/CdSe quantum dot composites under application of an electric field

Time- and temperature-resolved in situ birefringence measurements were applied to analyze the effect of nanoparticles on the electric field-induced alignment of a microphase separated solution of poly(styrene)-block-poly(isoprene) in toluene. Through the incorporation of isoprene-confined CdSe quantum dots the reorientation behavior is altered. Particle loading lowers the order–disorder transition temperature, and increases the defect density, favoring nucleation and growth as an alignment mechanism over rotation of grains. The temperature dependent alteration in the reorientation mechanism is analyzed via a combination of birefringence and synchrotron SAXS. The detailed understanding of the effect of nanoparticles on the reorientation mechanism is an important prerequisite for optimization of electric-field-induced alignment of block copolymer/nanoparticle composites where the block copolymer guides the nanoparticle self-assembly into anisotropic structures

Evaluation of two rapid commercial assays for detection of Streptococcus agalactiae from vaginal samples

IntroductionStreptococcus agalactiae, also known as group B streptococci (GBS), is associated with invasive infections in neonates. Identification of GBS vaginal colonization in pregnant women before delivery is essential for treatment with antibiotics to prevent intrapartum vertical transmission to the newborn. This study was designed to evaluate applicability of two rapid real‐time PCRs in comparison to standard culture identification.Material and methodsWe compared the Xpert GBS assay, hereafter referred to as Xpert, and GenomEra GBS PCR, hereafter referred to as GenomEra. The standard culture identification consisted of two different agar plates as well as an enrichment broth.ResultsWe analyzed vaginal samples of 260 pregnant women; 42 samples were tested GBS‐positive by using standard culture as a gold standard, 30 by Xpert, and 37 by GenomEra. Xpert and GenomEra assays performed with sensitivities of 71.4% and 88.1% as well as specificities of 98.6% and 99.1%, respectively. Twelve vaginal samples were false‐negative by Xpert and five samples by GenomEra. Interestingly, three negative Xpert results of standard culture‐positive samples exhibited high Ct‐values indicating the presence of GBS. If higher Ct‐values are taken into consideration, the sensitivity of Xpert increases up to 78.6%. Moreover, only three Xpert PCRs had to be repeated, whereas two Genomera were invalid even after repetition and further 15 GenomEra PCRs were repeated because of borderline results or inhibition of the PCR test.ConclusionsIn this study, GenomEra assay performed with a higher sensitivity than the Xpert PCR. On the other hand, the Xpert assay needs less hands‐on‐time for a sample preparation and requires approximately four‐fold less repetitions as compared to the GenomEra assay. This robust performance of the Xpert assay make it applicable as a rapid intrapartum point‐of‐care test, although a higher sensitivity would be desirable. Therefore, culture in the 35–37 week of gestation remains the gold standard to detect vaginal colonization

Scavenging patterns of an inbred wolf population in a landscape with a pulse of human-provided carrion

Scavenging is an important part of food acquisition for many carnivore species that switch between scavenging and predation. In landscapes with anthropogenic impact, humans provide food that scavenging species can utilize. We quantified the magnitude of killing versus scavenging by gray wolves (Canis lupus) in Scandinavia where humans impact the ecosystem through hunter harvest, land use practices, and infrastructure. We investigated the cause of death of different animals utilized by wolves, and examined how the proportion of their consumption time spent scavenging was influenced by season, wolf social affiliation, level of inbreeding, density of moose (Alces alces) as their main prey, density of brown bear (Ursus arctos) as an intraguild competitor, and human density. We used data from 39 GPS-collared wolves covering 3198 study days (2001–2019),including 14,205 feeding locations within space–time clusters, and 1362 carcasses utilized by wolves. Most carcasses were wolf-killed (80.5%) while a small part had died from other natural causes (1.9%). The remaining had either anthropogenic mortality causes (4.7%), or the cause of death was unknown (12.9%). Time spent scavenging was higher during winter than during summer and autumn. Solitary wolves spent more time scavenging than pack-living individuals, likely because individual hunting success is lower than pack success. Scavenging time increased with the mean inbreeding coefficient of the adult wolves, possibly indicating that more inbred individuals resort to scavenging, which requires less body strength. There was weak evidence for competition between wolves and brown bears as well as a positive relationship between human density and time spent scavenging. This study shows how both intrinsic and extrinsic factors drive wolf scavenging behavior, and that despite a high level of inbreeding and access to carrion of anthropogenic origin, wolves mainly utilized their own kills. Canis lupus, consumption time, human density, inbreeding, intraguild competition, prey density, social affiliationpublishedVersio

Toward high-efficiency hybrid (electricity and heat) high concentration photovoltaic systems

Paper presented to the 3rd Southern African Solar Energy Conference, South Africa, 11-13 May, 2015.Photovoltaic power generation is a growing renewable primary energy source, expected to assume a major role as we strive toward fossil fuel free energy production. However, the rather low photovoltaic efficiencies limit the conversion of solar radiation into useful power output. Hybrid systems extend the functionality of concentrating photovoltaics (CPV) from simply generating electricity, to providing simultaneously electricity and heat. The utilization of otherwise wasted heat significantly enhances the overall system efficiency and boosts the economic value of the generated power output. The system presented in this lecture is the outcome of collaborative research in my research group, with the IBM research lab in Zurich and the Fraunhofer Institute for solar energy systems in Freiburg, Germany. It consists of a scalable hybrid photovoltaic-thermal receiver package, cooled with an integrated high performance microchannel heat sink we initially developed and optimized for the efficient cooling of electronics. The package can be operated at elevated temperatures due to its overall low thermal resistance between solar cell and coolant. The effect of the harvested elevated coolant temperature on the photovoltaic efficiency is investigated. The higher-level available heat can be suitable for sophisticated thermal applications such as space heating, desalination or cooling (polygeneration approaches). A total hybrid conversion efficiency of solar radiation into useful power of 60% has been realized. The exergy content of the overall output power was increased by 50% through the exergy content of the extracted heat.dc201

Longitudinal Experience-Wide Association Studies-A Framework for Studying Personality Change

The importance of personality for predicting life outcomes in the domains of love, work, and health is well established, as is evidence that personality traits, while relatively stable, can change. However, little is known about the sources and processes that drive changes in personality traits and how such changes might impact important life outcomes. In this paper, we make the case that the research paradigms and methodological approaches commonly used in personality psychology need to be revised to advance our understanding of the sources and processes of personality change. We proposeLongitudinal Experience-Wide Association Studiesas a framework for studying personality change that can address the limitations of current methods, and we discuss strategies for overcoming some of the challenges associated withLongitudinal Experience-Wide Association Studies.Peer reviewe

Why stop at two opinions? Reply to McCrae (2020)

McCrae (2020) argues that it is premature to explore interventions focused on personality change. In his commentary, he suggests that interventions should be promoted only if their effects in self-report data are confirmed by the additional opinion of informants. We agree with the essence of his position and would go further by envisioning a new framework for rigorous collaborative research on personality change (Bleidorn et al., 2020). We nevertheless maintain that policymakers would benefit from considering the additional opinion of personality scientists. (PsycInfo Database Record (c) 2020 APA, all rights reserved)

Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load

Objective A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion. Design By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses. Results HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression. Conclusions Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure