UCLA researchers determine the structure of a toxin that kills malaria-carrying mosquitoes

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Results pave the way for genetically engineering the toxin to be lethal to other mosquito species transmitting Zika virus and dengue fever

By Katherine Kornei

Figure showing BinA and BinB folds and carbohydrate-binding modules. BinA and BinB are structurally similar to each other. The most noticeable differences correspond to insertions in surface loops on the trefoil domains (purple). UCLA researchers used an X-ray laser to determine the arrangement of atoms.

An international team of scientists, including five UCLA researchers, has used X-rays to reveal the structure of a molecule toxic to disease-carrying mosquitoes.

Nearly half of the world’s population is at risk of contracting malaria, a life-threatening disease transmitted by mosquitoes. Chemical insecticides are often a first line of defense against mosquitoes, but their application can result in both environmental pollution and resistance to the pesticide. The research was published in the journal Nature.

Countries around the globe have recently begun killing mosquito larvae using a natural toxin derived from bacteria. Now UCLA scientists and their collaborators have used X-rays to determine the atomic structure of this larvicide, which is lethal to mosquitoes transmitting malaria and West Nile virus. These results reveal how the toxin functions, knowledge that will inform future efforts to genetically engineer it to also kill mosquitoes carrying Zika virus and dengue fever.

“This is a chance to have a positive effect on a lot of the world’s population,” said senior author David Eisenberg, UCLA’s Paul D. Boyer Professor of Molecular Biology and a Howard Hughes Medical Institute investigator.

Eisenberg and his colleagues studied the larvicide known as BinAB, which is produced by soil-dwelling bacteria. The bacteria pack BinAB into tiny crystals, thousands of which could be stacked across the head of a pin. When these crystals are scattered into the watery environments in which mosquitoes thrive, hungry mosquito larvae eat the crystals. But the meal turns out to be a deadly one.

As the crystals pass through the larvae’s digestive tract, the gut juices of the larvae trigger the crystals to dissolve. The BinAB toxin is released, and its component molecules — called BinA and BinB — play distinct roles in entering the cells of the larvae’s guts and killing the young mosquitoes within 48 hours.

BinAB is toxic to the Culex and Anopheles species of mosquitoes — carriers of West Nile virus and malaria, respectively — but at this point is harmless to the Aedes species, the carriers of Zika virus and dengue fever.

“The toxin is this complex shape, and it has to fit with another shape on the intestine of the larvae. If the shapes don’t match up precisely, the toxin cannot get in the cell. It’s like a lock and key,” said Michael Sawaya, a staff scientist at UCLA involved in the study, to explain BinAB’s specificity.

Genetically engineering an effective toxin

Researchers are interested in genetically engineering BinAB to also kill the larvae of Aedes mosquitoes, work that requires a detailed understanding of BinAB’s atomic structure. However, the small size of the crystals containing BinAB has made it difficult for scientists to hold them securely in laboratory instruments for analysis.

The UCLA researchers and their colleagues, including Dr. Jacques-Philippe Colletier, a former UCLA researcher now working in France, overcame this size limitation by harvesting crystals from a particular strain of soil-dwelling bacteria engineered to produce larger crystals. The scientists then studied the precise shape of the BinAB toxin within the crystals using an X-ray laser. Eisenberg and his colleagues bombarded the crystals with an X-ray laser invented by a UCLA physicist.

“When we shine X-rays on the crystals, the X-rays are scattered into thousands of X-ray beams,” said Eisenberg, who is also a professor of chemistry, biochemistry and biological chemistry and a member of UCLA’s California NanoSystems Institute. “These beams contain information about the arrangement of the atoms that make up BinA and BinB.”

 

“It would be hard to find a problem that could potentially affect the health of more people.” –  Senior author David Eisenberg

 

Novel use of X-ray laser

This type of X-ray laser has never before been used to study a sample with an unknown structure. “We can do entirely new types of experiments using these X-ray lasers,” said co-author Jose Rodriguez, a UCLA assistant professor of chemistry and biochemistry.

The researchers found that the BinA and BinB molecules making up BinAB were crossed in an “X” shape. “They’re hugging each other,” Eisenberg said of the BinA and BinB molecules. This geometry helps ensure that the BinA and BinB molecules exist in equal numbers, which contributes to BinAB’s toxicity.

