A quantum computer (QC) can operate in parallel on all its possible inputs at once, but the amount of information that can be extracted from the result is limited by the phenomenon of wave function collapse. We present a new computational model, which differs from a QC only in that the result of a measurement is the expectation value of the observable, rather than a random eigenvalue thereof. Such an expectation value QC can solve nondeterministic polynomialtime complete problems in polynomial time. This observation is significant precisely because the computational model can be realized, to a certain extent, by NMR spectroscopy on macroscopic ensembles of quantum spins, namely molecules in a test tube. This is made possible by identifying a manifold of statistical spin states, called pseudo-pure states, the mathematical description of which is isomorphic to that of an isolated spin system. The result is a novel NMR computer that can be programmed much like a QC, but in other respects more closely resembles a DNA computer. Most notably, when applied to intractable combinatorial problems, an NMR computer can use an amount of sample, rather than time, which grows exponentially with the size of the problem. Although NMR computers will be limited by current technology to exhaustive searches over only 15 to 20 bits, searches over as much as 50 bits are in principle possible, and more advanced algorithms could greatly extend the range of applicability of such machines.Several physical implementations of computational models other than the standard von Neumann model have recently been proposed, which in principle scale better on certain types of computational problems. Most notably, Adleman (1) has solved a traveling salesman problem by DNA computing, and Shor (2) has shown theoretically that a quantum computer (QC) should be able to factorize integers in polynomial time. Nondeterministic polynomial-time complete (NP-complete) problems are a class of computationally intractable problems of particular interest, both because they are ''polynomially equivalent'' to one another and because they are encountered in many important applications (3-5). The traveling salesman problem includes a set of NP-complete instances, which indicates that DNA computing may someday be useful in solving NP-complete problems. In contrast, it is widely believed that a QC cannot solve NP-complete problems in polynomial time (6). Until now, however, only very small problems have been solved by DNA computing (7), and no one has yet succeeded in building a QC able to handle more than two bits of information (8-10).In this paper, we consider another physical mechanism that is capable of computation, namely NMR spectroscopy. This approach is based on the fact that the spins in each molecule of a liquid sample are largely isolated from the spins in all other molecules. As a result, each molecule is effectively an independent QC. Via radio-frequency electromagnetic pulses, it is straightforward to manipulate each of the spins in every molecule...
Assembly of the eIF4E/eIF4G complex has a central role in the regulation of gene expression at the level of translation initiation. This complex is regulated by the 4E-BPs, which compete with eIF4G for binding to eIF4E and which have tumor-suppressor activity. To pharmacologically mimic 4E-BP function we developed a high-throughput screening assay for identifying small-molecule inhibitors of the eIF4E/eIF4G interaction. The most potent compound identified, 4EGI-1, binds eIF4E, disrupts eIF4E/eIF4G association, and inhibits cap-dependent translation but not initiation factor-independent translation. While 4EGI-1 displaces eIF4G from eIF4E, it effectively enhances 4E-BP1 association both in vitro and in cells. 4EGI-1 inhibits cellular expression of oncogenic proteins encoded by weak mRNAs, exhibits activity against multiple cancer cell lines, and appears to have a preferential effect on transformed versus nontransformed cells. The identification of this compound provides a new tool for studying translational control and establishes a possible new strategy for cancer therapy.
Thymus-derived lymphocytes protect mammalian hosts against virus-or cancer-related cellular alterations through immune surveillance, eliminating diseased cells. In this process, T cell receptors (TCRs) mediate both recognition and T cell activation via their dimeric ␣, CD3⑀␥, CD3⑀␦, and CD3 subunits using an unknown structural mechanism. Here, site-specific binding topology of anti-CD3 monoclonal antibodies (mAbs) and dynamic TCR quaternary change provide key clues. Agonist mAbs footprint to the membrane distal CD3⑀ lobe that they approach diagonally, adjacent to the lever-like C FG loop that facilitates antigen (pMHC)-triggered activation. In contrast, a non-agonist mAb binds to the cleft between CD3⑀ and CD3␥ in a perpendicular mode and is stimulatory only subsequent to an external tangential but not a normal force (ϳ50 piconewtons) applied via optical tweezers. Specific pMHC but not irrelevant pMHC activates a T cell upon application of a similar force. These findings suggest that the TCR is an anisotropic mechanosensor, converting mechanical energy into a biochemical signal upon specific pMHC ligation during immune surveillance. Activating anti-CD3 mAbs mimic this force via their intrinsic binding mode. A common TCR quaternary change rather than conformational alterations can better facilitate structural signal initiation, given the vast array of TCRs and their specific pMHC ligands. The T cell receptor (TCR)3 is a multimeric transmembrane complex composed of a disulfide-linked antigen binding clonotypic heterodimer (␣ or ␥␦) in non-covalent association with the signal-transducing CD3 subunits (CD3⑀␥, CD3⑀␦, and CD3) (reviewed in Ref. 1). TCR signaling via CD3 dimers evokes T cell lineage commitment and repertoire selection during development, maintains the peripheral T cell pool, and further differentiates naïve T cells into effector or memory cell populations upon immune stimulation (2-5). The interaction between an Fab-like ␣ TCR heterodimer and an antigenic peptide bound to a major histocompatibility complex molecule (pMHC) initiates a cascade of downstream signaling events via the immunoreceptor tyrosine-based activation motif elements in the cytoplasmic tails of the associated CD3 subunits (6 -9). The length of these CD3 cytoplasmic tails is substantial, relative to those of the TCR ␣ and  chains (6, 7).How recognition of pMHC by a weakly interacting (ϳ1-100 M K d ) clonotypic heterodimer on the T cell surface evokes intracellular signaling via the adjacent CD3 components remains undefined (1). Solution structures of CD3⑀␥ and CD3⑀␦ heterodimers reveal a unique side-to-side hydrophobic interface with conjoined -sheets involving the G-strands of the two Ig-like ectodomains of the pair (10, 11). The squat and rigid CD3 connecting segments contrast sharply with the long and flexible TCR ␣ and  connecting peptides linking their respective constant domains to the transmembrane segments.To investigate the basis of signal transduction involving the ectodomain components within the TCR membrane complex,...
The human APOBEC3G (apolipoprotein B messenger-RNA-editing enzyme, catalytic polypeptide-like 3G) protein is a single-strand DNA deaminase that inhibits the replication of human immunodeficiency virus-1 (HIV-1), other retroviruses and retrotransposons. APOBEC3G anti-viral activity is circumvented by most retroelements, such as through degradation by HIV-1 Vif. APOBEC3G is a member of a family of polynucleotide cytosine deaminases, several of which also target distinct physiological substrates. For instance, APOBEC1 edits APOB mRNA and AID deaminates antibody gene DNA. Although structures of other family members exist, none of these proteins has elicited polynucleotide cytosine deaminase or anti-viral activity. Here we report a solution structure of the human APOBEC3G catalytic domain. Five alpha-helices, including two that form the zinc-coordinating active site, are arranged over a hydrophobic platform consisting of five beta-strands. NMR DNA titration experiments, computational modelling, phylogenetic conservation and Escherichia coli-based activity assays combine to suggest a DNA-binding model in which a brim of positively charged residues positions the target cytosine for catalysis. The structure of the APOBEC3G catalytic domain will help us to understand functions of other family members and interactions that occur with pathogenic proteins such as HIV-1 Vif.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.