From Vanderbilt: “Unraveling genetic mystery next step in Zika and dengue fight”

Vanderbilt U Bloc

Vanderbilt University

Apr. 23, 2018
Heidi Hall
(615) 322-NEWS
heidi.hall@vanderbilt.edu

A Vanderbilt team took the next leap forward in using a little-known bacteria to stop the spread of deadly mosquito-borne viruses such as Zika and dengue.

Wolbachia are bacteria that occur widely in insects and, once they do, inhibit certain pathogenic viruses the insects carry. The problem with using Wolbachia broadly to protect humans is that the bacteria do not normally occur in mosquitoes that transmit Zika and dengue. So success in modifying mosquitoes relies on the bacteria’s cunning ability to spread like wildfire into mosquito populations.

Wolbachia do so by hijacking the insect reproductive system in a process called cytoplasmic incompatibility, or CI. This makes the sperm of infected fathers lethal to eggs of uninfected mothers. However, if infected fathers mate with infected mothers, the eggs live, and the infected mothers carrying Wolbachia will also infect all her offspring with it. Then those offspring pass on Wolbachia to the next generation, and so on, until they eventually replace all of the resident mosquitoes. As Wolbachia spreads in the population, the risk of dengue and Zika virus transmission drops.

How that sperm and egg hijacking worked in infected fathers and mothers remained a mystery for decades, until Associate Professor of Biological Sciences Seth Bordenstein and his team helped solve it. They set out to dissect the number and types of genes that Wolbachia use to spread with the long-term goal of harnessing that genetic ability for protecting humans against diseases transmission.

“In this new study, we’ve dissected a simple set of Wolbachia genes that replicate how Wolbachia change sperm and egg” Bordenstein said. “There are two genes that cause the incompatibility, and one of those same genes rescues the incompatibility. Engineering mosquitoes or Wolbachia for expression of these two genes could enhance or cause the spread of Wolbachia through target mosquito populations.”

Their achievement is based on inserting genes into the genome of fruit flies. It is described in a paper appearing today in the Proceedings of the National Academy of Sciences.

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Wolbachia spreads itself by hijacking the insect reproductive system in a process called cytoplasmic incompatibility, or CI. (J. Dylan Shropshire/Vanderbilt University)

In a previous study last year Nature, the team identified the two genes in Wolbachia — named cytoplasmic incompatibility factors cifA and cifB — and learned that they modify the sperm to kill eggs. Now they solved the other half of the genetic mystery: cifA single-handedly can protect embryos from death.

“It’s a microbial encryption and de-encryptyion system that ensures Wolbachia spread through insect populations so they can adequately block the transmission of viruses and ultimately save lives” Bordenstein said.

Coauthors of the paper include Ph.D. student and National Science Foundation Graduate Research Fellow J. Dylan Shropshire and Vanderbilt undergraduates Emily Layton and Helen Zhou.

Vanderbilt University has filed patent applications on this new finding and seeks industry partners for further development through its Center for Technology Transfer and Commercialization.

This work was supported by National Institutes of Health (NIH) awards R01 AI132581 and R21 HD086833, National Science Foundation award IOS 1456778, a National Science Foundation Graduate Research Fellowship, and Vanderbilt University Medical Center Cell Imaging Shared Resources (supported by NIH grants CA68485, DK20593, DK58404, DK59637 and EY08126).

See the full article here .

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Commodore Cornelius Vanderbilt was in his 79th year when he decided to make the gift that founded Vanderbilt University in the spring of 1873.

The $1 million that he gave to endow and build the university was the commodore’s only major philanthropy. Methodist Bishop Holland N. McTyeire of Nashville, husband of Amelia Townsend who was a cousin of the commodore’s young second wife Frank Crawford, went to New York for medical treatment early in 1873 and spent time recovering in the Vanderbilt mansion. He won the commodore’s admiration and support for the project of building a university in the South that would “contribute to strengthening the ties which should exist between all sections of our common country.”

McTyeire chose the site for the campus, supervised the construction of buildings and personally planted many of the trees that today make Vanderbilt a national arboretum. At the outset, the university consisted of one Main Building (now Kirkland Hall), an astronomical observatory and houses for professors. Landon C. Garland was Vanderbilt’s first chancellor, serving from 1875 to 1893. He advised McTyeire in selecting the faculty, arranged the curriculum and set the policies of the university.

