Something in the Air

For the past month, Caltech scientists have been zigzagging across the Los Angeles basin. Using an orange and white DeHavilland Twin Otter aircraft packed with instruments, the researchers have been sampling the air, measuring particles and pollutants to help policymakers improve air quality and dampen the impacts of climate change.

"We want to understand very thoroughly where these particles come from, what they're made of, how they evolve, and eventually how they're removed," says chemical engineer John Seinfeld, who leads the Caltech group. The flights are just one element of a project dubbed CalNex—the nexus of pollution and climate over California—run by the National Oceanic and Atmospheric Administration (NOAA).

CalNex is one of the largest air-quality experiments ever done, says Jose-Luis Jimenez, a professor at the University of Colorado and a former Caltech postdoc. The project involves three other aircraft—including NOAA's Lockheed WP-3D Orion, a plane with a 100-foot wingspan whose resume includes missions into dozens of hurricanes—and the Atlantis, a research vessel operated by the Woods Hole Oceanographic Institution. There are also two ground stations, one in Bakersfield and the other on the Caltech campus. (You may have noticed the main part of the Caltech station: two towers of scaffolding and the huddle of trailers on the vacant lot north of the Holliston parking structure.) Such studies are so expensive that they only occur about once a decade in southern California—the crew on campus alone includes more than 60 people from around the world.

Every morning in May, the Caltech team gathers at Ontario International Airport, checking their equipment for the day's four-hour flight. Typically carrying up to 20 passengers when it operates as a commuter plane, the twin-engine turboprop is so stuffed with gizmos and computers that there's only room for one researcher—usually a grad student—who monitors all the instruments, fixing them if needed.


"The best part is getting to see all the instruments in action," says Andrew Metcalf, one of the graduate students who got to fly. Because he can watch the data being collected in real time, he gets a better sense of what each data point on the screen means—important when trying to analyze the information later. For most flights, the plane heads west over Pasadena and toward Long Beach, then crisscrosses back east—occasionally going as far as Palm Springs and the Salton Sea—following the changing chemistry of the particles as they travel with the eastward wind. The plane usually flies at 1,000 feet—as low as the FAA will allow. To measure how the air changes with elevation, the pilot sometimes executes missed approaches—a maneuver in which the plane approaches the runway but doesn't land—over many of the small airports that dot the L.A. basin. On occasion, the plane flies north to Bakersfield and the San Joaquin Valley to see how the air differs from that above the Los Angeles basin.

An inlet pipe jutting from the front of the plane collects the air and channels it through tubes to the instruments, which are lined in racks on one side of the plane. The devices collect an assortment of data, such as the size distribution of particles and their chemical constituents.

Grad student Jill Craven gets to the airport at 6 a.m., having to boot up her mass spectrometer, a powerful but temperamental instrument. "When it breaks down, I get really stressed out," she says. "Field campaigns are wonderful because you're not in the lab. The hard part is that you're under pressure to perform in a month, because we only have four weeks to collect data for the entire year."

Airsickness can also be a challenge. "I flew the first flight and I got really sick," Metcalf recalls. As it happened, there was no airsickness bag on board that day, and one of the pilots had to sacrifice his lunch bag. "It was about a week and a half before I got up the nerve to try it again. Now I take motion-sickness drugs to help me out." Still, it's much more fun to be up in the air than cooped up in a lab, he says. "It's exciting to fly around and see exactly what's out there in the L.A. basin."

So what is out there? It will be years before scientists finish analyzing all the data. The results, however, will have a global impact. CalNex is designed to help untangle the complex ways in which particles affect air quality and climate. For example, tiny particles are bad for air quality, but they can also scatter sunlight, counteracting the warming effect of greenhouse gases. "If you go anywhere in the world," Seinfeld explains, "particles in the air are a mixture of the same kitchen sink of compounds. A large urban area like Los Angeles, with sources ranging from traffic, industry, and ships to vegetation, is the perfect staging area to study how such particles are formed and how they evolve."

Seinfeld, the Nohl Professor and professor of chemical engineering, leads the Caltech team, which includes Richard Flagan, the McCollum-Corcoran Professor of Chemical Engineering and professor of environmental science and engineering.

View our narrated slideshow of the Calnex plane and its instrumentation.

Marcus Woo
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Adaptable, New Building is Catalyst for Discovery

Caltech Opens the Schlinger Laboratory for Chemistry and Chemical Engineering

To facilitate the ever-evolving advancements in the chemical field today, the California Institute of Technology (Caltech) is opening the new Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering.

The state-of-the-art, sustainable Schlinger Laboratory will provide a custom-designed, adaptable facility for a number of Caltech's chemists and chemical engineers.  The laboratory will house research groups in synthetic chemistry and chemical engineering, enabling new research in catalysis, materials, and the atmosphere. 

The laboratory has been named in honor of Warren and Katharine Schlinger, benefactors of the Institute for more than 60 years. Support for the building and its research was provided by the Gordon and Betty Moore Foundation, Will and Helen Webster, Victor and Elizabeth Atkins, the John Stauffer Charitable Trust, Barbara Dickinson, and the Ralph M. Parsons Foundation.

Jacqueline Barton, chair of the Division of Chemistry and Chemical Engineering, and Arthur and Marian Hanisch Memorial Professor, states, "We are excited to bring together chemists and chemical engineers under one roof for new discovery and innovation.  This new laboratory is a realization of the vision of Warren and Katharine Schlinger to create a state-of-the-art facility linking chemists with chemical engineers."

The Science

Synthetic chemists Brian Stoltz, the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry, and Sarah Reisman, assistant professor of chemistry, along with their research groups, will focus on the design of new catalysts and new routes to the preparation of pharmaceuticals.  Jonas Peters, the Bren Professor of Chemistry, and his group will conduct research designing new catalysts that may be critical in solar energy conversion. Richard Flagan, the Irma and Ross McCollum-William H. Corcoran Professor of Chemical Engineering and professor of environmental science and engineering, and John Seinfeld, the Louis E. Nohl Professor and professor of chemical engineering, will conduct research in atmospheric chemistry, focusing on aerosol processes and the control of air pollution.  Julia Kornfield, professor of chemical engineering, and her research group will characterize new polymers with broad applications in everything from liquid-crystal displays to intraocular lenses.  The Schlinger laboratory will also house the Center for Catalysis and Chemical Synthesis, led by Nobel laureate Robert Grubbs, the Victor and Elizabeth Atkins Professor of Chemistry.

