Microsoft unveils new mobile Web browser

REDMOND, Wash. - Microsoft Corp. has unveiled an early version of a new Web browser for mobile devices that it said will make browsing full-sized Web pages faster and easier on small smart-phone screens.

To date, most Web browsers for mobile phones work best with pared-down versions of existing sites, limiting mobile users' access to the Internet to a sliver of what's available to desktop Web surfers.
Microsoft said on the Live Labs Web site that the Deepfish technology is in very early stages, and "still a few releases from beta quality."
Deepfish's unveiling Wednesday followed another mobile Web browser development from Microsoft. ZenZui, a startup that used technology developed at Microsoft's research lab, on Monday showed off a visual way to store and navigate bookmarked Web pages on a mobile phone.
For now, a limited number of users with smart phones or Pocket PCs running Windows Mobile 5.0 or later can download Deepfish from the Live Labs Web site.

Protein Factory Reveals Its Secrets (Part 4 End)

A similar proton-shuttle mechanism had been proposed earlier by professor of theoretical chemistry Johan Åqvist of Uppsala University, in Sweden, and coworkers. They based their proposal on molecular dynamics and combined quantum mechanical/molecular mechanics simulations. Similar simulations by chemistry professor Arieh Warshel and coworkers at the University of Southern California, Los Angeles, support the proton-shuttle mechanism as well, although the USC group found that electrostatic stabilization-not substrate assistance or orientational entropy-accounts for most of the catalytic effect.
Computation and simulation are likely to be extraordinarily useful for further clarifying the ribosome's mechanism, because these techniques currently represent "the only way to study the ribosome in motion in atomic detail," says theoretical biologist Kevin Sanbonmatsu of Los Alamos National Laboratory. Sanbonmatsu and coworkers have used a supercomputer to simulate a working ribosome, identifying eight new potential antibiotic target sites. "The study is the largest simulation performed to date in biology," Sanbonmatsu says.
Last year, Yonath, chemistry professor Lou Massa of Hunter College of the City University of New York, crystallographer Jerome Karle of the Naval Research Laboratory, Washington, D.C., and coworkers turned to density functional theory to model ribosome catalysis. They reported a quantum mechanical transition state for peptide bond formation in the ribosome. The study also "defined the activation energy of the reaction and identified ribosomal interactions that seem to stabilize the transition state, which is formed while the A-site tRNA is rotating into the P site," Yonath says.
Such revelations notwithstanding, the ribosome continues to hold onto a few secrets. "There have always been researchers who think that we understand how the ribosome works," Noller says. However, "at this point, in spite of high-resolution crystal structures and decades of biochemical, genetic, and biophysical studies, I don't think we understand the fundamental mechanisms at all," he says,
"How do tRNAs and mRNA move during translocation, a process that involves molecular movements of many tens of angstroms every 50 milliseconds or so?" Noller asks. "What is the role of EF-G in that process? How does EF-Tu speed up binding of aminoacyl-tRNA to the A site by several thousandfold? The ribosome is enormous and tremendously conserved phylogenetically, yet the things we claim to understand at this point involve only a handful of nucleotides."
"The questions are getting finer, and they're also getting harder to ask," Strobel notes. "Where one person says we have the answers, the next person says we have the questions."

Protein Factory Reveals Its Secrets (Part 3)

