The role of FAM134B for intracellular organelle architecture and axon function

Inhalt: Degeneration of sensory fibres is characteristic for hereditary sensory and autonomic neuropathies (HSANs). Affected patients share typical symptoms featured by a diminished sensation of temperature, touch and pain. However, the spectrum of disease-associated genes in patients is broad and frequently remains unclear. A previous study had shown that homozygous loss-of-function mutations of FAM134B are causative for severe HSAN classified as type 2B (HSAN2B). Within this thesis the pathophysiology of HSAN2B was addressed by analyzing transgenic Fam134b-knockout mice with biochemical approaches and cell culture assays. It was aimed to resolve the Fam134b protein localization, its topology, possible interaction partners and function. Fam134b-knockout mice manifested a progressive sensory neuropathy. Detailed analysis of sensory ganglion tissue sections of aged animals revealed ultrastructural alterations of the endoplasmic reticulum (ER) and Golgi cisternae by electron microscopy. Co immunoprecipitation studies demonstrated binding of FAM134B to autophagy-related ubiquitin-like proteins - also known as LC3-like modifiers or Atg8s. These interactions were mediated by the LC3-interacting region (LIR) that is conserved among members of the FAM134 protein family. Moreover, experiments addressing the topology of FAM134B showed that the C-terminally located LIR of FAM134B faces towards the cytoplasm and thus is accessible to various cytosolic proteins such as LC3. Overexpression studies in cell culture systems revealed FAM134B-mediated delivery of ER fragments into autophagosomal compartments, which was dependent on its functional LIR domain. Further, endogenous Fam134b protein expression was decreased under conditions of starvation. In conclusion, the data suggest that FAM134B serves as an ER-specific autophagy receptor. Hence, FAM134B may regulate ER turnover and maintain long-term homeostasis and survival especially of long-projecting sensory neurons

Long-term Sequential and Temporal Dynamics in Online Consumer Ratings

Online consumer ratings provide important feedback for businesses and yield essential purchase information for consumers. Extant literature has recognized the importance of sequential and temporal dynamics of consumer ratings, but has shed light upon short-term dynamics (e.g., an initial decreasing rating trend) and lacks analyses of long-term dynamics. Existing findings thus cannot explain these long-term dynamics, which are particularly important as many items receive ratings over the long term. In this paper, we therefore examine long-term sequential and temporal dynamics in consumer ratings and in particular whether initial rating dynamics influence average ratings in the long-term. To do so, we apply regression models to an extensive long-term review dataset. First, we find and explain a new long-term sequentially increasing rating trend which leads to a U-shaped relationship between ratings and their order. Second, we reveal that strong initial rating dynamics have significant negative impact on long-term average ratings

Alkaline phosphatase in metastatic castration-resistant prostate cancer: reassessment of an older biomarker

Since most patients with metastatic castration-resistant prostate cancer (mCRPC) have bone metastases, it is important to understand the potential impact of therapies on prognostic biomarkers, such as ALP. Clinical studies involving mCRPC life-prolonging agents (i.e., sipuleucel-T, abiraterone, enzalutamide, docetaxel, cabazitaxel, and radium-223) have shown that baseline ALP level is prognostic for overall survival, and may be a better prognostic marker for overall survival than prostate-specific antigen in patients with bone-dominant mCRPC. Mechanism of action differences between therapies may partly explain ALP dynamics during treatment. ALP changes can be interpreted within the context of other parameters while monitoring disease activity to better understand the underlying pathology. This review evaluates the current role of ALP in mCRPC

State-of-play in international carbon markets in 2024

This policy brief, written in May 2024, provides an overview of the international carbon market landscape and describes the status quo in terms of the degree of its integration and the use of the mechanisms set out in Article 6 of the Paris Agreement. It assesses the linkability of existing emissions trading systems (ETSs) and discusses the emerging topics of sector expansion and the role of removals in compliance markets

Enhanced expression of the stemness-related factors OCT4, SOX15 and TWIST1 in ectopic endometrium of endometriosis patients

