Interpreting the Activity of Metastasis-Promoting PRL-3 Through the Total Synthesis of Phosphatidylinositol Analogues

The discovery of phosphatidylinositol-phosphates (PIPn) within cell membranes, in the early 1950’s, ignited the interest in their biological roles, and soon after scientific evidence proposed their tight association with processes involving cell signaling, cell adhesion, polarization and migration, as well as membrane trafficking and oncogenesis. PRL-3, an oncogenic phosphatase, has been recently shown to adopt phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2) as a natural substrate, through which it orchestrates several hallmarks of cancer, culminating in metastasis. Therefore, the PIPn-metabolizing enzyme PRL-3 became of great interest in biomedical research. To understand the binding mechanisms of PI(4,5)P2 with PRL-3, the development of synthetic approaches to synthesize analogues of this natural product is paramount. The goal of this work was to develop an approach to synthesize PI(4,5)P2 mimetics with alkylation(s) on the inositol ring. The newly established synthetic route was first tested with the chiral 6-O-methoxy PI(4,5)P2, after many arising synthetic challenges were overcome. The chemical literature is abundant with PI(4,5)P2 analogues bearing thiophosphate groups, different lipid tail composition, and novel functional groups, but none with direct changes to the hydroxyl groups on the inositol ring have been reported so far. Within the resulting collection of novel, inositol-modified analogues, some showed significant biological activity with PRL-3, compared to the lipid tail-modified analogues and the one containing the natural PI(4,5)P2 head group, which were also synthesized as part of this work. These active analogues were specific to PRL-3 as they did not show major activity with other PI(4,5)P2 –metabolizing enzymes. In parallel, in silico shape similarity screening methods were applied using PI(4,5)P2 as a template, to look for specific PRL-3-active small molecule inhibitors. This led to an active compound, which stresses the potential of prediction tools in finding inhibitors for challenging targets. Future applications of the synthesized PI(4,5)P2 analogues can be numerous: investigating the binding requirements of specific PIPn- metabolizing phosphatases, understanding the biology of specific PIPn, designing ligands through in silico and synthetic methods to modulate their interaction, and probing their usefulness in the treatment of diseases

Development of a novel, multifunctional, membrane-interactive pyridinium salt with potent anticancer activity

The synthesis and biological evaluation of a novel pyridinium salt is reported. Initial membrane interaction with isolated phospholipid monolayers was obtained with the pyridinium salt, and two neutral analogues for comparison, and the anticancer effects of the best compound established using a cytotoxicity screening assay against glioma cells using both an established cell line and three short-term cell cultures – one of which has been largely resistant to all chemotherapeutic drugs tested to date. The results indicate that the pyridinium salt exhibits potent anticancer activity (EC50s = 9.8-312.5 μM) on all cell types, including the resistant one, for a continuous treatment of 72 hours. Microscopic examination of the treated cells using a trypan blue exclusion assay showed membrane lysis had occurred. Therefore, this letter highlights the potential for a new class of pyridinium salt to be developed as a much needed alternative treatment for glioma chemotherapy

Post-postfeminism? New feminist visibilities in postfeminist times

This article contributes to debates about the value and utility of the notion of postfeminism for a seemingly “new” moment marked by a resurgence of interest in feminism in the media and among young women. The paper reviews current understandings of postfeminism and criticisms of the term’s failure to speak to or connect with contemporary feminism. It offers a defence of the continued importance of a critical notion of postfeminism, used as an analytical category to capture a distinctive contradictory-but-patterned sensibility intimately connected to neoliberalism. The paper raises questions about the meaning of the apparent new visibility of feminism and highlights the multiplicity of different feminisms currently circulating in mainstream media culture – which exist in tension with each other. I argue for the importance of being able to “think together” the rise of popular feminism alongside and in tandem with intensified misogyny. I further show how a postfeminist sensibility informs even those media productions that ostensibly celebrate the new feminism. Ultimately, the paper argues that claims that we have moved “beyond” postfeminism are (sadly) premature, and the notion still has much to offer feminist cultural critics

Reflectance and fluorescence characteristics of PTFE coated with TPB at visible, UV, and VUV as a function of thickness

NEXT collaboration: et al.Polytetrafluoroethylene (PTFE) is an excellent diffuse reflector widely used in light collection systems for particle physics experiments. In noble element systems, it is often coated with tetraphenyl butadiene (TPB) to allow detection of vacuum ultraviolet scintillation light. In this work this dependence is investigated for PTFE coated with TPB in air for light of wavelengths of 200 nm, 260 nm, and 450 nm. The results show that TPB-coated PTFE has a reflectance of approximately 92% for thicknesses ranging from 5 mm to 10 mm at 450 nm, with negligible variation as a function of thickness within this range. A cross-check of these results using an argon chamber supports the conclusion that the change in thickness from 5 mm to 10 mm does not affect significantly the light response at 128 nm. Our results indicate that pieces of TPB-coated PTFE thinner than the typical 10 mm can be used in particle physics detectors without compromising the light signal.The NEXT collaboration acknowledges support from the following agencies and institutions: the European Research Council (ERC) under Grant Agreement No. 951281-BOLD; the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under Grant Agreement No. 957202-HIDDEN; the MCIN/AEI of Spain and ERDF A way of making Europe under grants RTI2018-095979 and PID2021-125475NB, the Severo Ochoa Program grant CEX2018-000867-S and the Ramon y Cajal program grant RYC-2015-18820; the Generalitat Valenciana of Spain under grants PROMETEO/2021/087 and CIDEGENT/2019/049; the Department of Education of the Basque Government of Spain under the predoctoral training program of nondoctoral research personnel; the Portuguese FCT under project UID/FIS/04559/2020 to fund the activities of LIBPhys-UC; the Pazy Foundation (Israel) under grants 877040 and 877041; the U.S. Department of Energy under contracts number DE-AC02-06CH11357 (Argonne National Laboratory), DE-AC02-07CH11359 (Fermi National Accelerator Laboratory), DE-FG02-13ER42020 (Texas A&M), DE-SC0019054 (Texas Arlington) and DE-SC0019223 (Texas Arlington); the U.S. National Science Foundation under award number NSF CHE 2004111; the Robert A Welch Foundation under award number Y-2031-20200401.With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2018-000867-S).Peer reviewe

Working at the crossroads of pleasure and danger: Feminist perspectives on doing critical sexuality studies

For those entering the field of sexuality studies, there is often little advice or guidance on the many facets of the work, some of which are pleasurable and some of which are dangerous. Drawing from our personal and professional conflicts surrounding our work as feminist psychologists and sociologists studying women’s sexuality, we extend Carole Vance’s (1984) claims about pleasure and danger by arguing that, for the sex researcher, pleasure and danger are in fact inverted. That which should give us pleasure (e.g. having our work promoted to the public; teaching critical material about sexuality; thinking deeply about our personal relationships) ends up feeling dangerous, and that which should feel dangerous (e.g. saying and doing and working on taboo things; calling out homophobia, racism, classism, and sexism) ends up giving us pleasure. We examine several areas where we experience personal and professional costs and benefits of doing feminist sex research, including relationships with partners, communication with research participants, pedagogical challenges and conflicts, the interface between the sex-researcher identity and university/institutional practices, and, finally, our interface with the public world and the mass media. In doing so, we aim to use our personal experiences to highlight just a few of the areas that emerging sexuality researchers may encounter. In addition, we extend Vance’s framework of pleasure and danger beyond the experiences of women having sex and into the realm of those seeking to understand, research, write about, theorize, and assess the complicated terrain of women’s sexuality

Approaches to Study Phosphatases

Phosphatases play key roles in normal physiology and diseases. Studying phosphatases has been both essential and challenging, and the application of conventional genetic and biochemical methods has led to crucial but still limited understanding of their mechanisms, substrates, and exclusive functions within highly intricate networks. With the advances in technologies such as cellular imaging and molecular and chemical biology in terms of sensitive tools and methods, the phosphatase field has thrived in the past years and has set new insights for cell signaling studies and for therapeutic development. In this review, we give an overview of the existing interdisciplinary tools for phosphatases, give examples on how they have been applied to increase our understanding of these enzymes, and suggest how theyand other tools yet barely used in the phosphatase fieldmight be adapted to address future questions and challenges

On the Validity of the Null Current Assumption for Modeling Sorptive Reactive Transport and Electro-Diffusion in Porous Media

International audienceIn multispecies electrolyte solutions, each individual species can migrate according to its specific ionic properties. This process is called electrochemical migration or electro-diffusion and is well-described by the Nernst–Planck equation. The common approach for solving the corresponding mathematical system is based on the null current (NC) assumption, which expresses the electric potential in terms of charges and concentrations of chemical components. This assumption has a great advantage as it eliminates the electric potential from the Nernst–Planck equation. However, the NC assumption has limited capacities in describing electro-diffusion processes when the domain is subjected to an external electric field. The validity of the NC assumption could be questionable, even in the absence of an external electric field. This topic has never been investigated in the past. The main goal of this work is to evaluate the validity of the NC assumption and to understand its effect on the model outputs. Thus, we present a new reactive transport model that allows for a reliable representation of the electrochemical migration process. This model is based on the Nernst–Planck and Poisson (NPP) equations which are solved together. We also implement a model based on the NC assumption. Both models have been validated by comparison with CrunchFlow, based on several benchmarks. The results show that in the case of high sorptivity, the NC assumption is no longer valid. Therefore, in the case of sorption processes, the NPP should be used to simulate coulombic interactions

Coupled fluid flow, solute transport and dissolution processes in discrete fracture networks: An advanced Discontinuous Galerkin model

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Effect of temperature on convective-reactive transport of CO2 in geological formations

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Extra-articular Synovial Chondromatosis Eroding and Penetrating the Acromion

Synovial chondromatosis of the shoulder is an uncommon disorder. It usually affects the glenohumeral joint and is characterized by metaplasia of the synovium leading to the formation of osteochondral loose bodies. Few cases of extra-articular subacromial synovial chondromatosis involving the rotator cuff tendon have been reported in the literature. The treatment of previously reported cases consisted of open bursectomy and removal of loose bodies. We report a case of subacromial synovial chondromatosis without rotator cuff involvement but with severe erosion and fracture of the acromion. Treatment consisted of shoulder arthroscopy to remove all loose bodies, total bursectomy, and debridement of the acromion. Potential benefits of arthroscopy were also evaluated