ALBERT

Description: This paper presents an optimization design method for centrifugal compressors based on one-dimensional calculations and analyses. It consists of two parts: (1) centrifugal compressor geometry optimization based on one-dimensional calculations and (2) matching optimization of the vaned diffuser with an impeller based on the required throat area. A low pressure stage centrifugal compressor in a MW level gas turbine is optimized by this method. One-dimensional calculation results show that D3/D2 is too large in the original design, resulting in the low efficiency of the entire stage. Based on the one-dimensional optimization results, the geometry of the diffuser has been redesigned. The outlet diameter of the vaneless diffuser has been reduced, and the original single stage diffuser has been replaced by a tandem vaned diffuser. After optimization, the entire stage pressure ratio is increased by approximately 4%, and the efficiency is increased by approximately 2%.

Description: In today’s research environment, children’s diet, physical activity, and other lifestyle factors are commonly studied in the context of health, independent of their effect on cognition and learning. Moreover, there is little overlap between the two literatures, although it is reasonable to expect that the lifestyle factors explored in the health-focused research are intertwined with cognition and learning processes. This thematic review provides an overview of knowledge connecting the selected lifestyle factors of diet, physical activity, and sleep hygiene to children’s cognition and learning. Research from studies of diet and nutrition, physical activity and fitness, sleep, and broader influences of cultural and socioeconomic factors related to health and learning, were summarized to offer examples of research that integrate lifestyle factors and cognition with learning. The literature review demonstrates that the associations and causal relationships between these factors are vastly understudied. As a result, current knowledge on predictors of optimal cognition and learning is incomplete, and likely lacks understanding of many critical facts and relationships, their interactions, and the nature of their relationships, such as there being mediating or confounding factors that could provide important knowledge to increase the efficacy of learning-focused interventions. This review provides information focused on studies in children. Although basic research in cells or animal studies are available and indicate a number of possible physiological pathways, inclusion of those data would distract from the fact that there is a significant gap in knowledge on lifestyle factors and optimal learning in children. In a climate where childcare and school feeding policies are continuously discussed, this thematic review aims to provide an impulse for discussion and a call for more holistic approaches to support child development.

Description: Microfluidics is facing critical challenges in the quest of miniaturizing, integrating, and automating in vitro diagnostics, including the increasing complexity of assays, the gap between the macroscale world and the microscale devices, and the diverse throughput demands in various clinical settings. Here, a “3D extensible” microfluidic design paradigm that consists of a set of basic structures and unit operations was developed for constructing any application-specific assay. Four basic structures—check valve (in), check valve (out), double-check valve (in and out), and on–off valve—were designed to mimic basic acts in biochemical assays. By combining these structures linearly, a series of unit operations can be readily formed. We then proposed a “3D extensible” architecture to fulfill the needs of the function integration, the adaptive “world-to-chip” interface, and the adjustable throughput in the X, Y, and Z directions, respectively. To verify this design paradigm, we developed a fully integrated loop-mediated isothermal amplification microsystem that can directly accept swab samples and detect Chlamydia trachomatis automatically with a sensitivity one order higher than that of the conventional kit. This demonstration validated the feasibility of using this paradigm to develop integrated and automated microsystems in a less risky and more consistent manner.

Description: Chronic myeloid leukemia (CML) is a pluripotent hematopoietic stem cell disorder characterized by accumulation of mature and immature granulocytes in peripheral blood and bone marrow due to uncontrolled growth and resistance to apoptosis. The dysregulated activity of the bcr/abl oncoprotein tyrosine kinase, which is encoded by the bcr-abl fusion gene generated from the chromosomal translocation of t(9; 22) and present in approximately 95% of CML patients, has been shown to be responsible for these malignant phenotypes. Numerous studies have demonstrated that only being phosphorylated that p210bcr/abl oncoprotein can promote cell proliferation and survival, and block apoptosis of tumor cells. Bcr/abl tyrosine kinase has chaperone association with heat shock protein 90 (Hsp90), which plays an essential role in stabilization of bcr/abl protein. Here we describe the activity of a natural small molecular compound, berbamine from plant Berberis amurensis that can selectively induce cell death of both Gleevecsensitive and -resistant Ph+ CML cells, but little is known about its exact mechanisms. We investigated the the expression levels of phosphorylated p210bcr/abl protein and Hsp90 protein in apoptosis induced by berbamine in K562 cells by means of various technologies, including cell culture system, flow cytomerty, western blot and immunoprecipitation (IP). Methods: Human Ph+ CML leukemia K562 cells, which express endogenous p210bcr/abl protein, were cultured in RPMI 1640 and treated with berbamine as indicated time and dose. Flow cytometry (FCM) and Annexin V-FLUOS/PI staining kit were used to evaluate apoptosis of leukemic cells; FCM and cytoperm/cytofix plus Caspase-3-McAb-PE were employed to measure leukemic cells with activated Caspase-3. Phosphorylation of p210bcr/abl protein in leukemic cells were assessed by a combination of immunoprecipitation (IP) with c-abl antibody and Western blot with p-Tyr(pY99)antibody. The protein levels of P210bcr/abl, Hsp90 and Hsp70 in leukemic cells were determined by Western blot with antibodies to c-abl, Hsp90 and Hsp70, respectively. Results: After treatment with berbamine at 8 μg/ml for 48 h, the percentages of leukemic cells expressing activated caspase-3 and apoptotic cells were 45.69% and 48.43%, respectively. IP and WB results showed that berbamine at low concentration markedly inhibited phosphorylation of p210bcr/abl protein in leukemia cells, and the amount of phosphorylated p210bcr/abl in leukemia cells exposured to berbamine at 8 μg/ml for 6 h were only 8.41% of that of untreated leukemia cells without the protein levels of P210bcr/abl down-regulated. Berbamine also down-regulated chaperone Hsp90 protein, and the amount of Hsp90 protein in leukemia cells treated with berbamine at 8 μg/ml for 48 h accounted for 18.37% of that of untreated leukemia cells. Interestingly, berbamine at 8 μg/ml had no obvious effects on chaperone Hsp70 protein expression associated with the resistance of leukemia cells to apoptosis. Conclusions: Berbamine could induce caspase-3-mediated apoptosis of Ph+ leukemia cells through inhibiting phosphorylation of p210bcr/abl protein and down-regulating its chaperone Hsp90 protein. Unlike Hsp90 inhibitor GA that could upregulate Hsp70, berbamine had no obvious effects on chaperone Hsp70 protein expression in leukemia cells, suggesting that berbamine may be a novel class of Hsp90 inhibitor, and further study is required.