The scientists also isolated four special sites on the BinAB toxin that were most likely to be involved in the larvicide splitting into BinA and BinB, a transformation critical to the lethal nature of the toxin.

“You can think of the molecule as…having four latches,” Rodriguez said. “When these latches open, the molecule can change its shape. These crystals have to go through a lot of transformations before they actually reach the target location.”

The scientific world is now one step closer to genetically engineering BinAB to be lethal to the mosquitoes that carry Zika virus and dengue fever.

Eisenberg is optimistic. “It would be hard to find a problem that could potentially affect the health of more people,” he said.

Funding sources for the research include the Howard Hughes Medical Institute, W.M. Keck Foundation, National Science Foundation, National Institutes of Health, and the U.S. Department of Energy Office of Science and Office of Basic Energy Sciences.

David Eisenberg, UCLA’s Paul D. Boyer Professor of Molecular Biology

‘Jump-starting’ the brain of a patient recovering from a coma

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Image: Representation of ultrasonic stimulation of the brain’s thalamus in a post-comatose patient.

New noninvasive technique could result in low-cost therapy for patients with severe brain injury

By Stuart Wolpert

A 25-year-old man recovering from a coma has made remarkable progress following a treatment to “restart” his brain using ultrasounds, a team of UCLA scientists reported in a letter published in the journal Brain Stimulation. This is the first time such an approach to severe brain injury has been tried.

“Our technique uses sonic stimulation to excite the neurons in the thalamus – almost as if we were jump-starting them back into function,” said lead author Martin Monti, associate professor of psychology and neurosurgery. “Until now, the only way of achieving this was for a patient to undergo brain surgery and have electrodes implanted directly inside the thalamus – an egg-shaped structure which serves as the bustling central hub for information flow within the brain – a risky procedure known as deep brain stimulation. Our approach directly targets the thalamus, but is noninvasive.”

This new technique, called low intensity focused ultrasound pulsation (LIFUP), has been pioneered by co-author Alexander Bystritsky, professor of psychiatry and biobehavioral sciences in the Semel Institute for Neuroscience and Human Behavior and founder of Brainsonix, which provided the experimental device for this research. In this approach, a small device, about the size of a coffee cup saucer, is placed by the side of a patient’s head. The device creates a small sphere of acoustic energy that can be aimed at different regions of the brain to excite or inhibit brain tissue. Monti said the technique is quite safe, partly because the amount of energy from each stimulation is small. The researchers repeated it 10 times over 10 minutes.

The changes in the patient’s brain were remarkable, Monti said. Before sonic stimulation, the patient could show only minimal signs of being conscious and of understanding speech. By the day after the sonic stimulation, he was able to show greater responses and started vocalizing responses. Three days later, the patient was fully conscious, had regained full language comprehension, could reliably communicate by gesturing “yes” or “no” with his head, and even gave a fist-bump.

“This result is exactly what we expected,” Monti said.

However, he cautioned that this is only one patient. “It is possible that we were just very lucky and happened to have stimulated the patient just as he

was spontaneously recovering,” Monti said. “This is why it is so crucial, before we get too excited, that we repeat this procedure in more patients.”

Joining with Ronald Reagan UCLA Medical Center

Monti and his colleagues, under the direction of UCLA professor Paul Vespa, are planning to perform this procedure in several more patients at the Ronald Reagan UCLA Medical Center, working with UCLA’s Brain Injury Research Center, and with funding from the Dana Foundation and the Tiny Blue Dot Foundation.

If the researchers are able to demonstrate that the recovery in this patient was linked to the ultrasound stimulation, the potential for this technique could be very large. There are currently few effective treatment options for patients in a coma, Monti said.

Monti’s long-term goal is to one day be able to build a small portable device, perhaps a helmet, that could be brought to the bedside of a patient who is in a coma and, with no surgery, help the brain return to normal levels of function, leading to the return of cognitive functions and consciousness.

