Field-Dependent Critical Current in Type-II Superconducting Strips: Combined Effect of Bulk Pinning and Geometrical Edge Barrier

Recent theoretical and experimental research on low-bulk-pinning superconducting strips has revealed striking dome-like magnetic-field distributions due to geometrical edge barriers. The observed magnetic-flux profiles differ strongly from those in strips in which bulk pinning is dominant. In this paper we theoretically describe the current and field distributions of a superconducting strip under the combined influence of both a geometrical edge barrier and bulk pinning at the strip's critical current Ic, where a longitudinal voltage first appears. We calculate Ic and find its dependence upon a perpendicular applied magnetic field Ha. The behavior is governed by a parameter p, defined as the ratio of the bulk-pinning critical current Ip to the geometrical-barrier critical current Is0. We find that when p > 2/pi and Ip is field-independent, Ic vs Ha exhibits a plateau for small Ha, followed by the dependence Ic-Ip ~ 1/Ha in higher magnetic fields.Comment: 4 pages, 2 figures, Fig. 1 revised, submitted to Phys. Rev.

Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader

Protein degradation via the use of bivalent chemical degraders provides an alternative strategy to block protein function and assess the biological roles of putative drug targets. This approach capitalizes on the advantages of small-molecule inhibitors while moving beyond the restrictions of traditional pharmacology. Here, we report a chemical degrader (UNC6852) that targets polycomb repressive complex 2 (PRC2). UNC6852 contains an EED226-derived ligand and a ligand for VHL which bind to the WD40 aromatic cage of EED and CRL2VHL, respectively, to induce proteasomal degradation of PRC2 components, EED, EZH2, and SUZ12. Degradation of PRC2 with UNC6852 blocks the histone methyltransferase activity of EZH2, decreasing H3K27me3 levels in HeLa cells and diffuse large B cell lymphoma (DLBCL) cells containing EZH2 gain-of-function mutations. UNC6852 degrades both wild-type and mutant EZH2, and additionally displays anti-proliferative effects in this cancer model system. Using an EED-targeted chemical degrader, Potjewyd et al. demonstrate successful degradation of the PRC2 complex. UNC6852 provides a unique tool to study PRC2 function and downregulation of PRC2 activity in cancer and demonstrates the feasibility of developing PRC2-targeted degraders as potential therapeutics

The meaning of negation in the second language classroom: evidence from 'any'

This article brings together an experimental study involving L2 knowledge of negation in English and an analysis of how English language textbooks treat negation, in order to consider whether textbook explanations of negation could better exploit linguistic insights into negation. We focus on the English negative polarity item any, whose distribution is contingent on negation, whether through the explicit negator not or through lexical semantic negators (e.g. hardly). Our experiment compares Chinese-speaking learners with existing data from Arabic-speaking learners, finding lower accuracy on any with lexical semantic negators in both groups. Our textbook analysis reveals an approach to negation that is limited to form, focusing on the explicit negator not without explicit treatment of other types of negation. We propose that emphasizing the meaning of negation, with explicit treatment of the full range of negative forms could facilitate more complete acquisition across a range of grammatical properties where negation plays a role

Discovery and Characterization of Peptide Inhibitors for Calcium and Integrin Binding Protein 1

Calcium and integrin binding protein 1 (CIB1) is an EF-hand-containing, small intracellular protein that has recently been implicated in cancer cell survival and proliferation. In particular, CIB1 depletion significantly impairs tumor growth in triple-negative breast cancer (TNBC). Thus, CIB1 is a potentially attractive target for cancer chemotherapy that has yet to be validated by a chemical probe. To produce a probe molecule to the CIB1 helix 10 (H10) pocket and demonstrate that it is a viable target for molecular intervention, we employed random peptide phage display to screen and select CIB1-binding peptides. The top peptide sequence selected, UNC10245092, was produced synthetically, and binding to CIB1 was confirmed by isothermal titration calorimetry (ITC) and a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Both assays showed that the peptide bound to CIB1 with low nanomolar affinity. CIB1 was cocrystallized with UNC10245092, and the 2.1 Å resolution structure revealed that the peptide binds as an α-helix in the H10 pocket, displacing the CIB1 C-terminal H10 helix and causing conformational changes in H7 and H8. UNC10245092 was further derivatized with a C-terminal Tat-derived cell penetrating peptide (CPP) to demonstrate its effects on TNBC cells in culture, which are consistent with results of CIB1 depletion. These studies provide a first-in-class chemical tool for CIB1 inhibition in cell culture and validate the CIB1 H10 pocket for future probe and drug discovery efforts

A Peptidomimetic Ligand Targeting the Chromodomain of MPP8 Reveals HRP2's Association with the HUSH Complex

The interpretation of histone post-translational modifications (PTMs), specifically lysine methylation, by specific classes of "reader"proteins marks an important aspect of epigenetic control of gene expression. Methyl-lysine (Kme) readers often regulate gene expression patterns through the recognition of a specific Kme PTM while participating in or recruiting large protein complexes that contain enzymatic or chromatin remodeling activity. Understanding the composition of these Kme-reader-containing protein complexes can serve to further our understanding of the biological roles of Kme readers, while small molecule chemical tools can be valuable reagents in interrogating novel protein-protein interactions. Here, we describe our efforts to target the chromodomain of M-phase phosphoprotein 8 (MPP8), a member of the human silencing hub (HUSH) complex and a histone 3 lysine 9 trimethyl (H3K9me3) reader that is vital for heterochromatin formation and has specific roles in cancer metastasis. Utilizing a one-bead, one-compound (OBOC) combinatorial screening approach, we identified UNC5246, a peptidomimetic ligand capable of interacting with the MPP8 chromodomain in the context of the HUSH complex. Additionally, a biotinylated derivative of UNC5246 facilitated chemoproteomics studies which revealed hepatoma-derived growth factor-related protein 2 (HRP2) as a novel protein associated with MPP8. HRP2 was further shown to colocalize with MPP8 at the E-cadherin gene locus, suggesting a possible role in cancer cell plasticity

Upstream Solutions: Does the Supplemental Security Income Program Reduce Disability in the Elderly?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72843/1/j.1468-0009.2007.00512.x.pd