Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice

BACKGROUND: Pim (proviral insertion in murine lymphoma) kinases are a small family of constitutively active, highly conservative serine/threonine oncogenic kinases and have 3 members: Pim1, Pim2, and Pim3. Pim kinases are also implicated in the regulation of B- and T- cell responses to cytokines and hematopoietic growth factors. The roles of Pim kinases in the regulation of primitive hematopoietic stem cells (HSCs) are largely unknown. METHODS: In the current study, Pim1(−/−)2(−/−)3(−/−) triple knockout (TKO) mice were used to determine the role of Pim kinases in hematopoiesis. Peripheral blood hematological parameters were measured in Pim TKO mice and age-matched wild-type (WT) controls. Primary, secondary, and competitive transplantations were performed to assay the long-term repopulating HSCs in Pim TKO mice. In vivo BrdU incorporation assay and ex vivo Ki67 staining and caspase 3 labeling were performed to evaluate the proliferation and apoptosis of HSCs in Pim TKO mice. RESULTS: Compared to age-matched WT controls, Pim TKO mice had lower peripheral blood platelet count and exhibited erythrocyte hypochromic microcytosis. The bone marrow cells from Pim TKO mice demonstrated decreased hematopoietic progenitor colony-forming ability. Importantly, Pim TKO bone marrow cells had significantly impaired capacity in rescuing lethally irradiated mice and reconstituting hematopoiesis in primary, secondary and competitive transplant models. In vivo BrdU incorporation in long-term HSCs was reduced in Pim TKO mice. Finally, cultured HSCs from Pim TKO mice showed reduced proliferation evaluated by Ki67 staining and higher rate of apoptosis via caspase 3 activation. CONCLUSIONS: Pim kinases are not only essential in the hematopoietic lineage cell development, but also important in HSC expansion, self-renewal, and long-term repopulation

Bulk photovoltaic effect in two-dimensional ferroelectric semiconductor α\alpha-In2_2Se3_3

Bulk photovoltaic effect, which arises from crystal symmetry-driven charge carrier separation, is an intriguing physical phenomenon that has attracted extensive interest in photovoltaic application due to its junction-free photovoltaic and potential to surpass Shockley-Queisser limit. Whereas conventional ferroelectric materials mostly suffer from extremely low photocurrent density and weak photovoltaic response at visible light wavelengths. Emerging two-dimensional ferroelectric semiconductors with coupled visible light absorption and spontaneous polarization characteristics are a promising alternative for making functional photoferroelectrics. Herein, we report the experimental demonstration of the bulk photovoltaic effect behavior based on the 2D ferroelectric semiconductor {$\alpha$-InSe caused by an out-of-plane polarization induced depolarization field. The {$\alpha$-InSe device exhibits enhanced bulk photovoltaic response in the visible light spectrum owing to its narrow bandgap. It was demonstrated that the generated photovoltaic current density was nearly two orders of magnitude greater than conventional bulk ferroelectric materials. These findings highlight the potential of 2D ferroelectric semiconductor materials for bulk photovoltaic applications in a broad spectral region

3D fracture propagation simulation and pressure decline analysis research for I-shaped fracture of coalbed

After hydraulic fracturing, some treatments intended for production enhancement fail to yield predetermined effects. The main reason is the insufficient research about the fracture propagation mechanism. There is compelling evidence that I-shaped fracture, two horizontal fractures at the junction of coalbed and cover/bottom layer, and one vertical fracture in the coalbed have formed in part of the coalbed after hydraulic fracturing. Therefore, this paper aims at I-shaped fracture propagation simulation. A novel propagation model is derived on the basis of a three-dimensional (3D) model, and the coupling conditions of vertical fracture and horizontal fractures are established based on the flow rate distribution and the bottom-hole pressure equality, respectively. Moreover, an associated PDA (pressure decline analysis of post-fracturing) model is established. Both models complement with each other and work together to guide fracturing treatment. Finally, a field case is studied to show that the proposed models can effectively investigate and simulate fracture initiation/propagation and pressure decline

In vivo tomographic imaging based on bioluminescence

The most important task for bioluminescence imaging is to identify the emission source from the captured bioluminescent signal on the surface of a small tested animal. Quantitative information on the source location, geometry and intensity serves for in-vivo monitoring of infectious diseases, tumor growth, metastases in the small animal. In this paper, we present a point-spread function-based method for reconstructing the internal bioluminescent source from the surface light output flux signal. The method is evaluated for sensing the internal emission sources in nylon phantoms and within a live mouse. The surface bioluminescent signal is taken with a highly sensitive CCD camera. The results show the feasibility and efficiency of the proposed point-spread function-based method

