Journal of Scientific & Industrial Research Vol. 59, June 2000, pp 517-530

SCI-TECH UPDATE

Giant computer solves protein mystery

The world' s fastest supercomputer has been designed to provide unique insights into human diseases.

The gargantuan number-cruncher, named Blue Gene, will be around 500-times more powerful than today' s fastest computers. Its creators hope it will take just one year to solve a problem that is fundamental to under­standing human disease-protein folding . This challenge would take centuries using the most advanced technolo­gies currently available.

Proteins, which are strings of amino acids, control all living processes. They make up enzymes which catalyse chemical reactions and as antibodies they fight disease. Their function is largely determined by the way they fold : the same sequence of amino acids can turn from helpful to harmful simply by changing shape.

IBM scientists hope to be able to write a modelling programme that will predict the way any given protein folds - in particular the shape it takes on when it be­comes diseased. Researchers would then use this infor­mation to develop drug molecules with the right shape to latch onto the diseased protein and stop it causing harm.

Paul Horn, senior vice president of IBM Research says that breakthoughs in computers and information technology have created new frontiers in biology. If this computer unlocks thN}1ystery of how proteins fold it will be an important milestone in the future of medicine and healthcare.

IBP predicts that eventually, Blue Gene will help pharmaceutical companies design drugs customised to an individual's genetic make up just by analysing tissue samples. The company says the computer will also allow medical researchers to respond rapidly to the genetic mutations in bacteria that lead to drug resistance.

Blue Gene is based on a radical new computer design nicknamed SMASH- 'simple, many and self-healing.' It will be able to handle more than 8 million threads of computation simultaneously, compared with the current maximum of 5000, and will be the first of a new genera­tion of self-stabilising computers that can automatically fix themselves when individual components fail.

IBP hopes to work with some of the world's leading drug makers and research centres on the Blue Gene project [Chern lnd, 24 (1999) p. 951].

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Microchips deliver drugs and reagents on command

Professor Robert S Langer and his colleagues at Mas­sachusetts Institute of Technology have deleloped micro­chips that deliver drugs and reagents in a controlled manner on electronic command which could be useful in medical therapeutics and diagnostics, analytical chemis­try, industrial process monitoring and control, combina­tional chemistry, and microbiology. The microchips contain tiny reservoirs with different solid, liquid, or gel materials inside. When an electric potential is applied to an electrode, a thin gold membrane over a reservoir dissolves electrochemically, opening the reservoir and allowing the material inside to come out. Various mate­rials can be loaded into reservoirs on the same microchip and released at any time and in any order desired .

So far, the automated release of drugs and chemicals has generally involved controlling the rate of dissolution (e.g. tablet the rate of degradation. For instance contain­ing polymer) or the rate of diffusion such as of a drug from a tablet. However the MIT microchips have made it possible to control not only the rate of release but also the exact time of release of each component in a set of reagents. MIT microchips are only distantly related to the tiny microfluidics (liquid-handling) devices currently being developed by several companies because they do not contain any channels or pumps, as most rnicrofluidics devices do, and thus have no mechanism for liquid flow . They just have the ability to store and release chemicals.

Langer and coworkers have reported that a microchip they constructed successfully releases fluoroscent dyes and radio labeled compounds in a controlled manner. The prototype chip, which measures 17mm on a side, contains 34 reservoirs of above 25 nl capacity each. A chip of that size actually has enough surface area to accomodate about 1000 reservoirs. The researchers have came up with the mechanism with the electrochemical dissolution of membranes, get rid of all movable parts. When po-

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tential is applied to a membrane it dissolves and the reservoir opens.

A primary application of the technology will be in drug delivery. The MIT microchips could be implanted sub­cutaneously and used to deliver potent drugs, such as hormones, steroids or painkillers. Chips could be inte­grated will transdermal devices for patch type drug-deliv­

ery applications.

One will be able to program into these chips any pattern of release that one wants. All the individual packets of drugs are individually adressable, so multiple drugs can be put into any sort of array which has the potential to be a very versatile and powerful technique.

Diagnostics applications can also be anticipated. Cus­tomized chips could be used to release reagents needed for specific assays or tests on clinical samples. Biosen­

sors could potentially be incorporated into chip surfaces, making it possible for the chips not only to initiate assay reactions but also to detect and quantitate compounds produced in those reactions. Handled probes containing the chips could be used to release test reagents into small volume samples of body fluids, such as urine or blood.

The MIT microchips could complement microfluids, microreaction, and DNA-chip technologies. Currently, reagents must be provided to such devices from the outside. The ability of these devices to store reagents onboard and then release them on command could open up some new possibilities.

The MIT researchers have found three possible ways of controlling reagent release from the chips: remote control, preprogramming, and biofeedback. Remote control could be carried out with radio transmitters and tiny on-chip receivers preprogramming would involve the use of on-chip memory, and biofeedback could be accomplished by equipping the chips with sensors and transducers, enabling them to trigger release of reagents in response to signals they detect. The group orted that the chips had wires attached to it and is thus not exactly ready to be swallowed. And it has to be bathed in a salt solution for the electrochemical-membrane-dissolution

mechanism to work. [Chem Eng News, 77(5)(1999)p.301; For more information see: Nature,

397( 1999)p.335].

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Imaging 3-D fluorescence technique

The resolution of focusing light microscopes is tradi­tionally limited by the wave nature of light. This limit was overcome by scientists at the Max Planck Institute (MPI) for Biophysical Chemistry in Gbttingen, Ger­many, by using two laser beams in which one beam illuminated the sample while the second beam sculpted the fluorescence spot generated by first.

In biological research, use of the focusing light micro­scope is the only way to allow the imaging of intact transparent specimens in 3-D, especially when tagged with fluorescent dyes. However the resolution is ham­pered by diffraction. Thomas A Klar and Stefan W Hell of MPI have reported that in order to inhibit the fluores­cence from its rim the fluorescence spot must be de­creased.

To sculpt the fluorescence spot the researchers used two beams of different colours, each of them involving ps pulses. Whereas the first pulse excites the fluoroplore the slightly red-shifted pulse is able to induce the effect of stimulated emission. The stimulated emission forces the molecule to the ground state by carrying away their energy. So the stimulating red pulse instantaneously "cools off" the excited fluorophore without distroying it. By moving the stimulating pulse to the rim of the excita­tion spot the researchers switched off the fluorescance from the outer part of it. It was reported that "for a l.4 aperture and 388 nm excitation wavelength spatial reso­lution is increased from 150 8 nm to 106 8 nm with a single offset beam. They achieved superior lateral reso­lution by separating of adjacent Pyridine 2 nanocrystal s that are otherwise indiscernible [M R S Bull, 24 (No. I 0) (1999) p. 1 0].

