155 research outputs found
Market Feminism in Morocco
Despite widespread views of âMoroccan Exceptionalism,â Morocco continues to rank poorly on international evaluations of gender equality. This project seeks to understand the extent of the influence neoliberal economic forces in Morocco have had on the feminist landscape. Analysis of Moroccan political history, Foucauldian theories of power relations, and relevant literature on state feminism set the groundwork for the evaluation of the extent state feminism in Morocco can be understood as market-based, in accordance with the definition from From State Feminism to Market Feminsim (2012) by Kantola and Squires. Through interviews of three experts, three meetings with womenâs empowerment NGOs, and a review of relevant literature, it is theorized that neoliberalism has played a role in the development of Islamic state feminism under King Mohammed VI, which has in turn led to womenâs NGO dynamics as more professional, transnational, and controlled by the state. In other words, feminism in Morocco is utilized by the state to create a balance between a positive international image and control of cultural and religious Islamic identity. This balance serves the country\u27s foreign policy and economic goals which have merged through war-on-terror neoliberalism, as well as the ruling monarchy\u27s desire for domestic control. This project concludes that market forces are just one variable affecting the success of feminist activism in Morocco, but should be part of the discussion when considering best practices moving forward
Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation
More than 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, the therapeutic window of the current generation of AKT inhibitors could be improved. Here, we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-dependent phenotypes in breast cancer cell lines. A growth inhibition screen with 288 cancer cell lines confirmed that INY-05-040 had a substantially higher potency than our first-generation AKT degrader (INY-03-041), with both compounds outperforming catalytic AKT inhibition by GDC-0068. Using multiomic profiling and causal network integration in breast cancer cells, we demonstrated that the enhanced efficacy of INY-05-040 was associated with sustained suppression of AKT signaling, which was followed by induction of the stress mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low basal JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Together, our study presents a framework for mapping the network-wide signaling effects of therapeutically relevant compounds and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling
Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation
More than 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, the therapeutic window of the current generation of AKT inhibitors could be improved. Here, we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-dependent phenotypes in breast cancer cell lines. A growth inhibition screen with 288 cancer cell lines confirmed that INY-05-040 had a substantially higher potency than our first-generation AKT degrader (INY-03-041), with both compounds outperforming catalytic AKT inhibition by GDC-0068. Using multiomic profiling and causal network integration in breast cancer cells, we demonstrated that the enhanced efficacy of INY-05-040 was associated with sustained suppression of AKT signaling, which was followed by induction of the stress mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low basal JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Together, our study presents a framework for mapping the network-wide signaling effects of therapeutically relevant compounds and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling
Delayed Goblet Cell Hyperplasia, Acetylcholine Receptor Expression, and Worm Expulsion in SMC-Specific IL-4R뱉Deficient Mice
Interleukin 4 receptor α (IL-4Rα) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune responseâdriven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility. Inhibition of the IL-4Rα pathway inhibits this response. How this response manifests itself in vivo is unknown. In this study, smooth muscle cell IL-4Rαâdeficient mice (SM-MHC(Cre)IL-4Rα(â/lox)) were generated and characterized to uncover any role for IL-4/IL-13 in this nonâimmune cell type in response to Nippostrongylus brasiliensis infection. IL-4Rα was absent from α-actinâpositive smooth muscle cells, while other cell types showed normal IL-4Rα expression, thus demonstrating efficient cell-typeâspecific deletion of the IL-4Rα gene. N. brasiliensisâinfected SM-MHC(Cre)IL-4Rα(â/lox) mice showed delayed ability to resolve infection with significantly prolonged fecal egg recovery and delayed worm expulsion. The delayed expulsion was related to a delayed intestinal goblet cell hyperplasia, reduced T helper 2 cytokine production in the mesenteric lymph node, and reduced M3 muscarinic receptor expression during infection. Together, these results demonstrate that in vivo IL-4Rαâresponsive smooth muscle cells are beneficial for N. brasiliensis expulsion by coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine responsiveness, which drive smooth muscle cell contractions
No phenotypic or genotypic evidence for a link between sleep duration and brain atrophy
Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-shaped relationships, where a duration of 6.5 (95% confidence interval, (5.7, 7.3)) hours was associated with the thickest cortex and largest volumes relative to intracranial volume. This fits converging evidence from research on mortality, health and cognition that points to roughly seven hours being associated with good health. Genome-wide association analyses suggested that genes associated with longer sleep for below-average sleepers were linked to shorter sleep for above-average sleepers. Mendelian randomization did not yield evidence for causal impacts of sleep on brain structure. The combined results challenge the notion that habitual short sleep causes brain atrophy, suggesting that normal brains promote adequate sleep durationâwhich is shorter than current recommendations
A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain
Maladaptive plasticity involving increased expression of AMPAâtype glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cellâpermeable, highâaffinity (~2 nM) peptide inhibitor, TatâPâ(C5), of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent TatâPâ(C5) disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPAâreceptor surface expression in vivo. Moreover, TatâPâ(C5) administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal TatâPâ(C5) as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to nonâtandem proteinâprotein interaction domains
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