Description: CXCR4 is a chemokine receptor that belongs to the G-coupled protein receptor (GPCR) family. It is over-expressed in various cancers, including solid tumors and hematological malignancies, and correlates with poor prognosis. CXCR4 expressing cells actively respond to CXCL12 (SDF-1), a chemokine constitutively secreted by stromal cells in bone marrow. Activation of CXCR4 induces cell trafficking and homing to the marrow microenvironment, where CXCL12 retains these cells in close contact with marrow stromal cells that provide growth signals, promote self-renewal, and contribute to drug resistance, leading to poor prognosis and relapse. Here we describe the generation of a highly potent and selective anti-CXCR4 humanized IgG1 antagonist Ab (PF-06747143) that binds to human CXCR4 with high affinity and blocks SDF-1-induced Calcium flux and cAMP signaling. We have also characterized the ability of PF-06747143 to induce cell death through three different mechanisms: a) mobilization of cells from CXCL12-rich niches, making them more sensitive to chemotherapy b) direct cell-death through a mechanism dependent on the antibody’s bivalency; c) ADCC- and CDC-dependent cell death through the Fc-region in IgG1 backbone, when in the presence of effector cells or serum proteins. Weekly administration of PF-06747143 at 10 mg/kg, as a monotherapy, significantly improved survival, induced sustained regression and reduced bone marrow tumor burden in various patient population relevant murine disseminated tumor models of Acute Myeloid Leukemia (MV4-11, PDXs), Non Hodgkin Lymphoma (Raji and Ramos), Chronic Lymphocytic Leukemia (JVM-13) and Multiple Myeloma (OPM-2). The CXCR4 IgG1 antibody was also shown to be similar or more efficacious than approved standards of care agents currently employed for treatment of hematological malignancies. The safety and PK/PD profile of PF-06747143 were evaluated in a Non-Human Primate (NHP) exploratory toxicology study. Results from this study indicate that the CXCR4 IgG1 Ab was well tolerated in a two-week exploratory study at pharmacologically relevant doses. Upon treatment with PF-06747143, egression of white blood cells (WBC) from bone marrow (leukocytosis) was noted, which is consistent with target (CXCR4) modulation. Following the peak of leukocytosis between 1-6 hours post antibody administration, the number of circulating WBCs rapidly decreased back to baseline levels at 24 hrs. These results are likely explained by the direct cell killing through the effector function of this IgG1 CXCR4 antibody. Altogether, the promising preclinical efficacy and safety data support clinical evaluation of PF-06747143 in hematological malignacies. Disclosures Pernasetti: Pfizer: Employment. Liu:Pfizer: Employment. Hallin:Pfizer: Employment. Gu:Pfizer: Employment. Ho:Pfizer: Employment. Zhang:Pfizer: Employment. Pascual:Pfizer: Employment. Simmons:Pfizer: Employment. Yan:Pfizer: Employment. Huser:Pfizer: Employment. Wang:Pfizer: Employment. Lam:Pfizer: Employment. Spilker:Pfizer: Employment. Blasi:Pfizer: Employment. Tran:Pfizer: Employment. Kudaravalli:Pfizer: Employment. Ma:Pfizer: Employment. Chin:Pfizer: Employment. Shelton:Pfizer: Employment. Smeal:Pfizer: Employment. Fantin:Pfizer: Employment.

Description: A separated foundation model was proposed in order to reduce the calculation scale of the numerical model for analyzing soil-bridge structure dynamics. The essence of the wave input analysis model considering soil-structure interaction was analyzed. Based on the large mass method, a one-dimensional time-domain algorithm of the free field was derived. This algorithm could simulate the specified ground motion input well. The displacement expansion solution of the free wave field was solved based on the propagation law of waves in a medium. By separating the soil foundations around the pile foundations of the bridge, the ground motion was transformed into an equivalent load applied on an artificial boundary. The separated foundation model could consider the incoherence effect and soil-structure interaction simultaneously; the number of model elements were reduced, and the computational efficiency was improved. In order to investigate the seismic response of a curved bridge considering soil-structure interaction under spatially varied earthquakes, a curved bridge with small radius was adopted in practical engineering. Spatially correlated multi-point ground motion time histories were generated, and the nonuniform ground motion field was simulated based on the wave input method on an artificial viscoelastic boundary. The effects of different apparent wave velocities, coherence values, and site conditions on the seismic response of the bridge were analyzed. The results showed that the spatial variation of seismic ground motion had a considerable effect on the bending moment and the torsion of the girder. The site effect had great influence on the bending moment of the pier bottom. When considering soil-structure interaction, the spatial variation of ground motion should be fully considered to avoid underestimating the structural response.