N-Cadherin Expression Level Distinguishes Reserved versus Primed States of Hematopoietic Stem Cells

SummaryOsteoblasts expressing the homophilic adhesion molecule N-cadherin form a hematopoietic stem cell (HSC) niche. Therefore, we examined how N-cadherin expression in HSCs relates to their function. We found that bone marrow (BM) cells highly expressing N-cadherin (N-cadherinhi) are not stem cells, being largely devoid of a Lineage−Sca1+cKit+ population and unable to reconstitute hematopoietic lineages in irradiated recipient mice. Instead, long-term HSCs form distinct populations expressing N-cadherin at intermediate (N-cadherinint) or low (N-cadherinlo) levels. The minority N-cadherinlo population can robustly reconstitute the hematopoietic system, express genes that may prime them to mobilize, and predominate among HSCs mobilized from BM to spleen. The larger N-cadherinint population performs poorly in reconstitution assays when freshly isolated but improves in response to overnight in vitro culture. Their expression profile and lower cell-cycle entry rate suggest N-cadherinint cells are being held in reserve. Thus, differential N-cadherin expression reflects functional distinctions between two HSC subpopulations

Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt–β-catenin and PI3K–Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt–β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape

An examination of the self-referent executive processing model of test anxiety: control, emotional regulation, self-handicapping, and examination performance

According to the self-referent executive processing (S-REF) model, test anxiety develops from interactions between three systems: executive self-regulation processes, self-beliefs, and maladaptive situational interactions. Studies have tended to examine one system at a time, often in conjunction with how test anxiety relates to achievement outcomes. The aim of this study was to enable a more thorough test of the S-REF model by examining one key construct from each of these systems simultaneously. These were control (a self-belief construct), emotional regulation through suppression and reappraisal (an executive process), and self-handicapping (a maladaptive situational interaction). Relations were examined from control, emotional regulation, and self-handicapping to cognitive test anxiety (worry), and subsequent examination performance on a high-stakes test. Data were collected from 273 participants in their final year of secondary education. A structural equation model showed that higher control was indirectly related to better examination performance through lower worry, higher reappraisal was indirectly related to worse examination performance through higher worry, and higher self-handicapping was related to worse examination performance through lower control and higher worry. These findings suggest that increasing control and reducing self-handicapping would be key foci for test anxiety interventions to incorporate. © 2018 The Author(s

Medical Marijuana Laws and Teen Marijuana Use

While at least a dozen state legislatures are considering bills to allow the consumption of marijuana for medicinal purposes, the federal government has recently intensified its efforts to close medical marijuana dispensaries. Federal officials contend that the legalization of medical marijuana encourages teenagers to use marijuana and have targeted dispensaries operating within 1,000 feet of schools, parks and playgrounds. Using data from the national and state Youth Risk Behavior Surveys, the National Longitudinal Survey of Youth 1997 and the Treatment Episode Data Set, we estimate the relationship between medical marijuana laws and marijuana use. Our results are not consistent with the hypothesis that legalization leads to increased use of marijuana by teenagers

Influence of amalgam, alloy, and mercury on the in vitro growth of Streptococcus mutans: I. Biological test system

A procedure is presented for the in vitro growth of Streptococcus mutans in a dextrose-beef extract medium. Growth was estimated spectrophotometrically. The amount of amalgam, alloy, or mercury that was added to the sealed test tube influenced the rate and extent of growth

Influence of amalgam, alloy, and Hg on the in vitro growth of Streptococcus mutans: III. Effect of specimen age and composition

We will now summarize the conclusions from parts I, II and III of this study. A test procedure has been developed that provides a simple, quick, and nondestructive means of monitoring the in vitro growth of S mutans in the presence of amalgams and alloys. The spectrophotometric readings are related in a simple way to growth expressed as dry weight of bacteria and metabolic products. Results are expressed as growth relative to controls which represent bacteria growing under identical conditions but not in contact with metals. The %RA60 value that represents growth after 60 hours relative to controls is used as a measure of growth in the presence of alloys or amalgams. Spherical, fine cut, and dispersion alloys were studied as well as amalgams prepared from these alloys. The dispersion alloy inhibits growth less than the spherical alloy which in turn inhibits growth less than the fine cut alloy. The results for amalgams prepared from the alloys are reversed. At an aging time of two hours, dispersion alloy amalgams inhibit growth more than spherical alloy amalgams and fine cut alloy amalgams. Aging time of amalgams greatly influences the growth inhibition. Immediately after trituration growth is inhibited, but this inhibition is lost with aging. Different types of amalgams seem to lose growth inhibition at different rates. Hg composition in the range of 48 to 52% seems to have little effect on growth inhibition. It remains for clinical studies, which are concerned with the incidence of secondary caries associated with amalgams, to demonstrate that the age and nature of the amalgam are significant

Influence of amalgam, alloy, and mercury on the in vitro growth of Streptococcus mutans: II. Comparison of amalgams and alloys

The influence of three alloys and their amalgams on the in vitro growth of Streptococcus mutans has been estimated. Spherical, fine cut, and dispersion alloys were studied. Dispersion alloy amalgams seem to inhibit bacterial growth more than amalgams prepared from the other alloys in a similar fashion