Stochastic phenotype transition of a single cell in an intermediate region of gene-state switching

Multiple phenotypic states often arise in a single cell with different gene-expression states that undergo transcription regulation with positive feedback. Recent experiments have shown that at least in E. coli, the gene state switching can be neither extremely slow nor exceedingly rapid as many previous theoretical treatments assumed. Rather it is in the intermediate region which is difficult to handle mathematically.Under this condition, from a full chemical-master-equation description we derive a model in which the protein copy-number, for a given gene state, follow a deterministic mean-field description while the protein synthesis rates fluctuate due to stochastic gene-state switching. The simplified kinetics yields a nonequilibrium landscape function, which, similar to the energy function for equilibrium fluctuation, provides the leading orders of fluctuations around each phenotypic state, as well as the transition rates between the two phenotypic states. This rate formula is analogous to Kramers theory for chemical reactions. The resulting behaviors are significantly different from the two limiting cases studied previously.Comment: 6 pages,4 figure

Increased Expression of the Tail-Anchored Membrane Protein SLMAP in Adipose Tissue from Type 2 Tally Ho Diabetic Mice

The tail-anchored membrane protein, sarcolemmal membrane associated protein (SLMAP) is encoded to a single gene that maps to the chromosome 3p14 region and has also been reported in certain diabetic populations. Our previous studies with db/db mice shown that a deregulation of SLMAP expression plays an important role in type 2 diabetes. Male Tally Ho mice were bred to present with either normoglycemia (NG) or hyperglycemia (HG). Abdominal adipose tissue from male Tally Ho mice of the HG group was found to have a significantly lower expression of the membrane associated glucose transporter-4 (GLUT-4) and higher expression of SLMAP compared to tissue from NG mice. There were 3 isoforms expressed in the abdominal adipose tissue, but only 45 kDa isoform of SLMAP was associated with the GLUT-4 revealed by immunoprecipitation data. Knock down studies using SLMAP siRNA with adipocytes resulted in a significant reduction in SLMAP and a decrease in glucose uptake. Thus, SLMAP may be an important regulator of glucose uptake or involved in GLUT-4 fusion/translocation into the plasma membrane of mouse abdominal adipose tissue and changes in SLMAP expression are linked to hyperglycemia and diabetes

FE-BASED MAGNETIC NANOMATERIALS: WET CHEMICAL SYNTHESIS, MAGNETIC PROPERTIES AND EXPLORATION ON APPLICATIONS

Ph.DDOCTOR OF PHILOSOPH

Effects of ulinastatin and docetaxel on breast cancer invasion and expression of uPA, uPAR and ERK

<p>Abstract</p> <p>Objective</p> <p>To investigate the effects of ulinastatin and docetaxel on invasion of breast cancer cells and expression of uPA, uPAR and ERK, breast cancer MDA-MB-231 and MCF-7 cells.</p> <p>Methods</p> <p>The nude mice were treated with PBS, ulinastatin, docetaxel, and ulinastatin plus docetaxel, respectively. Their effects on 1) cell invasion ability was assayed using Transwell; 2) expression of uPA, uPAR and ERK was detected by real time PCR and Western blot; 3) uPA, uPAR and p-ERK protein level in nude mice was quantified by immunohistochemistry.</p> <p>Results</p> <p>1) Treatment with ulinastatin, docetaxel, and ulinastatin plus docetaxel, respectively, significantly inhibited MDA-MB-231 and MCF-7 cell invasion; 2) mRNA and protein levels of uPA, uPAR and ERK1/2 were inhibited by ulinastatin, but enhanced by docetaxel.</p> <p>Conclusion</p> <p>Ulinastatin can enhance the effects of docetaxel on invasion of breast cancer cells. And that uPA, uPAR and p-ERK expression is obviously inhibited by ulinastatin.</p

Relatively slow stochastic gene-state switching in the presence of positive feedback significantly broadens the region of bimodality through stabilizing the uninduced phenotypic state

Within an isogenic population, even in the same extracellular environment, individual cells can exhibit various phenotypic states. The exact role of stochastic gene-state switching regulating the transition among these phenotypic states in a single cell is not fully understood, especially in the presence of positive feedback. Recent high-precision single-cell measurements showed that, at least in bacteria, switching in gene states is slow relative to the typical rates of active transcription and translation. Hence using the lac operon as an archetype, in such a region of operon-state switching, we present a fluctuating-rate model for this classical gene regulation module, incorporating the more realistic operon-state switching mechanism that was recently elucidated. We found that the positive feedback mechanism induces bistability (referred to as deterministic bistability), and that the parameter range for its occurrence is significantly broadened by stochastic operon-state switching. We further show that in the absence of positive feedback, operon-state switching must be extremely slow to trigger bistability by itself. However, in the presence of positive feedback, which stabilizes the induced state, the relatively slow operon-state switching kinetics within the physiological region are sufficient to stabilize the uninduced state, together generating a broadened parameter region of bistability (referred to as stochastic bistability). We illustrate the opposite phenotype-transition rate dependence upon the operon-state switching rates in the two types of bistability, with the aid of a recently proposed rate formula for fluctuating-rate models. The rate formula also predicts a maximal transition rate in the intermediate region of operon-state switching, which is validated by numerical simulations in our model. Overall, our findings suggest a biological function of transcriptional “variations” among genetically identical cells, for the emergence of bistability and transition between phenotypic states