New direction of research for industrial catalysis

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T 0 Noda of MCC, Japan has given an overview of research for industrial catalysis at MCC and the recent trends to accelerate technology development. Four exam­ples of concurrent technology development, computa­tional chemistry, hybrid process development, and development of new hydrogenation processes have been discussed . Businesses which are linked to catalysis are areas of synthetic chemicals, environmental catalysis, petroleum refining, and catalyst production and sales managing of hybrid process of organic synthesis, biosyn­thesis, and catalysis can be a strong tools. Technology development requires synergy of Catalyst development,

SCI-TECH UPDATE 1 SCI IND RES VOL. 59 JUNE 2000 519

Reaction analysis, Process analysis, Process synthesis on one side and cost engineering; Equipment diagnosis, Safety engineering, Optimum production from the other side. Research, Development, Engineering and Produc­tion Technology are part cl' one organisation. Organisa­tional partition walls in a company must be lowered . MCC is intensifying its efforts on propane to acryloni­trile, which includes recovery of unconverted propane for recycle.

Computational approach has been applied to the oxo­reaction of propylene to maximise n-butyraldehyde. The design of the ligand is crucial. Here, based on the reaction mechanism and molecular mechanics, structure of biphosphate ligands has been worked out and is to be tested commercially .

An example of a hybrid process is provided for making 5- aminomethyl-2-chloropyridine (CPMA). 3-Cy­anopyridine is converted to 6-hydroxy derivative via biosynthesis and then chemical synthesis converts -OH to -Cl (chlorination with thionyl chloride by acid-amide catalyst) and subsequent hydrogenation with Raney­Nickel catalyst. On ROA basis, this is an excellent busi­ness.

L Aspartic acid from maleic acid via fumaric acid is also reported using aspartase. The separation and recy­cling of cells from the reaction mixture is done by an u/f system. Now R-DNA technologies are being applied to impose productivity. L-aspartic acid is crystallised by adding fumaric acid.

A new hydrogenation process for converting succinic anhydride (from MAN) to gamma-butyrolactone with a new homogeneous Ru- complex catalyst, at low pres­sures, is reported and in 1997 a plant of I 0000 tpa was established. Hydrogenation of aromatic carboxylic acid, e.g., benzoic, o-toluic, p-toluic m-chlorobenzoic acid etc., to aldehydes with 82 to 98 per cent conversion and 75 to 96 per cent selectivity has been covered. Aliphatic acids to aldehyde is also converted and I 0- undeceny I aldehyde is being commercially produced since 1996 [Chem Week, 65 (No. 22) (2000) p. 64].

For further information read:

Sci Tee/mol in Catal, 1998,

published in I999 by Kodansha Ltd, pp 33-40.

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Biosensors for detecting deadly land mines developed

Carl Flierman and his colleagues at the Savannah River Technology Center in South Carolina have devel­oped biosensors that are more effective and less expen­sive systems for detecting deadly land mines. Current methods for locating mines are archaic-visual sighting and digging in suspected mine areas-which include the use of metal detectors. Given that most areas containing land mines also contain metal shell casings, and benign metal fragments , however, the use of metal detectors that lack the capacity to distinguish between a mine and a metal container wastes valuable time. Furthermore, met­al detectors are useless in locating the many newer land mines made of plastic material . These must be sought out by dogs or again by hand.

Flierman method uses bacteria that have been geneti­cally altered to glow when they feed on the trinitrotoluene (TNT) chemicals that leach out of most land mines­some 90 per cent of them. Taking advantage of the process by which, when these bacteria ingest TNT com­ponents, they begin to convert their 'meal' into energy, and then gene is inserted for luminescence or fluores­cence beside the gene that controls digestion. Whenever the bacteria begin to digest TNT, it glows, and signal the presence of the deadly mines. Luminescent bacteria are visible to the naked eye; Fluorescent bacteria require night vision goggles. Once identified the mines could be flagged and removed safely. Once the mines are removed the bacteria die off [Chem Week, 45(24) (2000) p. 132; Nature Biotechnol, 17 (8) (1999) p. 732].

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Polymeric thin film sensors detect microbes and toxic gases

Subhas Chander and colleagues at the Polymer Elec­tronics group at National Physical Laboratory (NPL), New Delhi, have developed plastic thin film sensors to detect the presence of microbes in food, and poisonous gases in mines. Based on the plastic counterpa1t of semiconductors (materials whose conductivity is inter­mediate between that of a metal and an insulator) the sensors have been developed by depositing a thin film (thickness of ten-millionth of a metre) of the polymer on an appropriate substrate.

Subhas Chander claim that these polymeric thin film sensors could be used in the mining industry, food proc­essing units, and environment monitoring. Conducting

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polymers are made by doping ordinary polymers with element like boron, aluminium, iron, copper, and nickel.

-The sensors were successfully tested to detect a score of microbes, including yeast, Escherichia coli, Pseudo­monas, Salmonella, Staphylococcus aureus and Rhizo­biaceae which are known to rot food. The sensors have also been tested for detecting trace amounts of carbon monoxide in underground mines successfully. The NPL team is currently optimising the sensors to detect other gases like ammonia, hydrochloric acid, hydrocyanic acid, nitrogen oxides and sulphur dioxide. The sensitivity of these detectors depends on the concentration of the gases and microbes as well as on the exposure time.

According to Subhas Chander the low-cost, fast-re­sponse sensors could be deployed in food processing units which suffer from the problem of microbial con­taminations that could lead to serious health hazards. They could be positioned remotely to provide an alaram in underground mines, when levels of toxic gases exceed safety limits.

The NPL team, however, concedes that it does not know the exact working mechanism of such sensors. The researchers have tested these sensors repeatedly and it works well and these probably work on the principle of charge transfer between the sensors and the subject to be sensed as microbe cell walls are known to contain charges. Though, multinational companies including

Hoechst, Ciba-Geigy, and Deyer are manufacturing such sensors, Indian companies have not yet shown inter­est in commercialising them [Chem Week, 44 (No. 50) (1999) p. 37; PTI Sci Serv, (May 1-15, 1999) p. 4].