Hope for an entirely new treatment

Monti said he hopes his technique could be the beginning of a new noninvasive, low-cost therapy to help wake up patients in a coma — perhaps even patients in a vegetative state and in a minimally conscious state, for whom there is almost no effective treatment.

The idea behind this new approach is that when patients fail to fully recover from a coma, and awaken to a state of deeply impaired mental function, this is due partly to an impairment in the functioning of the thalamus. Pharmacological treatment targets the thalamus only indirectly.

Co-authors are Vespa, who holds UCLA’s Gary L. Brinderson Family Chair in Neurocritical Care, and is a professor of neurology and neurosurgery at the UCLA David Geffen School of Medicine, and director of neurocritical care at the Ronald Reagan UCLA Medical Center; Caroline Schnakers, a UCLA researcher in neurosurgery; Bystritsky; and Alexander Korb, a researcher in the Semel Institute.

 

Meet the Professor- In his own words

By Martin Monti

In my laboratory we focus on two of the most fundamental aspects of being human:
1. What is the relationship between language and thought?
Does language make us special? One of the most striking features of human cognition is the ability to generate an infinite number of ideas by combining a finite set of elements according to structure-dependent principles. This ability is most clearly displayed in language, but also characterizes other aspects of our cognition such as drawing inferences, performing mental arithmetic or music cognition. Does language enable other types of structure-dependent cognition? Does the structure of natural language provide a scaffolding on which to build other forms of high-level cognition? In my research I employ behavioral and fMRI tools in healthy volunteers and patients to address these questions.
2. How is consciousness lost and recovered after severe brain injury?
How do we ever know that someone, other than ourselves, is conscious? Philosophical considerations aside, this issue is at the heart of one of the most challenging and least understood conditions of the human brain: the Vegetative State. This is a condition in which, after severe brain injury, patients are awake but not aware. In my research I focus on brain processing and consciousness in these patients, to try to ameliorate diagnostic procedures and to develop new interventions that may help recovery.

 

Watch it here Professor Monti on “The Mystery of Consciousness and the Vegetative State” at TEDx Claremont Colleges

 

 

$5 million gift from Meyer Luskin establishes research center for history and policy at UCLA

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Thanks to a $5 million gift from longtime supporter Meyer Luskin, UCLA will establish the Luskin Center for History and Policy, the first academic research center on the West Coast devoted to using history to publish knowledge that promotes solutions to present-day issues.

Meyer Luskin

The new center will foster teaching, research and collaborations across campus and beyond the university that will direct historical insights to shaping policies and solving problems.

“I believe we can use history to better our lives,” said Luskin, the chairman, president and CEO of Scope Industries. “The best way to choose the path to the future is to know the roads that brought us to the present.”

The Luskin Center for History and Policy will be a pioneer in translating historical research into tangible and accessible sources of knowledge. The center will support policy-oriented projects developed by UCLA history faculty and their colleagues across campus, host visiting scholars and postdoctoral fellows and provide funding for graduate students. It will also sponsor new courses that will train students to analyze historical events and apply their knowledge to current issues.

“Meyer Luskin has given UCLA the means to build a new pathway to using historical knowledge for the greater good,” said Scott Waugh, UCLA’s executive vice chancellor and provost. “Situated in a global university with a public mission, the new center is well placed to have a decisive impact, from the local level all the way to the international level.”

The history department can already cite at least one recent example of the influence of historical research on public action. In 2015, Zev Yaroslavsky, a former Los Angeles County supervisor and now a senior fellow in history at UCLA, led a project examining the city’s bidding process for the 1984 Olympics. The resulting position paper was distilled into an op-ed published in the Los Angeles Times and contributed to the decision by the Los Angeles City Council to delay a vote on the Olympic bid until all its provisions could be properly debated.

Stephen Aron, the Robert N. Burr Department Chair of the history department, said the center would be a hub for collaborative projects engaging researchers from the social sciences and the humanities as well as campus units including the UCLA Fielding School of Public Health and the UCLA Luskin School of Public Affairs.

“My goal is to make history matter more to more people, and I can’t think of a better way to do that than through this center,” Aron said. “We are indebted to Meyer for his generous and visionary action.”

Initially, the center will be under the direction of history professor and former department chair David Myers, working closely with Aron.

