Allosteric inhibition of a stem cell RNA-binding protein by an intermediary metabolite

Gene expression and metabolism are coupled at numerous levels. Cells must sense and respond to nutrients in their environment, and specialized cells must synthesize metabolic products required for their function. Pluripotent stem cells have the ability to differentiate into a wide variety of specialized cells. How metabolic state contributes to stem cell differentiation is not understood. In this study, we show that RNA-binding by the stem cell translation regulator Musashi-1 (MSI1) is allosterically inhibited by 18-22 carbon omega-9 monounsaturated fatty acids. The fatty acid binds to the N-terminal RNA Recognition Motif (RRM) and induces a conformational change that prevents RNA association. Musashi proteins are critical for development of the brain, blood, and epithelium. We identify stearoyl-CoA desaturase-1 as a MSI1 target, revealing a feedback loop between omega-9 fatty acid biosynthesis and MSI1 activity. We propose that other RRM proteins could act as metabolite sensors to couple gene expression changes to physiological state

Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity

Nucleic acid editing enzymes are essential components of the immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins, and contribute to the diversification and lethality of cancers. Among these enzymes are the seven human APOBEC3 deoxycytidine deaminases, each with unique target sequence specificity and subcellular localization. While the enzymology and biological consequences have been extensively studied, the mechanism by which APOBEC3s recognize and edit DNA remains elusive. Here we present the crystal structure of a complex of a cytidine deaminase with ssDNA bound in the active site at 2.2 A. This structure not only visualizes the active site poised for catalysis of APOBEC3A, but pinpoints the residues that confer specificity towards CC/TC motifs. The APOBEC3A-ssDNA complex defines the 5\u27-3\u27 directionality and subtle conformational changes that clench the ssDNA within the binding groove, revealing the architecture and mechanism of ssDNA recognition that is likely conserved among all polynucleotide deaminases, thereby opening the door for the design of mechanistic-based therapeutics

Energy Transition in Urban Water Infrastructures towards Sustainable Cities

[EN] The world's water infrastructures suffer from inefficiencies, such as high energy consumption and water losses due to inadequate management practices and feeble pressure regulation, leading to frequent water and energy losses. This strains vital water and energy resources, especially in the face of the worsening challenges of climate change and population growth. A novel method is presented that integrates micro-hydropower plants, with pumps as turbines (PATs), in the water network in the city of Funchal. Sensitivity analyses evaluated the microgrid's response to variations in the cost of energy components, showing favorable outcomes with positive net present value (NPV). PV solar and micro-wind turbines installed exclusively at the selected PRV sites within the Funchal hydro grid generate a combined 153 and 55 MWh/year, respectively, supplementing the 406 MWh/year generated by PATs. It should be noted that PATs consistently have the lowest cost of electricity (LCOE), confirming their economic viability and efficiency across different scenarios, even after accounting for reductions in alternative energy sources and grid infrastructure costs.This research was supported by Foundation for Science and Technology of Portugal, grant number UIDB/04625/2020; HY4RES-Hybrid solutions for Renewable Energy Systems: achieving net-zero Atlantic area energy consumers & communities, Interreg project EAPA_0001/2022; and Spanish State Research Plan Scientific and Technical and Innovation 2017-2020 PID2020-114781RAI00.Ramos, HM.; Pérez-Sánchez, M.; Mullur Gurupr, PS.; Carraveta, A.; Kuriqui, A.; Coronado-Hernández, OE.; Fernandes, JF.... (2024). Energy Transition in Urban Water Infrastructures towards Sustainable Cities. Water. 16(3). https://doi.org/10.3390/w1603050416

Politics of #LoSha: using naming and shaming as a feminist tool on Facebook

This chapter examines the new feminist intervention in India against sexual harassment (SH) through the online weapon of anonymously listing sexual offenders. The publication of the list on Facebook—known as the List of Shame (or #LoSha)—was inspired by the #metoo campaign following the Hollywood Weinstein affair and was composed through a collection of first-hand survivor narratives. A list of 70 names of alleged academic sexual offenders was first shared by a lawyer based in the US, and became viral on Facebook. This chapter will look at how this campaign used naming as a risk-taking tool to point at the lack of institutional frameworks within academic spaces. In doing so, it successfully used the online space of Facebook to create a feminist debate around the issue of sexual harassment transcending geographical and hierarchical barriers and to raise questions regarding the viability of the established feminist recourses against SH. Using the methodological tool of situated critique (Bannerji, Thinking Through: Essays on Feminism, Marxism, and Anti-Racism. Toronto: Women’s Press, 1995), in this chapter I will utilize my own experience of participating in the list as well as in the larger feminist debate to discuss the politics of risk-taking and solidarity and the implications of list-activism. In doing so, it has re-established the role of cyberfeminism (Daniels, Women’s Studies Quarterly, 37 (1 & 2): 101–124, 2009) in India and surfaced a new intersectional autocritique of the academia based on caste, class and gender. Though questions regarding the method remain, the use of Facebook for providing survivors a voice with anonymity promises new boundaries of empowerment and fear

PP1γ2 and PPP1R11 Are Parts of a Multimeric Complex in Developing Testicular Germ Cells in which their Steady State Levels Are Reciprocally Related

Mice lacking the protein phosphatase 1 gamma isoforms, PP1γ1 and PP1γ2, are male-sterile due to defective germ cell morphogenesis and apoptosis. However, this deficiency causes no obvious abnormality in other tissues. A biochemical approach was employed to learn how expression versus deficiency of PP1γ2, the predominant PP1 isoform in male germ cells, affects spermatogenesis. Methods used in this study include column chromatography, western blot and northern blot analyses, GST pull-down assays, immunoprecipitation, non-denaturing gel electrophoresis, phosphatase enzyme assays, protein sequencing, and immunohistochemistry. We report for the first time that in wild-type testis, PP1γ2 forms an inactive complex with actin, protein phosphatase 1 regulatory subunit 7 (PPP1R7), and protein phosphatase 1 regulatory subunit 11 (PPP1R11), the latter, a potent PP1 inhibitor. Interestingly, PPP1R11 protein, but not its mRNA level, falls significantly in PP1γ-null testis where mature sperm are virtually absent. Conversely, both mature sperm numbers and the PPP1R11 level increase substantially in PP1γ-null testis expressing transgenic PP1γ2. PPP1R11 also appears to be ubiquitinated in PP1γ-null testis. The levels of PP1γ2 and PPP1R11 were increased in phenotypically normal PP1α-null testis. However, in PP1α-null spleen, where PP1γ2 normally is not expressed, PPP1R11 levels remained unchanged. Our data clearly show a direct reciprocal relationship between the levels of the protein phosphatase isoform PP1γ2 and its regulator PPP1R11, and suggest that complex formation between these polypeptides in testis may prevent proteolysis of PPP1R11 and thus, germ cell apoptosis