Cascade Use and the Management of Product Lifecycles

This paper explores the challenges related to the End-Of-Life phase of products and circular systems of reuse and recycling within the commonly established frameworks of product lifecycles. Typically, Original Equipment Manufacturer-centric supply chain perspectives neglect the complexity at the End-Of-Life where many third-parties are involved in reuse and recycling activities. Based on a review of product lifecycle and related recycling literature, this study proposes the application of ‘cascades’, a term originally coined within the biomass domain. We propose and subsequently apply the ‘cascade use methodology’ and identify additional and value-adding End-Of-Life solutions for products and materials. The adoption of cascade utilization into product lifecycles is analyzed and critically discussed using case studies from independent remanufacturing and tire recycling, focusing on the End-Of-Life while excluding business models as renting or sharing. Although theoretically feasible, we argue that the practical adoption of ‘cascade use’ deserves more attention from researchers and practitioners in order to become an integral part of the comprehensive management of product lifecycles

Senescence rewires microenvironment sensing to facilitate anti-tumor immunity

Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent liver cancer model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels the cell surface proteome to alter how tumor cells sense environmental factors, as exemplified by Type II interferon (IFN-y). Compared to proliferating cells, senescent cells upregulate the IFN-y receptor, become hypersensitized to microenvironmental IFN-y, and more robustly induce the antigen presenting machinery--effects also recapitulated in human tumor cells undergoing therapy-induced senescence. Disruption of IFN-y sensing in senescent cells blunts their immune-mediated clearance without disabling the senescence state or its characteristic secretory program. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance

Cascade Use and the Management of Product Lifecycles

This paper explores the challenges related to the End-Of-Life phase of products and circular systems of reuse and recycling within the commonly established frameworks of product lifecycles. Typically, Original Equipment Manufacturer-centric supply chain perspectives neglect the complexity at the End-Of-Life where many third-parties are involved in reuse and recycling activities. Based on a review of product lifecycle and related recycling literature, this study proposes the application of ‘cascades’, a term originally coined within the biomass domain. We propose and subsequently apply the ‘cascade use methodology’ and identify additional and value-adding End-Of-Life solutions for products and materials. The adoption of cascade utilization into product lifecycles is analyzed and critically discussed using case studies from independent remanufacturing and tire recycling, focusing on the End-Of-Life while excluding business models as renting or sharing. Although theoretically feasible, we argue that the practical adoption of ‘cascade use’ deserves more attention from researchers and practitioners in order to become an integral part of the comprehensive management of product lifecycles

Bispecific PSMA-617 / RM2 Heterodimer for Theranostics Applications in Prostate Cancer

PSMA and GRPR protein receptors are upregulated during prostate cancer (PCa) progression, and thus they have both been used for diagnostic molecular imaging and therapy of the disease. To address tumor heterogeneity, we synthesized and evaluated the bispecific PSMA/GRPR ligand (3) with a 10 atom spacer between PSMA-617 (1) and the GRPR antagonist RM2 (2) generated with click chemistry and coupled with chelator DOTA, to enable radiolabelling. Ligand 3 was radiolabelled with 68Ga, [68Ga]Ga-3 and 177Lu, [177Lu]Lu-3. [68Ga]Ga-3 was tested with PCa cell lines PC-3 and LNCaP for its affinity for GRPR and PSMA receptors, lipophilicity, for its cell-binding specificity, time kinetic binding affinities and cell-internalization. Heterodimer 3 showed specific cell binding, similar affinities for PSMA receptor and GRPR and higher lipophilicity compared to monomers PSMA-617 (1) and RM2 (2), while total internalization rates and cell-binding were superior over monomers. Docking calculations showed that the PSMA-617 (1) /RM2 (2) heterodimer 3 can have binding interactions of PSMA-617 (1) inside the PSMA receptor funnel and of RM2 (2) inside the GRPR. In vivo biodistribution studies for [68Ga]Ga-3 showed dual targeting of PSMA-positive tumors and GRPR-positive tumors and fast pharmacokinetic properties, higher cancer cell-uptake and lower kidney uptake in comparison to the monomers