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Lower cost method for fabricating thin-film transistors

Physicist Joseph M Jacobson, Brent A Ridley and Babak Nivi at Massachusetts Institute of Technology' s Media Laboratory have demonstrated a simpler, lower temperature, and potentially lower cost method for fab­ricating thin-film transistors by "printing" the semicon­ductor. Solutions of Cdh and N a2Se are added to pyrindine, producing cadmium selenide (CdSe) nanocrystals . After purifying this product, a single drop of a CdSe nanocrystal solution is deposited in the area between the source and drain electrodes of a transistor test structure on a wafer. The wafer is heated on a hot plate to 350°C, sintering the CdSe nanocrystals into a polycrystalline film.

This device-an all-inorganic field-effect transistor­exhibits charge-carrier mobilities up to 1 sq crnN s. This is an older of magnitude greater than mobilities reported for printed organic transistors, although it is well below those ofhigh-performace devices. Jacobson and cowork­ers are still far from a fully printable inorganic device, but their work eventually may allow "inorganic logic" to be printed on plastic substrates [Chem Eng News, 77 (43) (1999) p. 37; Science, 286 (1999) p. 746].

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A technique to analyse total antioxidant power of olive oil developed

Saverio Mannino and his colleagues at Milan Univer­sity, Italy, have developed a technique for analysing the total antioxidant power of one of the most promising natural foods- oilve oil. It is claimed that use of a flow injection analysis system, combined with electrochemi­cal detection avoid some of the problems of standard techniques. The technique can process 90 per cent sam­ples/h. This can also be done at a lower concentration than is possible with the common Rancimat method.

According to Mannino, exidative rancidity is the criti­cal factor affecting the shelf-life of many fuels, and it is the auto-oxidation of fatty acids that causes food to smell and taste foul, and become unfit to eat.

The hunt for so-called 'natural ' antioxidants for the food industry has desired the need for a quick and easy way to assess how effective a particular substance is at inhibiting oxidation. For decades, various additives have been used to inhibit oxidation and so keep processed foods 'fresh' for longer. However, consumer pressure has led the industry to search for alternative 'natural' ingredients and to avoid synthetic antioxidants, even though several of these are simply manufactured vita­mins.

Olive oils are well-known for their antioxidant com­ponents, and this property has been partly used to explain the role they are thought to play in reducing cardiovascu­lar disease. Various polar phenolic compounds such as tocopherols , phenolic derivatives of cinnamic and ben­zoic acid, and oily (oleosidic) versions of tyrosol and its derivatives are present in olive oil.

According to Mannino, each component may have a role to play in reducing oxidation but assesing the overall effectiveness of the oil has relied en questionable meth­ods. The standard tests usually apply oxidative condi­tions to food samples using light or metal cataiysis,

SCI-TECH UPDATE J SCI IND RES VOL. 59 JUNE 2000 521

high-temperature oxygen 'bombs' and active oxidation. These methods are rather severe in their oxidation and do not represent the normal auto-oxidation of foods. Be­cause the electrochemical method developed by the Mi­lan team avoids the severity of oxidation, it provides a much more representative method of assessing antioxi­dant power. Mannio believes the technique will be at once adopted by the industry [Chern Br, 3S(No. 10)(1999)p.19; The Analyst, 124(1999)p.lll5].

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Holographic 3-D camera detects stealth aircraft defects

A lenseless imaging system that uses Fourier trans­form algorithms to verify the condition of a stealth air­craft's radar absorbing material has been developed by a group working at the Department of Energy's Pacific Northwest National Laboratory.

The holographic 3-D radar camera increases the num­ber of tools that ground crews and pilots can use to assess the integrity of multi-million dollar fighter aircraft. Point contact tools that are being currently used are pushed onto the aircraft and pulled off again. This action increases the chances of damage to the aircraft skin.

The handheld camera developed at Pacific Northwest never touches the aircraft. Working about 2ft from the target zone, an operator takes snapshots of the entire plane using low-power electromagnetic waves. The camera consists of an array of256 radar antennas th'at receive and transmit the amplitude and phase of reflected energy in a 1 x 1 less ft zone to a computer for processing. The Kuband camera operates at 12-18 GHz and the X-band camera operates at 8-12 GHz. Evaluating the aircraft across a range offrequencies is important because longer­range search or surveillance radar usually operate on lower frequencies. Shorter range radar such as those used by missile and artillery targeting systems, operate on higher frequencies.

To determine the aircraft's ability to repel radar, a radar signature is generated from the computer data and projected into an off the shelfhead-mounted display worn by the operator. The display goggles are high resolution VGA screens. A green signature in the head mounted display means the inspected area is nearly invisible to radar; a red signature warns that the inspected area has a high level of reflection and may be more visible to radar; and a yellow signature suggests the area has degraded, but not necessarily to the point at which repairs are needed.

Although the main uses of the camera are for low observance materials and quality control during aircraft manufacturing, future applications include detecting plastic explosives worn by humans [Opt Photon News, 10(No.7)(1999)p.12].

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New paradigm in environmental problem solving

When we try to pick out anything by itself, we find it hitched to everything else in the universe, says environ­mentalist John Muir.

Now researchers are discovering the wisdom of Muir's observation: When it comes to the environment, every­thing is indeed interconnected.

According to biogeochemist Pamela A Matson, if we want a future in which people can live in balance with nature, then scientists and policy-makers must join forces and take an integrated approach to solving environmental problems.

Matson, a professor of environmental studies in the Department of Geological and Environmental Sciences and the Institute for International Studies at Stanford, has issued her call for "a new paradigm in environmental problem solving" at the annual meeting of the American Association for the Advancement of Science (AAAS) on February 20, 2000 in Washington, DC.

In the past the research, management and policy com­munities have tended to think about environmental prob­lems like air pollution, water pollution, over-fishing or climate change in isolation from each other.

Today and in the future, we will have to discuss their interacting effects. Solving air-or water-resource prob­lems will require working in an integrative way across multiple sectors (industry, agriculture, urban users) and with multiple stakeholders.

Because environmental problems and their causes play out in different ways in different places, Matson suggests that generic solutions may not be possible, and that "place-based, integrative approaches will be necessary".

