Advance toward an imaging agent for diagnosing Alzheimer's disease

Masahiro Ono and colleagues explain that no proven laboratory test or medical scan now exists for AD, which is claiming an increasingly heavy toll with the graying of the world's population. Patients now get a diagnosis of AD based on their medical history and symptoms, and symptoms like memory loss often are identical to those of normal aging. Currently, the only definitive way to diagnose AD involves an autopsy with examination of brain samples for the presence of the clumps and tangles of abnormal protein that occur in the disease.

The scientists describe the synthesis and lab testing of a new imaging agent (called FPPDB), which bound tightly to ß-amyloid plaques and neurofibrillary tangles — signs of AD — in human brain samples. In normal laboratory mice, which served as stand-ins for humans, FPPDB stayed in the body long enough for a PET scan (a sophisticated medical imaging technique). With further development, the imaging agent may allow early AD diagnosis in humans, the scientists indicate.

More information: 18F-Labeled Phenyldiazenyl Benzothiazole for in Vivo Imaging of Neurofibrillary Tangles in Alzheimer's Disease Brains, ACS Med. Chem. Lett., Article ASAP. DOI: 10.1021/ml200230e

Abstract
We synthesized and evaluated (E)-4-((6-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzo[d]thiazol-2-yl)diazenyl)-N,N-dimethylaniline (FPPDB) as a probe for the imaging of neurofibrillary tangles (NFTs) in patients with Alzheimer's disease (AD). In assays using thioflavin S (ThS) as a competitive ligand, FPPDB competed with ThS well and showed high affinity for both tau and Aß1–42 aggregates (Ki = 13.0 and 20.0 nM, respectively). The results of saturation binding assays also verified that FPPDB bound to both tau and Aß1–42 aggregates with high affinity (Kd = 44.8 nM and Bmax = 45.8 pmol/nmol protein for tau aggregates and Kd = 45.4 nM and Bmax = 38.9 pmol/nmol protein for Aß1–42 aggregates). Furthermore, [18F]FPPDB substantially labeled NFTs and senile plaques in AD brain sections but not control brain sections. In biodistribution experiments using normal mice, [18F]FPPDB displayed higher uptake (4.28% ID/g at 2 min postinjection) into and washout (2.53% ID/g at 60 min postinjection) from the brain with time. On the basis of the chemical structure of FPPDB, further increases in selective binding to tau aggregates may lead to the development of more useful probes for the imaging of NFTs in AD brains.

Provided by American Chemical Society (news : web)

Why do dew drops do what they do on leaves?

In the study, Martin E. R. Shanahan observes that drops of water have a preference for exactly where they collect on leaves as their surfaces cool in the morning and afternoon. Those droplets, which condense from water vapor — moisture — in the air, collect randomly across the surfaces of flat leaves. However, dew drops tend to accumulate at the tips of spindly leaves, even if that means defying gravity by moving upwards. He explains that an inherent "unwillingness" or "lack of necessity" of water drops to move on a dry surface governs their positioning on flat leaves, causing them to stay where they form. Dew's tendency to head to the end of finely pointed leaves, however, sent Shanahan looking for a different explanation.

The answer is based on the fundamental principle of free energy, that everything in nature seeks the lowest possible energy state. Shanahan modeled two types of dew drops on a theoretical (simplified) cone-shaped leaf: a thin, cylindrical sheath of water and a spherical drop centered on the cone's axis. In both cases, he found that the drop lowered its energy by moving toward the point of the leaf.

More information: On the Behavior of Dew Drops, Langmuir, 2011, 27 (24), pp 14919–14922. DOI: 10.1021/la203316k

Abstract
It may be observed that, when dew drops form, although they may be positioned randomly on flat leaves, they tend to accumulate at the pointed ends of thin, slightly conical growths. We discuss here the basic physics leading to this phenomenon.

Provided by American Chemical Society (news : web)

Metal oxide simulations could help green technology

The new paradigm could lead to a better understanding of corrosion and how toxic minerals leach from rocks and soil. It could also help in the development of “green” technology: new types of batteries, for example, or catalysts for splitting water to produce hydrogen fuel.

“This is a global change in how people should view these processes,” said William Casey, UC Davis professor of chemistry and co-author of the study with James Rustad, a former geology professor at UC Davis who now works as a scientist at Corning Inc. in New York.

Previously, when studying the interactions of water with clusters of metal oxides, researchers tried to pick and study individual atoms to assess their reactivity. But “none of it really made sense,” Rustad said.

Using computer simulations developed by Rustad, and comparing the resulting animations with lab experiments by Casey, the two found that the behavior of an atom on the surface of the cluster can be affected by an atom some distance away.

Instead of moving through a sequence of transitional forms, as had been assumed, metal oxides interacting with water fall into a variety of “metastable states” — short-lived intermediates, the researchers found.

For example, in one of Rustad’s animations, a water molecule approaches an oxygen atom on the surface of a cluster. The oxygen suddenly pulls away from another atom binding it into the middle of the cluster and leaps to the water molecule. Then the structure collapses back into place, ejecting a spare oxygen atom and incorporating the new one.

Provided by UC Davis (news : web)

The path less traveled: Research is driving solutions to improve unpaved roads

Wilson Smith, master's student in civil engineering, Independence, Mo., is working with lignin, a plant-based sustainable material that can be added to improve the quality of unpaved roads throughout Kansas.

More than 70 percent of the 98,000 miles of roads in Kansas are unpaved, Smith said.