The Facility

The 62,300-square-foot, four-story Schlinger Laboratory blends innovative research design elements with contemporary and classic elements.  Expansive glass facades on north and south sides of the reinforced concrete structure are enhanced with one terracotta accent wall at the building's west entrance.  

The laboratory features a "green," eco-conscious design, furthering the campus-wide commitment to sustainability.  The facility is on target to obtain gold certification from the Leadership in Energy and Environmental Design (LEED) Green Building Rating System, which requires projects to meet stringent energy and water efficiency standards.  The Schlinger Laboratory has been designed with energy-conscious equipment and lighting, for a 28 percent reduction in energy usage and a 30 percent reduction in water usage.  The building utilizes locally derived and recycled building materials.

Maximizing the natural lighting in the new laboratory was an essential design element for the chemists.  Expansive, floor-to-ceiling windows illuminate 90 percent of the labs and conference rooms in the building and provide engaging, panoramic views.

Designed with flexible lab space, research areas can be adapted or reconfigured for specific uses.  Each of the highly specialized research areas was custom designed to meet the distinct specifications of the resident professors. The laboratory also offers an abundance of ventilated chemical fume hoods, providing a high ratio of workstations per student or researcher.

Throughout the building, contemporary stainless-steel components complement the classic maple cabinetry and millwork, much of which was custom built by Caltech carpenters.  Caltech painters also assisted on the project.  Recycled slate boards from the early 1900s were utilized as the main writing surfaces in the conference rooms.  Caltech electricians installed the computer network and data systems.

"The Institute is recognized for having made some of the most significant scientific achievements of the past century in chemistry and chemical engineering—with three Nobel laureates in chemistry currently in residence.  The Schlinger Laboratory will help to position Caltech for continued leadership in this critical area, helping to shape the future.  Warren and Katharine Schlinger's steadfast dedication and commitment to scientific achievement, particularly at Caltech, are exemplary and visionary," states Caltech president Jean-Lou Chameau.

The architectural firm of Bohlin Cywinski Jackson, known for leadership in sustainable design, was selected for this project.  The award-winning firm has designed diverse, high-end laboratories and academic facilities throughout the nation, ranging from biotechnology centers to software engineering institutes.

The building features

  • Six faculty offices within two faculty suites
  • Office space for over 100 postdoctoral and graduate students
  • A 50-person undergraduate teaching classroom/faculty conference room
  • Multiple interactive lounge areas
  • A central recycling room
  • Individual office climate control and auto-sensor lighting
  • A dual-glazed curtain wall system for window shading and reduced heat gain
  • 70 German-engineered Waldner fume hoods  (total capacity 110)
Deborah Williams-Hedges
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Young Caltech Innovators Recognized for Their Work in Advanced Disease Therapies

$30,000 Lemelson-MIT Collegiate Student Prizes Awarded to Students Nationwide; Four Leading Institutes Celebrate Winners

PASADENA, Calif.—California Institute of Technology (Caltech) graduate student Heather D. Agnew is the recipient of the 2010 $30,000 Lemelson-MIT Caltech Student Prize. 

Agnew was among the four $30,000 Lemelson-MIT Collegiate Student Prize winners announced Wednesday, March 3, 2010. She was recognized for her integral contributions to the development of innovative biochemical protocols that can be utilized for more stable, robust—and inexpensive—detection of diseases like cancer, HIV, or malaria.

The Lemelson-MIT Caltech Student Prize is supported through a partnership with the Lemelson-MIT Program, a nonprofit dedicated to celebrating innovation and inspiring youth. The Lemelson-MIT Student Prize has been awarded at the Massachusetts Institute of Technology since 1995 and at Rensselaer Polytechnic Institute and University of Illinois at Urbana-Champaign since 2007; in 2009, the program expanded with a similar award given to Caltech students. Caltech's Division of Engineering and Applied Science administers the Lemelson-MIT Caltech Student Prize. 

The Caltech selection committee also acknowledged a finalist, Yvonne Y. Chen, also a Caltech graduate student, who will receive a $10,000 award made possible through the support of Caltech alumnus Michael Hunkapiller.

Agnew, a graduate student in chemistry, has been working in the laboratory of James R. Heath, the Elizabeth W. Gilloon Professor and professor of chemistry.  Agnew contributed to the development of a progressive technique to create inexpensive, yet highly reliable and stable biochemical compounds that have the potential to replace antibodies (blood proteins produced in response to specific toxins or antigens) used in many standard medical diagnostic tests.  This antibody equivalent, or "protein capture agent" protocol, allows for more efficient, inexpensive diagnostics.

In her presentation, entitled "Protein Capture Agents for Improving the Performance and Stability of Point-of-Care Diagnostics," Agnew explained the stable and robust nature of the protein capture agents.  Their ability to withstand higher temperatures enhances their applications, paving the way for more reliable, inexpensive, and readily available medical diagnostic testing for use not only in the United States, but also in developing countries.

According to Heath, "Heather has led this project from start to finish, and it has involved innovation every step of the way.  In terms of public benefit, I believe that the stable, scalable protein capture agents truly have the chance to revolutionize in vitro diagnostics by putting them onto the path of increased capability at lower cost—similar to what has happened for genome sequencing."

Agnew was born and raised in Allentown, Pennsylvania.  She received dual undergraduate degrees in chemistry and in biochemistry and molecular biology from the Pennsylvania State University.  As a Gates Scholar, she received her master's degree in chemistry from the University of Cambridge.  Throughout her academic career, Agnew has received numerous honors and awards, and has continually volunteered as a research mentor and teacher for youth.  Agnew plans to continue her pursuit of biochemical solutions as a principal research investigator in a start-up commercialization venture.  Agnew may also pursue a teaching career at a leading research institution.

The Lemelson-MIT Caltech Student Prize finalist is Yvonne Y. Chen, a graduate student in chemical engineering at Caltech who worked in the lab of Christina D. Smolke, assistant professor of chemical engineering.  Chen will receive a $10,000 prize for her work on improving advanced, cell-based solutions for the treatment of certain incurable diseases, including various cancers and inoperable tumors. In her presentation, entitled "Improving Cell-Based Cancer Therapy with RNA Regulatory Systems," Chen describes an innovative T-cell (a type of white blood cell) therapy for treating aggressive, inoperable tumors.