During her presentation at AAAS session on "Sustain­ability Science for an Uncertain Century," Matson cites the CALFED Bay- Delta Prgram and the Southern Oxi­dants Study as examples of fledgling integrative ap­proaches to research and problem solving.

The Bay-Delta program is a consortium of state and federal agencies that works with agricultural , environ­mental and urban stakeholders to restore ecological health to the San Francisco Bay and Sacramento-San Joaquin River Delta system. The long- range objective

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of the program is to provide a reliable water supply to all users while improving water quality and aquatic habitats in California.

The Southern Oxidants Study (SOS) is an effort by social and biophysical scientists, engineers and air-qual­ity managers to understand the complex causes and con­sequences of smog and ozone pollution that occur across large regions of the southeastern United States, and to provide that information to policy makers and managers .

Matson notes that both SOS and the Bay-Delta pro­gram are "just starting, and it will be critically important to understand why they work or do not work, and what the impediments to their success are."

Matson also cites work she and others have done in the Yaqui Basin in Sonora, Mexico, one of Mexico's major breadbaskets. The valley has enjoyed a dramatic rise in wheat production in recent years, due to the increased use of pesticides and nitrogen-based fertilizers.

But modem agriculture also has an environmental downside, as farmers inadvertently release high levels of nitrogen into the air and water supply through excess fertilization .

Matson demonstrates that by using less fertilizer, farmers could save up to $30 I ac and still produce as much wheat as before- with the added bonus of reducing nitrogen pollution in the region.

Matson notes that understanding the connection be­tween farm economics and nitrogen pollution results in a "win-win solution" for both the farmer and the environ­ment.

Matson points out that researchers from Stanford and four other

U S and Mexican institutions are also attempting to look at the big picture-to understand the policy drivers and environmental and resource consequences of agricul­tural and urban development in the Yaqui Basin.

If the people of the region are interested in sustaining fisheries, or conserving wetlands or equitably allocating water then they have to understand and manage both the upland agricultural area and the coastal zone as a linked system.

The ultimate objective of such an integrative, place­based approach is to create a sustainable planet where we can feed, house and employ all people while maintaining our natural resources and our global life support systems [Stanford News, 17 February 2000].

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Improving the weather forecasts

For studying climate mechanisms that behave errati­cally from season to season, it becomes difficult for the farmers to predict weather with regard to developing winter crops. Therefore, ARS atmospheric scientist Steven A Mauget and soil physicist Dan R Upchurch have tested the forecasts based on various mechanisms that can give edge to farmers in real sense.

Through, a search of 103y of climate data, researchers found significant climate effects due to El Nino and La Nina phases of El Nino-Southern Oscillation (ENSO) phenomena, with the strongest effects occurring during the winter in northern US.Their work suggests that ENSO-based forecasts may help farmers manage winter crops, such as winter wheat.

Maught and Upchurch have suggested that during severe winter wheat yields during El Nino's cool, wet winters and lower yields during La Nina's warm, dry winters. They believe that such forecasts could be valu­able in managing other winter crops, such as citrus and winter produce.

In future, these researchers plan to search ocean tem­perature and surface pressure records over the past cen­tury for clues to 12 and 20-y rainfall cycles observed over the Midwest. If they succeed in pinpainting the source of these cycles and the cycles prove predictable, they be­lieve that it might be possible to improve the conditions on climate over longer durations and to place these im­provements further in advance.

Finally, Mauget and Upchurch want to test whether those loaded dice will be a help or a fatal lure. They have done this by using computer simulations of a hypothetical grower's management practices over the course of two parallel farming careers.

During the farmer's first career, she/he will have ac­cess to seasonal climate informat ion, but not during the second career. By comparing the difference in net profits between the careers, they hope to estimate the value of such forecasts.

According to Mauget, their role is to see that if these predictions actually translate into higher profits, or whether they cause so much risk-taking that profits de­crease.

For further information contact: Dan R Upchurch and Steven A Mauget USDA-ARS Cropping Systems Research Laboratory, 3810 4th St, Lubbock. TX 79415; Ph. (806) 749-5560; Fax: (806) 723-5272

SCI-TECH UPDATE J SCI IND RES VOL. 59 JUNE 2000 523

e-mail : dupchurch @lbk.ars.usda.gov ;smauget @ lbk.ars.usda. gov [Agric Res, 47 (No. 12) (1999) p. 19].

Label finishing range with high performance

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Two US companies have collaborated in producing a label finishing range that offers better performance in a smaller range. The Verdium Woven Label Pad Finishing range machine developed by Verduin Machinery, Inc. and Radiant Energy Systems, Inc., is designed to apply a controlled amount of coating to reels of woven labels and cure them in an efficient and productive manners. Ver­duin provides the finishing expertise and technology, and Radiant provided the equipment and knowhow for effi­cient and gentle drying. Reels of woven labels are deliv­ered to a three-roll air loaded padder by a cantilever multi-spindle unwind that also features tension control. The coating is applied in a controlled manner by an application roll.

This has precise nip adjustments for squeezing off the labels. Dip coating or kiss coating is handled, as a result of the various lacing patterns of the range. A Predryer, supplied by Radiant Energy Systems enhances the re­moval of moisture and also speeds up the production process for dip coated labels. The efficiency of the drying process is enhanced by the infrared heaters, which give off energy at wavelengths that are readily absorbed by water. The system gently dries the material so that it is not overheated. Final drying is achieved in a six drum vertical dry can station using steam heating. [For further reading see; Tnt Dyer, 184(5) (1999); Chern Week, 45(24)(2000)p.l41].

Long decay phosphor developed

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Long decay phosphor is a coating of a special lumines­cent material which has been developed at the National Physical Laboratory (NPL), New Delhi. This phosphor has a property that it can be excited by an ordinary lamp or tube light and its glow can be observed after switching off light. It stores the light. This energy is released in the form of visible light which decays slowly and takes hours to completly die out.

The advantage of the above special property is its use as light source and signs. In the event of a sudden power failure, when our vision is momentarily blacked out due to sudden transition from bright light these signs are highly visible. In continued darkness, depending on our

dark adaptation, these are visible for 6 h. These find some strategic defense applications in specific uses as escape route indicators and signs during fire or black outs at times of air raids, etc.

Other areas of applications of this material are as follows:

Photoluminescence escape routes and residue guid­ance system.

Warning signs and accident prevention.

Marking of important machinery.

Producing special effects in bars, discotheques, etc.

Flexible and rigid plastics for switches and co11sumer goods.