"One of the problems with unpaved roads is that they are made from loose granular soils with particles that are not bound to each other on the road surface," Smith said. "This limits the speed of vehicles and often generates a lot of dust, denigrating the quality of the road."

But possible solutions could come from lignin, a biomass product that is present in all plants, including wheat straw, sugar cane and corn stover. Lignin is a waste product from other industries, including the production of biofuel and paper. These industries take plant mass and use the process of hydrolysis to separate useful materials, including cellulose and hemicellulose, from lignin.

"What we're trying to do is find new uses for this lignin co-product, which ties into sustainability," Smith said.

Several properties make lignin a valuable material. It is adhesive when it becomes moist, making it good for binding soil particles together and providing cohesion. As a result, lignin works very well on unpaved roads by providing better support for vehicles and protecting the road from erosion.

Because Kansas is an agricultural state, lignin is an abundant resource and has the potential to improve unpaved roads, leading to less maintenance costs throughout the state, Smith said.

"Lignin can be extracted from many types of crop residue, and it can also be an extra source of income to farmers and the agricultural community if there is a demand for this crop residue," Smith said. "Lignin is a sustainable product. It's 100 percent nontoxic, unlike traditional soil stabilizers such as flash or cement, which do have some heavy materials in them that could contaminate soil."

Smith is working under the direction of Dunja Peric, associate professor of civil engineering.

"Kansas is strategically positioned for using lignin to stabilize unpaved roads," Peric said. "Kansas is located in the midst of the Great Plains, which is one of the largest wheat producing areas in the world. In addition, the construction of the nation's first commercial-scale cellulosic ethanol plant has recently begun in Hugoton."

For his research, Smith takes soil and mixes it with different amounts of water and lignin. He is testing five different lignin concentrations -- 2 percent, 4 percent, 6 percent, 9 percent and 14 percent -- to understand how different levels of lignin affect the soil cohesion and, consequently, road erosion.

Smith then lets the mixture dry in a controlled environment for different periods of time to understand how much it increases the strength of the samples. Other members of Peric's research team have been testing the strength of lignin samples immediately after they are mixed rather than allowing them to dry.

Once the materials are dry, Smith uses a direct shear device to determine the strength of the different mixtures. The direct shear device simulates the stress that unpaved roads experience when cars and heavy machinery drive on them.

"When vehicles drive on unpaved roads, there is a lot of dust that is thrown into the air," Smith said. "In addition, travel is impaired because of raveling and washboarding, which are forms of soil collapse on the top surface of the road. These are all things that can be mitigated by lignin because it holds the soil particles together and in place."

Based on early results, the materials with lignin concentrations of 4 percent, 6 percent and 9 percent show the highest strength benefits. Smith will spend the spring semester further testing all of the different concentrations and how their strength develops with the amount of elapsed time.

"We want to get an exhaustive analysis of how the cohesion varies when you change the concentration of lignin, the water content and the compaction," Smith said. "That will determine in the field, what percentage of lignin is the best concentration to stabilize the soil."

Smith will give a research presentation titled "Feasibility of Using Lignin: Plant Derived Material for Stabilization of Unpaved Roads" at the Capitol Graduate Research Summit in Topeka in February.

Provided by Kansas State University (news : web)

Scientists paint new picture of dance between protein and binding partners

Instead, the situation resembles a kind of complex but carefully organized dance routine, where the ligand samples a variety of binding modes while the protein also modifies its shape, a process that results in their pairing and changes in the protein critical for its function.

These new findings, published in the January 11, 2012 edition of the journal Structure, could affect future drug design.

"Using a multidisciplinary approach, we gleaned something from our data that no one else has," said Douglas Kojetin, an assistant professor on the Scripps Florida campus who led the study. "The conventional wisdom is that ligands bind in one orientation but our study shows that they can bind in multiple modes. That means if we can optimize a ligand to bind in mode B rather than mode A, we might be able to select the therapeutic results we want."

The new study—which used a number of complementary technologies including NMR spectroscopy and hydrogen/deuterium exchange (HDX) coupled to mass spectrometery, combined with previous x-ray crystallography analyses—provides detailed insights into the real-time actions of molecules that could never be determined with a single technology.

Specifically, the researchers revealed insights into ligand and receptor dynamics in the nuclear receptor known as PPAR? (peroxisome-proliferator-activated receptor). PPAR? has been implicated in metabolic diseases including obesity, diabetes, and atherosclerosis.

The study also found that various gradations in these ligands influence the dynamics of this exchange, adding another layer of complexity. "One of the compounds, MRL24, binds to the receptor and has anti-diabetic efficacy, but doesn't activate it very well," Kojetin said. "This is what you want because when the receptor is activated you get side effects such as weight gain and brittle bones."

"This study in particular highlights the importance of multidisciplinary collaborative efforts to truly understand the molecular details of drug-receptor interactions", says Kojetin. "This work is an excellent example of the strong campus collaborations we have with the laboratories of Patrick Griffin, Thomas Burris, and Theodore Kamenecka."

More information: The first author of the study, "Ligand and Receptor Dynamics Contribute to the Mechanism of Graded PPAR ? Agonism," is Travis S. Hughes of Scripps Research. Other authors include Michael J. Chalmers, Scott Novick, Dana S. Kuruvilla, Mi Ra Chang, Theodore M. Kamenecka ,Thomas P. Burris, and Patrick R. Griffin of Scripps Research; Mark Rance of the University of Cincinnati; and Bruce A. Johnson of One Moon Scientific Inc.

Provided by The Scripps Research Institute (news : web)