For the first 40 years of its existence, Vanderbilt was under the auspices of the Methodist Episcopal Church, South. The Vanderbilt Board of Trust severed its ties with the church in June 1914 as a result of a dispute with the bishops over who would appoint university trustees.

kirkland hallFrom the outset, Vanderbilt met two definitions of a university: It offered work in the liberal arts and sciences beyond the baccalaureate degree and it embraced several professional schools in addition to its college. James H. Kirkland, the longest serving chancellor in university history (1893-1937), followed Chancellor Garland. He guided Vanderbilt to rebuild after a fire in 1905 that consumed the main building, which was renamed in Kirkland’s honor, and all its contents. He also navigated the university through the separation from the Methodist Church. Notable advances in graduate studies were made under the third chancellor, Oliver Cromwell Carmichael (1937-46). He also created the Joint University Library, brought about by a coalition of Vanderbilt, Peabody College and Scarritt College.

Remarkable continuity has characterized the government of Vanderbilt. The original charter, issued in 1872, was amended in 1873 to make the legal name of the corporation “The Vanderbilt University.” The charter has not been altered since.

The university is self-governing under a Board of Trust that, since the beginning, has elected its own members and officers. The university’s general government is vested in the Board of Trust. The immediate government of the university is committed to the chancellor, who is elected by the Board of Trust.

The original Vanderbilt campus consisted of 75 acres. By 1960, the campus had spread to about 260 acres of land. When George Peabody College for Teachers merged with Vanderbilt in 1979, about 53 acres were added.

wyatt centerVanderbilt’s student enrollment tended to double itself each 25 years during the first century of the university’s history: 307 in the fall of 1875; 754 in 1900; 1,377 in 1925; 3,529 in 1950; 7,034 in 1975. In the fall of 1999 the enrollment was 10,127.

In the planning of Vanderbilt, the assumption seemed to be that it would be an all-male institution. Yet the board never enacted rules prohibiting women. At least one woman attended Vanderbilt classes every year from 1875 on. Most came to classes by courtesy of professors or as special or irregular (non-degree) students. From 1892 to 1901 women at Vanderbilt gained full legal equality except in one respect — access to dorms. In 1894 the faculty and board allowed women to compete for academic prizes. By 1897, four or five women entered with each freshman class. By 1913 the student body contained 78 women, or just more than 20 percent of the academic enrollment.

National recognition of the university’s status came in 1949 with election of Vanderbilt to membership in the select Association of American Universities. In the 1950s Vanderbilt began to outgrow its provincial roots and to measure its achievements by national standards under the leadership of Chancellor Harvie Branscomb. By its 90th anniversary in 1963, Vanderbilt for the first time ranked in the top 20 private universities in the United States.

Vanderbilt continued to excel in research, and the number of university buildings more than doubled under the leadership of Chancellors Alexander Heard (1963-1982) and Joe B. Wyatt (1982-2000), only the fifth and sixth chancellors in Vanderbilt’s long and distinguished history. Heard added three schools (Blair, the Owen Graduate School of Management and Peabody College) to the seven already existing and constructed three dozen buildings. During Wyatt’s tenure, Vanderbilt acquired or built one-third of the campus buildings and made great strides in diversity, volunteerism and technology.

The university grew and changed significantly under its seventh chancellor, Gordon Gee, who served from 2000 to 2007. Vanderbilt led the country in the rate of growth for academic research funding, which increased to more than $450 million and became one of the most selective undergraduate institutions in the country.

On March 1, 2008, Nicholas S. Zeppos was named Vanderbilt’s eighth chancellor after serving as interim chancellor beginning Aug. 1, 2007. Prior to that, he spent 2002-2008 as Vanderbilt’s provost, overseeing undergraduate, graduate and professional education programs as well as development, alumni relations and research efforts in liberal arts and sciences, engineering, music, education, business, law and divinity. He first came to Vanderbilt in 1987 as an assistant professor in the law school. In his first five years, Zeppos led the university through the most challenging economic times since the Great Depression, while continuing to attract the best students and faculty from across the country and around the world. Vanderbilt got through the economic crisis notably less scathed than many of its peers and began and remained committed to its much-praised enhanced financial aid policy for all undergraduates during the same timespan. The Martha Rivers Ingram Commons for first-year students opened in 2008 and College Halls, the next phase in the residential education system at Vanderbilt, is on track to open in the fall of 2014. During Zeppos’ first five years, Vanderbilt has drawn robust support from federal funding agencies, and the Medical Center entered into agreements with regional hospitals and health care systems in middle and east Tennessee that will bring Vanderbilt care to patients across the state.

studentsToday, Vanderbilt University is a private research university of about 6,500 undergraduates and 5,300 graduate and professional students. The university comprises 10 schools, a public policy center and The Freedom Forum First Amendment Center. Vanderbilt offers undergraduate programs in the liberal arts and sciences, engineering, music, education and human development as well as a full range of graduate and professional degrees. The university is consistently ranked as one of the nation’s top 20 universities by publications such as U.S. News & World Report, with several programs and disciplines ranking in the top 10.