Traditional chemotherapy and radiotherapy have often proved unable to eradicate diffusive tumors such as glioblastoma (the most common type of primary brain tumor in adults), and these therapies can have severe side effects.  And conventional immunotherapy, which enlists the body's immune system to fight diseases, while conceptually well suited to cancer treatment, has had limited success—efforts to improve its efficacy have raised safety concerns for leukemic growth. Chen's research has the potential to greatly increase both the safety and the efficacy of immunotherapy by controlling T-cell proliferation with regulatory systems based on engineered RNA (ribonucleic acid) devices—thus avoiding risks of uncontrolled T-cell proliferation and eventual leukemic side effects. Chen's novel RNA-based technology is a promising therapeutic candidate for clinical applications in the fight against cancer, and is adaptable to a wide range of disease treatment strategies. 

Chen was born in Taipei, Taiwan, and moved with her family to Rowland Heights, California, when she was 13 years old.  She earned her BS in chemical engineering from Stanford University and her MS in chemical engineering from Caltech.  Chen plans to pursue a career in academia as a researcher at a major institution or in public policy as it relates to scientific research.

According to Ares Rosakis, division chair and Theodore von Kármán Professor of Aeronautics and professor of mechanical engineering, "The Engineering and Applied Science Division is proud to support such real-world applications of science by student researchers at the Institute.  These innovations have the potential for creating significant advances in the future."

"This year's winners from the California Institute of Technology, Massachusetts Institute of Technology, Rensselaer Polytechnic Institute, and University of Illinois at Urbana-Champaign shine light on the significance of collegiate invention. They have the ability to transform seemingly implausible ideas into reality and are the true entrepreneurial leaders of their generation," states Joshua Schuler, executive director of the Lemelson-MIT Program. 

Lemelson-MIT Collegiate Student Prizes

In addition to Agnew's pioneering work, the other winners of the annual Lemelson-MIT Collegiate Student Prize were announced today at their respective universities:

·      Lemelson-MIT Illinois Student Prize winner Jonathan Naber and the Illini Prosthetics Team developed an affordable, durable, extremely functional prosthetic arm for people in underdeveloped countries, made from recycled materials.

·      Lemelson-MIT Student Prize winner Erez Lieberman-Aiden demonstrated creativity and innovation across several disciplines, most recently with his invention of "Hi-C", a three-dimensional genome sequencing method that will enable an entirely new understanding of cell state, genetic regulation and disease.

·      Lemelson-MIT Rensselaer Student Prize winner Javad Rafiee developed a new method for manufacturing and using graphene, an atom-thick sheet of carbon atoms arranged like a nanoscale chain-link fence, to store hydrogen at room temperature – opening the door to better and safer on-board fuel storage systems for hydrogen vehicles. 


Celebrating innovation, inspiring youth

The Lemelson-MIT Program recognizes the outstanding inventors and innovators transforming our world, and inspires young people to pursue creative lives and careers through innovation.

Jerome H. Lemelson, one of U.S. history's most prolific inventors, and his wife Dorothy founded the Lemelson-MIT Program at the Massachusetts Institute of Technology in 1994. It is funded by the Lemelson Foundation and administered by the School of Engineering. The Foundation sparks, sustains and celebrates innovation and the inventive spirit. It supports projects in the U.S. and developing countries that nurture innovators and unleash invention to advance economic, social and environmentally sustainable development. To date the Lemelson Foundation has donated or committed more than U.S. $150 million in support of its mission.

About the Lemelson-MIT Caltech Student Prize
Administered by the Caltech Division of Engineering and Applied Science, the Lemelson-MIT Caltech Student Prize is awarded to a student at Caltech who has demonstrated remarkable inventiveness and innovation.

Funded through a partnership with the Lemelson-MIT Program, the Lemelson-MIT Student Prize has recognized outstanding student inventors at MIT since 1995 (see: 

For more information, go to:

Lemelson-MIT Caltech Student Prize:

Deborah Williams-Hedges
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Caltech Receives More than $33 Million from American Recovery and Reinvestment Act

Neuroeconomics and the fundamentals of jet noise just some of the many projects supported

PASADENA, Calif.-Research in genomic sciences, astronomy, seismology, and neuroeconomics are some of the many projects being funded at the California Institute of Technology (Caltech) by the American Recovery and Reinvestment Act (ARRA).

As part of the federal government program of stimulating the economy, ARRA is providing approximately $21 billion for research and development. The goal is for the funding to lead to new scientific discoveries and to support jobs.

ARRA provides the funds to federal research agencies such as the National Institutes of Health, the National Science Foundation, and the Department of Energy, which then support proposals submitted by universities and other research institutions from across the country.

Caltech has received 82 awards to date, totaling more than $33 million. Spending from the grants began in the spring of 2009 and thus far has led to the support of 93 jobs at the Institute.

"This funding will help lead to substantive and important work here at Caltech," says Caltech president Jean-Lou Chameau. "We're grateful to have this opportunity to advance research designed to benefit the entire country."

For biologist Paul Sternberg, the Thomas Hunt Morgan Professor of Biology at Caltech and a Howard Hughes Medical Institute investigator, the ARRA funds mean an opportunity to improve upon WormBase, an ongoing multi-institutional effort to make genetic information on the experimental animal C. elegans freely available to the world.

"All biological and biomedical researchers rely on publicly available databases of genetic information," says Sternberg. "But it has been expensive and difficult to extract information from scientific research articles. We have developed some tools to make it less expensive and less tedious to get the job done, for WormBase and many other groups."

Sternberg's ARRA funds-$989,492-will go towards developing a more efficient approach to extracting key facts from published biological-science papers.

Among the other diverse Caltech projects receiving ARRA funds are:

  • a catalog of jellyfish DNA;
  • improving the speed of data collection at Caltech's Center of Excellence in Genomic Science;
  • studies into the fundamentals of particle physics;
  • the California High School Cosmic Ray Observatory (CHICOS) program, which provides high school students access to cosmic ray research;
  • the search for new astronomical objects such as flare stars and gamma-ray bursts, and the means to make those discoveries accessible to the public; and
  • a $1 million upgrade of the Southern California Seismic Network.

Caltech Professor of Mechanical Engineering Tim Colonius received ARRA funds for research into better understanding how noise is created by turbulence in the exhaust of turbofan aircraft engines and what might be done to mitigate it. Jet noise is an environmental problem subject to increasingly severe regulation throughout the world.

"To meet the ambitious noise-reduction goals under discussion, a greatly enhanced understanding of the basic physics is needed," says Colonius. "Very large-scale computer simulations and follow-up analyses will bring us much closer to the goal of discovering the subtle physical mechanisms responsible for the radiation of jet noise and allow us to develop methods for suppressing it."

Colonius received $987,032 in ARRA funds from the National Science Foundation.

Colin Camerer, the Robert Kirby Professor of Behavioral Economics, received his ARRA funds to explore the application of neurotechnologies to solving real-life economic problems.

"Our project, with my Caltech colleague Antonio Rangel, will explore the psychological and neural correlates of value and decision-making and their use in improving the efficiency of social allocations," says Camerer.

Camerer and his colleagues previously found that they could use information obtained through functional magnetic resonance imaging measurements to develop solutions to economic challenges.

Rangel, an associate professor of economics, has a second ARRA-funded project to analyze the neuroeconomics of self-control in dieting populations.

"Funding of this nature is critical to much of the work we do here at Caltech," adds Chameau. "And with ARRA support, dramatic discoveries may be just around the corner."

For a complete list of ARRA projects, visit:

# # #

About Caltech:

Caltech is recognized for its highly select student body of 900 undergraduates and 1,200 graduate students, and for its outstanding faculty. Since 1923, Caltech faculty and alumni have garnered 32 Nobel Prizes and five Crafoord Prizes.

In addition to its prestigious on-campus research programs, Caltech operates the Jet Propulsion Laboratory (JPL), the W. M. Keck Observatory in Mauna Kea, the Palomar Observatory, and the Laser Interferometer Gravitational-Wave Observatory (LIGO). Caltech is a private university in Pasadena, California. For more information, visit

Jon Weiner
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Estate Gift of $3.9 Million Will Help Caltech Chemists Focus on Innovative Research

Gift comes from the estate of longtime Caltech supporters Edward and Ruth Hughes

PASADENA, CALIF. - A deep appreciation for the sciences has led to a gift of $3.9 million from the estate of Edward and Ruth Hughes to the California Institute of Technology (Caltech) and its Division of Chemistry and Chemical Engineering (CCE).

The funds will be used by the division to support highly innovative research proposals that might not otherwise be funded by traditional means.

The Hughes funds will help support eight graduate research fellowships. These fellowships will allow students to focus on challenging problems and find innovative solutions.

Helping support that goal is a matching gift of $2 million from the Gordon and Betty Moore Matching Program.

"This is an extraordinary gift from two special members of the CCE family, Ruth and Eddie Hughes," says Jackie Barton, chair of the division. "During their lives they made a difference to chemistry and to the Caltech community. Now, with this gift, they are going to make a difference to generations of graduate students trained in CCE."

The Division of Chemistry and Chemical Engineering currently has more than 40 faculty members and offers three degree programs. 

Edward Hughes passed away in 1987 and his wife, Ruth, in February 2009. Both were close friends of Caltech, though neither was an alumnus.

Edward was born in 1904, and first became enamored with chemistry in high school. In 1938, he came to Caltech at the invitation of Linus Pauling to help with the editing of Pauling's book, The Nature of the Chemical Bond and the Structure of Molecules and Crystals: An Introduction to Modern Structural Chemistry, and to conduct independent research in crystallography. During World War II he trained X-ray technicians and participated in research directed at isolating oxygen from the air at low pressure for high altitude use in bombers subject to enemy machine-gun fire. After working for the Shell Development Company, he returned to Caltech in 1946 as a Senior Research Associate in chemistry, a position he retained until 1974.  

Born in 1915 and educated in Germany, Ruth Hughes was unable to attend a university because of her Jewish heritage and instead trained as a nurse. Recognizing the dangers of staying in Germany, her family emigrated west in the late 1930s. Ruth was the last to leave, moving to London in 1939. It was after then moving to Boston that, coming from the hospital in a very bloody nursing uniform, she first met Edward. They were married on Halloween Day in 1951.

In September 1952, and after a stay at the Athenaeum, they bought a house within walking distance of the Caltech campus and became one of the most popular couples in the Caltech community, helping Pauling with his work and acting as hosts to visiting faculty.

An active member of the Caltech Women's Club, Ruth became a Life Member of the Caltech Associates in 1971, and in 1992 established a Summer Undergraduate Research Fellowship (SURF) endowment at Caltech in Edward's memory.

# # #

About Caltech:

Caltech is recognized for its highly select student body of 900 undergraduates and 1,200 graduate students, and for its outstanding faculty. Since 1923, Caltech faculty and alumni have garnered 32 Nobel Prizes and five Crafoord Prizes.

In addition to its prestigious on-campus research programs, Caltech operates the Jet Propulsion Laboratory (JPL), the W. M. Keck Observatory in Mauna Kea, the Palomar Observatory, and the Laser Interferometer Gravitational-Wave Observatory (LIGO). Caltech is a private university in Pasadena, California. For more information, visit

Jon Weiner
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Caltech Scientists Film Photons with Electrons

4D electron microscopy makes it possible to image photons of nanoscale structures and visualize their architecture

PASADENA, Calif.—Techniques recently invented by researchers at the California Institute of Technology (Caltech)—which allow the real-time, real-space visualization of fleeting changes in the structure of nanoscale matter—have been used to image the evanescent electrical fields produced by the interaction of electrons and photons, and to track changes in atomic-scale structures.

Papers describing the novel technologies appear in the December 17 issue of Nature and the October 30 issue of Science.

Four-dimensional (4D) microscopy-the methodology upon which the new techniques were based-was developed at Caltech's Physical Biology Center for Ultrafast Science and Technology. The center is directed by Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics at Caltech, and winner of the 1999 Nobel Prize in Chemistry. 

