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Copepods of the genus Salmincola (gill lice) parasitize salmonids. We collected kokanee salmon (Oncorhynchus nerka) from a reservoir in Colorado to identify the species of gill lice present and investigate intensity and prevalence of infestations. We observed increasing intensity and prevalence with age of fish. Our study adds to limited knowledge of infestations of Salmincola in Colorado and the western United States.

Recent progress in targeting KRAS G12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS G12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS G12D with K D and IC 50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS G12D as compared to KRAS WT . MRTX1133 also demonstrated potent inhibition of activated KRAS G12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRAS G12D -mutant cell lines, with median IC 50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRAS WT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRAS G12D -mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS G12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRAS G12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival. A potent and selective inhibitor of KRAS G12D , the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.

Copepods of the genus Salmincola (gill lice) parasitize salmonids. We collected kokanee salmon (Oncorhynchus nerka) from a reservoir in Colorado to identify the species of gill lice present and investigate intensity and prevalence of infestations. We observed increasing intensity and prevalence with age of fish. Our study adds to limited knowledge of infestations of Salmincola in Colorado and the western united States.

Transcriptional regulatory proteins are frequent drivers of oncogenesis and common targets for drug discovery. The transcriptional co-activator, ENL, which is localized to chromatin through its acetyllysine-binding YEATS domain, is preferentially required for the survival and pathogenesis of acute leukemia. Small molecules that inhibit the ENL YEATS domain show anti-leukemia effects in preclinical models, which is thought to be caused by the downregulation of pro-leukemic ENL target genes. However, the transcriptional effects of ENL YEATS domain inhibitors have not been studied in models of intrinsic or acquired resistance and, therefore, the connection between proximal transcriptional effects and downstream anti-proliferative response is poorly understood. To address this, we identified models of intrinsic and acquired resistance and used them to study the effects of ENL YEATS domain inhibitors. We first discovered that ENL YEATS domain inhibition produces similar transcriptional responses in naive models of sensitive and resistant leukemia. We then performed a CRISPR/Cas9-based genetic modifier screen and identified in-frame deletions of the essential transcriptional regulator, PAF1, that confer resistance to ENL YEATS domain inhibitors. Using these drug-resistance alleles of to construct isogenic models, we again found that the downregulation of ENL target genes is shared in both sensitive and resistant leukemia. Altogether, these data support the conclusion that the suppression of ENL target genes is not sufficient to explain the anti-leukemia effects of ENL antagonists.

Chemical inducers of proximity (CIPs) can elicit durable-and often neomorphic-biological effects through the formation of a ternary complex, even at low equilibrium occupancy of their targets. This \"event-driven\" pharmacology is exemplified by CIPs that promote targeted protein degradation, but other applications remain underexplored. We developed a generalizable strategy to discover event-driven CIPs by tracking the cellular effects of heterobifunctional small molecules alongside quantitative measures of intracellular target engagement. Using this approach, we discovered PCIP-1, which inhibits DNA repair by recruiting BET proteins to PARP2. Unlike conventional PARP inhibitors, PCIP-1 activity is observed at low equilibrium occupancy of PARP1/2 and without inhibition of PARP-catalyzed PARylation, yet it retains synthetic lethality in cancer cells with homologous recombination deficiencies. knockout, which confers resistance to conventional PARP drugs, increases sensitivity to PCIP-1, offering a potential new mechanism to overcome clinical resistance. Through these studies, we demonstrate that DNA repair can be rewired by CIPs and introduce a new form of event-driven pharmacology.

Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of heterobifunctional CIPs, monovalent, molecular glue-like CIPs have relied predominantly on serendipity. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to empirically discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Here, we used sulfur(VI)-fluoride exchange (SuFEx)-based high-throughput chemistry (HTC) to install 3,163 structurally diverse chemical building blocks onto ENL and BRD4 ligands and then screened the crude products for degrader activity. This revealed dHTC1, a potent, selective, and stereochemistry-dependent degrader of ENL. It recruits CRL4 to ENL through an extended interface of protein-protein and protein-ligand contacts, but only after pre-forming the ENL:dHTC1 complex. We also characterized two structurally distinct BRD4 degraders, including dHTC3, a molecular glue that selectively dimerizes the first bromodomain of BRD4 to SCF , an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and actionable cellular effectors of proximity pharmacology.

Pioneer transcription factors (TFs) exhibit a specialized ability to bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic small molecules that stereoselectively and site-specifically bind the pioneer TF, FOXA1, at a cysteine (C258) within the forkhead DNA-binding domain. We show that these covalent ligands react with FOXA1 in a DNA-dependent manner and rapidly remodel its pioneer activity in prostate cancer cells reflected in redistribution of FOXA1 binding across the genome and directionally correlated changes in chromatin accessibility. Motif analysis supports a mechanism where the covalent ligands relax the canonical DNA binding preference of FOXA1 by strengthening interactions with suboptimal ancillary sequences in predicted proximity to C258. Our findings reveal a striking plasticity underpinning the pioneering function of FOXA1 that can be controlled by small molecules.

Recent progress in targeting KRAS has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS with K and IC values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS as compared to KRAS . MRTX1133 also demonstrated potent inhibition of activated KRAS based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRAS -mutant cell lines, with median IC values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRAS cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRAS -mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRAS mutation-positive tumors on mutant KRAS for tumor cell growth and survival.

Copepods of the genus Salmincola (gill lice) parasitize salmonids. We collected kokanee salmon (Oncorhynchus nerka) from a reservoir in Colorado to identify the species of gill lice present and investigate intensity and prevalence of infestations. We observed increasing intensity and prevalence with age of fish. Our study adds to limited knowledge of infestations of Salmincola in Colorado and the western united States. Copepodos del genero Salmincola parasitan salmonidos. Colectamos individuos de Oncorhynchus nerka de un embalse de agua en Colorado para identificar las especies de piojos presentes en las branquias de los peces para estimar la prevalencia e intensidad de las infecciones. Observamos que ambos prevalencia e intensidad aumentan con la edad de los peces. Nuestro estudio aporta al conocimiento limitado sobre las infestaciones de Salmincola en Colorado y la region occidental de los Estados Unidos.

Although cognitive offloading, or the use of physical action to reduce internal cognitive demands, is a commonly used strategy in everyday life, relatively little is known about the conditions that encourage offloading and the memorial consequences of different offloading strategies for performance. Much of the extant work in this domain has focused on laboratory-based tasks consisting of word lists, letter strings, or numerical stimuli and thus makes little contact with real-world scenarios under which engaging in cognitive offloading might be likely. Accordingly, the current work examines offloading choice behavior and potential benefits afforded by offloading health-related information. Experiment 1 tests for internal memory performance for different pieces of missing medication interaction information. Experiment 2 tests internal memory and offloading under full offloading and partial offloading instructions for interaction outcomes that are relatively low severity (e.g., sweating). Experiment 3 extends Experiment 2 by testing offloading behavior and benefit in low-severity, medium-severity (e.g., backache), and high-severity interaction outcomes (e.g., heart attack). Here, we aimed to elucidate the potential benefits afforded by partial offloading and to examine whether there appears to be a preference for choosing to offload (i) difficult-to-remember information across outcomes that vary in severity, as well as (ii) information from more severe interaction outcomes. Results suggest that partial offloading benefits performance compared to relying on internal memory alone, but full offloading is more beneficial to performance than partial offloading.