Alpha helix nucleation by a simple cyclic tetrapeptide

The simple cyclic tetrapeptide cyclo-(1,4)-[Ala-Arg-Ala-homoGlu]-NH2 (3) is shown to adopt an unusual alpha-turn structure, which is not alpha-helical but can nucleate alpha-helicity when attached to the N-terminus of either model peptides or two biologically relevant peptides. This new N-terminal helix-capping macrocycle provides very simple and rapid synthetic access to alpha-helical peptide structures

Distributionally robust L1-estimation in multiple linear regression

Linear regression is one of the most important and widely used techniques in data analysis, for which a key step is the estimation of the unknown parameters. However, it is often carried out under the assumption that the full information of the error distribution is available. This is clearly unrealistic in practice. In this paper, we propose a distributionally robust formulation of L1-estimation (or the least absolute value estimation) problem, where the only knowledge on the error distribution is that it belongs to a well-defined ambiguity set. We then reformulate the estimation problem as a computationally tractable conic optimization problem by using duality theory. Finally, a numerical example is solved as a conic optimization problem to demonstrate the effectiveness of the proposed approach

14-3-3ζ Interacts with Stat3 and Regulates Its Constitutive Activation in Multiple Myeloma Cells

The 14-3-3 proteins are a family of regulatory signaling molecules that interact with other proteins in a phosphorylation-dependent manner and function as adapter or scaffold proteins in signal transduction pathways. One family member, 14-3-3ζ, is believed to function in cell signaling, cycle control, and apoptotic death. A systematic proteomic analysis done in our laboratory has identified signal transducers and activators of transcription 3 (Stat3) as a novel 14-3-3ζ interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3ζ interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3ζ interaction and mutation of Ser727 to Alanine abolished 14-3-3ζ/Stat3 association. Inhibition of 14-3-3ζ protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3ζ is involved in the regulation of protein kinase C (PKC) activity and 14-3-3ζ binding to Stat3 protects Ser727 dephosphorylation from protein phosphatase 2A (PP2A). Taken together, our findings support the model that multiple signaling events impinge on Stat3 and that 14-3-3ζ serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells

MecVax supplemented with CFA MEFA-II induces functional antibodies against 12 adhesins (CFA/I, CS1–CS7, CS12, CS14, CS17, and CS21) and 2 toxins (STa, LT) of enterotoxigenic Escherichia coli (ETEC)

ABSTRACTEnterotoxigenic Escherichia coli (ETEC) strains that produce various adhesins and one or two enterotoxins are the leading causes of children’s diarrhea and travelers’ diarrhea. MecVax, a multivalent ETEC vaccine candidate, consists of two proteins, an adhesin multiepitope fusion antigen (MEFA) that stimulates antibodies to the seven most important ETEC adhesins (CFA/I and CS1–CS6) and a toxoid fusion antigen which stimulates antibodies against ETEC enterotoxins (heat-labile toxin and heat-stable toxin). CFA MEFA-II, another polyvalent MEFA protein, has been demonstrated to stimulate antibodies to another five important ETEC adhesins (CS7, CS12, CS14, CS17, and CS21). We hypothesize that MecVax coverage and efficacy can be expanded if MecVax could stimulate antibodies to all 12 adhesins. In this study, we supplemented MecVax with CFA MEFA-II, examined broad immunity to the 12 targeted ETEC adhesins and 2 ETEC toxins (STa, LT) in mice, and assessed mouse antibody functions for inhibiting the adherence of the 12 adhesins and neutralizing the enterotoxicity of 2 toxins, thus assessing the potential application of a broadly protective pan-ETEC vaccine. Mice intramuscularly immunized with MecVax and CFA MEFA-II developed robust antibody responses to the 12 ETEC adhesins and 2 toxins; furthermore, mouse serum antibodies showed functional activities against the adherence from each of the targeted adhesins and the enterotoxicity of either toxin. Data also indicated that CFA MEFA-II was antigenically compatible with MecVax. These results demonstrated that the inclusion of CFA MEFA-II further expands MecVax broad immunogenicity and protection coverage, suggesting the feasibility of developing a vaccine against all important diarrheal ETEC strains.IMPORTANCEThere are no vaccines licensed for Enterotoxigenic Escherichia coli (ETEC), a leading cause of children’s diarrhea and the most common cause of travelers’ diarrhea. Since ETEC strains produce over 25 adhesins and 2 distinctive enterotoxins, heterogeneity is a key obstacle to vaccine development. MecVax, a multivalent ETEC vaccine candidate, induces protective antibodies against the seven most important adhesins (CFA/I and CS1–CS6) associated with two-thirds of ETEC clinical cases. However, ETEC prevalence shifts chronically and geographically, and other adhesins are also associated with clinical cases. MecVax would become a pan-ETEC vaccine if it also protects against the remaining important adhesins. This study demonstrated that MecVax supplemented with adhesin protein CFA MEFA-II induces functional antibodies against 12 important ETEC adhesins (CFA/I, CS1–CS7, CS12, CS14, CS17, and CS21), enabling the development of a more broadly protective ETEC vaccine and further validating the application of the MEFA vaccinology platform for multivalent vaccine development

Pixel front-end with synchronous discriminator and fast charge measurement for the upgrades of HL-LHC experiments

The upgrade of the silicon pixel sensors for the HL-LHC experiments requires the development of new readout integrated circuits due to unprecedented radiation levels, very high hit rates and increased pixel granularity. The design of a very compact, low power, low threshold analog very front-end in CMOS 65 nm technology is described. It contains a synchronous comparator which uses an offset compensation technique based on storing the offset in output. The latch can be turned into a local oscillator using an asynchronous logic feedback loop to implement a fast time-over-threshold counting. This design has been submitted and the measurement results are presented