Abstract Background The extent to which students view their intelligence as improvable (i.e., “mindset”) influences students’ thoughts, behaviors, and ultimately academic success. Thus, understanding the development of mindsets is great interest education scholars working understand promote student Recent evidence suggests that continue develop change during first year college. We built on this work by characterizing how identifying factors may be influencing among upper-level STEM students....

Background Natural Killer (NK) cells have intrinsic anticancer activity that can be redirected toward acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) engineering. Here, we study the functional consequences of CAR binding affinity and targeted epitope on CAR-NK cell activation, cytolytic synapse formation, antitumor activity. Methods We characterized NK-92 primary NK populations expressing variant AML-specific CARs containing single-chain variable fragments (scFvs, 26292 or...

The cabbage, Brassica oleracea var. capitata L., has a distinguishable phenotype within the genus Brassica. Despite economic and genetic importance of there is little genomic data for most studies are focused on other species or B. subspecies. lack non-model organism, hinders research its molecular biology. Hence, construction reliable transcriptomic based high-throughput sequencing technologies needed to enhance our understanding cabbage provide information future work.We constructed cDNAs...

Whether students view intelligence as a fixed or malleable trait (i.e., their “mindset”) has significant implications for responses to failure and academic outcomes. Despite long history of research on mindset its growing popularity, recent meta-analyses suggest that does poor job predicting outcomes undergraduate populations. Here, we present evidence these mixed results could be due ambiguous language the scale. Specifically, term “intelligence” is referent in every item scale but never...

The COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection hospitalization, but there is still a need for acute treatment the disease. We investigate whether compounds that bind human angiotensin-converting enzyme 2 (ACE2) protein can decrease SARS-CoV-2 replication without impacting ACE2's natural enzymatic function. Initial screening diversity library resulted hit active an ACE2-binding assay, which showed...

Abstract The small GTPase Cdc42 is an integral component of the cytoskeleton, and its dysregulation leads to pathophysiological conditions, such as cancer. Binding scaffold protein IQGAP1 stabilizes in active form. interaction between enhances migration invasion cancer cells. Disrupting this association could impair neoplastic progression metastasis; however, no effective means achieve has been described. Here, we screened 78,500 compounds using a homogeneous time resolved fluorescence-based...

The National Center for Advancing Translational Sciences (NCATS) has been actively generating SARS-CoV-2 high-throughput screening data and disseminates it through the OpenData Portal (https://opendata.ncats.nih.gov/covid19/). Here, we provide a hybrid approach that utilizes NCATS from cytopathic effect reduction assay to build predictive models, using both machine learning pharmacophore-based modeling. Optimized models were used perform two iterative rounds of virtual predict small...

Chimeric antigen receptor (CAR) T cells can effectively treat leukemias, but sustained antitumor responses be hindered by a lack of CAR T-cell persistence. Cytotoxic effector are short-lived, and establishment CAR-T with memory to ensure immune surveillance is important. Memory depend on cytokine support, IL7 activation the (IL7R) being critical. However, IL7R surface expression negatively regulated exposure IL7. We aimed support persistence equipping IL7Rα signal. engineered constitutively...

<div>Abstract<p>Chimeric antigen receptor (CAR) T cells can effectively treat leukemias, but sustained antitumor responses be hindered by a lack of CAR T-cell persistence. Cytotoxic effector are short-lived, and establishment CAR-T with memory to ensure immune surveillance is important. Memory depend on cytokine support, IL7 activation the (IL7R) being critical. However, IL7R surface expression negatively regulated exposure IL7. We aimed support persistence equipping IL7Rα...

<p>Human primary T cells can be engineered for stable IL7 pathway activation. <b>A,</b> Schematic of CCR and sIL7, as well transgenes into cells. <b>B,</b> Transduction efficiency to express GFP only, IL7R + GFP, or secrete was measured by detecting eGFP positivity expression with flow cytometry. <b>C,</b> Concentration in the supernatant sIL7-transduced control (G-o) cytokine-free culture medium. <b>D,</b> Immunophenotype...

<p>T cells with IL7 pathway activation expand and circulate <i>in vivo</i>. <b>A,</b> Schematic of experimental design. NSG mice were injected on day 0 10<sup>7</sup> T expressing a ffLuc reporter. BLI was conducted biweekly, peripheral blood collected days 15 30. One group treated ffLuc-only–modified intraperitoneal injections daily from 1 to 21. <b>B,</b> monitoring T-cell expansion. <b>C,</b> Quantified radiance per mouse....

<p>Human primary T cells can be engineered for stable IL7 pathway activation. <b>A,</b> Schematic of CCR and sIL7, as well transgenes into cells. <b>B,</b> Transduction efficiency to express GFP only, IL7R + GFP, or secrete was measured by detecting eGFP positivity expression with flow cytometry. <b>C,</b> Concentration in the supernatant sIL7-transduced control (G-o) cytokine-free culture medium. <b>D,</b> Immunophenotype...

<div>Abstract<p>Chimeric antigen receptor (CAR) T cells can effectively treat leukemias, but sustained antitumor responses be hindered by a lack of CAR T-cell persistence. Cytotoxic effector are short-lived, and establishment CAR-T with memory to ensure immune surveillance is important. Memory depend on cytokine support, IL7 activation the (IL7R) being critical. However, IL7R surface expression negatively regulated exposure IL7. We aimed support persistence equipping IL7Rα...

