Treating a viral disease is no simple feat. Drug resistance, latent reservoirs in the body, emerging novel viruses, and a frequent lack of specific treatments all complicate antiviral therapy. For ...decades, antiviral polymers have been studied for a range of infectious diseases. The field has emerged, expanded, and adapted over the past 70 years, producing unique classes of materials that hold promise for overcoming these obstacles. Antiviral polymers can directly inhibit viral replication and infection, usually by binding to the virus and preventing it from invading a host cell. They can also serve as microbicides or antiviral drug-delivery vehicles. This Perspective outlines the significant advances and challenges in the field. We discuss polymers with activity against viruses with limited treatment options (hepatitis C), ubiquitous presence (influenza, norovirus), or long-term complications (HIV). We also explore insights into different mechanisms of action, and we offer ideas on how the field of antiviral polymers might advance in the future.
Tau protein is a key target of interest in developing therapeutics for neurodegenerative diseases. Here, we sought to develop a method that quantifies extracellular tau protein concentrations in ...human cerebrospinal fluid (CSF) without antibody-based enrichment strategies. We demonstrate that the fit-for-purpose validated method in Alzheimer's Disease CSF is limited to quasi quantitative measures of tau surrogate peptides. We also provide evidence that CSF total Tau measures by LC-MS are feasible in the presence of monoclonal therapeutic antibodies in human CSF. Our Tau LC-MS/MS method is a translational bioanalytical tool for assaying target engagement and pharmacodynamics for anti-tau antibody drug development campaigns.
ADMET: The Future Revealed Atallah, Pascale; Wagener, Kenneth B; Schulz, Michael D
Macromolecules,
06/2013, Volume:
46, Issue:
12
Journal Article
Peer reviewed
Olefin metathesis has been embraced by polymer chemists as a method for creating well-defined polymers. In particular, ADMET and ROMP have emerged as the primary modes of metathesis polymerization. ...ADMET reactions are now common, found in textbooks, and easy to perform if the proper techniques are chosen. Much remains to be done, however, with work now focusing on silicon chemistry, direct control of tacticity in precision polymers, biological applications, modeling crystal lattices in common polyolefins, exploring solid-state metathesis reactions, and creating water-soluble ADMET polymers.
Acyclic diene metathesis (ADMET) polymerization is a unique strategy for achieving polymers with precise control over the primary structure. This precision is obtained by specific monomer design and ...carefully controlled polymerization conditions. Over time, this approach has produced an array of sophisticated architectures ranging from precise polyethylenes, to hyperbranched polymers, to rotaxanes.
Acyclic diene metathesis (ADMET) polymerization is a powerful tool for creating precision polymers. This review summarizes the use of ADMET polymerization to synthesize precision polyethylene model compounds and various advanced polymer structures.
3D printing by fused deposition modelling (FDM) enables rapid prototyping and fabrication of parts with complex geometries. Unfortunately, most materials suitable for FDM 3D printing are ...non-degradable, petroleum-based polymers. The current ecological crisis caused by plastic waste has produced great interest in biodegradable materials for many applications, including 3D printing. Poly(lactic acid) (PLA), in particular, has been extensively investigated for FDM applications. However, most biodegradable polymers, including PLA, have insufficient mechanical properties for many applications. One approach to overcoming this challenge is to introduce additives that enhance the mechanical properties of PLA while maintaining FDM 3D printability. This review focuses on PLA-based nanocomposites with cellulose, metal-based nanoparticles, continuous fibers, carbon-based nanoparticles, or other additives. These additives impact both the physical properties and printability of the resulting nanocomposites. We also detail the optimal conditions for using these materials in FDM 3D printing. These approaches demonstrate the promise of developing nanocomposites that are both biodegradable and mechanically robust.
Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and therapeutic response. In the era ...of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ. It has long been regarded as an immunological sanctuary site where the presence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB) restricts the entry of immune cells from the periphery. Consequently, tumor cells that metastasize to the brain were thought to be shielded from systemic immune surveillance and destruction. However, the detailed characterization of the immune landscape within border-associated areas of the central nervous system (CNS), such as the meninges and the choroid plexus, as well as the discovery of lymphatics and channels that connect the CNS with the periphery, have recently challenged the dogma of the immune privileged status of the brain. Moreover, the presence of brain metastases (BrM) disrupts the integrity of the BBB and BCB. Indeed, BrM induce the recruitment of different immune cells from the myeloid and lymphoid lineage to the CNS. Blood-borne immune cells together with brain-resident cell-types, such as astrocytes, microglia, and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting steps of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM.