Toys, sports equipment, Enamels and ceramic tiles , Bank Notes

[NPL Rep, February 2000].

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A new way for detecting chemi cal signatures of life

Chemists have been asked to collaboration a UK gov­ernment- sponsored hunt for extraterrestrial life. The scientists included are physicists, geologists, biologists, and chemists collectively known as astrobiologists, will collaborate on earth- based analysis of other planets and moons, including some which are 50-100 light y away . The team will also increase the UK' s involvement in the European space Agency's Mars probe, Beagle 2, which is due to land on the red planet on board the European Mars Express in 2003.

Chemists will contribute to the initiative by devising new ways of detecting the chemical signatures of life, while astronomers will design missions to distant planets. Biologists will study how life survives in the extreme environments on earth. Finding evidence of life beyond earth is not the initiative's only aim. The research could also lead to spin-offs in areas such as drugs, smart fluids , and high performance sensors.

Many British scientists brought together they make a powerful force which will enable us to find out still more about where we come from and what other life might exist or have existed in the universe [Chern lnd, 24 (1999) p. 951].

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A New process makes fertilizers fron straw

A new process that utilises the straw to make fertilizers has been developed by a team lead by Tony Bridgewater, Professor of Aston University's Bio-energy Research Group in UK. The new process, straw will use straw to make substances that will result in various fuels, chemi­cals, fertilisers and glue. This would benefit industries based on horticulture and agriculture as it would provide a sustainable way of not only utilising agricultural waste but of obtaining a valuable, slow release fertiliser that wi II be environmentally sound. The possibilities are huge because the UK produces about 14 million tonnes of straw as by-product of cereal crops each year, only half of which has commercial value.

A new process is based on fast pyrolysis, a high temperature process in which biomass is rapidly heated up to 500 C in the absence of oxygen. After decomposing and cooling the biomass condenses into a dark brown liquid. The process has been developed for commercial production of the "green" fertiliser from straw. There­search on fast pyrolysis will have wider implications . A team at Aston University has developed a fuel from this technology that would be environmentally friendly. This resulted in the "bio-oil" plant the first of its kind in UK. The aim is to produce green fuel in commercial amounts to be used for generating energy [Down to Earth, 18(No.l4)(1999)p. 55].

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Sealing technology provides extra level of containment

A new sealing technology has been developed by A & A Environmental Seals Inc., USA. It captures and con­tains emission of gas, liquids and solids that may escape from primary seals on reciprocating or rotating equip­ment. The SAS technology provides backup or secon­dary containment for worn or improperly functioning primary seals.

It incorporates a patented gas jet/manifold that sweeps a surface - such as a pump shaft or compressor rod-en­training gas or liquid emissions or particulate material. The captured compounds are carried to a containment system. The secondary sealing system has been installed on pumps, compressors, valves, extruders, mixers, dry­ers, and other equipment. Benefits include:

(i) Extended service life for the primary seal.

(ii) Lower maintenance costs .

(iii) Reduced product losses; contained emissions.may be returned to process.

(iv) Continued unit operation in the event of a primary seal failure.

(v) Enhanced personal safety from added levels of containment

[Hydroc Process, 78,(No.l2)(1999)p.53].

Plant study precipitates silica revolution

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German biochemists discovered how tiny plants do what materials scientists just dream of - to produce intricate microscopic silica structures at room tempera­ture and pressure.

Their research would pave the way to nanotechnolo­gists to make silica structures such as resins, molecular sieves, and catalysts without resorting to the high tem­peratures and pressures and extremes of pH that are currently needed .

Nils Kroger and colieagues at the University of Re­gensburg made the discovery by studying diatoms, mi­croscopic algae which extract silica from sea water and use it to build fascinating and intricate cell walls .

Kroger says that it is not known how algae precipitated and patterned silica so quickly. But if one understands how diatoms make their cell walls , one can produce new materials.

Kroger's team took the diatom Cylindrotheca fusifor­mis and analysed the contents of its cell wall. They extracted a previously unknown dass of polypeptides which they say probably has a central role in extracting silica from the water.

This will be the first step in producing silica gently. It is easy to synthesise the polypeptides in large quantities and use them in an industrial process mimicking the biological deposition of silica.

The polypeptides, which the team has called silaffins, have an unusual polyamide side-chain with regularly spaced positive charges. Part of the molecules is also rich in hydroxyl groups. These features seem to have a dual purpose. They first catalyse the polymerisation of silica, then help it precipitate out of solution .

When the silaffins are added to a solution containing silicon dioxide, solid silica precipitates out at more than a million- times the natural rate. The polypeptides co-pre­cipitate with the silica to form an organic-inorganic com­plex called a siloxane, but Kroger says he has yet to collect enough of the solid to test how the presence of the silaffins affects the silica's physical properties.

SCI-TECH UPDATE J SCI IND RES VOL. 59 JUNE 2000 525

The team has identified three related silaffins and located the gene that encodes one of them. The groups is now looking for other components of the system. The silaffins may not be the whole story . They may be players in a more sophisticated patterning process [ Chem lnd, No. 22 (1999) p. 865; For further reading see: Science, 286 (1999)p. 1129] .

Silver bullet destroys chemical weapons

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A process has been developed in Britain based on silver ions that can be used to destroy the US Army's stockpiles of chemical weapons.

The silver II e lectrochemical oxidation process, devel­oped by AEA Technology , is capable of destroying a wide range of organic compounds including explosives, nerve agents, and mustard gas. The system uses a stand­ard electrochemical cell like those widely used elsewhere in the chemical industry .

The organic waste is fed into a reaction vessel contain­ing nitric ac id and silver nitrate, forming the anolyte solution. This solution is circulated through the e lectro­chemical cell , where the Ag + ions are converted into highly reactive Ag2+ ions. These Al+ ions attack the organic waste-breaking it down to carbon dioxide, water, and inorganic salts-and in doing so are reduced back to Ag +. As the solution is recycled through the cell the Ag2+ ions are regenerated.

The balancing cathodic reaction involves reducing nitric acid and protons to nitrous ac id, NOx, and water. The nitrous acid and NOx are then oxidised to form nitric acid.