“There is a new urgency to understand and apply our historical knowledge to today’s world,” said Myers, holder of the Sady and Ludwig Kahn Chair in Jewish History. “The new Luskin Center will be a national trend-setter in bringing many different angles of historical perspective to bear on key issues in the country — and world — today.”

Myers said the center would help develop new forms of teaching to equip students with the historical tools to make sense of the world around them and thrive in any number of careers.

Luskin, who graduated in 1949, and his wife, Renee, who graduated in 1953, are among UCLA’s most generous supporters. In 2011, they donated $100 million — the second-largest gift ever to the campus — to support academic programs and capital improvements. The gift was equally divided between the UCLA School of Public Affairs, which was renamed in their honor, and the UCLA Meyer and Renee Luskin Conference Center, which opened in 2016. Luskin co-chairs the UCLA Centennial Campaign Cabinet, serves on the campaign executive committee, and is a member of the UCLA Foundation board of directors.

Addressing graduates at the 2014 history department commencement, Luskin said, “The study of history creates important knowledge — but equally important is how you assemble and use that knowledge.”

Pourdavoud Center for the Study of the Iranian World established at UCLA

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UCLA has established the Pourdavoud Center for the Study of the Iranian World, the first center in the Western Hemisphere that aims to advance the knowledge of ancient Iranian languages, history and religions.

Anahita and James Lovelace

The Pourdavoud Center was named for the late Professor Ebrahim Pourdavoud, a pioneering scholar of ancient Persia, and was made possible by a gift from his granddaughter, Dr. Anahita Naficy Lovelace, and her husband, James B. Lovelace.

“My grandfather devoted a lifetime to the study of the history, languages, religions and culture of ancient Iran. I am so grateful that Jim and I have the good fortune to be able to honor and extend the impact of his important contributions,” Lovelace said.

The mission of the Pourdavoud Center is to engage in transformative research on all aspects of Iranian antiquity, including its reception in the medieval and modern periods, by expanding on the traditional domains of Old Iranian studies and promoting cross-cultural and interdisciplinary scholarship. The center will complement UCLA’s well-established doctoral program in Iranian Studies – founded more than half a century ago in 1963 – which attracts 1,000 students from all over campus to its courses each year.

“At UCLA, we recognize that the study of ancient cultures is more important today than ever,” said David Schaberg, dean of humanities in the UCLA College. “It reveals the rich tapestry of human history and identity, and allows us to understand and uphold the highest values our forebears espoused.”

Schaberg said he was confident that the Pourdavoud Center would inspire lively intellectual and cross-cultural discussions among students and scholars throughout campus, as well as members of the Los Angeles community.

“UCLA’s location in the principal metropolitan center for the Iranian-American community is ideal for the Pourdavoud Center,” he said.

The Pourdavoud Center will host lectures, seminars, workshops and conferences. It will also provide grants to established and emerging visiting scholars to generate and disseminate innovative scholarship on ancient Iran.

The center will draw on a wealth of campus resources including: the departments of Near Eastern Languages and Cultures, Classics, History, Art History, and Asian Languages and Cultures; the Indo-European Studies program; the Cotsen Institute for Archaeology; the Asia Institute; the Center for Medieval and Renaissance Studies; and the UCLA Alan D. Leve Center for Jewish Studies. Moreover, extensive collections of medieval Persian manuscripts and late antique Iranian inscriptions will be available to scholars working at the Pourdavoud Center.

UCLA’s Iranian Studies program, led by Professor M. Rahim Shayegan, is home to the largest and most comprehensive doctoral program of its kind in the Americas and is the only one to cover the entire spectrum of Iranian Studies across disciplines, linguistic boundaries and periods. Its distinctive strengths are Old and Middle Iranian philology, ancient Iranian history and religions, archaeology, and the study of classical Persian literature.

“We are very grateful to the Lovelaces for providing us crucial resources to revive the study of Iranian antiquity,” said Shayegan, holder of the Jahangir and Eleanor Amuzegar Chair of Iranian Studies. “A research institute of this magnitude can have a transformative impact on the fortunes of the whole discipline, decisively reversing its decline and reinforcing its foundation.”