Induction of hyporesponsiveness to intact foreign protein via retroviral-mediated gene expression: The IgG scaffold is important for induction and maintenance of immune hyporesponsiveness

IgG molecules can be highly tolerogenic carriers for associated antigens. Previously, we reported that recipients of bone marrow or lipopolysaccharide-stimulated B-cell blasts, both of which were retrovirally gene-transferred with an immunodominant peptide in-frame with the variable region of a murine IgG heavy chain, were rendered profoundly unresponsive to that epitope. To further investigate whether tolerance to larger molecules can be achieved via this approach and whether the IgG scaffold is important for induction and maintenance of immunological tolerance, we engineered two retroviral constructs encoding the cI λ repressor (MBAE-1–102 and MBAE-1–102-IgG) for gene transfer. Our results show that recipients of bone marrow or peripheral B cells, transduced with the MBAE-1–102-IgG recombinant, are hyporesponsive to p1–102. In addition, the self-IgG scaffold enhanced the induction and maintenance of such an immune hyporesponsiveness. Thus, our studies demonstrate that in vivo-expressed IgG heavy chain fusion protein can be processed and presented on the appropriate MHC class II, resulting in hyporesponsiveness to that antigen and offering an additional therapeutic approach to autoimmune diseases

In vivo tomographic imaging based on bioluminescence

The most important task for bioluminescence imaging is to identify the emission source from the captured bioluminescent signal on the surface of a small tested animal. Quantitative information on the source location, geometry and intensity serves for in-vivo monitoring of infectious diseases, tumor growth, metastases in the small animal. In this paper, we present a point-spread function-based method for reconstructing the internal bioluminescent source from the surface light output flux signal. The method is evaluated for sensing the internal emission sources in nylon phantoms and within a live mouse. The surface bioluminescent signal is taken with a highly sensitive CCD camera. The results show the feasibility and efficiency of the proposed point-spread function-based method

Clinical M2 Macrophage-Related Genes Can Serve as a Reliable Predictor of Lung Adenocarcinoma

BackgroundNumerous studies have found that infiltrating M2 macrophages play an important role in the tumor progression of lung adenocarcinoma (LUAD). However, the roles of M2 macrophage infiltration and M2 macrophage-related genes in immunotherapy and clinical outcomes remain obscure.MethodsSample information was extracted from TCGA and GEO databases. The TIME landscape was revealed using the CIBERSORT algorithm. Weighted gene co-expression network analysis (WGCNA) was used to find M2 macrophage-related gene modules. Through univariate Cox regression, lasso regression analysis, and multivariate Cox regression, the genes strongly associated with the prognosis of LUAD were screened out. Risk score (RS) was calculated, and all samples were divided into high-risk group (HRG) and low-risk group (LRG) according to the median RS. External validation of RS was performed using GSE68571 data information. Prognostic nomogram based on risk signatures and other clinical information were constructed and validated with calibration curves. Potential associations of tumor mutational burden (TMB) and risk signatures were analyzed. Finally, the potential association of risk signatures with chemotherapy efficacy was investigated using the pRRophetic algorithm.ResultsBased on 504 samples extracted from TCGA database, 183 core genes were identified using WGCNA. Through a series of screening, two M2 macrophage-related genes (GRIA1 and CLEC3B) strongly correlated with LUAD prognosis were finally selected. RS was calculated, and prognostic risk nomogram including gender, age, T, N, M stage, clinical stage, and RS were constructed. The calibration curve shows that our constructed model has good performance. HRG patients were suitable for new ICI immunotherapy, while LRG was more suitable for CTLA4-immunosuppressive therapy alone. The half-maximal inhibitory concentrations (IC50) of the four chemotherapeutic drugs (metformin, cisplatin, paclitaxel, and gemcitabine) showed significant differences in HRG/LRG.ConclusionsIn conclusion, a comprehensive analysis of the role of M2 macrophages in tumor progression will help predict prognosis and facilitate the advancement of therapeutic techniques

Selective Enhancement of Donor Hematopoietic Cell Engraftment by the CXCR4 Antagonist AMD3100 in a Mouse Transplantation Model

The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation