Elasticity model of a supercoiled DNA molecule

Within a simple elastic theory, we study the elongation versus force characteristics of a supercoiled DNA molecule at thermal equilibrium in the regime of small supercoiling. The partition function is mapped to the path integral representation for a quantum charged particle in the field of a magnetic monopole with unquantized charge. We show that the theory is singular in the continuum limit and must be regularised at an intermediate length scale. We find good agreement with existing experimental data, and point out how to measure the twist rigidity accurately.Comment: Latex, 4 pages. The figure contains new experimental data, giving a new determination of the twist rigidit

Fourteen propositions for resilience, fourteen years later

In 2006, Walker et al. published an article titled, “A Handful of Heuristics and Some Propositions for Understanding Resilience in Social-ecological Systems.” The article was incorporated into the Ecology and Society special feature, Exploring Resilience in Social-Ecological Systems. Walker et al. identified five heuristics and posed 14 propositions for understanding resilience in social-ecological systems. At the time, the authors hoped the paper would promote experimentation, critique, and application of these ideas in resilience and social-ecological systems research. To determine the extent to which these propositions have achieved the authors’ hopes, we reviewed the scientific literature on socialecological systems since the article was published. Using Scopus, we identified 627 articles that cited the Walker et al. article. We then identified and assessed the articles relative to each proposition. In addition, we conducted a more general Scopus review for articles that did not cite the Walker et al. article specifically but incorporated a proposition’s concepts. Overall, articles often cite Walker et al. as a reference for a definition of a heuristic or ecological resilience generally and not to reference a specific proposition. Nonetheless, every proposition was at least mentioned in the literature and used to advance resilience scholarship on social-ecological systems. Eleven propositions were tested by multiple articles through application of case studies or other research, and 7 of the 11 propositions were substantially discussed and advanced. Finally, three propositions were heavily critiqued either as concepts in resilience literature or in their application

MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells

<p>Abstract</p> <p>Background</p> <p>Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition.</p> <p>Results</p> <p>Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL), which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16^lowtargets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors.</p> <p>Conclusion</p> <p>MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in metastasizing within the peritoneal cavity and also at overcoming anti-tumor innate immune responses.</p

Characterization of the tumor marker muc16 (ca125) expressed by murine ovarian tumor cell lines and identification of a panel of cross-reactive monoclonal antibodies

<p>Abstract</p> <p>Objectives</p> <p>The ovarian tumor marker CA125 is expressed on human MUC16, a cell surface bound mucin that is also shed by proteolytic cleavage. Human MUC16 is overexpressed by ovarian cancer cells. MUC16 facilitates the binding of ovarian tumor cells to mesothelial cells lining the peritoneal cavity. Additionally, MUC16 also is a potent inhibitor of natural killer cell mediated anti-tumor cytotoxic responses. Extensive studies using human as well as murine ovarian tumor cell models are required to clearly define the function of MUC16 in the progression of ovarian tumors. The major objective of this study was to determine if the murine ovarian tumor cells, MOVCAR, express Muc16 and to characterize antibodies that recognize this mucin.</p> <p>Methods</p> <p>RT-PCR analysis was used for detecting the Muc16 message and size exclusion column chromatography for isolating Muc16 produced by MOVCAR cells. Soluble and cell-associated murine Muc16 were analyzed, respectively, by Western blotting and flow cytometry assays using a new panel of antibodies. The presence of N-linked oligosaccharides on murine Muc16 was determined by ConA chromatography.</p> <p>Results</p> <p>We demonstrate that murine Muc16 is expressed by mouse ovarian cancer cells as an ~250 kDa glycoprotein that carries both O-linked and N-linked oligosaccharides. In contrast to human MUC16, the murine ortholog is primarily released from the cells and cannot be detected on the cell surface. Since the released murine Muc16 is not detected by conventional anti-CA125 assays, we have for the first time identified a panel of anti-human MUC16 antibodies that also recognizes the murine counterpart.</p> <p>Conclusion</p> <p>The antibodies identified in this study can be used in future purification of murine Muc16 and exhaustive study of its properties. Furthermore, the initial identification and characterization of murine Muc16 is a vital preliminary step in the development of effective murine models of human ovarian cancer. These models will aid in the further elucidation of the role that human MUC16 plays in the etiology and progression of ovarian tumors.</p

Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes

<p>Abstract</p> <p>Background</p> <p>MUC16 is a cell surface mucin expressed at high levels by epithelial ovarian tumors. Following proteolytic cleavage, cell surface MUC16 (csMUC16) is shed in the extracellular milieu and is detected in the serum of cancer patients as the tumor marker CA125. csMUC16 acts as an adhesion molecule and facilitates peritoneal metastasis of ovarian tumors. Both sMUC16 and csMUC16 also protect cancer cells from cytotoxic responses of natural killer (NK) cells. In a previous study we demonstrated that sMUC16 binds to specific subset of NK cells. Here, we identify the csMUC16/sMUC16 binding partner expressed on immune cells.</p> <p>Results</p> <p>Analysis of immune cells from the peripheral blood and peritoneal fluid of ovarian cancer patients indicates that in addition to NK cells, sMUC16 also binds to B cells and monocytes isolated from the peripheral blood and peritoneal fluid. I-type lectin, Siglec-9, is identified as the sMUC16 receptor on these immune cells. Siglec-9 is expressed on approximately 30-40% of CD16^pos/CD56^dimNK cells, 20-30% of B cells and >95% of monocytes. sMUC16 binds to the majority of the Siglec-9^posNK cells, B cells and monocytes. sMUC16 is released from the immune cells following neuraminidase treatment. Siglec-9 transfected Jurkat cells and monocytes isolated from healthy donors bind to ovarian tumor cells via Siglec-9-csMUC16 interaction.</p> <p>Conclusions</p> <p>Recent studies indicate that csMUC16 can act as an anti-adhesive agent that blocks tumor-immune cell interactions. Our results demonstrate that similar to other mucins, csMUC16 can also facilitate cell adhesion by interacting with a suitable binding partner such as mesothelin or Siglec-9. Siglec-9 is an inhibitory receptor that attenuates T cell and NK cell function. sMUC16/csMUC16-Siglec-9 binding likely mediates inhibition of anti-tumor immune responses.</p

Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors

BACKGROUND: The mucin MUC16 and the glycosylphosphatidylinositol anchored glycoprotein mesothelin likely facilitate the peritoneal metastasis of ovarian tumors. The biochemical basis and the kinetics of the binding between these two glycoproteins are not clearly understood. Here we have addressed this deficit and provide further evidence supporting the role of the MUC16-mesothelin interaction in facilitating cell-cell binding under conditions that mimic the peritoneal environment. RESULTS: In this study we utilize recombinant-Fc tagged human mesothelin to measure the binding kinetics of this glycoprotein to MUC16 expressed on the ovarian tumor cell line OVCAR-3. OVCAR-3 derived sublines that did not express MUC16 showed no affinity for mesothelin. In a flow cytometry-based assay mesothelin binds with very high affinity to the MUC16 on the OVCAR-3 cells with an apparent K(d )of 5–10 nM. Maximum interaction occurs within 5 mins of incubation of the recombinant mesothelin with the OVCAR-3 cells and significant binding is observed even after 10 sec. A five-fold molar excess of soluble MUC16 was unable to completely inhibit the binding of mesothelin to the OVCAR-3 cells. Oxidation of the MUC16 glycans, removal of its N-linked oligosaccharides, and treatment of the mucin with wheat germ agglutinin and erythroagglutinating phytohemagglutinin abrogates its binding to mesothelin. These observations suggest that at least a subset of the MUC16-asscociated N-glycans is required for binding to mesothelin. We also demonstrate that MUC16 positive ovarian tumor cells exhibit increased adherence to A431 cells transfected with mesothelin (A431-Meso(+)). Only minimal adhesion is observed between MUC16 knockdown cells and A431-Meso(+ )cells. The binding between the MUC16 expressing ovarian tumor cells and the A431-Meso(+ )cells occurs even in the presence of ascites from patients with ovarian cancer. CONCLUSION: The strong binding kinetics of the mesothelin-MUC16 interaction and the cell adhesion between ovarian tumor cells and A431-Meso+ even in the presence of peritoneal fluid strongly support the importance of these two glycoproteins in the peritoneal metastasis of ovarian tumors. The demonstration that N-linked glycans are essential for mediating mesothlein-MUC16 binding may lead to novel therapeutic targets to control the spread of ovarian carcinoma

Perovskite-perovskite tandem photovoltaics with optimized bandgaps

We demonstrate four and two-terminal perovskite-perovskite tandem solar cells with ideally matched bandgaps. We develop an infrared absorbing 1.2eV bandgap perovskite, $FA_{0.75}Cs_{0.25}Sn_{0.5}Pb_{0.5}I_3$, that can deliver 14.8 % efficiency. By combining this material with a wider bandgap $FA_{0.83}Cs_{0.17}Pb(I_{0.5}Br_{0.5})_3$ material, we reach monolithic two terminal tandem efficiencies of 17.0 % with over 1.65 volts open-circuit voltage. We also make mechanically stacked four terminal tandem cells and obtain 20.3 % efficiency. Crucially, we find that our infrared absorbing perovskite cells exhibit excellent thermal and atmospheric stability, unprecedented for Sn based perovskites. This device architecture and materials set will enable 'all perovskite' thin film solar cells to reach the highest efficiencies in the long term at the lowest costs

HLA-E–dependent Presentation of Mtb-derived Antigen to Human CD8+ T Cells

Previous studies in mice and humans have suggested an important role for CD8+ T cells in host defense to Mtb. Recently, we have described human, Mtb-specific CD8+ cells that are neither HLA-A, B, or C nor group 1 CD1 restricted, and have found that these cells comprise the dominant CD8+ T cell response in latently infected individuals. In this report, three independent methods are used to demonstrate the ability of these cells to recognize Mtb-derived antigen in the context of the monomorphic HLA-E molecule. This is the first demonstration of the ability of HLA-E to present pathogen-derived antigen. Further definition of the HLA-E specific response may aid development of an effective vaccine against tuberculosis