Shayegan, who will guide the Pourdavoud Center as it launches its inaugural year, said that the center would launch in the spring with a two-day international workshop focused on strategies to strengthen the field of ancient Iranian studies and to bolster institutional links among other centers of excellence.

Ebrahim Pourdavoud

Ebrahim Pourdavoud (1885-1968) was a dedicated scholar who pioneered the first Persian translation of the Avesta, the holy book of the ancient Zoroastrian religion. Over a span of 67 years, he conducted extensive research on ancient history and ancient Iranian languages, and trained many scholars and Iranists.

According to Shayegan, Pourdavoud profoundly affected Iranian society by resurrecting and identifying ancient Persia as a positive force for societal progress in contemporary Iran.

“The late Professor Pourdavoud greatly admired the ability of ancient Iranian universal empires to embrace diverse ethnicities, religions and languages, while allowing their individuality to thrive within a cohesive state structure,” Shayegan said. “This innate tolerance was, and still is, of great appeal, and a research center named after Pourdavoud ought to pay heed to this spirit of openness to the world.”

Lovelace, who spent the first 18 years of her life in Tehran, has fond memories of childhood visits to her grandparents’ home.

“Our grandfather would typically receive us in his study, where he spent most of his time,” she recalled. “He was surrounded by his beloved books on ancient Iran, in different languages, alongside encyclopedias, reference books, dictionaries and books on a variety of related subjects. Though a formal man, he was very warm and lighthearted at the same time. He had a wonderful sense of humor and always looked for ways to engage us, his grandchildren, during these visits.”

“I am grateful to my grandfather and my parents for giving me such wonderful early exposure to the ethos of ancient Iran. I have found this immeasurably helpful both in my personal as well as my professional life,” she said.

As for the gift to UCLA, Lovelace said that she was impressed by the caliber of the program of Iranian Studies and faculty, and that she anticipated the field would thrive in such a vibrant setting.

“With new tools for discovery and expanding opportunities for exchange of ideas, it behooves us all to work together to keep our ancient civilizations alive and relevant for future generations,” she said.

Lovelace is a clinical psychologist practicing in Los Angeles. She holds a bachelor of arts in psychology from Princeton University and a Ph.D. in clinical psychology from The University of Texas at Austin. A native Californian and graduate of Swarthmore College, James Lovelace is an equity portfolio manager at Capital Group, a global financial services company based in Los Angeles.

To learn more, please visit the Pourdavoud Center’s web site.

UCLA faculty voice: Americans tend to be married to their political party

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People often ask me “who these people are” — those who elected Donald J. Trump or those who voted for Hillary Clinton. They’ll ask, “What’s the single best description of Trump supporters?” My answer often disappoints them.

The Wellsprings of Our Moralities

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In response to the question series “What can evolution tell us about morality?” professor of anthropology Daniel M.T. Fessler reflects on how natural selection allows the flexibility to adapt to the moral system we are born into.

Political affiliation can predict how people will react to false information about threats

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The study, which will be published in the journal Psychological Science, found that people who hold more socially conservative views were significantly more likely than people with liberal beliefs to find false information about threats credible.

Digital humanities students shine a light on the history of African American filmmakers

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By Jessica Wolf

While the #OscarsSoWhite controversy raged over the dearth of people of color nominated for Academy Awards this past year, a group of digital humanities students at UCLA channeled their frustration into meticulously building the little-known history of silent films made for and by African Americans in the early 20th century.

 

Photo from Within Our Gates (1919), the oldest known surviving film made by an African American director.

What they found, and sought to highlight, is that African American artists are deeply entwined in the history of filmmaking,  and can be traced back to the medium’s beginnings.

The result of their efforts is “Early African American Film: Reconstructing the History of Silent Race Films, 1909-1930,” an informational website and searchable database that tracks the African American actors, crew members, writers, producers and other artists who were making films during the silent era.

“We were venturing into pretty unknown territory and I really wanted to be a part of telling the stories of this generation of African American people and their contributions,” said Shayna Norman, who graduated last spring. “The fact that the #OscarsSoWhite controversy blew up at the same time we worked on it made this project feel even more relevant and important.”