<p>T cells with IL7 pathway activation expand and circulate <i>in vivo</i>. <b>A,</b> Schematic of experimental design. NSG mice were injected on day 0 10<sup>7</sup> T expressing a ffLuc reporter. BLI was conducted biweekly, peripheral blood collected days 15 30. One group treated ffLuc-only–modified intraperitoneal injections daily from 1 to 21. <b>B,</b> monitoring T-cell expansion. <b>C,</b> Quantified radiance per mouse....

<p>CCR expression does not diminish CAR T-cell antitumor activity. <b>A,</b> Schematic of the xenograft model. On day 0, NSG mice were injected via tail vein with 1 × 10<sup>6</sup> CD123<sup>+</sup> MV-4-11.ffLuc cells. In treatment groups, 2 T cells administered on 7. Cohorts: unmodified (NT), CD28.ζ CAR, and + IL7Rα CCR-T <b>B,</b> Leukemia proliferation was monitored BLI, whole-animal radiance recorded...

<p>Single-chain proximal IL7Rα CAR-T cells have decreased <i>in vivo</i> antileukemia activity. <b>A,</b> Schematic of the xenograft model. On day 0, NSG mice were injected via tail vein with 1 × 10<sup>6</sup> CD123<sup>+</sup> MV-4-11.ffLuc cells. In treatment groups, 2 CAR<sup>+</sup> T administered on 7. Cohorts: unmodified (NT, <i>n</i> = 2), CD28.ζ + sIL7 (<i>n</i> 6), CD28.IL7R.ζ and IL7R.CD28.ζ...

<p>CD123-targeted CAR and CCR can be coexpressed with maintained functionality. <b>A,</b> Schematic showing structures. <b>B,</b> Transduction efficiency measured using flow cytometric staining of Halo SNAP tags. <i>n</i> = 3 to 6 unique T-cell donors, unless noted no significant difference between groups. <b>C,</b> Measurement phosphorylated STAT5 percentage in cytokine starved, engineered T cells without activation on the immobilized...

<p>CCR expression does not diminish CAR T-cell antitumor activity. <b>A,</b> Schematic of the xenograft model. On day 0, NSG mice were injected via tail vein with 1 × 10<sup>6</sup> CD123<sup>+</sup> MV-4-11.ffLuc cells. In treatment groups, 2 T cells administered on 7. Cohorts: unmodified (NT), CD28.ζ CAR, and + IL7Rα CCR-T <b>B,</b> Leukemia proliferation was monitored BLI, whole-animal radiance recorded...

<p>Hinge modifications do not improve antigen specificity of CD123-targeted chimeric IL7Rα. <b>A,</b> Amino acid sequences hinge regions used in functional studies. <b>B,</b> Transduction efficiency measured using his-tagged rhCD123 binding engineered receptors and flow cytometry. <i>n</i> = 3 unique T-cell donors. <b>C,</b> Quantification phosphorylated STAT5 percentage CCR-T cells with without activation on the immobilized target....

<p>CD123-targeted CAR and CCR can be coexpressed with maintained functionality. <b>A,</b> Schematic showing structures. <b>B,</b> Transduction efficiency measured using flow cytometric staining of Halo SNAP tags. <i>n</i> = 3 to 6 unique T-cell donors, unless noted no significant difference between groups. <b>C,</b> Measurement phosphorylated STAT5 percentage in cytokine starved, engineered T cells without activation on the immobilized...

<p>Single-chain IL7Rα signaling stimulates STAT5 activation in CAR-T cells. <b>A,</b> Schema of the compared T-cell conditions. A: CAR and sIL7; B: with distal domain; C: proximal domain. <b>B,</b> Levels phosphorylation before after exposure to plate-bound recombinant antigen (rhCD123) for 30 minutes, measured a TR-FRET assay. Comparison between conditions without rhCD123 stimulation. <i>n</i> = 3 donors, performed duplicate. <b>C,</b>...

<p>Single-chain proximal IL7Rα CAR-T cells have decreased <i>in vivo</i> antileukemia activity. <b>A,</b> Schematic of the xenograft model. On day 0, NSG mice were injected via tail vein with 1 × 10<sup>6</sup> CD123<sup>+</sup> MV-4-11.ffLuc cells. In treatment groups, 2 CAR<sup>+</sup> T administered on 7. Cohorts: unmodified (NT, <i>n</i> = 2), CD28.ζ + sIL7 (<i>n</i> 6), CD28.IL7R.ζ and IL7R.CD28.ζ...

<p>Single-chain IL7Rα signaling stimulates STAT5 activation in CAR-T cells. <b>A,</b> Schema of the compared T-cell conditions. A: CAR and sIL7; B: with distal domain; C: proximal domain. <b>B,</b> Levels phosphorylation before after exposure to plate-bound recombinant antigen (rhCD123) for 30 minutes, measured a TR-FRET assay. Comparison between conditions without rhCD123 stimulation. <i>n</i> = 3 donors, performed duplicate. <b>C,</b>...

<p>Hinge modifications do not improve antigen specificity of CD123-targeted chimeric IL7Rα. <b>A,</b> Amino acid sequences hinge regions used in functional studies. <b>B,</b> Transduction efficiency measured using his-tagged rhCD123 binding engineered receptors and flow cytometry. <i>n</i> = 3 unique T-cell donors. <b>C,</b> Quantification phosphorylated STAT5 percentage CCR-T cells with without activation on the immobilized target....

<p>Supplementary Figure 4</p>