Cutting-edge research and liberal arts, combined with strong ties to a distinguished medical center, creates an invigorating atmosphere where students tailor their education to meet their goals and researchers collaborate to solve complex questions affecting our health, culture and society.

Vanderbilt, an independent, privately supported university, and the separate, non-profit Vanderbilt University Medical Center share a respected name and enjoy close collaboration through education and research. Together, the number of people employed by these two organizations exceeds that of the largest private employer in the Middle Tennessee region.
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From MIT: “Progress toward a Zika vaccine” A lot of Zika News Lately

MIT News

MIT Widget

MIT News

March 29, 2017
Anne Trafton

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MIT researchers have devised a new vaccine candidate for the Zika virus. “It functions almost like a synthetic virus, except it’s not pathogenic and it doesn’t spread,” says postdoc Omar Khan. Image: Jose-Luis Olivares/MIT

Researchers program RNA nanoparticles that could protect against the virus.

Using a new strategy that can rapidly generate customized RNA vaccines, MIT researchers have devised a new vaccine candidate for the Zika virus.

The vaccine consists of strands of genetic material known as messenger RNA, which are packaged into a nanoparticle that delivers the RNA into cells. Once inside cells, the RNA is translated into proteins that provoke an immune response from the host, but the RNA does not integrate itself into the host genome, making it potentially safer than a DNA vaccine or vaccinating with the virus itself.

“It functions almost like a synthetic virus, except it’s not pathogenic and it doesn’t spread,” says Omar Khan, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and an author of the new study. “We can control how long it’s expressed, and it’s RNA so it will never integrate into the host genome.”

This research also yielded a new benchmark for evaluating the effectiveness of other Zika vaccine candidates, which could help others who are working toward the same goal.

Jasdave Chahal, a postdoc at MIT’s Whitehead Institute for Biomedical Research, is the first author of the paper, which appears in Scientific Reports. The paper’s senior author is Hidde Ploegh, a former MIT biology professor and Whitehead Institute member who is now a senior investigator in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital.

Other authors of the paper are Tao Fang and Andrew Woodham, both former Whitehead Institute postdocs in the Ploegh lab; Jingjing Ling, an MIT graduate student; and Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of the Koch Institute and MIT’s Institute for Medical Engineering and Science (IMES).

Programmable vaccines

The MIT team first reported its new approach to programmable RNA vaccines last year. RNA vaccines are appealing because they induce host cells to produce many copies of the proteins encoded by the RNA. This provokes a stronger immune reaction than if the proteins were administered on their own. However, finding a safe and effective way to deliver these vaccines has proven challenging.

The researchers devised an approach in which they package RNA sequences into a nanoparticle made from a branched molecule that is based on fractal-patterned dendrimers. This modified-dendrimer-RNA structure can be induced to fold over itself many times, producing a spherical particle about 150 nanometers in diameter. This is similar in size to a typical virus, allowing the particles to enter cells through the same viral entry mechanisms. In their 2016 paper, the researchers used this nanoparticle approach to generate experimental vaccines for Ebola, H1N1 influenza, and the parasite Toxoplasma gondii.

In the new study, the researchers tackled Zika virus, which emerged as an epidemic centered in Brazil in 2015 and has since spread around the world, causing serious birth defects in babies born to infected mothers. Since the MIT method does not require working with the virus itself, the researchers believe they might be able to explore potential vaccines more rapidly than scientists pursuing a more traditional approach.

Instead of using viral proteins or weakened forms of the virus as vaccines, which are the most common strategies, the researchers simply programmed their RNA nanoparticles with the sequences that encode Zika virus proteins. Once injected into the body, these molecules replicate themselves inside cells and instruct cells to produce the viral proteins.

The entire process of designing, producing, and testing the vaccine in mice took less time than it took for the researchers to obtain permission to work with samples of the Zika virus, which they eventually did get.

“That’s the beauty of it,” Chahal says. “Once we decided to do it, in two weeks we were ready to vaccinate mice. Access to virus itself was not necessary.”

Measuring response

When developing a vaccine, researchers usually aim to generate a response from both arms of the immune system — the adaptive arm, mediated by T cells and antibodies, and the innate arm, which is necessary to amplify the adaptive response. To measure whether an experimental vaccine has generated a strong T cell response, researchers can remove T cells from the body and then measure how they respond to fragments of the viral protein.

Until now, researchers working on Zika vaccines have had to buy libraries of different protein fragments and then test T cells on them, which is an expensive and time-consuming process. Because the MIT researchers could generate so many T cells from their vaccinated mice, they were able to rapidly screen them against this library. They identified a sequence of eight amino acids that the activated T cells in the mouse respond to. Now that this sequence, also called an epitope, is known, other researchers can use it to test their own experimental Zika vaccines in the appropriate mouse models.

“We can synthetically make these vaccines that are almost like infecting someone with the actual virus, and then generate an immune response and use the data from that response to help other people predict if their vaccines would work, if they bind to the same epitopes,” Khan says. The researchers hope to eventually move their Zika vaccine into tests in humans.

“The identification and characterization of CD8 T cell epitopes in mice immunized with a Zika RNA vaccine is a very useful reference for all those working in the field of Zika vaccine development,” says Katja Fink, a principal investigator at the A*STAR Singapore Immunology Network. “RNA vaccines have received much attention in the last few years, and while the big breakthrough in humans has not been achieved yet, the technology holds promise to become a flexible platform that could provide rapid solutions for emerging viruses.”

Fink, who was not involved in the research, added that the “initial data are promising but the Zika RNA vaccine approach described needs further testing to prove efficacy.”

Another major area of focus for the researchers is cancer vaccines. Many scientists are working on vaccines that could program a patient’s immune system to attack tumor cells, but in order to do that, they need to know what the vaccine should target. The new MIT strategy could allow scientists to quickly generate personalized RNA vaccines based on the genetic sequence of an individual patient’s tumor cells.

The research was funded by the National Institutes of Health, a Fujifilm/MediVector grant, the Lustgarten Foundation, a Koch Institute and Dana-Farber/Harvard Center Center Bridge Project award, the Department of Defense Office of Congressionally Directed Medical Research’s Joint Warfighter Medical Research Program, and the Cancer Center Support Grant from the National Cancer Institute.

See the full article here .

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The mission of MIT is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the MIT community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

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From UC Riverside: “Researchers Crack Structure of Key Protein in Zika Virus”

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UC Riverside

March 27, 2017
Iqbal Pittalwala

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The image shows the crystal structure of ZIKV NS5 protein. The regions with different colors represent individual domains or motifs of ZIKV NS5. The black circle marks the location of the potential inhibitor-binding site. Image credit: Song lab, UC Riverside.

Zika virus (ZIKV), which causes Zika virus disease, is spread to people primarily through the bite of an infected Aedes aegypti or Aedes albopictus mosquito. An infected pregnant woman can pass ZIKV to her fetus during pregnancy or around the time of birth. Sex is yet another way for infected persons to transmit ZIKV to others.

The genomic replication of the virus is made possible by its “NS5” protein. This function of ZIKV NS5 is unique to the virus, making it an ideal target for anti-viral drug development. Currently, there is no vaccine or medicine to fight ZIKV infection.

In a research paper just published in Nature Communications, University of California, Riverside scientists report that they have determined the crystal structure of the entire ZIKV NS5 protein and demonstrated that NS5 is functional when purified in vitro. Knowing the structure of ZIKV NS5 helps the researchers understand how ZIKV replicates itself.

Furthermore, the researchers’ structural analysis of ZIKV NS5 reveals a potential binding site in the protein for an inhibitor, thereby providing a strong basis for developing potential inhibitors against ZIKV NS5 to suppress ZIKV infection. The identification of the inhibitor-binding site of NS5 can now enable scientists to design potential potent drugs to fight ZIKV.

“We started this work realizing that the full structure of ZIKV NS5 was missing,” said Jikui Song, an assistant professor of biochemistry, who co-led the research with Rong Hai, an assistant professor of plant pathology and microbiology. “The main challenge for us occurred during the protein’s purification process when ZIKV NS5 got degraded – chopped up – by bacterial enzymes.”

Song, Hai and their colleagues overcame this challenge by developing an efficient protocol for protein purification, which in essence minimizes the purification time for NS5.

“Our work provides a framework for future studies of ZIKV NS5 and opportunities for drug development against ZIKV based on its structural similarity to the NS5 protein of other flaviviruses, such as the dengue virus,” Hai said. “No doubt, ZIKV therapeutics can benefit from the wealth of knowledge that has already been generated in the dengue virus field.”