Abstract Background Current evidence suggests that endometrial-derived stem cells, spilled in the peritoneal cavity via retrograde menstruation, are key players in the establishment of endometriotic lesions. The aim of this study was to determine the presence and distribution of the stemness-related factors OCT4, SOX15, TWIST1 and DCAMLK1 in women with and without endometriosis. Methods Immunohistochemical analysis was used to determine stromal and epithelial expression of OCT4, SOX15, TWIST1 and DCAMLK1 in endometriosis patient (EP) endometrium (n = 69) and endometriotic tissue (n = 90) and in control endometrium (n = 50). Quantitative Real-Time PCR of OCT4, SOX15 TWIST1 and DCAMLK1 was performed in paired samples of EP endometrium and endometriotic tissue. Co-immunofluorescence staining was performed for OCT4 and SOX15. For statistical analyses we used unpaired t-test, Fisher combination test and Spearman test. For paired analyses, paired t-test and McNemar test were used. Results We detected a significant correlation between the expression of the established stem cell marker OCT4 and the stemness-related markers SOX15 (p < 0.001) and TWIST1 (p = 0.002) but not DCAMLK1. We showed a colocalization of SOX15 and OCT4 in epithelial and stromal cells of endometriotic tissue by coimmunofluorescence. A concordant expression of OCT4 and SOX15 in the same sample was observed in epithelial cells of the endometriotic tissue (71.7%). The expression of stemness-related factors was not associated with proliferative or secretory phase of the menstrual cycle in endometriosis patients but was found to be differentially expressed during the menstrual cycle in the control group. Increased expression of epithelial OCT4, SOX15 and TWIST1 was detected in endometriotic tissue compared to EP endometrium in paired (p = 0.021, p < 0.001 and p < 0.001) and unpaired analysis (p = 0.040, p < 0.001 and p = 0.001). Conclusion Our findings support the hypothesis that upregulation of stem cell-related factors contribute to the establishment of endometriotic lesions. Trial registration The study was approved by the institutional review board (545/2010 on 6th of May 2014) of the Medical University of Vienna ( http://ethikkommission.meduniwien.ac.at/fileadmin/ethik/media/dokumente/register/alle_2010.pdf )

State-of-play in international carbon markets in 2023

- This policy brief gives an overview of existing carbon pricing mechanisms and outlines the trends of mandatory and voluntary carbon markets (VCMs) in 2023. It also reviews the integration of carbon markets. - As of April 2023, 73 carbon taxes and emissions trading systems (ETSs) were in operation, covering approximately 23% of global GHG emissions. - 28 of these compliance carbon pricing instruments were ETSs at regional, national or subnational levels and covered about 17% of global GHG emissions. The number of ETSs in force will likely rise in the coming years as 8 systems are currently under development and 11 are under consideration. - After growing rapidly in 2020 and 2021, the issuance of offset credits declined slightly in 2022. Several factors contributed to this decline, including the challenging macroeconomic conditions, public skepticism about the quality of credits, and the absence of commonly accepted guidance on best-practice for the use of credits to support net-zero claims. - Linked ETSs include: the EU and Swiss ETSs since 2020, the California and Québec Cap-and-Trade Programs since 2014, an evolving set of US states participating in the Regional Greenhouse Gas Initiative (RGGI) since 2009, and the Tokyo Cap-and-Trade Program and the Saitama ETS since 2011. - Progress on the integration of compliance carbon markets via linking has not been rapid. Each system is tailored to its domestic circumstances which makes the required level of alignment for successful links difficult to achieve. Moreover, the potential increase in regulatory uncertainty and the expected negative impacts on the robustness of each system act as strong barriers to linking. - Connecting ETSs with VCMs should be treated with great caution due to concerns about credit quality as well as monitoring, reporting and verification issues connected with offsets

Heterologous expression of plasmodial proteins for structural studies and functional annotation

Malaria remains the world's most devastating tropical infectious disease with as many as 40% of the world population living in risk areas. The widespread resistance of Plasmodium parasites to the cost-effective chloroquine and antifolates has forced the introduction of more costly drug combinations, such as Coartem®. In the absence of a vaccine in the foreseeable future, one strategy to address the growing malaria problem is to identify and characterize new and durable antimalarial drug targets, the majority of which are parasite proteins. Biochemical and structure-activity analysis of these proteins is ultimately essential in the characterization of such targets but requires large amounts of functional protein. Even though heterologous protein production has now become a relatively routine endeavour for most proteins of diverse origins, the functional expression of soluble plasmodial proteins is highly problematic and slows the progress of antimalarial drug target discovery. Here the status quo of heterologous production of plasmodial proteins is presented, constraints are highlighted and alternative strategies and hosts for functional expression and annotation of plasmodial proteins are reviewed

Impacts and evolution of emissions trading systems : insights from research and regulation

As part of the LIFE COASE project, the first Net Zero Carbon Market Policy Dialogue (NZCMPD) was held in September 2023 to discuss the latest developments and challenges faced by carbon market regulators across the world. This event focused on competitiveness effects, carbon leakage, distributional effects, and social implications of emissions trading systems (ETSs) and brought together researchers, regulators and stakeholders. To inform the debate, a background report was shared with the participants ahead of the event. The present document synthesises both the background report and key points which emerged from the Policy Dialogue. The first chapter gives an overview of existing carbon pricing mechanisms and outlines the trends of carbon markets in 2023. The second chapter compares ex-ante permit trading models, and the third chapter summarises insights gained from assessing the ex-post impacts of emissions trading. The NZCMPD highlighted the challenges currently faced by experts assessing permit markets and the potential research gaps that still need to be addressed

The Lantern Vol. 47, No. 2, May 1981

• Festival • Ode to Old Tom • Living Room • Writing a Poem • Mission Impossible • The Hinge is Oiled • The Potter\u27s Field at Malvern • Points of Time • Attempted Autonomy • My Love • Love, not War • Death Comes Quickly • You Can\u27t Always Get What You Don\u27t Really Want • You See (Johnny\u27s Tale): An Elegy • Sanguine Hopeshttps://digitalcommons.ursinus.edu/lantern/1118/thumbnail.jp