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The safety and efficacy of kratom (Mitragyna speciosa ) for treatment of pain is highly controversial. Kratom produces more than 40 structurally related alkaloids, but most studies have focused on just two of these, mitragynine and 7-hydroxymitragynine. Here, we profiled 53 commercial kratom products using untargeted LC–MS metabolomics, revealing two distinct chemotypes that contain different levels of the alkaloid speciofoline. Both chemotypes were confirmed with DNA barcoding to be M. speciosa. To evaluate the biological relevance of variable speciofoline levels in kratom, we compared the opioid receptor binding activity of speciofoline, mitragynine, and 7-hydroxymitragynine. Mitragynine and 7-hydroxymitragynine function as partial agonists of the human µ-opioid receptor, while speciofoline does not exhibit measurable binding affinity at the µ-, δ- or ƙ-opioid receptors. Importantly, mitragynine and 7-hydroxymitragynine demonstrate functional selectivity for G-protein signaling, with no measurable recruitment of β-arrestin. Overall, the study demonstrates the unique binding and functional profiles of the kratom alkaloids, suggesting potential utility for managing pain, but further studies are needed to follow up on these in vitro findings. All three kratom alkaloids tested inhibited select cytochrome P450 enzymes, suggesting a potential risk for adverse interactions when kratom is co-consumed with drugs metabolized by these enzymes.

Herb–drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb–drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and (S)‐warfarin AUC by 5% and 4%, respectively. A proof‐of‐concept clinical study confirmed minimal interaction between high‐dose silibinin and both midazolam and (S)‐warfarin (9 and 13% increase in AUC, respectively). Unexpectedly, (R)‐warfarin AUC decreased (by 15%), but this is unlikely to be clinically important. Application of this PBPK modeling framework to other herb–drug interactions could facilitate development of guidelines for quantitative prediction of clinically relevant interactions. CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e107; doi: 10.1038/psp.2013.69; advance online publication 26 March 2014

Sulfite oxidase catalyzes the terminal reaction in the degradation of sulfur amino acids. Genetic deficiency of sulfite oxidase results in neurological abnormalities and often leads to death at an early age. The mutation in the sulfite oxidase gene responsible for sulfite oxidase deficiency in a 5-year-old girl was identified by sequence analysis of cDNA obtained from fibroblast mRNA to be a guanine to adenine transition at nucleotide 479 resulting in the amino acid substitution of Arg-160 to Gln. Recombinant protein containing the R160Q mutation was expressed in Escherichia coli, purified, and characterized. The mutant protein contained its full complement of molybdenum and heme, but exhibited 2% of native activity under standard assay conditions. Absorption spectroscopy of the isolated molybdenum domains of native sulfite oxidase and of the R160Q mutant showed significant differences in the 480- and 350-nm absorption bands, suggestive of altered geometry at the molybdenum center. Kinetic analysis of the R160Q protein showed an increase in Kmfor sulfite combined with a decrease in kcatresulting in a decrease of nearly 1,000-fold in the apparent second-order rate constant kcat/Km. Kinetic parameters for the in vitro generated R160K mutant were found to be intermediate in value between those of the native protein and the R160Q mutant. Native sulfite oxidase was rapidly inactivated by phenylglyoxal, yielding a modified protein with kinetic parameters mimicking those of the R160Q mutant. It is proposed that Arg-160 attracts the anionic substrate sulfite to the binding site near the molybdenum.

\"Sometimes rankings can make small gaps appear big and vice versa,\" says researcher Tom Loveless of the Brookings Institution, whose new analysis, out today, looks at statistics showing that the USA in 2007 ranked 11th among 36 countries in fourth-grade math. Nobody ever digs that deep,\" Loveless says. \"They just want the scores and the rankings and they don't ever really look at this part of it.\" \"If this were part of a voucher debate, there'd be huge questions about whether the kids in the district schools and the private schools were being given the same assessment in the same way,\" he says. \"But that has somehow just kind of been brushed aside when we're talking about the international context.\"