Multiplexed Serum Biomarkers for the Detection of Lung Cancer

AbstractCurrently, there is no available biomarker for lung cancer diagnosis. Here we recruited 844 lung cancer patients and 620 healthy participants from six hospitals. A total of four serum proteins was identified and subsequently assessed in the training and validation cohorts. The concentrations of four serum proteins were found to be significantly higher in lung cancer patients compared with healthy participants. The area under the curve (AUC) for the 4-biomarker were 0.86 in the training cohort, and 0.87 in the validation cohort. The classification improved to a corrected AUC of 0.90 and 0.89 respectively following addition of sex, age and smoking status. Similar results were observed for early-stage lung cancer. Remarkably, in a blinded test with a suspicious pulmonary nodule, the adjusted prediction model correctly discriminated the patients with 86.96% sensitivity and 98.25% specificity. These results demonstrated the 4-biomarker panel improved lung cancer prediction beyond that of known risk factors. Moreover, the biomarkers were valuable in differentiating benign nodules which will remain indolent from those that are likely to progress and therefore might serve as an adjuvant diagnosis tool for LDCT scanning

Interfacial electronic structure at the CH3NH3PbI3/MoOx interface

Interfacial electronic properties of the CH3NH3PbI3 (MAPbI3)/MoOx interface are investigated using ultraviolet photoemission spectroscopy and X-ray photoemission spectroscopy. It is found that the pristine MAPbI3 film coated onto the substrate of poly (3,4-ethylenedioxythiophene) poly(styrenesulfonate)/indium tin oxide by two-step method behaves as an n-type semiconductor, with a band gap of ~1.7 eV and a valence band edge of 1.40 eV below the Fermi energy (EF). With the MoOx deposition of 64A ° upon MAPbI3, the energy levels of MAPbI3 shift toward higher binding energy by 0.25 eV due to electron transfer from MAPbI3 to MoOx. Its conduction band edge is observed to almost pin to the EF, indicating a significant enhancement of conductivity. Meanwhile, the energy levels of MoOx shift toward lower binding energy by ~0.30 eV, and an interface dipole of 2.13 eV is observed at the interface of MAPbI3/MoOx. Most importantly, the chemical reaction taking place at this interface results in unfavorable interface energy level alignment for hole extraction. A potential barrier of ~1.36 eV observed for hole transport will impede the hole extraction from MAPbI3 to MoOx. On the other hand, a potential barrier of ~0.14 eV for electron extraction is too small to efficiently suppress electrons extracted from MAPbI3 to MoOx. Therefore, such an interface is not an ideal choice for hole extraction in organic photovoltaic devices

Silicon-Encapsulated Hollow Carbon Nanofiber Networks as Binder-Free Anodes for Lithium Ion Battery

Silicon-encapsulated hollow carbon nanofiber networks with ample space around the Si nanoparticles (hollow Si/C composites) were successfully synthesized by dip-coating phenolic resin onto the surface of electrospun Si/PVA nanofibers along with the subsequent solidification and carbonization. More importantly, the structure and Si content of hollow Si/C composite nanofibers can be effectively tuned by merely varying the concentration of dip solution. As-synthesized hollow Si/C composites show excellent electrochemical performance when they are used as binder-free anodes for Li-ion batteries (LIBs). In particular, when the concentration of resol/ethanol solution is 3.0%, the product exhibits a large capacity of 841 mAh g−1 in the first cycle, prominent cycling stability, and good rate capability. The discharge capacity retention of it was ~90%, with 745 mAh g−1 after 50 cycles. The results demonstrate that the hollow Si/C composites are very promising as alternative anode candidates for high-performance LIBs

Enhancement of Canonical Wnt/β-Catenin Signaling Activity by HCV Core Protein Promotes Cell Growth of Hepatocellular Carcinoma Cells

BACKGROUND: The Hepatitis C virus (HCV) core protein has been implicated as a potential oncogene or a cofactor in HCV-related hepatocellular carcinoma (HCC), but the underlying mechanisms are unknown. Overactivation of the Wnt/β-catenin signaling is a major factor in oncogenesis of HCC. However, the pathogenesis of HCV core-associated Wnt/β-catenin activation remains to be further characterized. Therefore, we attempted to determine whether HCV core protein plays an important role in regulating Wnt/β-catenin signaling in HCC cells. METHODOLOGY: Wnt/β-catenin signaling activity was investigated in core-expressing hepatoma cells. Protein and gene expression were examined by Western blot, immunofluorescence staining, RT-qPCR, and reporter assay. PRINCIPAL FINDINGS: HCV core protein significantly enhances Tcf-dependent transcriptional activity induced by Wnt3A in HCC cell lines. Additionally, core protein increases and stabilizes β-catenin levels in hepatoma cell line Huh7 through inactivation of GSK-3β, which contributes to the up-regulation of downstream target genes, such as c-Myc, cyclin D1, WISP2 and CTGF. Also, core protein increases cell proliferation rate and promotes Wnt3A-induced tumor growth in the xenograft tumor model of human HCC. CONCLUSIONS/SIGNIFICANCE: HCV core protein enhances Wnt/β-catenin signaling activity, hence playing an important role in HCV-associated carcinogenesis