Zewail was awarded the Nobel Prize for pioneering the science of femtochemistry, the use of ultrashort laser flashes to observe fundamental chemical reactions occurring at the timescale of the femtosecond (one-millionth of a billionth of a second). The work "captured atoms and molecules in motion," Zewail says, but while snapshots of such molecules provide the "time dimension" of chemical reactions, they don't give the dimensions of space of those reactions-that is, their structure or architecture.

Zewail and his colleagues were able to visualize the missing architecture through 4D microscopy, which employs single electrons to introduce the dimension of time into traditional high-resolution electron microscopy, thus providing a way to see the changing structure of complex systems at the atomic scale. (See

In the research detailed in the Science paper, Zewail and postdoctoral scholar Aycan Yurtsever were able to focus an electron beam onto a specific nanoscale-sized site in a specimen, making it possible to observe structures within that localized area at the atomic level.

In electron diffraction, an object is illuminated with a beam of electrons. The electrons bounce off the atoms in the object, then scatter and strike a detector. The patterns produced on the detector provide information about the arrangement of the atoms in the material. However, if the atoms are in motion, the patterns will be blurred, obscuring details about small-scale variations in the material.

The new technique devised by Zewail and Yurtsever addresses the blurring problem by using electron pulses instead of a steady electron beam. The sample under study-in the case of the Science paper, a wafer of crystalline silicon-is first heated by being struck with a short pulse of laser light. The sample is then hit with a femtosecond pulse of electrons, which bounce off the atoms, producing a diffraction pattern on a detector. 

Since the electron pulses are so incredibly brief, the heated atoms don't have time to move much; this shorter "exposure time" produces a sharp image. By adjusting the delay between when the sample is heated and when the image is taken, the scientists can build up a library of still images that can be strung together into a movie.

"Essentially all of the specimens we deal with are heterogeneous," Zewail explains, with varying compositions over very small areas. "This technique provides the means for examining local sites in materials and biological structures, with a spatial resolution of a nanometer or less, and time resolution of femtoseconds."

The new diffraction method allows the structures of materials to be mapped out at an atomic scale. With the second technique-introduced in the Nature paper, which was coauthored by postdoctoral scholars Brett Barwick and David Flannigan-the light produced by such nanostructures can be imaged and mapped. 

The concept behind this technique involves the interaction between electrons and photons. Photons generate an evanescent field in nanostructures, and electrons can gain energy from such fields, which makes them visible in the 4D microscope.

Photons imaged in nanoscale structures (carbon nanotubes) using pulsed electrons at very high speed. Shown are the evanescent fields for two time frames and for two polarizations.
Credit: Zewail/Caltech

In what is known as the photon-induced near-field electron microscopy (PINEM) effect, certain materials-after being hit with laser pulses-continue to "glow" for a short but measurable amount of time (on the order of tens to hundreds of femtoseconds).

In their experiment, the researchers illuminated carbon nanotubes and silver nanowires with short pulses of laser light as electrons were being shot past. The evanescent field persisted for femtoseconds, and the electrons picked up energy during this time in discrete amounts (or quanta) corresponding to the wavelength of the laser light. The energy of an electron at 200 kilo-electron volts (keV) increased by 2.4 electron volts (eV), or by 4.8 eV, or by 7.2 eV, etc.; alternatively, an electron might not change in energy at all. The number of electrons showing a change is more striking if the timing is just right, i.e., if the electrons are passing the material when the field is at its strongest.

The power of this technique is that it provides a way to visualize the evanescent field when the electrons that have gained energy are selectively identified, and to image the nanostructures themselves when electrons that have not gained energy are selected.

"As noted by the reviewers of this paper, this technique of visualization opens new vistas of imaging with the potential to impact fields such as plasmonics, photonics, and related disciplines," Zewail says. "What is interesting from a fundamental physics point of view is that we are able to image photons using electrons. Traditionally, because of the mismatch between the energy and momentum of electrons and photons, we did not expect the strength of the PINEM effect, or the ability to visualize it in space and time."

The work in the Nature paper, "Photon-Induced Near-Field Electron Microscopy," and the Science paper, "4D Nanoscale Diffraction Observed by Convergent-Beam Ultrafast Electron Microscopy," was supported by the National Science Foundation, the Air Force Office of Scientific Research, and the Gordon and Betty Moore Foundation at the Center for Physical Biology at Caltech.

Kathy Svitil

Caltech Scientists Show How Ubiquitin Chains are Added to Cell-Cycle Proteins

Findings could one day lead to the development of targeted cancer therapies

PASADENA, Calif.—Researchers from the California Institute of Technology (Caltech) have been able to view in detail, and for the first time, the previously mysterious process by which long chains of a protein called ubiquitin are added by enzymes called ubiquitin ligases to proteins that control the cell cycle. Ubiquitin chains tag target proteins for destruction by protein-degrading complexes in the cell.

"We found that ubiquitin ligases build ubiquitin chains very rapidly by transferring ubiquitins one at a time," says Raymond Deshaies, professor of biology at Caltech and Howard Hughes Medical Institute investigator.

Their findings, and the innovative process by which they were obtained, are described in this week's issue of the journal Nature.

Ubiquitin is one of nature's most unusual proteins. Unlike most of its protein brethren, ubiquitin has to be physically attached to other proteins to do its job.

“As its name implies, ubiquitin is found in essentially every kind of eukaryotic cell," says Caltech graduate student Nathan Pierce, the Nature paper's lead author.

In their Nature paper, the Caltech team looked at the process of ubiquitylation, the method by which ubiquitin and ubiquitin chains are added to target proteins. The target proteins used in the study, cyclin E and β-Catenin, are both involved in controlling the cell cycle.

It was already known, Pierce explains, that the addition of a chain of four or more ubiquitins to a target protein marks that protein for annihilation.

The destruction of cyclin E is critical for the accurate replication of DNA, while the degradation of β-Catenin keeps cells from dividing during development at the wrong time. If β-Catenin is not degraded, cells proliferate excessively and become predisposed to tumorigenesis. Meanwhile, cells that don't degrade cyclin E accumulate DNA damage and mutations, which can help fuel the unchecked growth of a tumor.