Also in 2000, Yonath and coworkers obtained a structure of the small subunit and analyzed its structure with each of four antibiotics bound. The study revealed the antibiotics' binding sites and enabled the researchers to propose modes of action for these drugs. The team also obtained a structure of the large ribosomal subunit.
About the same time, structural biologist Venki Ramakrishnan of the MRC Laboratory of Molecular Biology at the University of Cambridge and coworkers obtained a crystal structure of the small subunit and also determined its structure with different antibiotics bound to it. Their study focused particularly on quality control of the decoding process, the way the ribosome checks codon-anticodon interactions between mRNA and newly arrived tRNAs.
The ribosome is strict about correct base pairing between the first two positions of three-nucleotide codons and anticodons. But it is more tolerant at the third; in fact, a handful of different synonymous codons (C&EN, Jan. 22, page 38) that differ only in their third positions can encode a single amino acid. The study revealed the structural basis for this redundancy in the genetic code. "We showed how the ribosome can discriminate between correct and incorrect tRNAs," Ramakrishnan says.
In 2001, a 5.5-Å resolution map of a whole ribosome with mRNA bound and tRNAs in the A, P, and E sites was obtained by Noller; Jamie H. D. Cate, now associate professor of chemistry, biochemistry, and molecular biology at UC Berkeley; Marat Yusupov of the Structural Biology & Genomics Laboratory, Strasbourg, France; and coworkers. The work revealed more about the relative orientation of the two subunits and their interactions with tRNAs. More recently, Cate and coworkers independently published a map of the whole ribosome, and Yusupov and coworkers independently obtained the structure of the ribosome with mRNA bound.
Last year, three more structures of the whole ribosome appeared. Ramakrishnan and coworkers obtained a 2.8-Å structure of the ribosome with mRNA and tRNAs bound. The study revealed that a kink in mRNA between the A and P sites is probably essential for maintaining the correct mRNA reading frame during translation. Noller and coworkers mapped the whole ribosome at 3.7-Å resolution with an mRNA mimic and two tRNAs in place. And Cate and coworkers obtained a 3.5-Å structure of the ribosome with mRNA and a tRNA mimic attached.
Such structural studies have opened the floodgates for a range of biochemical and computational research on the mechanism of action of the ribosome. "Lots of tidbits about the ribosome were out there already, but the structural work is what's 'crystallized' it all," says Rachel Green, professor of molecular biology and genetics at Johns Hopkins School of Medicine. "It's led to all the biochemistry that our group and several others have done on the ribosome."
For example, the idea that a specific RNA nucleotide in the ribosome active site accelerates peptidyl transfer by acting as a base was proposed by Steitz, Moore, molecular biophysics and biochemistry professor Scott A. Strobel, and coworkers at Yale. But results of mutational studies by Rodnina and coworkers and by Green's group contradicted that idea.
So did a subsequent study in which the entropy and enthalpy of the ribosome reaction were assessed by Rodnina; Richard V. Wolfenden, professor of chemistry, biochemistry, and biophysics at the University of North Carolina, Chapel Hill; and coworkers. If the peptide transfer reaction were base-catalyzed, it would be expected to have a large enthalpic component. But Rodnina, Wolfenden, and coworkers found that the origin of the 107-fold rate enhancement produced by the ribosome is entirely entropic and due to juxtaposition or desolvation of the substrates, not to base catalysis.
"The view accepted by most people now is that the active-site nucleotide does not play a dramatic role in peptidyl transfer," Green says. The general consensus, she says, is that orientation and positioning of substrates by the ribosome structure accelerates ribosome catalysis much more than any specific chemical effect.
Although the ribosome per se may not promote peptidyl transfer in a very active chemical manner, it's possible that the P-site tRNA substrate does catalyze the reaction-a proposed case of substrate-assisted catalysis. The growing protein chain is attached by an ester to a 3′-hydroxyl on one of the P-site tRNA nucleotide residues. In 2004, Strobel, Green, and coworkers confirmed earlier hints that peptidyl transfer is accelerated by a neighboring 2′-hydroxyl group on the same nucleotide. They found that deleting that 2′-hydroxyl causes a millionfold reduction in ribosome catalytic activity.
"The current model that everybody's discussing and likes is that that 2′-hydroxyl is essentially acting as a proton shuttle," Green says. The proton released from the A-site tRNA's nucleophilic amine apparently gets passed along to the 2′-hydroxyl. From there, it's passed to the protein's ester leaving group, which needs a proton to balance its negative charge. Strobel's group is currently carrying out experiments to further test the proposal.