Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

Timing the initiation of multiple myeloma

The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2nd-3rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection

Effectiveness of a smartphone app in increasing physical activity amongst male adults: a randomised controlled trial.

BACKGROUND: Smartphones are ideal for promoting physical activity in those with little intrinsic motivation for exercise. This study tested three hypotheses: H1 - receipt of social feedback generates higher step-counts than receipt of no feedback; H2 - receipt of social feedback generates higher step-counts than only receiving feedback on one's own walking; H3 - receipt of feedback on one's own walking generates higher step-counts than no feedback (H3). METHODS: A parallel group randomised controlled trial measured the impact of feedback on steps-counts. Healthy male participants (n = 165) aged 18-40 were given phones pre-installed with an app that recorded steps continuously, without the need for user activation. Participants carried these with them as their main phones for a two-week run-in and six-week trial. Randomisation was to three groups: no feedback (control); personal feedback on step-counts; group feedback comparing step-counts against those taken by others in their group. The primary outcome measure, steps per day, was assessed using longitudinal multilevel regression analysis. Control variables included attitude to physical activity and perceived barriers to physical activity. RESULTS: Fifty-five participants were allocated to each group; 152 completed the study and were included in the analysis: n = 49, no feedback; n = 53, individual feedback; n = 50, individual and social feedback. The study provided support for H1 and H3 but not H2. Receipt of either form of feedback explained 7.7 % of between-subject variability in step-count (F = 6.626, p < 0.0005). Compared to the control, the expected step-count for the individual feedback group was 60 % higher (effect on log step-count = 0.474, 95 % CI = 0.166-0.782) and that for the social feedback group, 69 % higher (effect on log step-count = 0.526, 95 % CI = 0.212-0.840). The difference between the two feedback groups (individual vs social feedback) was not statistically significant. CONCLUSIONS: Always-on smartphone apps that provide step-counts can increase physical activity in young to early-middle-aged men but the provision of social feedback has no apparent incremental impact. This approach may be particularly suitable for inactive people with low levels of physical activity; it should now be tested with this population

Effect of silver nanoparticles on the physicochemical and antimicrobial properties of an orthodontic adhesive

ABSTRACT Orthodontic treatment with fixed brackets plays a major role on the formation of white spot lesions. Objective This study aimed to incorporate silver nanoparticle solutions (AgNP) in an orthodontic adhesive and evaluate its physicochemical and antimicrobial properties. Material and Methods Silver nanoparticle solutions were added to a commercial adhesive in different concentrations (w/w): 0%, 0.11%, 0.18%, and 0.33%. Shear bond strength (SBS) test was performed after bonding metal brackets to enamel. Raman spectroscopy was used to analyze in situ the degree of conversion (DC) of the adhesive layer. The surface free energy (SFE) was evaluated after the measurement of contact angles. Growth inhibition of Streptococcus mutans in liquid and solid media was determined by colony-forming unit count and inhibition halo, respectively. One-way ANOVA was performed for SBS, DC, SFE, and growth inhibition. Results The incorporation of AgNP solution decreased the SBS (p<0.001) and DC in situ (p<0.001) values. SFE decreased after addition of 0.18% and 0.33% AgNP. Growth inhibition of S. mutans in liquid media was obtained after silver addition (p<0.05). Conclusions The addition of AgNP solutions to Transbond&#8482; XT adhesive primer inhibited S. mutans growth. SBS, DC, and SFE values decreased after incorporation up to 0.33% AgNP solution without compromising the chemical and physical properties of the adhesive

NPR3 and NPR4 are receptors for the immune signal salicylic acid in plants

Salicylic acid (SA) is a plant immune signal produced upon pathogen challenge to induce systemic acquired resistance (SAR). It is the only major plant hormone for which the receptor has not been firmly identified. SAR in Arabidopsis requires the transcription cofactor NPR1 (nonexpresser of PR genes 1), whose degradation serves as a molecular switch for SAR. Here we show that NPR1 paralogues, NPR3 and NPR4, are SA receptors that bind SA with different affinities and function as adaptors of the Cullin 3 ubiquitin E3 ligase to mediate NPR1 degradation in an SA-regulated manner. Accordingly, the npr3 npr4 mutant accumulates higher levels of NPR1 and is insensitive to SAR induction. Moreover, this mutant is defective in pathogen effector-triggered programmed cell death and immunity. Our study reveals the mechanism of SA perception in determining cell death and survival in response to pathogen challenge

Integrin CD11b positively regulates TLR4-induced signalling pathways in dendritic cells but not in macrophages.

Tuned and distinct responses of macrophages and dendritic cells to Toll-like receptor 4 (TLR4) activation induced by lipopolysaccharide (LPS) underpin the balance between innate and adaptive immunity. However, the molecule(s) that confer these cell-type-specific LPS-induced effects remain poorly understood. Here we report that the integrin α(M) (CD11b) positively regulates LPS-induced signalling pathways selectively in myeloid dendritic cells but not in macrophages. In dendritic cells, which express lower levels of CD14 and TLR4 than macrophages, CD11b promotes MyD88-dependent and MyD88-independent signalling pathways. In particular, in dendritic cells CD11b facilitates LPS-induced TLR4 endocytosis and is required for the subsequent signalling in the endosomes. Consistent with this, CD11b deficiency dampens dendritic cell-mediated TLR4-triggered responses in vivo leading to impaired T-cell activation. Thus, by modulating the trafficking and signalling functions of TLR4 in a cell-type-specific manner CD11b fine tunes the balance between adaptive and innate immune responses initiated by LPS