Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations

Activating mutations, such as E76K and D61Y, in PTPN11 (SHP2), a protein tyrosine phosphatase implicated in multiple cell signaling processes, are associated with 35% of patients with juvenile myelomonocytic leukemia (JMML), an aggressive childhood myeloproliferative neoplasm (MPN). Here we show that the interaction between leukemia-associated mutant Shp2 and Gab2, a scaffolding protein important for cytokine-induced PI3K/Akt signaling, was enhanced, and that the mTOR pathway was elevated in Ptpn11E76K/+ leukemic cells. Importantly, MPN induced by the Ptpn11E76K/+ mutation was markedly attenuated in Ptpn11E76K/+/Gab2-/- double mutant mice-overproduction of myeloid cells was alleviated, splenomegaly was diminished and myeloid cell infiltration in nonhematopoietic organs was decreased in these double mutants. Excessive myeloid differentiation of stem cells was also normalized by depletion of Gab2. Acute leukemia progression of MPN was reduced in the double mutant mice and, as such, their survival was much prolonged. Furthermore, treatment of Ptpn11E76K/+ mice with Rapamycin, a specific and potent mTOR inhibitor, mitigated MPN phenotypes. Collectively, this study reveals an important role of the Gab2/PI3K/mTOR pathway in mediating the pathogenic signaling of the PTPN11 gain-of-function mutations and a therapeutic potential of Rapamycin for PTPN11 mutation-associated JMML

Transcriptome and Network Changes in Climbers at Extreme Altitudes

Extreme altitude can induce a range of cellular and systemic responses. Although it is known that hypoxia underlies the major changes and that the physiological responses include hemodynamic changes and erythropoiesis, the molecular mechanisms and signaling pathways mediating such changes are largely unknown. To obtain a more complete picture of the transcriptional regulatory landscape and networks involved in extreme altitude response, we followed four climbers on an expedition up Mount Xixiabangma (8,012 m), and collected blood samples at four stages during the climb for mRNA and miRNA expression assays. By analyzing dynamic changes of gene networks in response to extreme altitudes, we uncovered a highly modular network with 7 modules of various functions that changed in response to extreme altitudes. The erythrocyte differentiation module is the most prominently up-regulated, reflecting increased erythrocyte differentiation from hematopoietic stem cells, probably at the expense of differentiation into other cell lineages. These changes are accompanied by coordinated down-regulation of general translation. Network topology and flow analyses also uncovered regulators known to modulate hypoxia responses and erythrocyte development, as well as unknown regulators, such as the OCT4 gene, an important regulator in stem cells and assumed to only function in stem cells. We predicted computationally and validated experimentally that increased OCT4 expression at extreme altitude can directly elevate the expression of hemoglobin genes. Our approach established a new framework for analyzing the transcriptional regulatory network from a very limited number of samples

Study of the doubly Cabibbo-suppressed decays Ds+→K+K+π−D^+_s\to K^+K^+\pi^- and Ds+→K+K+π−π0D^+_s\to K^+K^+\pi^-\pi^0

Based on 7.33 fb$^{-1}$ of $e^+e^-$ collision data collected at center-of-mass energies between 4.128 and 4.226 GeV with the BESIII detector, the experimental studies of the doubly Cabibbo-suppressed decays $D^+_s\to K^+K^+\pi^-$ and $D^+_s\to K^+K^+\pi^-\pi^0$ are reported. We determine the absolute branching fraction of $D^+_s\to K^+K^+\pi^-$ to be (${1.23^{+0.28}_{-0.25}}({\rm stat})\pm0.06({\rm syst})$) $\times 10^{-4}$. No significant signal of $D^+_s\to K^+K^+\pi^-\pi^0$ is observed and the upper limit on its decay branching fraction at 90\% confidence level is set to be $1.7\times10^{-4}$.Comment: 10 pages, 4 figures, 4 table

Observation of the Singly Cabibbo-Suppressed Decay Λc+→Σ−K+π+\Lambda_{c}^{+}\to \Sigma^{-}K^{+}\pi^{+}