Silver II process has many safety and environmental benefits over incineration, the method used for des troying

weapons, it operates at low temperature (90°C) and pres­sure (1 atms); it is easily controllable by switching off the power to the electrochemical cell ; and the effluent con­sists only of di i. nitric acid and neutral mixed salt solu­tions , rather than the large volumes of gas produced by incineration. Furthermore, no dioxins or dibenzofuran waste products are formed in the process [ Chem Brit, 35 (No. 12) (1999) p 31].

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Silicon shows carbon how to act tough

Using experimental and theoretical methods to inves­tigate properties of silicon-based materials that serve as models for new forms of carbon compounds, researchers in France have determined that silicon clathrates (open cagelike structures) exhibit high hardness and remain stable even under very high pressure. The study suggests that analogues carbon clathrates, which have not yet been synthesized, should be nearly as hard as diamond or in certain cases even harder than diamond. The investiga­tion, conducted by physicist Alfonso San Miguel of Claude Bernard University, Lyons, and coworkers, may lead to new procedures for synthesizing hard material s that can be used industrially to Coat drilling and cutting tools. The researchers prepared silicon clathrates by de­composing a sodium silicon precursor at high tempera­tures. This produces Sizo and Sizs cages and crystals consisting of a combination of these fullerene-like si Iicon cages. Recently reported synthesis of cagelike covalent carbon crystals strongly suggest that carbon c lathrates "are within reach of current synthesis technologies" [Phys Rev Lett, 83 (No.5290) (1999); Chem Eng News, 78(1) (2000) p.34].

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Method for sequencing tiny amounts of polysaccharides developed

Ram Sasisekharan and colleagues at the Massachusetts Institute of Technology, the US have developed a method for sequencing tiqy amounts of polysaccharides the com­plex sugar chains that are gaining recognition as impor­tant biological molecules. Thus, scientists may soon be able to obtain sequence data from pico- or even femto­molar quantities of polysaccharide.

Researchers are already able to sequence DNA and proteins. But the structural and chemical complexity of sugar chains have held back attempts to do the same for polysaccharides . They devised a notation system which , together with matrix-assisted laser desorption ionisation mass spectrometry, can quickly and accurately pin down the structures of some of the most complex chains.

It even works with heparin-like glycosaminogl ycans, complex polysaccharides found on cell surfaces. These have 32 building blocks which can be arranged in more than a million different sequences, making them the most information-dense biopolymers in nature. They are known to be critical to many functions including cell

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growth and differentiation [ Chem lnd No.20 ( 1999) p.78l ; Science, 286( 1999)p.537].

Reusuable catalyst for making chiral diols

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Osmium-catalysed asymmetric dihydroxylation of olefins is an efficient route to chiral diols. It has been applied to the synthesis of natural products, pharmaceu­ticals, and fine chemicals. But the high cost of osmium and the required chiral ligands, as well as osmium's toxicity, have precluded wider use of the reaction. Chem­istry professor Shu Kobayashi and coworkers at the Uni­versity of Tokyo Graduate School of Pharmaceutical Sciences have developed a method involving microen­capsulation of osmium tetroxide in a polymer which will allow the catalyst and ligands to be recovered and reused.

The microencapsu lated catalyst converts trans­methylstyrene to (lR 2R)-I-phenyl-l, 2-propanediol in high yield and enantiomeric excess (ee) with I ,4-bis (9-0-dihydroquinidinyl)phthalazine as the chiral source and N- methyl morpho lineN-oxide as a co-oxidant. The catalyst is recovered by filtration , and the ligands, by acid/base extraction. The recovered catalyst and ligands remain active even after five rounds of reaction, giving up to 97 per cent yield and up to 96 per cent ee [Chem Eng News, 77(50)( 1999)p.35; J Am Chem Soc, 121( 1999)p.ll229].

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Anti-cancer drugs inhibiting prostate-specific antigen (PSA)

John Holaday and hi s colleagues at the pharmaceuti­cals company EntreMed in Rockville, Maryland, have studied the effect of prostate-specific antigen (PSA) on cancer cells. PSA is a blood level of a protein, which is measured to test prostate cancer in men . Men with pros­tate cancer have usually high levels of PSA. High PSA levels are also found in some other cancers, suggesting the protein may encourage the uncontrolled cell division that occurs in tumours . One study found that breast cancer patients with high PSA levels have a better prog­nosis .

Holaday and his colleagues have found that the protein did not alter the growth rate of prostate cancer cells or melanoma cells, but it did slow the growth of cells that make up blood vessels. Cancer researchers hope to starve tumours by blocking the blood vessels that feed them.

To find out if PSA can be beneficial, Holaday and hi s colleagues injected mice with melanoma cells and treated some of the animals with PSA. In those treated, there were 40 per cent fewer secondary tumours in the lungs than in untreated mice.

Some researchers are deve loping anti-cancer drugs that actually inhibit PSA. The findings might challenge that concept [New Sci, 164 (2208) (1999) p . 16 ; J Natn Cancer lnst, 91 ( 1999) p. 1635].

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New mass spectrometry method developed for cell protein analysis

Richard D Smith of the Environmental Molecular Sciences Laboratory at Pacific Northwest National Labo­ratory, Richland, alongwith Wash and colleagues have developed a new mass spectrometry method could do for prote in analysis what oligonucleotide arrays have done for nucleic acid analysis. They have used Fourier-trans­form ion cyclotron resonance MS to measure changes in protein abundance caused by stresses to bacterial cells.

The researchers gre . · unstressed Escherichia coli in media having natural isotopic abundances and stressed E. coli (for exam~le, exposed to Cd2+ ions) in media de­pleted in 13c, 1 N, and 2H. Stressed and unstressed cells were mixed and analysed together because they express two isotopically distinct versions of the proteins that are resolvable. Looking at the 200 most abundant proteins in E. coli ., Smith and coworkers found a broad range of cellular responses to cadmium-the expression of differ­ent proteins is suppressed or induced to varying degrees. Variation between replicate analysis is less than \0 per cent.

"This improves data quality" relative 2-D polyacry­lamide gel electrophoresis, the gold standard , "should be particularly important for those working to understand complex cellular pathways", according to Smith [Chem Eng News, 77 (36) (1999) p. 27; JAm Chem Soc, 121 (1999) p. 7949] .

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Accelerating healing of bone fracture using gene therapy

Researchers at the University of Michigan Medical School (Ann Arbor, MI) have developed a new technique

SCI-TECH UPDATE J SCI I D RES VOL. 59 JUNE 2000 527

for localized delivery of gene products that accelerates healing of a bone fracture. The technique uses a system in which plasmid DNA encoding human parathyroid hormone is trapped within polymer gene-activated matrix (GAM) carrier. The polymer, which is biodegradable, can be implanted near a broken bone. Fibroblasts arriv­ing at the site take up the DNA and act as in vivo bioreactors, generating a high local concentration of the hormone, which in turn accelerates bone healing.

The system avoids the side effects associated with systemic overexpression of genes because expression of the introduced gene is limited to cell near the wound . Beagles with surgically induced gaps in their leg bones regrew histologically normal bona ti ssue with the GAM treatment in a dose-dependent manner. According to Jeffrey Bonadio at Selective Genetics (San Diego, CA), "In principle, the GAM technology can deploy any plas­mid- gene, so a wide variety of cytokines, growth factors, and hormones could be used". Selective genetics is cur­rently planning clinical trials to test the technology for fracture repair in the elderly and as a bona-graft substitute [Nature Biotechno l, 17(7)p.625 ; Nature Med, 5(1999)p.753].

Mercury is harmful to the brain

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Scientists at Canada's Maurice La Montagne Institute and the University of Agricultural Sciences in Sweden have found an evidence that the blood-brain barrier the nearly impenetrable membrane preventing entry of toxins into the brain, can be successfully invaded by the metal mercury. In a study conducted by them they found that mercury dissolved in lakewater and river water can enter the nerves that connect water-exposed sensory receptors for odour, taste, vibration and touch to the brain of brown and rainbow trout.

Though the studies were conducted on fish the findings have implications for humans too, specially children. This is the first study concerning mercury level s in fish brains, as opposed to levels accomulated in other body areas, and for the first time it has been established that mercury can enter the brain through sensory receptors and their connected nerves. Fish use their nerves systems to find food, communicate, migrate, orient themselves and recognise predators.

Exposure to mercury can damage the brain and the nervous system, affecting language abilities, attentive-

ness, and memory, particularly in children. The environ­mental group Clean Water Action has calculated that the average mercury level in the fish tuna is so high that eating as little as 20z (about 57 g) of tuna a week would be unsafe for child weighing about 16 kg.

The accumulation of mercury or other toxic chemicals in the brain through water-exposed nerve terminals may result in an alternation of these functions and jeopardise fi sh survival.

While most people do not eat fish brain the survival of the species does affect us . The most important fear is that mercury may reach brains of humans in similar ways [Down to Earth, 8 (No. 14) (1999) p. 49].

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Estrogen replacement therapy for Alzheimer's disease in women

According to a new research, estrogen replacement therapy (ERT) does not improve the memory or function of hysterectomized women with mild to moderate Alzhe­imer's disease (AD). The findings from the largest and longest clinical trial to date examining the effects of estrogen therapy on AD, suggest that estrogen should not be used to treat the dementia once the disease is estab­lished in women who have had a hysterectomy.

Researchers involved in the study emphasize, how­ever, that estrogen therapy may still play an important role in fighting AD in women at an earlier point in the disease process. Many epidemiological studies have in­dicated that estrogen therapy might prevent AD or delay its onset, and clinical trials to validate the usefulness of estrogen to prevent or delay AD are now underway.

The research was conducted by Rutt Mulnard, at the University of California, Irvine, and colleagues from 32 Alzheimer's Disease Cooperative Study (ADCS) sites across the US with estrogen therapy for women with mild to moderate dementia.

Neil Buckholtz who directs NIA' s Dementias of Aging Program says that a negative finding, particularly one from a study of this size and scope, is critically important in our search for such treatments. We have to determine where estrogens may or may not be effective for people with AD. This study gives our attention to how estrogens may help protect women, who at the start of therapy , are cognitively healthy . It is also not clear at this time whether estrogen therapy may be effective in women with AD who have an intact uterus .

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The 120 hysterectomized women age 60 and above involved in the study had mild to moderate AD. They were divided into three groups of women taking 0.625 mg I d of estrogen, 1.25 mg of estrogen, or place pills that looked like the estrogen medication . The women were followed for 15 months (12 months on estrogen therapy with 3 months of additional followup ); researchers tested for cognitive or functional changes at 2,6, 12 and 15 months. Primarily they were examining the overall rate of change the women may have experienced on a scale developed by the ADCS for pinpointing clinical changes in patients with the disease. In addition, they looked for specific effects on mood, certain cognitive functions such as memory, attention, and language, motor functioning ; and standard measures of activities of daily living.

At the end of the study, no significant differences were seen in any of the areas studied, indicating that the ERT had no effect. Estrogen did neither improve cognitive function nor did it delay progression of the disease by any of the measures used by Mulnard's group.

Mulnard says that the positive effects of ERT seen in smaller and shorter studies might have been due to short­term effects that estrogen might have had on neuro-trans­mitters in the brain, as seen in animal studies. But according to Mulnard the short-term effects could not be sustained over a longer direction. Basic research on the etiology of AD may help explain ERT' s failure to make a difference in women who already have AD. Studies on the mechanisms of the disease have indicated that AD may have at least two phases, one called an 'initiation ' phase and other a 'propagation ' phase when the disease has seen set in motion. Cell culture studied show that the action of estrogens may only be effective against some of the mechanisms of the disease, effectively countering those that occur earlier in the disease process. Estrogen receptors, e.g., are concentrated in the regions of the brai n affected first by AD, and ERT may work best before these brain regions are compromised. Mulard also points to research indicating that estrogen is a relatively weak antioxidant when compared witn Vitami n E, which has been shown to have some effect at later stages of the disease.

Research on the basic meahanisms of AD and a range of diseases shows that certain things happen at certain stages [NIH News Rep, 22 February 2000].

For more information on federally funded AD research and the possibility of participating in a study, contact the NIA's Alzheimer's Disease Education· and Referral (ADEAR) Center at 1- 800 - 438 - 4380, or adear @

alzheimers,org For further information on AD see Website at httpl//www.alzheimers .org.

X-ray found useful for better Alzeimer's drugs

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The exact nature of the 3-D interaction between galan­thamine, a natural substance extracted from the common snowdrop (Galanthus nivalis) and the brain enzyme ace­tylcholinesterase (AChE) have been revealed by the re­searchers at Weizmann Institute, Rehovot, Israel. The findings will be beneficial in designing a new family of Alzheimer's drugs.

