MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade

About 15–20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.

EVALI Vaping Liquids Part 1: GC-MS Cannabinoids Profiles and Identification of Unnatural THC Isomers

Tetrahydrocannabinol (THC)-containing products played a major role in the 2019 US nationwide outbreak of pulmonary lung illness associated with e-cigarettes or vaping liquids (EVALI). Due to the severity of the illness which resulted in 68 deaths, a comprehensive identification of the components in the vaping liquids was required. Our laboratory received over 1000 vaping liquid products for analysis including hundreds of vaping products from EVALI patients. In this work, we present the results for the GC-MS identification of the cannabinoids from a large subset of ca. 300 Cannabis-based vaping liquids, with emphasis on the identification of a series of unnatural THC isomers. GC-MS analysis was conducted using a validated, published method in which the cannabinoids were identified as the trimethylsilyl derivatives after separation on a commercial 35% silphenylene phase. Δ9- Tetrahydrocannabinol is the naturally occurring THC isomer found in the Cannabis plant, and was found in the majority of the vaping liquids. However, we also identified the presence of one or more additional THC isomers in many of the vaping liquids including Δ8-tetrahydrocannabinol, Δ6a,10a–tetrahydrocannabinol, Δ10-tetrahydrocannabinol, and exo-tetrahydrocannabinol. Significant or major amounts of unnatural THC isomers were found in over 10% of the THC vaping liquids, with lesser amounts found in another 60% of the vaping liquids. Exposure of the Cannabis source materials (such as marijuana concentrates or converted hemp materials) to chemical and thermal treatments during manufacturing, is proposed as the primary cause for the THC isomerizations.

Ties That Bind

Many assume that atheists and atheist scientists rarely interact with religious individuals. Yet, a large subset of atheist scientists—29 percent in the U.S. and 21 percent in the U.K.—have sustained patterns of interaction with religious individuals and organizations, making them the most unlike the New Atheists. This group includes scientists raised within religious traditions such as Judaism, Catholicism, and Islam who now belong without believing, an orientation that often involves secular participation in religious services and practices. Others participate in services or send their children to religious schools as a way to cultivate cultural capital and social standing. Another dimension of culturally religious atheism involves partnering with or marrying someone who is religious.

Understudied G Protein-Coupled Receptors in the Kidney

G protein-coupled receptors (GPCRs) are cell surface proteins which play a key role in allowing cells, tissues, and organs to respond to changes in the external environment in order to maintain homeostasis. Despite the fact that GPCRs are known to play key roles in a variety of tissues, there are a large subset of GPCRs that remain poorly studied. In this minireview, we will summarize what is known regarding the “understudied” GPCRs with respect to renal function, and in so doing will highlight the promise represented by studying this gene family.

Clinical Trials of COVID-19 Therapies Should Account for Diabetes and Hyperglycemia

Complications of Coronavirus Disease 2019 (COVID-19) occur with increased frequency in people admitted to the hospital with diabetes or hyperglycemia. The increased risk for COVID-19 infections in the presence of these metabolic conditions is in part due to overlapping pathophysiologic features of COVID-19, diabetes, and glucose control. Various antiviral treatments are being tested in COVID-19 patients. We believe that in these trials, it will be useful to evaluate treatment effect differences in patients stratified according to whether they have diabetes or hyperglycemia. In this way, it will be possible to better facilitate development of antiviral treatments that are most specifically beneficial for the large subset of COVID-19 patients who have diabetes or hyperglycemia.

Lolisa: Formal Syntax and Semantics for a Subset of the Solidity Programming Language in Mathematical Tool Coq

The security of blockchain smart contracts is one of the most emerging issues of the greatest interest for researchers. This article presents an intermediate specification language for the formal verification of Ethereum-based smart contract in Coq, denoted as Lolisa. The formal syntax and semantics of Lolisa contain a large subset of the Solidity programming language developed for the Ethereum blockchain platform. To enhance type safety, the formal syntax of Lolisa adopts a stronger static type system than Solidity. In addition, Lolisa includes a large subset of Solidity syntax components as well as general-purpose programming language features. Therefore, Solidity programs can be directly translated into Lolisa with line-by-line correspondence. Lolisa is inherently generalizable and can be extended to express other programming languages. Finally, the syntax and semantics of Lolisa have been encapsulated as an interpreter in mathematical tool Coq. Hence, smart contracts written in Lolisa can be symbolically executed and verified in Coq.

Systematics of type IIA moduli stabilisation

We analyse the flux-induced scalar potential for type IIA orientifolds in the presence of p-form, geometric and non-geometric fluxes. Just like in the Calabi-Yau case, the potential presents a bilinear structure, with a factorised dependence on axions and saxions. This feature allows one to perform a systematic search for vacua, which we implement for the case of geometric backgrounds. Guided by stability criteria, we consider configurations with a particular on-shell F-term pattern, and show that no de Sitter extrema are allowed for them. We classify branches of supersymmetric and non-supersymmetric vacua, and argue that the latter are perturbatively stable for a large subset of them. Our solutions reproduce and generalise previous results in the literature, obtained either from the 4d or 10d viewpoint.