It was also already known that ubiquitin chains are added to the protein using three different enzymes, dubbed E1, E2, and E3. Simply put, E1 activates ubiquitin for transfer, then passes it over to E2. E3 then gets into the act. A form of E3 called a RING ligase (RING stands for "really interesting new gene") plays a key role in the tagging of cyclin E and β-Catenin; according to Pierce, the RING ligase  "simultaneously binds to E2 and the target protein (like cyclin E), and then causes E2 to transfer the ubiquitin to the target protein."

Despite all of this knowledge, one question has remained: is the chain transferred to the protein in an already assembled form, or are the ubiquitins moved over one at a time?

"The process is so complicated and so fast," Pierce notes, "that we weren't able to see how the chain is actually built."

To address that issue, Pierce created a sort of biological stop-motion animation that allowed the Caltech team to watch every step in the transfer of ubiquitin from E2 onto the cyclin E protein substrate.

"We devised methods to take snapshots of ubiquitin ligase reactions at a rate of up to 100 'pictures' every second," says Deshaies. "This enables us to see things that would normally evade detection. "

Previous studies had looked at the reaction on the scale of seconds or minutes, Pierce adds. But through an innovative use of a laboratory tool called a quench-flow machine—a machine that allows for extreme precision in the stopping, or "quenching," of a reaction—the team was able to look at what was going on over intervals of just 10 milliseconds in both yeast and human proteins.

"Prior methods did not have sufficient time resolution to see what was going on," says Deshaies. "It's as if you gave an ice-cream cone to a kid and took pictures every minute. You would see the ice cream disappear from the first photo to the next, but since the pictures are too far apart in time, you would have no idea whether the child ate the ice cream one bite at a time, or swallowed the entire scoop in one gulp."

The new method revealed the biological equivalent of small, single bites of ice cream. "Using our approach," Deshaies says, "we could see that our ubiquitin ligase builds ubiquitin chains one ubiquitin at a time."

"Once we knew what the steps were, we calculated the rates at which they occur," adds Pierce. "And from those rates, we were able to really describe the biology of how this system works."

The quest doesn't stop there, of course. "One thing we have to understand now is, how do ubiquitin ligases achieve the speeds that they do?" asks Deshaies. "What special mechanisms do they have to enable them to build chains rapidly? And the flip side of the coin: What sets the speed limit? Why can't our ubiquitin ligase work even faster?"

A recent paper published in the journal Cell by Gary Kleiger, a postdoctoral scholar in the Deshaies lab, answered some of these speed-related questions. By measuring the rates at which E2 and E3 interacted with one another, Kleiger was able to demonstrate their unusually fast association—faster than predicted for normal proteins. E2 and E3 use oppositely-charged surfaces to attract each other, thereby speeding up the formation of a functional complex of the two proteins. This helps explain how the rapid sequential additions of ubiquitin described in the Nature paper are possible.

Gaining these kinds of insights into the ubiquitin system is important, Deshaies says, because ubiquitin ligases play a critical role in a number of human diseases, including cancer, due to their role in the regulation of the cell cycle.

"Once we understand these aspects of how ubiquitin ligases work, and what limits their speed, we will be in an excellent position to think about how we might develop drugs that attack the ligase's Achilles' heel, to make its slowest step even slower," he says. "If we can slow down ubiquitin ligases enough, they may become too slow to get their job done—to build chains—in the time available to them to do so. Being able to develop drugs to block their function would open up a new frontier in medicine."

"We were able to invent HIV therapeutics because we understand how reverse transcriptase works," adds Pierce. "The same applies here. We need to understand how these enzymes work if we're ever going to be able to target them with therapeutics."

In addition to Pierce and Deshaies, other researchers involved in the study included Kleiger and Shu-ou Shan, assistant professor of chemistry at Caltech.

The work described in the Nature paper, "Detection of Sequential Polyubiquitylation on a Millisecond Time-Scale," was funded by a Gordon Ross Fellowship, National Institutes of Health training and research grants, and the Howard Hughes Medical Institute.

Lori Oliwenstein

Nobel Laureate Ahmed Zewail Named United States Science Envoy

Caltech scientist will promote science and technology partnerships among nations

PASADENA, CALIF. - Nobel Laureate Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics at the California Institute of Technology (Caltech), has been named an envoy in the new U.S. Science Envoy Program, created to foster science and technology collaborations between the United States and nations throughout the Middle East, North Africa, and South and Southeast Asia. Zewail, who was also appointed to President Obama's Council of Advisors on Science and Technology earlier this year, is one of three eminent Americans who will serve as the first scientist-diplomats in the new program.

Secretary of State Hillary Clinton announced the appointment of "three of America's leading scientists" in a major address on November 3 in Marrakesh, Morocco. She described the program as one of several partnerships in the key areas of economic opportunity, science and technology, and education that are being launched in the wake of President Obama's speech last June at Cairo University, in which he promised a "new beginning" in America's relationship with Muslim communities around the world.

"It is a great honor and humbling responsibility to take on such a challenge in a tumultuous and changing world," said Zewail, who received the 1999 Nobel Prize in Chemistry for groundbreaking research into how atoms join together to form molecules. "After years of research on the dynamics of chemical bonds, I look forward to helping to forge new bonds among nations."

The Egyptian-born Zewail will serve as science envoy to 10 nations of the Middle East, where, according to the State Department, he will "engage counterparts, deepen and develop partnerships in all areas of science and technology, and foster meaningful collaboration to meet the greatest challenges facing the world today in health, energy, the environment, as well as in water and resource management."

"Ahmed Zewail is an ideal choice for science envoy," said Caltech president Jean-Lou Chameau. "He brings to the post superb scientific credentials and an abiding commitment to promoting science and technology for both its own sake and the betterment of society, and he is held in high esteem throughout the world. I am delighted that he will have the opportunity to serve both our nation and the international community in this capacity."

Zewail is internationally known for his work in femtosecond chemistry, in which he pioneered the use of ultrafast laser techniques to record atoms in the act of making and breaking molecular bonds-the basis of all chemical reactions-on the timescale at which such reactions actually occur, about one millionth of a billionth of a second. He currently directs the Physical Biology Center for Ultrafast Science and Technology at Caltech, with a focus on the development of four-dimensional microscopy, a new field established to visualize the behavior in space and time of matter at the nanoscale.

