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The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain. The molecules displace CXCL12 binding with submicromolar potencies, similarly to AMD3100, the only marketed CXCR4 ligand. They also inhibit anti-CXCR4 mAb 12G5 binding, CXCL12-mediated chemotaxis and HIV-1 infection. Further studies with newly synthesized derivatives pointed out to a role of alkyl chain length on the bis-imidazoline properties, with molecules with an even number of carbons equal to 8, 10 or 12 being the most potent. Interestingly, these differ in the functions of CXCR4 that they influence. Site-directed mutagenesis and molecular docking predict that the alkyl chain folds in such a way that the two imidazole groups become lodged in the transmembrane binding cavity of CXCR4. Results also suggest that the alkyl chain length influences how the imidazole rings positions in the cavity. These results may provide a basis for the design of new CXCR4 antagonists targeting specific functions of the receptor.

Cancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal. Here, we characterize a new OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and uncoupling effect. MS-L6 is effective on both intact and sub-mitochondrial particles, indicating that its efficacy does not depend on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines. MS-L6 either dose-dependently inhibits cell proliferation or induces cell death in a variety of cancer cell lines, including B-cell and T-cell lymphomas as well as pediatric sarcoma. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI-1) partially restores the viability of B-lymphoma cells treated with MS-L6, demonstrating that the inhibition of NADH oxidation is functionally linked to its cytotoxic effect. Furthermore, MS-L6 administration induces robust inhibition of lymphoma tumor growth in two murine xenograft models without toxicity. Thus, our data present MS-L6 as an inhibitor of OXPHOS, with a dual mechanism of action on the respiratory chain and with potent antitumor properties in preclinical models, positioning it as the pioneering member of a promising drug class to be evaluated for cancer therapy. MS-L6 exerts dual mitochondrial effects: ETC-I inhibition and uncoupling of OXPHOS. In cancer cells, MS-L6 inhibited ETC-I at least 5 times more than in isolated rat hepatocytes. These mitochondrial effects lead to energy collapse in cancer cells, resulting in proliferation arrest and cell death. In contrast, hepatocytes which completely and rapidly inactivated this molecule, restored their energy status and survived exposure to MS-L6 without apparent toxicity.

Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for drugs which could potentiate its therapeutic effect. We have screened a chemical library and selected Carba1, a carbazolone, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. The Carba1-induced modulation of microtubule dynamics increases the accumulation of fluorescent paclitaxel inside microtubules, providing a mechanistic explanation of the observed synergy between Carba1 and paclitaxel. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel accumulation in microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

Advances in cancer treatment have led to a steady increase in the rate of disease remission. However, while many treatment-related adverse effects gradually resolve after therapy, chemotherapy-induced peripheral neuropathy (CIPN) often persists, with no means of prevention or direct treatment available. Herein, we present Carba1, a novel bi-functional carbazole that mitigates neuropathy through two distinct mechanisms. First, by interacting with tubulin, Carba1 reduces the required dose of taxanes, widely used chemotherapy drugs notorious for their toxic side effects, including CIPN. Second, Carba1 activates nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, triggering a metabolic rewiring that enhances the resilience of neurons and Schwann cells against chemotherapy-induced toxicity. We demonstrate the neuroprotective efficacy of Carba1 both against neurotoxicity induced by paclitaxel (PTX), cisplatin, and bortezomib, and in a rat model of PTX-induced neuropathy. Importantly, we establish that Carba1 does not compromise the therapeutic efficacy of PTX nor promotes tumor growth. Comparative analyses of Carba1 derivatives further suggest the potential of designing compounds with either dual synergistic and neuroprotective activity or exclusive neuroprotective properties. Altogether, our findings position Carba1 as a promising therapeutic candidate for preventing CIPN, with the potential, if successfully translated to clinical settings, to improve both the quality of life and treatment outcome for cancer patients.

Scope and Method of Study. The purpose of this study was to examine the influences on young children’s behavior, engagement level and representation during storytelling using an interactive whiteboard. The study consisted of observations and interviews of four pairs of students as they were re-telling the story of Goldilocks and the Three Bears on an interactive whiteboard. A first grade classroom was identified by a teacher responding to an email. The sole criterion that I gave the teacher was for her to select eight participants that have the ability to complete a storytelling activity independently while using an interactive whiteboard. Each participant was observed as they completed the storytelling and then immediately interviewed about their experience using an interactive whiteboard. The methodological framework was a qualitative, descriptive naturalistic study analyzed through the lens of the Interpretivist and Deconstructionist paradigms. Specifically, I used the Constructivist Theory and Poststructural perspective, Third Space, to explain the data from this study. Findings and Conclusions. The observations and interviews were transcribed and then coded in order to identify themes. Five themes emerged from the data analysis. The themes were Use of Technology, Representations, Peer Cooperation, Enjoyment, and Dissonance. The validity of the data was analyzed using rich, thick descriptions, peer debriefing, reflexivity, and methodological and theoretical triangulation of data. Interpretations from the data provided support for using interactive whiteboards in classrooms. Students used reasoning to choose images, determine placement of images and dimensions of images during their storytelling experiences. However, students did not make transformative representations. Students cooperated during storytelling, laughed, sang, provided instructional communication, responded with positive affirmations, and exclamations of amazement. Yet, students also engaged in power struggles, negative comments, statements of “no”, physically acted against each other, and had issues with technology. The most substantial theme was Dissonance. Since students were in a state of dissonance due to their inability to independently use an interactive whiteboard, the Lisenbee EMSCI Model was created for teachers to use so they could teach students to independently use technological tools.