Alheimer's disease is a severe degenerative disorder causing memory loss and other cognitive deficits in roughly 10 per cent of the elderly people. One of its pathological hall marks is the deterioration of nerve cell s releasing acetylcholine- a neurotransmitter that helps ferry 'messages' in the form of nerve impulses between brain cells. The acetylcholine shortage that ensues is compounded by the action of acetylcholinesterase (AChE) the enzyme which breaks down acetylcholine in the body at a rate of 20,000 mol /s.

The approach is to attempt to restore acetylcholine level by inhibiting AChE activity .

Using X-ray crystallography, Dr Harry Greemblatt of the Weizmann Institute's Department of Structural Biol­ogy , has revealed that galanthamine acts in a similar manner, replenishing acetylcholine levels by binding to AChE's active site and shutting off its 'cutting machin­ery'.

In addition to its effect on AChE, galanthamine also binds to acetylcholine receptors (proteins on the surface of the nerve cell which are activated by acetylcholine) thus directly stimulating neuronal function . Thi s dual mode of action , coupled with the evidence that galan­thamine has reduced side effects in comparison to tacrine make it a particular exciting candidate for designing improved potency drugs . It is this where the 'blue print' generated by the Weizmann team may prove high bene­fi cia l. One of the most important steps towards under­standing how a molecule works is to map it out. For instance, after

Waston and Crick demonstrated DNA ' s structure through their thinker-toy model the secret of genetic rep lication became suddenly, almost intuitively, clear. In a similar fashion , X-ray crystallography can be used to capture highly accurate 'snapshots' of natural complexes,

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such as that of galanthamine with AChE. By studying these interactions one can find how by modifying certain chemical properties can potentially enhance their bind­ing, leading to greater drug efficacy.

The scientists worked with high quality crystals of AChE derived from electric organ tissue of the Torpedo fish, one of the richest source of this enzyme. The Tor­pedo AChE crystals were soaked with galanthamine, and then exposed to a narrow X-ray beam, producing a dif­fraction pattern from which a 3-D computer image of the AChE galanthamine complex could be obtained.

The current Weizmann study is based on previous Adzhemier' s disease research done by Sarsman et al. of the Structural Biology Department . The research team solved the structure of complexes formed between AChe and diverse synthetic and natural compounds, including the synthetically produced Aricept, fasciculin-a snake venom toxin, and huperzine A - an extract from a Chinese herb used for centuries to treat memory disor­ders. All of these substances, as well as newly examined galanthamine, are joined by a common denominator. Although they differ in their mode of association, they inhibit AChE by blocking its active site located at the bottom of the aromatic gorge. AChE inhibition is also the principle mode of action of many pesticides [Weizmann lnst Sci Res News, ( 1999); For further reading see: FEBS Lett, 17 December 1999].

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New understanding of a key control mechanism in the brain

Despite more than a century of research on inhibitory neurons, very little is known on how this small population (10-20 per cent of brain neurons) exerts its controlling effect on the brain. Pivotal for normal brain development, learning, and memory, it is not surprising that inhibitory neurons are involved in most neurological disorders . A recent study at the Weizmann Institute, Department of Neurobiology, Rehovot, Israel reveals key principles un­derlying the design and function of this inhibitory system.

By repressing the level of activity in neighboring neu­rons, inhibitory neurons (/-neurons) prevent the brain from quickly spinning out of control into hyper-excited states or full-blown epilepsy. One of the problems that children with autism and attention deficit hyperactivity disorders (ADHD) have is /-neuron malfunction: their inhibitory system does not effectively suppress unwanted

information, impeding their ability to make choices. /­neuron malfunction is involved in memory disorders (such as Alzheimer's disease), neural trauma, and addic­tions . It also plays a role in a wide range of psychiatric disorders, such as depression, obsessive compulsive dis­orders, and schizophrenia.

In the past, researchers basically thought that /- neu­rons just sprayed an inhibitory neurotransmitter called GABA onto their neighbors. But this did not explain how they inhibited the right neurons at exactly the right time and to the right degree. The new study shows how the researchers achieve this.

The research team found new types of /-neurons, re­vealing that this tiny population is several-times more diverse than previously thought. Further, using new methods that they developed the researchers succeeded in recording directly how individual inhibitory neurons control their neighbors. They found that /-neurons build complex synapses (connections) onto their target neu­rons. The synapses selectively filter inhibitory messages, enabling /-neurons to shut down the activity in neighbors as required. These synapses act as fast- switching "if­then" filtering gates that allow inhibition to be applied only at the exact millisecond and to the right degree.

Each /-neuron establishes complex if-then gates onto thousands of neighboring neurons and is therefore "in charge" of controlling their activity . The gates allow /-neurons to rapidly switch their focus onto any one neuron that they are connected to . This ingenious design principle is what enables the small group of /-neurons to exert such a sophisticated effect, simultaneously "giving personal attention" to the activity of each of the neurons to which they are connected.

The researchers showed that a "discussion" between/­neurons and target neurons is involved in deciding which type of if-then gate should be set up to filter the inhibitory message. This decision-making process could allow each neuron in the brain to be inhibited in a potentially unique way. Dubbed the "interaction principle", this process generates maximal diversity of if-then gates, allowing more complex and finer control over large number of neurons .

The researchers went on to reveal a remarkable ability of /-neurons: they can sense neurons that share the same functions in the brain. /-neurons "select" groups of target neurons to construct the same type of if-then gates, pos­.> ibly enabling the /-neurons to control groups of neurons collectively. It also means that /-neurons can "smell-out" neurons in the brain that collaborate in the most elemen-

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tary functions even if they seem different in almost every other way (i.e. they can identify neurons descended from the same "ancestors").

/-neurons can trace family trees of neurons. In other words, they could help us to work out how neurons are related to each other. This could one day enable us to map the functional aspect of the brain according to the genealogy of neurons- an organizing principle that we never dreamt possible. The researchers believe that the ability to detect functionally related groups in the brain, called "the homogeneity principle,'' results from common signal molecules released by target cells. /-neurons may

use the signal molecules to determine what kind of if-then gates to build . Weizmann Institute findings may provide new insights into a wide range of neurological disorders, including Alzheimer's disease, autism, and epilepsy.

A color image of an inhibitory neuron interconnecting to three excitatory neurons is available upon request. The image is also posted at: http://www.weizmann.ac.i!(Me­dia Information) [Res News, 13 January 2000; For further details see: Science, January 2000] .

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