Knight Ridder Newspapers President Clinton is fond of describing himself as \"technologically challenged,\" but the Internet has advanced to the point where he will only have to speak into a computer microphone to chat in the first online presidential \"town hall\" meeting today. Clinton will be joined via the World Wide Web by five Democratic elected officials from around the country in promoting the centrist political agenda of the Democratic Leadership Council. They will field questions from an audience of up to 50,000 people logged onto the Excite Web site. \"Our ultimate goal for this event is to give Americans a real voice,\" said Matthew Frankel, an official of the Democratic Leadership Council, which promotes \"progressive center-left\" politics such as free trade, welfare reform and national service. \"Just as FDR in the 1930s spoke to Americans in fireside chats, a president is once again going to be using modern technology to communicate with Americans. But the great thing about the Web ... is he's also going to be able to interact with Americans.\"

\"CAAP bears all the hallmarks of a front group,\" said Michael Keegan of the liberal People for the American Way. \"[William Owens] presents himself and his group as non-partisan or, if anything, leaning in the direction of the Democrats. That makes him more useful to religious-right groups and easier to book on cable news.\" NOM set out to find African-American spokespeople to develop \"a media campaign around their objection to gay marriage as a civil right\" and \"provoke the gay marriage base into ... denouncing these spokesmen and women as bigots,\" according to internal documents unveiled earlier this year in a Maine lawsuit. Maggie Gallagher, co-founder of NOM, called the language in the internal documents \"regrettable\" but denied that the group's alliance with Owens reflects a wedge strategy. \"The belief that this is somehow a front group, I think, is unfair to the majority of black pastors that have appeared with Rev. Owens.\"

Brian Zimmer, president of the Coalition for a Secure Driver's License, said the ease with which people can get fake documents is alarming. \"If the ID buyers are terrorists, the list of protected targets they can now access is a Homeland Security nightmare,\" he said. The website \"Link-i-d\" is another popular source of identification registered in Panama. According to its website, the company sells ID cards that will pass security scans and have accurate holograms and ultraviolet-sensitive ink. Customers can send a money order of $100 for two cards. The website launched this year. According to [David Huff] of the Virginia agency, it has always been easy for the untrained eye to be fooled by fake IDs. The difference is, Huff said, that the new generation of forged IDs is \"good enough to fool the trained eye.\"

A growing body of evidence demonstrates that Atlantic-style passive margins have experienced episodes of uplift and volcanism in response to changes in mantle circulation long after cessation of rifting. Passive margins are thus an attractive archive from which to retrieve records of mantle circulation and lithospheric alteration. However, this archive remains under-utilized due to difficulty in deciphering the surficial records of passive margin tectonism and linking them to seismic velocity structure. Here we present a new approach to unraveling the tectonic history of passive margins using U-Pb dating of calcite in faults and fractures along the eastern North American margin. These ages show a 40 Myr long period of continuous fracturing and faulting from ~115 to 75 Ma followed by another episode in Mio-Pliocene time. We argue that the former event represents a response to Cretaceous lithospheric alteration whereas the latter records development of modern relief in the northern Appalachians. It is thought that Atlantic style passive margins have experienced episodes of uplift and volcanism in response to changes in mantle circulation. The authors here employ U-Pb dating of calcite in faults and fractures along the eastern North American margin and find a 40 Myr long period of fracturing and faulting from 115 to 75 Ma.

\"We have very few conservatives on the faculty here at Harvard Law School, and until that changes, we're going to have a real lack of intellectual diversity here,\" says Joel Alicea, president of the Harvard branch of the conservative-libertarian Federalist Society, an organizer of the conference. \"Students are not well served by having such an intellectually monolithic faculty.\" \"It's overwhelmingly one way still,\" he says. \"Things are maybe somewhat better, but it's not dramatically changed.\"

In a randomized study involving 582 patients with advanced nonsquamous lung cancer that had progressed after primary treatment, nivolumab produced a higher response rate and longer overall survival than standard docetaxel. Effective options are limited for patients with nonsquamous non–small-cell lung cancer (NSCLC) whose disease progresses after first-line chemotherapy. Docetaxel was approved as a second-line treatment for advanced NSCLC on the basis of longer survival than that with best supportive care. 1 – 3 Newer agents, such as pemetrexed and erlotinib, which have a better side-effect profile than docetaxel, have either been shown to be noninferior to docetaxel or have failed to show superiority to docetaxel with respect to overall survival when they are used as second-line therapy. 4 , 5 The programmed death 1 (PD-1) receptor expressed on activated T cells is engaged by . . .