This study was performed to determine the source of recharge to MC Spring, which is home to the endangered Mohave tui chub. MC Spring is located at the Zzyzx Desert Studies Center, east of Limestone Hill. The water level in MC Spring is constant year-round, though the groundwater elevation in the adjacent playa aquifer of Soda Lake fluctuates seasonally as much as 1.5 meters and the elevation of the surface of MC Spring and groundwater in the alluvial aquifer is 1 to 2 meters higher than the elevation of the playa aquifer groundwater. The electroconductivity of the water in MC Spring and alluvial aquifer groundwater is an order of magnitude lower than the electroconductivity of the playa aquifer groundwater. A hydrogeologic model was prepared using monitoring well data, alluvial aquifer recharge, and fracture measurements to determine a flow path to MC Spring. The evapotranspiration of Lake Tuende of 28.5 acre-feet per year was determined by the pumping data and used to calculate a water budget for MC Spring. The balanced water budget supports the observed stability of the surface elevation of MC Spring. Results of this study suggest that the source of water for MC Spring is alluvial and fractures in Limestone Hill provide a path for recharge.

Tumor heterogeneity and plasticity, driven by Epithelial-Mesenchymal Transition (EMT), enable cancer therapeutic resistance. We previously showed that EMT promotes primary cilia formation, which enables stemness and tumorigenesis in triple-negative breast cancer (TNBC). Here, we establish a role for primary cilia in human TNBC chemotherapeutic resistance. We developed patient-derived organoids, and showed that these recapitulated the cellular heterogeneity of TNBC biopsies. Notably, one of the identified cell states bore a quasi-mesenchymal phenotype, primary cilia, and stemness signatures. We treated our TNBC organoids with chemotherapeutics and observed partial killing. The surviving cells with organoid-reconstituting capacity showed selective enrichment for the quasi-mesenchymal ciliated cell subpopulation. Genomic analyses argue that this enrichment reflects a combination of pre-existing cells and ones that arose through drug-induced cellular plasticity. We developed a family of small-molecule inhibitors of ciliogenesis and show that these, or genetic ablation of primary cilia, suppress chemoresistance. We conclude that primary cilia help TNBC to evade chemotherapy. Cancer cells that activate EMT to acquire a quasi-mesenchymal state form primary cilia to evade chemotherapy in human triple-negative breast cancer. Pharmacological inhibition of primary ciliogenesis counteracts EMT-induced chemoresistance.

The Child: An Encyclopedic Companion offers both parents and professionals access to the best scholarship from all areas of child studies in a remarkable one-volume reference. Bringing together contemporary research on children and childhood from pediatrics, child psychology, childhood studies, education, sociology, history, law, anthropology, and other related areas, The Child contains more than 500 articles—all written by experts in their fields and overseen by a panel of distinguished editors led by anthropologist Richard A. Shweder. Each entry provides a concise and accessible synopsis of the topic at hand. For example, the entry “Adoption” begins with a general definition, followed by a detailed look at adoption in different cultures and at different times, a summary of the associated mental and developmental issues that can arise, and an overview of applicable legal and public policy. While presenting certain universal facts about children’s development from birth through adolescence, the entries also address the many worlds of childhood both within the United States and around the globe. They consider the ways that in which race, ethnicity, gender, socioeconomic status, and cultural traditions of child rearing can affect children’s experiences of physical and mental health, education, and family. Alongside the topical entries, The Child includes more than forty “Imagining Each Other” essays, which focus on the particular experiences of children in different cultures. In “Work before Play for Yucatec Maya Children,” for example, readers learn of the work responsibilities of some modern-day Mexican children, while in “A Hindu Brahman Boy Is Born Again,” they witness a coming-of-age ritual in contemporary India. Compiled by some of the most distinguished child development researchers in the world, The Child will broaden the current scope of knowledge on children and childhood. It is an unparalleled resource for parents, social workers, researchers, educators, and others who work with children.

Dengue fever represents a significant medical and socio-economic burden in (sub)tropical regions, yet antivirals for treatment or prophylaxis are lacking. JNJ-A07 was described as highly active against the different genotypes within each serotype of the disease-causing dengue virus (DENV). Based on clustering of resistance mutations it has been assumed to target DENV non-structural protein 4B (NS4B). Using a photoaffinity labeling compound with high structural similarity to JNJ-A07, here we demonstrate binding to NS4B and its precursor NS4A-2K-NS4B. Consistently, we report recruitment of the compound to intracellular sites enriched for these proteins. We further specify the mechanism-of-action of JNJ-A07, which has virtually no effect on viral polyprotein cleavage, but targets the interaction between the NS2B/NS3 protease/helicase complex and the NS4A-2K-NS4B cleavage intermediate. This interaction is functionally linked to de novo formation of vesicle packets (VPs), the sites of DENV RNA replication. JNJ-A07 blocks VPs biogenesis with little effect on established ones. A similar mechanism-of-action was found for another NS4B inhibitor, NITD-688. In summary, we unravel the antiviral mechanism of these NS4B-targeting molecules and show how DENV employs a short-lived cleavage intermediate to carry out an early step of the viral life cycle. JNJ-A07 is a highly potent pan-serotype dengue virus inhibitor but the mechanism is not fully understood. Here, the authors show that JNJ-A07 blocks interaction between the viral protease/helicase complex NS2B/NS3 and the viral NS4A-2K-NS4B precursor, which then prevents formation of membranous replication organelles.