Expediency of photographs to study the distribution of wildcats in South-west Asia

By compiling a wildcat catalogue of georeferenced digital photographs from Southwest Asia, we investigated the plausibility of phenotypically identifying Felis silvestris caucasica (Caucasian wildcat), Felis lybica ornata (Asiatic wildcat) and Felis lybica lybica (African wildcat) through external phenotypic traits, in order to verify their known distribution, and identify any inconsistencies or gaps of knowledge. With this approach, we expect to move away from depending on wildcat distribution information being based primarily on expert opinion, and establish a more systematic approach to determine areas in need of further investigation, survey and monitoring with robust methods. We identified the Lesser Caucasus as an area containing possible hybrid individuals between these taxa. Further “ground truthing” may also be required to understand the distribution ranges of the Caucasian and Asiatic wildcats in the Caucasus and western Kazakhstan/southern Russia. We suspect their actual distributions may differ from the information currently published, with a possible range expansion in the north, as well as an overlap area in the Lesser Caucasus. The African wildcat was underrepresented in our image collection and therefore no firm conclusions could be formulated, emphasizing the need for further data. The wildcat catalogue is available as an online resource, and we emphasize the importance of such resource compilations, given the ever-increasing flood of digital imagery. We recommend the use of such tools for identifying areas in need of further “ground truthing” by means of robust genetic analyses. This plays an important role in addressing potential conservation concerns, such as the extent of hybridization between wildcat species, as well as with the domestic cat, the influence and extent of habitat loss, climate change, and species range shifts

Retrograde Analysis of Calcium Signaling by CaMPARI2 Shows Cytosolic Calcium in Chondrocytes Is Unaffected by Parabolic Flights

Calcium (Ca2+) elevation is an essential secondary messenger in many cellular processes, including disease progression and adaptation to external stimuli, e.g., gravitational load. Therefore, mapping and quantifying Ca2+ signaling with a high spatiotemporal resolution is a key challenge. However, particularly on microgravity platforms, experiment time is limited, allowing only a small number of replicates. Furthermore, experiment hardware is exposed to changes in gravity levels, causing experimental artifacts unless appropriately controlled. We introduce a new experimental setup based on the fluorescent Ca2+ reporter CaMPARI2, onboard LED arrays, and subsequent microscopic analysis on the ground. This setup allows for higher throughput and accuracy due to its retrograde nature. The excellent performance of CaMPARI2 was demonstrated with human chondrocytes during the 75th ESA parabolic flight campaign. CaMPARI2 revealed a strong Ca2+ response triggered by histamine but was not affected by the alternating gravitational load of a parabolic flight

Use of complementary and alternative medicine by children in Europe: Published data and expert perspectives

Introduction: Few data document the use of complementary and alternative medicine (CAM) in Europe, with even fewer investigating use by children

Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants

Base editing can be applied to characterize single nucleotide variants of unknown function, yet defining effective combinations of single guide RNAs (sgRNAs) and base editors remains challenging. Here, we describe modular base-editing-activity 'sensors' that link sgRNAs and cognate target sites in cis and use them to systematically measure the editing efficiency and precision of thousands of sgRNAs paired with functionally distinct base editors. By quantifying sensor editing across >200,000 editor-sgRNA combinations, we provide a comprehensive resource of sgRNAs for introducing and interrogating cancer-associated single nucleotide variants in multiple model systems. We demonstrate that sensor-validated tools streamline production of in vivo cancer models and that integrating sensor modules in pooled sgRNA libraries can aid interpretation of high-throughput base editing screens. Using this approach, we identify several previously uncharacterized mutant TP53 alleles as drivers of cancer cell proliferation and in vivo tumor development. We anticipate that the framework described here will facilitate the functional interrogation of cancer variants in cell and animal models