Hands-on research

Students worked closely with UCLA Library Special Collections, combing through old journals, production notes, posters and fliers to reconstruct what was once a thriving and collaborative network of African American writers, directors, actors and producers who were making what were known as “race films.”

Relying partially on the work of historians who have unearthed documentation of these forgotten filmmakers, the UCLA student team set its parameters to include films from 1909 to 1930 that featured African American cast members, were produced by an independent production company and discussed or advertised as a race film in the African American press.

While the community was vibrant, it struggled to gain mainstream traction. In the silent-film era, productions that fit the “race films”description, like those produced by the Hampton and Tuskegee Institutes, A Trip to Tuskegee (1909), John Henry at Hampton (1913) and A Day at Tuskegee (1913), could be shown only in certain theaters, or often in African American churches, and were played to segregated audiences. Most of these films, therefore, received scant mainstream media attention. The actual film reels were not preserved in any systematic way or protected in hermetically sealed vaults, which has led to physical degradation.

Motion picture director Oscar Micheaux (center) with an actor and a possible crew member appearing in an advertisement for the Micheaux Film Corporation.

Finding forgotten films

Few films survive, though Miriam Posner, core faculty and program coordinator for the digital humanities at UCLA, was partially inspired to ignite the project thanks to the recent release of a compilation of films from Kino Lorber called Pioneers of African-American Cinema.

The scarcity drove the students.

Coming up empty on internet searches caught students particularly off guard, Norman said.

“We’re not used to that kind of obscurity, but so much of the data has been lost or damaged, is not in any history textbooks in our educational system, and is not easily searchable,” she said.

A centering figure in the students’ archival exploration was Oscar Micheaux, author, filmmaker and founder of the Micheaux Film Corporation, one of the most prominent producers of the era’s race films. He kept copious notes and records on the actors and crew members he worked with, providing much-needed fodder for the database. Micheaux’s Within Our Gates (1919) is one of the few examples of a race film that garnered some attention — and an audience — from the white press.

Making data accessible worldwide

The project exists as a perusable database on the code-sharing site GitHub that others may use, build upon and correct. The site maintains a trail of attribution to the UCLA project.

“Not everyone knows how to work with data like ours, so we also spent a lot of time building tutorials that show people exactly how to create their own network graphs, maps and other kinds of analysis using our data,” Posner said.

Capstone activities like this are extremely important in the digital humanities field because students have the best, most meaningful experiences while apprenticing on an active project, she said.

“We love the way that students and faculty come to rely on each other, developing mutual respect for each other’s skills and abilities,” Posner said. “In a lot of cases, the capstone projects like this are specifically designed to live on after the q

Poster for Black Gold, Richard E. Norman’s lost final feature. Norman was a pioneer in the development of films for African American audiences.

uarter has ended. In all cases, we ensure that we preserve a ‘snapshot’ of the work from the time the quarter ended, and that all students are credited for their work.”

Working on a project like this has made lasting impact on the students.

“We get to work on a project that leaves an important footprint,” Girma said. “That’s the amazing part of the digital humanities.” A World Arts and Cultures major, Girma said she added a digital humanities minor in her fourth year after she heard from a friend that the coursework was “life-changing.”

Norman said that she hopes to pursue a career that allows her to continue working at the intersection of entertainment and digital technology.

“I’m a media junkie and by being involved in digital humanities projects like this one, I can see how such digital research methods and skills are relevant and needed in this growing age of mass consumer media.”

LEARN MORE:
Explore the students’ research,
“Early African American Film: Reconstructing the History of Silent Race Films, 1909-1930,”on their website at http://ucla.in/2fhm3BQ

 

 

 

Watch race film Within Our Gates at https://youtu.be/h1E0NrcnwAE

 

The Brain: Our Next Frontier

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Cover Story

UCLA faculty and students are at the brink of historic breakthroughs in the most complex and least understood organ in the body. Through the use of the latest technology, the top-rated UCLA Department of Psychology is studying all aspects of brain health.

UCLA faculty voice: Obama should not feel obligated to go quietly

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If Mr. Trump expected Barack Obama, who will be the first president since Woodrow Wilson to continue living in Washington, to retire to silence, he got a rude awakening on Wednesday.