Zewail has a long-standing interest in global affairs, particularly as they relate to science, technology, and higher education, and his commentaries have appeared in Britain's Independent and the Wall Street Journal, among other publications. In a piece published earlier this fall in the Boston Globe and the International Herald Tribune, he called on Muslim nations to join with the West in new science and technology partnerships, an agenda that he will now be in a unique position to advance as U.S. science envoy.

The Caltech professor's numerous honors include the Albert Einstein World Award of Science, the Benjamin Franklin Medal, the Robert A. Welch Award, the Leonardo da Vinci Award, the Wolf Prize, and the King Faisal Prize. He has been awarded the Order of the Grand Collar of the Nile, Egypt's highest state honor, and has been featured on postage stamps issued to honor his contributions to science and humanity. He holds honorary degrees from 35 universities around the world, and is an elected member of many professional academies and societies, including the National Academy of Sciences, the Royal Society of London, and the Swedish, Russian, and French academies.

Zewail's fellow envoys are Bruce Alberts, president of the National Academy of Sciences from 1993 to 2005, and Elias Zerhouni, director of the U.S. National Institutes of Health from 2002 to 2008. Alberts, professor emeritus of biochemistry at the University of California, San Francisco, and editor in chief of Science magazine, will serve as the envoy to South and Southeast Asia. Zerhouni, a native of Algeria and professor of radiology and biomedical engineering at Johns Hopkins University, will be the envoy to North Africa.

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Jon Weiner
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Caltech and Dow Chemical Team Up in Solar Materials Effort

Collaboration includes the creation of Dow Graduate Fellowship in Chemical Sciences and Engineering

PASADENA, Calif.—The California Institute of Technology (Caltech) and the Dow Chemical Company today announced a new solar-research collaboration aimed at developing the use of semiconductor materials that are less expensive and more abundant than those used in many of today's solar cells.

In addition, they announced the creation of the Dow Chemical Company Graduate Fellowship in Chemical Sciences and Engineering.

The fellowship will be granted to a second- or third-year doctoral student who shows excellence in research, leadership, and interpersonal effectiveness, and whose research program aligns with broad areas of interest to Dow, such as alternative energy sources, the development of novel specialty chemicals, and the investigation of new polymer systems. Dow's $500,000 gift will be matched by $250,000 in funds from the Gordon and Betty Moore Matching Program.

Each recipient will be selected by the chair of the Division of Chemistry and Chemical Engineering, and will hold the fellowship for up to two years.

"We are pleased that Dow and Caltech are building this relationship to support innovative research as a basis for new technologies," says Jacqueline K. Barton, the division's current chair.

The solar-research collaboration will be a four-year, $4.2 million effort to explore earth-abundant materials for solar-energy applications. The project is led by applied physicist Harry Atwater, Caltech's Howard Hughes Professor, and chemist Nate Lewis, Caltech's George L. Argyros Professor.

"In combining the R&D strengths of Dow and Caltech, we have created a powerful alliance for innovation in the field of photovoltaics," says Bill Banholzer, executive vice president and chief technology officer of Dow. "This alliance will allow the best scientists the opportunity to work together to achieve the kinds of breakthrough technologies that will be game-changing in solar-energy capture."

The new Dow/Caltech solar-research initiative is one of the company's largest externally funded research agreements, Banholzer notes.

As part of the agreement, Atwater, Lewis, and their team will develop new mineral-like electronic materials suitable for use in thin-film solar-energy-conversion devices. 

"Development of materials that are abundant in the earth's crust will enable solar-energy technologies to ultimately scale to large volumes at low cost without concern about the materials' availability," says Atwater.

Most solar cells today are made with silicon, which is itself an abundant material. Still, silicon solar technology has a relatively higher cost than that of current thin-film solar materials like cadmium telluride and copper indium diselenide. But these inexpensive semiconductors pose a problem of their own: they contain materials too scarce to ultimately meet the demands of full-scale solar-energy technologies.

That's why Atwater and Lewis are turning their attention to semiconductors found in the earth's crust.

"Use of earth-abundant materials can provide new technology options and could open new areas of design space," Lewis notes. "But it also brings new challenges. This project will develop the science and technology base for thin-film solar-energy conversion using these widely available materials."

"This is an example of industry stepping up to the plate with a long-term vision that acknowledges the importance of supporting research in its most fundamental forms," says Ares Rosakis, chair of the Division of Engineering and Applied Science at Caltech and Theodore von Kármán Professor of Aeronautics and Mechanical Engineering.

"Dow understands that high-quality research is occurring in both industrial and academic laboratories. We believe that partnerships like this one are crucial to our success in the development of efficient, affordable energy solutions," says Banholzer.

Lori Oliwenstein
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Caltech Scientists Develop DNA Origami Nanoscale Breadboards for Carbon Nanotube Circuits

PASADENA, Calif.—In work that someday may lead to the development of novel types of nanoscale electronic devices, an interdisciplinary team of researchers at the California Institute of Technology (Caltech) has combined DNA's talent for self-assembly with the remarkable electronic properties of carbon nanotubes, thereby suggesting a solution to the long-standing problem of organizing carbon nanotubes into nanoscale electronic circuits.

A paper about the work appeared November 8 in the early online edition of Nature Nanotechnology

"This project is one of those great 'Where else but at Caltech?' stories," says Erik Winfree, associate professor of computer science, computation and neural systems, and bioengineering at Caltech, and one of four faculty members supervising the project.

Both the initial idea for the project and its eventual execution came from three students: Hareem T. Maune, a graduate student studying carbon nanotube physics in the laboratory of Marc Bockrath (then Caltech assistant professor of applied physics, now at the University of California, Riverside); Si-ping Han, a theorist in materials science, investigating the interactions between carbon nanotubes and DNA in the Caltech laboratory of William A. Goddard III, Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics; and Robert D. Barish, an undergraduate majoring in computer science who was working on complex DNA self-assembly in Winfree's lab.

The project began in 2005, shortly after Paul W. K. Rothemund invented his revolutionary DNA origami technique. At the time, Rothemund was a postdoctoral scholar in Winfree's laboratory; today, he is a senior research associate in bioengineering, computer science, and computation and neural systems.

Rothemund's work gave Maune, Han, and Barish the idea to use DNA origami to build carbon nanotube circuits. 