The singly Cabibbo-suppressed decay $\Lambda_{c}^{+}\to \Sigma^{-}K^{+}\pi^{+}$ is observed for the first time with a statistical significance of $6.4\sigma$ by using 4.5 fb$^{-1}$ of $e^+e^-$ collision data collected at center-of-mass energies between 4.600 and 4.699 GeV with the BESIII detector at BEPCII. The absolute branching fraction of $\Lambda_{c}^{+}\to \Sigma^{-}K^{+}\pi^{+}$ is measured to be $(3.8\pm1.3_{\rm stat}\pm0.2_{\rm syst})\times 10^{-4}$ in a model-independent approach. This is the first observation of a Cabibbo-suppressed $\Lambda_{c}^{+}$ decay involving $\Sigma^-$ in the final state. The ratio of branching fractions between $\Lambda_{c}^{+}\to \Sigma^{-}K^{+}\pi^{+}$ and the Cabibbo-favored decay $\Lambda_{c}^{+}\to \Sigma^- \pi^+\pi^+$ is calculated to be $(0.4 \pm 0.1)s_{c}^{2}$, where $s_{c} \equiv \sin\theta_c = 0.2248$ with $\theta_c$ the Cabibbo mixing angle. This ratio significantly deviates from $1.0s_{c}^{2}$ and provides important information for the understanding of nonfactorization contributions in $\Lambda_{c}^{+}$ decays.Comment: 8 pages, 2 figure

Updated measurements of the M1 transition ψ(3686)→γηc(2S)\psi(3686) \to \gamma \eta_{c}(2S) with ηc(2S)→KKˉπ\eta_{c}(2S) \to K \bar{K} \pi

Based on a data sample of $(27.08 \pm 0.14 ) \times 10^8~\psi(3686)$ events collected with the BESIII detector at the BEPCII collider, the M1 transition $\psi(3686) \to \gamma \eta_{c}(2S)$ with $\eta_{c}(2S) \to K\bar{K}\pi$ is studied, where $K\bar{K}\pi$ is $K^{+} K^{-} \pi^{0}$ or $K_{S}^{0}K^{\pm}\pi^{\mp}$. The mass and width of the $\eta_{c}(2S)$ are measured to be $(3637.8 \pm 0.8 (\rm {stat}) \pm 0.2 (\rm {syst}))$ MeV/$c^{2}$ and $(10.5 \pm 1.7 (\rm {stat}) \pm 3.5 (\rm {syst}))$ MeV, respectively. The product branching fraction $\mathcal{B}\left(\psi(3686) \rightarrow \gamma \eta_{c}(2 S)\right) \times \mathcal{B}(\eta_{c}(2 S) \rightarrow K \bar{K} \pi)$ is determined to be $(0.97 \pm 0.06 (\rm {stat}) \pm 0.09 (\rm {syst})) \times 10^{-5}$. Using $\mathcal{BR}(\eta_{c}(2S)\to K\bar{K}\pi)=(1.86^{+0.68}_{-0.49})\%$, we obtain the branching fraction of the radiative transition to be $\mathcal{BR}(\psi(3686) \to \gamma \eta_{c}(2S)) = (5.2 \pm 0.3 (\rm {stat}) \pm 0.5 (\rm {syst}) ^{+1.9}_{-1.4} (extr)) \times 10^{-4}$, where the third uncertainty is due to the quoted $\mathcal{BR}(\eta_{c}(2S) \to K\bar{K}\pi)$

Chem. Eng. Technol.

A green process for the production of chromate compounds from chromite ore was simulated using process simulation software. Firstly, the phase equilibria of the KOH-K2CrO4-H2O system were investigated to determine the feasible operating conditions for the separation of K2CrO4 from the KOH alkaline solution. The green process model of chromate production was developed and three cases with different concentrations of alkali solution were simulated based on several assumptions. The mass and energy balances in the three cases were simulated, showing that the energy consumption of the evaporation unit is the largest in the whole process. The simulation results provide important information for the implementation of this green chromate production process.A green process for the production of chromate compounds from chromite ore was simulated using process simulation software. Firstly, the phase equilibria of the KOH-K2CrO4-H2O system were investigated to determine the feasible operating conditions for the separation of K2CrO4 from the KOH alkaline solution. The green process model of chromate production was developed and three cases with different concentrations of alkali solution were simulated based on several assumptions. The mass and energy balances in the three cases were simulated, showing that the energy consumption of the evaporation unit is the largest in the whole process. The simulation results provide important information for the implementation of this green chromate production process