Book review

Book review

Cytisine, a natural product with high affinity for clinically relevant nicotinic acetylcholine receptors (nAChRs), is used as a smoking-cessation agent. The compound displays an excellent clinical profile and hence there is an interest in derivatives that may be further improved or find use in the treatment of other conditions. Here, the binding of a cytisine derivative modified by the addition of a 3-(hydroxypropyl) moiety (ligand 4) to Aplysia californica acetylcholine-binding protein (AcAChBP), a surrogate for nAChR orthosteric binding sites, was investigated. Isothermal titration calorimetry revealed that the favorable binding of cytisine and its derivative to AcAChBP is driven by the enthalpic contribution, which dominates an unfavorable entropic component. Although ligand 4 had a less unfavorable entropic contribution compared with cytisine, the affinity for AcAChBP was significantly diminished owing to the magnitude of the reduction in the enthalpic component. The high-resolution crystal structure of the AcAChBP–4 complex indicated close similarities in the protein–ligand interactions involving the parts of 4 common to cytisine. The point of difference, the 3-(hydroxypropyl) substituent, appears to influence the conformation of the Met133 side chain and helps to form an ordered solvent structure at the edge of the orthosteric binding site.

The Smithsonian Center for Education and Museum Studies is hosting “Climate Change,” a three-day, free, education online conference Tuesday, Sept. 29 through Thursday, Oct. 1. This […]

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Snowflake Study through Photomicrography, 1890 Wilson A. Bentley became fascinated with the crystalline structure of individual snowflakes on his parent’s Vermont farm. By adapting a […]

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A new species of Brazilian leaf beetle named Cachiporra extremaglobosa, (which translated means the “extremely globular billy club leaf beetle,”) was recently discovered by scientists at the Smithsonian’s National Museum of Natural History.

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BROOKINGS, S.D. — Julie DeJong can’t set foot on the ground of an Oregon marsh to gather duck eggs on a spring day in 1875. […]

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Collecting trips for Charles Doolittle Walcott (1850-1927), paleontologist and fourth Secretary of the Smithsonian Institution, were often a family affair. This 1910 photograph shows their […]

The post Charles Doolittle Walcott (1850-1927) family campsite in the Canadian Rockies appeared first on Smithsonian Insider.

An excavation at a site in South Africa has unearthed the 190-million-year-old dinosaur nesting site of the prosauropod dinosaur Massospondylus–revealing significant clues about the evolution of complex reproductive behavior in early dinosaurs.

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On the Origin of Species by Charles Darwin, 1859 This week’s Smithsonian Snapshot marks the May 11, 1820, anniversary of the launch of HMS Beagle, the […]

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Parents normally feel the need to provide well for their kids. For humans, that number of offspring is usually in the single digits, but a […]

The post The secret formula to feeding 900 babies: Scientists uncover milk composition of naked mole-rat queens appeared first on Smithsonian Insider.

Earlier this year scientists presented evidence for Planet Nine, a Neptune-mass planet in an elliptical orbit 10 times farther from our Sun than Pluto. Since […]

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Thanksgiving Menu, 1905 Smithsonian Snapshot celebrates the Thanksgiving season with this 1905 Thanksgiving menu by George Elbert Burr from the Smithsonian American Art Museum. In […]

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Every day, astronomers at the Harvard-Smithsonian Center for Astrophysics depend on computers to help them solve the mysteries of the universe, just as they did […]

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Archan Chakraborty, Wei-Cheng Lin, Yu-Tsun Lin, Kuang-Jing Huang, Pei-Yu Wang, Yi-Feng Chang, Hsiang-Iu Wang, Kung-Ting Ma, Chun-Yen Wang, Xuan-Rong Huang, Yen-Hsien Lee, Bi-Chang Chen, Ya-Ju Hsieh, Kun-Yi Chien, Tzu-Yang Lin, Ji-Long Liu, Li-Ying Sung, Jau-Song Yu, Yu-Sun Chang, and Li-Mei Pai

