Immune Checkpoint PD‐1/PD‐L1: Is There Life Beyond Antibodies?

The PD‐1/PD‐L1 interaction has emerged as a significant target in cancer immunotherapy. Current medications include monoclonal antibodies, which have shown impressive clinical results in the treatment of several types of tumors. The cocrystal structure of human PD‐1 and PD‐L1 is expected to be a valuable starting point for the design of novel inhibitors, along with the recent crystal structures with monoclonal antibodies, small molecules, and macrocycles.     

Mechanistic Studies Relevant to Bromouridine-Enhanced Nucleoprotein Photocrosslinking: Possible Involvement of an Excited Tyrosine Residue of the Protein

The results of mechanistic studies on formation of uridine (U) and N-acetyl-in-(5-uridinyl)tyrosine N-ethylam-ide (2) from irradiation of aqueous, pH 7 solutions of bromouridine (BrU) and N-acetyltyrosine JV-ethylamide (1) are reported. Solutions were irradiated with monochromatic laser emission at 266, 308 and 325 nm. Quantum yield measurements as a function of excitation wavelength suggest that both products result from excitation of the tyrosine derivative followed by electron transfer to BrU, possibly with intermediacy of the hydrated electron. The BrU radical anion ejects bromide to form the uri-dinyl radical, which then abstracts a hydrogen atom from 1 or adds to the aromatic ring of 1. Formation of adduct 2 is a model for photocrosslinking of nucleic acids bearing the bromouracil chromophore to adjacent tyrosine residues of proteins in nucleoprotein complexes. The value of 325 nm excitation in photocrosslinking, where the tyrosine chromophore is more competitive for photons, was demonstrated with an RNA bound to the MS2 bacteriophage coat protein; more than a 60% increase in the yield of photocrosslinking relative to that obtained with 308 nm excitation was achieved.     

Content and Organization of Teacher's Manuals: An Analysis of Japanese Elementary Mathematics Teacher's Manuals

In this paper, results from a study that analyzed the content and organization of teacher's manuals for elementary school mathematics from Japan and the United States are presented. Studies have shown that the nature of mathematics instruction in Japan is different from instruction commonly observed in the United States. Moreover, other scholars have noted that elementary school teachers, both in the United States and Japan, rely heavily on textbooks to teach mathematics. Thus, teacher's manuals accompanying textbook series may be a contributing factor to this difference. The results of the analysis showed that there are some significant differences in the way Japanese teachers' manuals are prepared from those of the US series. The findings suggest that curriculum developers should critically reflect on how to prepare teacher's manuals so that they become useful resources for teachers.     

Water Injection into a Low-Permeability Rock - 2: Control Model

In Part 1, we have demonstrated the inevitable growth of the fluid injection hydrofractures in low-permeability rocks. Thus, a smart controller that manages fluid injection in the presence of hydrofracture extension is highly desirable. Such a controller will be an essential part of automated waterflood project surveillance and control. Here we design an optimal injection controller using methods of optimal control theory. The controller inputs are the history of the injection pressure and the cumulative injection, along with the fracture size. The output parameter is the injection pressure and the control objective is the injection rate. We demonstrate that the optimal injection pressure depends not only on the instantaneous measurements, but it is determined by the whole history of the injection and of the fracture area growth. We show the controller robustness when the inputs are delayed and noisy and when the fracture undergoes abrupt extensions. Finally, we propose a procedure that allows estimation of the hydrofracture size at no additional cost.     

A Model of Buoyancy-Driven Two-Phase Countercurrent Fluid Flow

We seek simple analytical solutions in a model of gas flow driven by a combination of buoyancy, viscous, and capillary forces. Traveling-wave solutions describe propagation of the top and bottom of the gas plume. The top of the plume has low gas saturation, but propagates much faster than the bottom. The theoretical maximum of the velocity of propagation of the top of the plume provides a simple conservative estimate of the time until plume evolution will dramatically slow down. A sequence of rarefaction and traveling-wave solutions characterizes the transition zones between the top and bottom stable regions. The analytical results are applied to studying carbon dioxide flow caused by leaks from deep geological formations used for CO₂ storage. The results are also applicable for modeling flow of natural gas leaking from seasonal gas storage, or for modeling of secondary hydrocarbon migration.     

Wavelet approach incorporated with optimization for solving stiff systems

Wavelet-based methods open a door for numerical solution of differential equations. Stiff systems, a special type of differential equation systems, have the solutions with the components that exhibit complex dynamic behaviours such as singularities and abrupt transitions, which are hard to be captured by the typical numerical method or incur the computing complexity. This paper proposed to use the Wavelet-Galerkin scheme for solving stiff systems. Daubechies wavelet based connection coefficients, required in the Wavelet-Galerkin scheme, were computed using an algorithm that we recently rectified. The Lagrange multiplier method was incorporated into the wavelet approach in order to optimise the fitting of the initial conditions. Comparative studies were also carried out between the proposed approach and the Haar wavelet approach.     

Monitoring the effects of antagonists on protein-protein interactions with NMR spectroscopy

We describe an NMR method that directly monitors the influence of ligands on protein-protein interactions. For a two-protein interaction complex, the size of one component should be small enough (less than ca. 15 kDa) to provide a good quality (15)N((13)C) HSQC spectrum after (15)N((13)C) labeling. The size of the second unlabeled component should be large enough so that the molecular weight of the preformed complex is larger than ca. 40 kDa. When the smaller protein binds to a larger one, broadening of NMR resonances results in the disappearance of most of its cross-peaks in the HSQC spectrum. Addition of an antagonist that can dissociate the complex would restore the HSQC spectrum of the smaller component. The method directly shows whether an antagonist releases proteins in their wild-type folded states or whether it induces their denaturation, partial unfolding, or precipitation. We illustrate the method by studying lead compounds that have recently been reported to block the MDM2-p53 interaction. Activation of p53 in tumor cells by inhibiting its interaction with MDM2 offers new strategy for cancer therapy.