The Copernicus Atmosphere Monitoring Service (CAMS)
reanalysis is the latest global reanalysis dataset of atmospheric
composition produced by the European Centre for Medium-Range Weather
Forecasts ...(ECMWF), consisting of three-dimensional time-consistent atmospheric
composition fields, including aerosols and chemical species. The dataset
currently covers the period 2003–2016 and will be extended in the future by
adding 1 year each year. A reanalysis for greenhouse gases is being
produced separately. The CAMS reanalysis builds on the experience gained
during the production of the earlier Monitoring Atmospheric Composition and
Climate (MACC) reanalysis and CAMS interim reanalysis. Satellite retrievals
of total column CO; tropospheric column NO2; aerosol optical depth (AOD); and
total column, partial column and profile ozone retrievals were assimilated
for the CAMS reanalysis with ECMWF's Integrated Forecasting System. The new
reanalysis has an increased horizontal resolution of about 80 km and
provides more chemical species at a better temporal resolution (3-hourly
analysis fields, 3-hourly forecast fields and hourly surface forecast
fields) than the previously produced CAMS interim reanalysis. The CAMS
reanalysis has smaller biases compared with most of the independent ozone,
carbon monoxide, nitrogen dioxide and aerosol optical depth observations
used for validation in this paper than the previous two reanalyses and is
much improved and more consistent in time, especially compared to the MACC
reanalysis. The CAMS reanalysis is a dataset that can be used to compute
climatologies, study trends, evaluate models, benchmark other reanalyses or
serve as boundary conditions for regional models for past periods.
Macrophages not only represent an integral part of innate immunity but also critically contribute to tissue and organ homeostasis. Moreover, disease progression is accompanied by macrophage ...accumulation in many cancer types and is often associated with poor prognosis and therapy resistance. Given their critical role in modulating tumor immunity in primary and metastatic brain cancers, macrophages are emerging as promising therapeutic targets. Different types of macrophages infiltrate brain cancers, including (i) CNS resident macrophages that comprise microglia (TAM-MG) as well as border-associated macrophages and (ii) monocyte-derived macrophages (TAM-MDM) that are recruited from the periphery. Controversy remained about their disease-associated functions since classical approaches did not reliably distinguish between macrophage subpopulations. Recent conceptual and technological advances, such as large-scale omic approaches, provided new insight into molecular profiles of TAMs based on their cellular origin. In this review, we summarize insight from recent studies highlighting similarities and differences of TAM-MG and TAM-MDM at the molecular level. We will focus on data obtained from RNA sequencing and mass cytometry approaches. Together, this knowledge significantly contributes to our understanding of transcriptional and translational programs that define disease-associated TAM functions. Cross-species meta-analyses will further help to evaluate the translational significance of preclinical findings as part of the effort to identify candidates for macrophage-targeted therapy against brain metastasis.
The importance of software based on machine learning is growing rapidly, but the potential of prototypes may not be realized in operation. This study identified six categories of challenges for ...verification and validation of machine learning applications during production. Subsequently, monitoring was analyzed as a possible solution to mitigate those challenges. Capturing relevant data and model metrics may reveal problems at an early stage, allowing for targeted countermeasures. This study presents a taxonomy of methods and metrics currently addressed in scientific literature and compares these categories with case studies from practice.
Resumo Este artigo mostra como, embasado em princípios epistemológicos partilhados, Greimas e Geninasca situaram suas pesquisas a níveis de pertinência diferentes e alimentaram dois projetos ...semióticos distintos, um voltado para a “língua”, outro para a “fala”. Greimas coloca a coerência e a inteligibilidade dos discursos sob a dependência de uma – e de somente uma – estrutura da significação, ao mesmo tempo elementar e universal. Essa estrutura, da qual o quadrado semiótico é o modelo, seria anterior e independente da atividade enunciativa. Na economia global da teoria semiótica de Greimas ela faz parte das estruturas profundas, situadas na “língua”. Geninasca, por seu lado, procura analisar as estratégias de coerência que permitem instaurar os textos em “discursos”, isto é, em objetos semióticos. Fazendo isso, ele coloca a emergência da significação no final de uma atividade atribuível à instância enunciativa. Ao privilegiar o nível discursivo, ele define a semiótica como uma teoria das “condições para a instauração dos discursos”, o que equivale a orientá-la para a “fala” e abre um conjunto de questões novas. A teoria semiótica se define desde então em relação a um novo conjunto de questões. Em particular, ao problema das conversões entre os níveis de profundidade previstos pelo percurso gerativo da significação de Greimas, Geninasca substitui a questão da integração de uma pluralidade de linguagens, de apreensões do sentido e de racionalidades.
Abstract This article concentrates on demonstrating how Greimas and Geninasca, while sharing the same epistemological principles, have positioned their respective research at different levels and pioneered two distinct semiotic projects, one orientated towards the langue, the other towards the parole, as defined by F. de Saussure. For Greimas indeed, the coherence and intelligibility of texts depends on one – and only one – elementary and universal structure of signification. This structure, the model of which is the semiotic square, is supposed to be prior to, and independent of any enunciative activity. Within the general framework of Greimas’ semiotic theory, it lies in the deep structures, located in the langue. Geninasca’s approach is different. He aims at conceptualising different strategies of coherence allowing to construct texts as ‘discourses’, that is, as semiotic objects. In doing so, he approaches the emergence of signification as the result of an activity attributable to a subject of enunciation. Favouring the surface structures, he assigns the semiotic theory the task to describe the “prerequisites for building discourses”, which is a way to focus on what Saussure calls parole. In this light, the semiotic theory concentrates on a different series of questions. Rather than tackling the problem of the conversion between different levels of depth, constitutive of Greimas’ generative path of signification, it addresses the question of the integration, by a subject of enunciation, of multiple languages, rationalities and ways of creating sense and meaning.
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