Under metabolic stress, cellular components can assemble into distinct membraneless organelles for adaptation. One such example is cytidine 5'-triphosphate synthase (CTPS), which forms filamentous structures under glutamine deprivation. We have previously demonstrated that histidine (His)-mediated methylation regulates the formation of CTPS filaments to suppress enzymatic activity and preserve the CTPS protein under Gln deprivation, which promotes cancer cell growth after stress alleviation. However, it remains unclear where and how these enigmatic structures are assembled. Using CTPS-APEX2-mediated in vivo proximity labeling, we found that SNAP29 regulates the spatiotemporal filament assembly of CTPS along the cytokeratin network in a keratin 8 (KRT8)-dependent manner. Knockdown of synaptosome-associated protein 29 (SNAP29) interfered with assembly and relaxed the filament-induced suppression of CTPS enzymatic activity. Furthermore, APEX2 proximity labeling of keratin 18 (KRT18) revealed a spatiotemporal association of SNAP29 with cytokeratin in response to stress. Super-resolution imaging suggests that during CTPS filament formation, SNAP29 interacts with CTPS along the cytokeratin network. This study links the cytokeratin network to the regulation of metabolism by compartmentalization of metabolic enzymes during nutrient deprivation.

Laura O'Regan, Giancarlo Barone, Rozita Adib, Chang Gok Woo, Hui Jeong Jeong, Emily L. Richardson, Mark W. Richards, Patricia A.J. Muller, Spencer J. Collis, Dean A. Fennell, Jene Choi, Richard Bayliss, and Andrew M. Fry

EML4-ALK is an oncogenic fusion present in ~5% non-small cell lung cancers. However, alternative breakpoints in the EML4 gene lead to distinct variants with different patient outcomes. Here, we show in cell models that EML4-ALK variant 3 (V3), which is linked to accelerated metastatic spread, causes microtubule stabilization, formation of extended cytoplasmic protrusions and increased cell migration. It also recruits the NEK9 and NEK7 kinase to microtubules via the N-terminal EML4 microtubule-binding region. Overexpression of wild-type EML4 as well as constitutive activation of NEK9 also perturb cell morphology and accelerate migration in a microtubule-dependent manner that requires the downstream kinase NEK7 but not ALK activity. Strikingly, elevated NEK9 expression is associated with reduced progression-free survival in EML4-ALK patients. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through NEK9 and NEK7 leading to increased cell migration. This represents a novel actionable pathway that could drive metastatic disease progression in EML4-ALK lung cancer.

Samantha-Su Z. Taylor, Nicole L. Jacobsen, Tasha K. Pontifex, Paul Langlais, and Janis M. Burt

Connexin 37 (Cx37) expression profoundly suppresses proliferation of rat insulinoma (Rin) cells in a manner dependent on gap junction channel (GJCh) functionality and the presence and phosphorylation status of its carboxyl-terminus (CT). In Rin cells growth arrested by induced Cx37 expression, serine 319 (S319) is frequently phosphorylated. Preventing phosphorylation at this site (alanine substitution; S319A) relieved Cx37 of its growth suppressive effect whereas mimicking phosphorylation at this site (aspartate substitution; S319D) enhanced Cx37's growth suppressive properties. Like Cx37-WT, -S319D GJChs and hemichannels (HChs) preferred the closed state, rarely opening fully, and gated slowly. In contrast, Cx37-S319A channels preferred open states, opened fully, and gated rapidly. These data indicate that phosphorylation-dependent conformational differences in Cx37 protein and channel function underlie Cx37-induced growth arrest vs. growth permissive phenotypes. That the closed state of -WT and Cx37-S319D GJChs and HChs favors growth arrest suggests that rather than specific permeants mediating cell cycle arrest, the closed conformation instead supports interaction of Cx37 with growth regulatory proteins that result in growth arrest.

"The Antarctic Treaty Summit: Science-Policy Interactions in International Governance" will be convened at the Smithsonian Institution, National Museum of Natural History in Washington, DC from Nov. 30 to Dec. 3 2009. More information on this event can be found at the Web site: www.atsummit50.aq/

To assess legacy lessons about managing nearly 10% of the Earth "for peaceful purposes only"

Find out how you can be involved:

www.atsummit50.aq

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The three male cheetahs that left the Zoo's D.C. campus in 2009 returned in November and are now on exhibit. The five-and-a-half-year-old brothers―Draco, Granger, and Zabini, named after characters in the Harry Potter stories―have been living at the Zoo's Smithsonian Conservation Biology Institute's Cheetah Science Facility in Front Royal, Virginia.

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This film is from the collections of the Human Studies Film Archives, Smithsonian Institution. Clip from silent film, Beautiful Japan (1917-18), by travel-lecturer Benjamin Brodsky. Benten Festival is celebrated on Shiraishi Island. Benten (Benzaiten) is the Goddess of the Sea and one of the Seven Lucky Gods of Japan.

The post Beautiful Japan: Benten Festival 1917-1918, from the Smithsonian’s Human Studies Film Archive appeared first on Smithsonian Insider.

Silent black & white archival film clip from "Japan: Promotional and Theatrical Footage, ca. 1927". The full film, which is 17 minutes long, includes segments from what are believed to be a theatrical film, a promotional film and, possibly, amateur film - all of unknown origin.

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Click photo to take a tour of the 1903 Wright Flyer with Smithsonian X 3D Explorer. The Smithsonian X 3D Collection features objects from the […]

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 This film depicts the Onward Brass Band parading through the French Quarter of New Orleans and picking up second liners along the way. The […]

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When talk turns to the economy, it's clear that LA brings out the best and the worst.

Steve Julian: Business analyst Mark Lacter, where do you see the best of it here?

Mark Lacter: You see the best of the economy, Steve, with all kinds of startup activity - much of it tech-related - and you also see the large number of auto sales, the improved housing market, and the record number of people visiting Southern California - all indications of a growing economy.  But then, you have the other L.A. economy, with large numbers of families struggling to make ends meet, and seeing very little sign of recovery.  You know, the government has been releasing income data covering the last few years, and what you see is that the disparity between the richest 1 percent and the other 99 percent is at its widest point since the 1920s.  You especially see that kind of bifurcated economy in Southern California, which has some of the wealthiest people in the country, and also some of the poorest.

Julian: Now, the split between rich and poor has been happening for a good long time, hasn't it?

Lacter: Yes, but L.A. is in a special class because there are so many immigrants with limited job skills - in fact, a new study by the UCLA Anderson Forecast says it's a much higher percentage than immigrants living in Miami, San Francisco, and New York.  What's interesting is that 20 years ago the job skills among immigrants were significantly higher in L.A.  Limited job skills mean there's very little opportunity to move up the income ladder.  That factors into buying homes, sending your kids to college - really becoming part of the middle class.

Julian: I imagine that's particularly true for factory work…

Lacter: Yes, some of the same jobs that newly-arrived immigrants in previous generations would gravitate to.  Today, many of those jobs are gone, and they're being replaced by positions that require greater skill that's borne out of greater education.  And that, of course, is another problem: a sizable percentage of recently-arrived immigrants never finished high school, much less college, and that makes it even less likely that they'll be able to move up.

Julian: Related, or unrelated, to the recession?

Lacter: Actually, L.A. had serious income inequality in December of 2006, before the recession, when the county's unemployment rate was just 4.3 percent - a stunningly low rate when you consider that as of July, the jobless rate was almost 10 percent.  This points out that the division of haves and have-nots can happen even when the economy is doing well.

Julian: And it seems the last C-17 to be built for Air Force is a reminder of wage gap.

Lacter: That's right - it'll be up to foreign customers to keep the program in Long Beach alive.  Boeing currently has an order from India for 10 of the cargo planes, which will keep the line moving through the third quarter of next year.  Frankly, the only reason the C-17 has lasted this long is heavy political pressure by congressional lawmakers whose districts have an economic stake in the program.  At one time, as many as 16,000 people may have worked on the C-17 in Long Beach, but that number has fallen sharply over the years.

Julian: Still, this is the last airplane manufacturing plant in Southern California.

Lacter: And that, of course, speaks volumes about the state of the aerospace business, which had been one of the main economic drivers back in the days leading up to World War II.  Aerospace continued to be very important until the end of the Cold War, when you had a huge industry consolidation that resulted in the loss of tens of thousands of local jobs throughout the 1990s.  There's still quite a bit of aerospace activity locally that involves missiles, satellites, and electronics - both for the major defense contractors like Boeing and Northrop, and for smaller contractors and sub-subcontractors that still get a piece of the military pie.

Julian: But most of them require high skill levels…

Lacter: Yes, and that gets us back to the folks who are stuck in low-paying jobs with little prospect for moving up.  This is what the L.A. economy is all about, the good and the bad.

Mark Lacter writes for Los Angeles Magazine and pens the business blog at LA Observed.com.

This content is from Southern California Public Radio. View the original story at SCPR.org.

Sign ups for the Affordable Care Act start in a week, and the program is leading to changes in the way employers handle health coverage.

Steve Julian: Business analyst Mark Lacter, what's the most noticeable adjustment?

Mark Lacter: Steve, once you get beyond the squabbling over efforts to defund the new law, what's happening is quite remarkable: businesses are finding new ways to administer and pay for coverage - and some would say it's long overdue.  One interesting example: the grocery chain Trader Joe's, which is based in Monrovia, employs over 20,000 people, and shells out millions of dollars a year in helping provide its people with health insurance.  Well, Trader Joe's has decided to end coverage for part-timers working fewer than 30 hours a week - under the new law businesses are not obligated to provide benefits to employees who work less than that amount.  However, the company is giving those people $500 to go towards the purchase of premiums at the new public exchanges.  And that, along with the tax credits available, could make the new arrangement cost about the same or even cheaper than the current health care package.

Julian: How did TJ's explain this to its employees?

Lacter: The company cited the example of an employee with one child who makes $18 an hour and works 25 hours a week.  Under the old system, she pays $166 a month for coverage; under the new system, she can get a nearly identical plan for $70 a month.  Now, there are cases in which workers will end up paying more - usually it involves having a family member who makes more money, but who doesn't have access to coverage (good example would be an independent contractor or freelancer).  By the way, other companies - including the drug store chain Walgreen's - are also moving part-timers to the public market, and offering some sort of a subsidy.

Julian: I imagine not all companies are being as conscientious...

Lacter: No.  We've seen a number of corporations cut worker hours and not offer a supplemental payment.  Steve, it's worth remembering that administering health insurance is something that businesses fell into quite by accident 60 years or so ago - premiums cost next to nothing at the time, and it was seen as way of attracting workers without having to jack up wages.  The arrangement became more attractive over the years because of certain tax benefits.  But, it's far from ideal - workers move from job to job more often than they used to, and not all businesses are capable of handling the extra costs, especially small businesses.

Julian: Doesn't L.A. have a higher percentage of uninsured than elsewhere?

Lacter: Considerably higher - the Census Bureau show that 21 percent did not have coverage in 2012, which is higher than the overall national number.  Now, there are a bunch of reasons for this: L.A. has a large percentage of households that simply can't afford health insurance or don't have access to government programs, among them undocumented immigrants.  You also have big numbers of people who are self-employed and don't get covered - we're talking about freelancers or consultants of some sort.

Julian: …Or, they work for small businesses whose owners either can't afford, or don't want to provide coverage…

Lacter: That's right - the new law only requires businesses with more than 50 full-time workers to offer health insurance, and a lot of small businesses don't meet that threshold.  The Census Bureau says that in the L.A. area, one in four people with jobs do not have health insurance - and, by the way, there's been a drop-off both in the percentage of businesses in California that offer coverage.

Julian: Sounds dire.  Who picks up the cost?

Lacter: Well, we all do in one way or another - and that, of course, is the problem.  What the Affordable Care Act offers is a start in getting some of the uninsured onto the rolls.  Clearly, it's an imperfect solution that will require all sorts of adjustments, and even though everyone and their uncle seems to have formed a definitive opinion about the new law, it's going to be years before there's any real sense of how it's going.  And, let's remember, signing up for these programs is not some political act.  It's just a way for people to get health insurance for themselves and their families.

Mark Lacter writes for Los Angeles Magazine and pens the business blog at LA Observed.com.

This content is from Southern California Public Radio. View the original story at SCPR.org.