DNA origami is a type of self-assembled structure made from DNA that can be programmed to form nearly limitless shapes and patterns (such as smiley faces or maps of the Western Hemisphere or even electrical diagrams). Exploiting the sequence-recognition properties of DNA base pairing, DNA origami are created from a long single strand of viral DNA and a mixture of different short synthetic DNA strands that bind to and "staple" the viral DNA into the desired shape, typically about 100 nanometers (nm) on a side.

Single-wall carbon nanotubes are molecular tubes composed of rolled-up hexagonal mesh of carbon atoms. With diameters measuring less than 2 nm and yet with lengths of many microns, they have a reputation as some of the strongest, most heat-conductive, and most electronically interesting materials that are known. For years, researchers have been trying to harness their unique properties in nanoscale devices, but precisely arranging them into desirable geometric patterns has been a major stumbling block. 

"After hearing Paul's talk, Hareem got excited about the idea of putting nanotubes on origami," Winfree recalls. "Meanwhile, Rob had been talking to his friend Si-ping, and they independently had become excited about the same idea."

Underlying the students' excitement was the hope that DNA origami could be used as 100 nm by 100 nm molecular breadboards—construction bases for prototyping electronic circuits—on which researchers could build sophisticated devices simply by designing the sequences in the origami so that specific nanotubes would attach in preassigned positions. 

"Before talking with these students," Winfree continues, "I had zero interest in working with carbon nanotubes or applying our lab's DNA-engineering expertise toward such practical ends. But, seemingly out of nowhere, a team had self-assembled with a remarkable spectrum of skills and a lot of enthusiasm. Even Si-Ping, a consummate theorist, went into the lab to help make the idea become reality."

"This collaborative research project is evidence of how we at Caltech select the top students in science and engineering and place them in an environment where their creativity and imagination can thrive," says Ares Rosakis, chair of the Division of Engineering and Applied Science at Caltech and Theodore von Kármán Professor of Aeronautics and Professor of Mechanical Engineering.

Bringing the students' ideas to fruition wasn't easy. "Carbon nanotube chemistry is notoriously difficult and messy—the things are entirely carbon, after all, so it's extremely difficult to make a reaction happen at one chosen carbon atom and not at all the others," Winfree explains.

"This difficulty with chemically grabbing a nanotube at a well-defined 'handle' is the essence of the problem when you're trying to place nanotubes where you want them so you can build complex devices and circuits," he says.

The scientists' ingenious solution was to exploit the stickiness of single-stranded DNA to create those missing handles. It's this stickiness that unites the two strands that make up a DNA helix, through the pairing of DNA's nucleotide bases (A, T, C, and G) with those that have complementary sequences (A with T, C with G). 

"DNA is the perfect molecule for recognizing other strands of DNA, and single-stranded DNA also just happens to like sticking to carbon nanotubes," says Han, "so we mix bare nanotubes with DNA molecules in salt water, and they stick all over the nanotubes' surfaces. However, we make sure that a little bit of each DNA molecule is protected, so that that little portion doesn't stick to the nanotube, and we can use it to recognize DNA attached to the DNA origami instead."

The scientists created two batches of carbon nanotubes labeled by DNA with different sequences, which they called "red" and "blue."

"Metaphorically, we dipped one batch of nanotubes in red DNA paint, and dipped another batch of nanotubes in blue DNA paint," Winfree says. Remarkably, this DNA paint acts like color-specific Velcro.

"These DNA molecules served as handles because a pair of single-stranded DNA molecules with complementary sequences will wrap around each other to form a double helix. Thus," he says, "'red' can bind strongly to 'anti-red,' and 'blue' with 'anti-blue.'"

"Consequently," he adds, "if we draw a stripe of anti-red DNA on a surface, and pour the red-coated nanotubes over it, the nanotubes will stick on the line. But the blue-coated nanotubes won't stick, because they only stick to an anti-blue line."

To make nanometer-scale electronic circuits out of carbon nanotubes requires the ability to draw nanometer-scale stripes of DNA. Previously, this would have been an impossible task.

Rothemund's invention of DNA origami, however, made it possible.

"A standard DNA origami is a rectangle about 100 nm in size, with over 200 'pixel' positions where arbitrary DNA strands can be attached," Winfree says. To integrate the carbon nanotubes into this system, the scientists colored some of those pixels anti-red, and others anti-blue, effectively marking the positions where they wanted the color-matched nanotubes to stick. They then designed the origami so that the red-labeled nanotubes would cross perpendicular to the blue nanotubes, making what is known as a field-effect transistor (FET), one of the most basic devices for building semiconductor circuits.

Although their process is conceptually simple, the researchers had to work out many kinks, such as separating the bundles of carbon nanotubes into individual molecules and attaching the single-stranded DNA; finding the right protection for these DNA strands so they remained able to recognize their partners on the origami; and finding the right chemical conditions for self-assembly.

After about a year, the team had successfully placed crossed nanotubes on the origami; they were able to see the crossing via atomic force microscopy. These systems were removed from solution and placed on a surface, after which leads were attached to measure the device's electrical properties. When the team's simple device was wired up to electrodes, it indeed behaved like a field-effect transistor.  The "field effect" is useful because "the two components of the transistor, the channel and the gate, don't actually have to touch for there to be a switching effect," Rothemund explains. "One carbon nanotube can switch the conductivity of the other due only to the electric field that forms when a voltage is applied to it."

At this point, the researchers were confident that they had created a method that could construct a device from a mixture of nanotubes and origami.

"It worked," Winfree says. "I can't say perfectly—there's lots of room for improvement. But it was sufficient to demonstrate the controlled construction of a simple device, a cross-junction of a pair of carbon nanotubes."

"We expect that our approach can be improved and extended to reliably construct more complex circuits involving carbon nanotubes and perhaps other elements including electrodes and wiring," Goddard says, "which we anticipate will provide new ways to probe the behavior and properties of these remarkable molecules."

The real benefit of the approach, he points out, is that self-assembly doesn't just make one device at a time. "This is a scalable technology. That is, one can design the origami to construct complex logic units, and to do this for thousands or millions or billions of units that self-assemble in parallel."

The work in the paper, "Self-assembly of carbon nanotubes into two-dimensional geometries using DNA origami templates," was supported by the National Science Foundation, the Office of Naval Research, and the Center on Functional Engineered Nano Architectonics.

Kathy Svitil


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