We have taken advantage of the Cre/lox system to generate a mouse model with inducible deficiency of transforming growth factor ␤ receptor II (T␤RII). Using this approach, transforming growth factor ␤ (TGF-␤) signaling deficiency can be restricted to the hematopoietic system by bone marrow transplantation. Mice that received transplants with T␤RII ؊/؊ bone marrow develop a lethal inflammatory disorder closely resembling that of TGF-␤1-null mice. Previous in vitro studies have suggested multiple roles for TGF-␤ in T-cell development, including proliferation, apoptosis, and differentiation. We used our transplantation model to ask whether T-cell development is normal in the absence of TGF-␤ signaling. The findings show for the first time in vivo and in fetal thymus organ culture (FTOC) that TGF-␤ is not required for thymocytes to differentiate along the entire pathway of thymic T-cell development, as defined by the expression patterns of CD4, CD8, CD25, and CD44. In contrast to previous investigations, no increase of thymocyte apoptosis was observed. However, T␤RII-deficient CD8 ؉ thymocytes displayed a 2-fold increase in proliferation rate, as determined by bromodeoxyuridine ( IntroductionTransforming growth factor ␤ (TGF-␤) is a group of growth factor isoforms (TGF␤1, TGF␤2, and TGF␤3) involved in a multitude of physiologic functions including the immune system. They primarily interact with the TGF-␤ type I receptor (T␤RI) and type II receptor (T␤RII), both essential for propagation of the intracellular signal, including phosphorylation of Smad (small mother against decapentaplegic) proteins regulating transcriptional activation. The development of immature thymocytes to CD4 ϩ or CD8 ϩ singlepositive (SP) T cells is defined by their sequential expression of cell surface markers such as CD3, CD4, CD8, CD25, CD44, and the T-cell receptor (TCR). 1,2 Involvement of TGF-␤ in T-cell function has been suggested by in vitro studies demonstrating that TGF-␤ inhibits interleukin-1 (IL-1)-, IL-2-, and IL-7-dependent thymocyte proliferation. [3][4][5][6] Expansion of thymocytes may also be indirectly promoted by an inhibitory action of TGF-␤ on apoptosis. [7][8][9] Inhibitory effect of TGF-␤ on thymocyte development has been shown in fetal thymus organ culture (FTOC). 10 This study demonstrated that TGF-␤ causes a very early block in development within the CD4 Ϫ CD8 Ϫ population, affecting differentiation of the CD44 ϩ CD25 Ϫ into the CD44 ϩ CD25 ϩ subset of thymocytes. Further evidence for an inhibitory mode of action on T-cell development derives from the observation that TGF-␤ inhibits differentiation of CD4 ϩ thymocytes into the T helper 1 (Th1) and Th2 subsets of T helper cells. 11,12 A more complex immunoregulatory role of TGF-␤ emerged by the finding that TGF-␤ may also have stimulatory effects on immune functions. Thus, at certain stages of T-cell development, TGF-␤ stimulates, rather than inhibits, proliferation. 13 A critical role of TGF-␤ in T-cell homeostasis and function has been reinforced by studies using kn...

Background: Smartphones present a near-ubiquitous channel through which structured lifestyle change can reduce risk or progression of the most common noncommunicable diseases. We explored whether a digital structured lifestyle program enhances weight loss. Methods: We randomized overweight and obese participants attending a four-month lifestyle change program to either standard weekly coaching sessions (controls), or standard treatment supplemented with a digital therapeutic mobile application (intervention). Changes in body mass index after four months were the main outcome measure. Odds ratios of achieving 5% weight loss were estimated with unconditional logistic regression. Results: Of 234 eligible persons, 146 (62%) agreed to participate, were block-randomized, showed up for the baseline measures, and constituted the intention-to-treat (ITT) sample ( n = 95 intervention group, n = 51 control group). In the intervention group, 70 (74%) downloaded the mobile application and completed the program (intervention per-protocol). Significant weight loss and BMI reduction were observed for both the intention-to-treat intervention group ( P < 0.05, P = 0.01) and the per-protocol intervention group ( P < 0.0001, P < 0.0001). For the intervention per-protocol group, the odds ratio of achieving 5% weight loss, compared to not treated per-protocol, was 3.3 (95% CI 1.3-8.2), adjusting for age and weight at baseline.Attendance to weekly coaching sessions decreased by 18% during the program in the control group while it increased by 3% amongst the per-protocol group ( P = 0.004). Conclusions: These preliminary findings support the benefit of a digital therapeutic to enhance weight reduction and attendance in a structured lifestyle change program. Larger trials of longer duration are needed to confirm these findings.

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