Next, the researchers plan to investigate the antiviral potential on ZIKV NS5 of a chemical compound that has been shown to work effectively in inhibiting the NS5 protein in the dengue virus.

Song and Hai were joined in the research by graduate students Boxiao Wang (first author), Xiao-Feng Tan, Stephanie Thurmond, Zhi-Min Zhang, and Asher Lin.

The research was supported by grants to Song from the March of Dimes Foundation, the Sidney Kimmel Foundation for Cancer Research and the National Institutes of Health.

See the full article here .

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UC Riverside Campus

The University of California, Riverside is one of 10 universities within the prestigious University of California system, and the only UC located in Inland Southern California.

Widely recognized as one of the most ethnically diverse research universities in the nation, UCR’s current enrollment is more than 21,000 students, with a goal of 25,000 students by 2020. The campus is in the midst of a tremendous growth spurt with new and remodeled facilities coming on-line on a regular basis.

We are located approximately 50 miles east of downtown Los Angeles. UCR is also within easy driving distance of dozens of major cultural and recreational sites, as well as desert, mountain and coastal destinations.

#applied-research, #medicine, #uc-riverside, #zika

From UCLA: “Zika-linked birth defects more extensive than previously thought, UCLA-led research finds”

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UCLA

December 15, 2016
Enrique Rivero

New UCLA-led research finds that Zika-linked abnormalities that occur in human fetuses are more extensive — and severe — than previously thought, with 46 percent of 125 pregnancies among Zika-infected women resulting in birth defects in newborns or ending in fetal death.

The study, published in the New England Journal of Medicine, suggests that damage during fetal development from the mosquito-borne virus can occur throughout pregnancy and that other birth defects are more common than microcephaly, when babies are born with very small heads. Further, these defects may only be detected weeks or months after the baby is born, said Dr. Karin Nielsen, the study’s senior author and a professor of clinical pediatrics in the division of pediatric infectious diseases at the David Geffen School of Medicine at UCLA and Mattel Children’s Hospital.

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Dr. Karin Nielsen. UCLA

“This means that microcephaly is not the most common congenital defect from the Zika virus,” Nielsen said. The absence of that condition does not mean the baby will be free of birth defects, she added, because “there are problems that are not apparent at birth” and such difficulties may not be evident until the age of six months.

“These are sobering results,” Nielsen said.

The results are a follow-up to a smaller Brazilian study published in March that used molecular testing to find an association between Zika infection in pregnant women and a series of serious outcomes that included fetal deaths (miscarriages and stillbirths), abnormal fetal growth and damage to the central nervous system. This is the largest study to date of Zika-affected pregnancies in which the women were followed from the time they were infected to the end of their pregnancies. All the women were enrolled before any abnormalities in their pregnancies had been identified.

The new study was based on a larger sample size of 345 women in Rio de Janeiro, Brazil, who were enrolled from September 2015 through May 2016. Of those women, 182, or 53 percent, tested positive for Zika in the blood, urine or both. In addition, 42 percent of the women who did not have Zika were found to be infected with chikungunya, another mosquito-borne virus; 3 percent of Zika-positive women also had chikungunya.

From there, the researchers evaluated 125 women infected with Zika and 61 who were not infected with the virus who had given birth by July 2016. The previous study was based mainly on prenatal ultrasound findings; by contrast, the current research evaluated infants from Zika-affected pregnancies through physical examination and brain imaging. Among the findings:

There were nine fetal deaths among women with Zika infection during pregnancy, five of those in the first trimester.
Fetal deaths or abnormalities in the infants were present in 46 percent of Zika-positive women, contrasted with 11.5 percent of Zika-negative women.
Forty-two percent of infants born to the Zika-infected mothers were found to have microcephaly, brain lesions or brain calcifications seen in imaging studies, lesions in the retina, deafness, feeding difficulties and other complications.

The risks occurred at all stages of pregnancy: 55 percent of pregnancies were affected in the first trimester, 51 percent in the second trimester and 29 percent in the third trimester.

The researchers noted that they examined the babies during their early infancy, when “more subtle neurologic manifestations of disease are not identified.” So follow-up examinations could turn up evidence of more neurologic diseases that couldn’t be detected earlier in the babies’ lives.

“Our data show that the risk of severe adverse pregnancy and infant outcomes after maternal Zika infection was substantial,” the authors wrote.

Supporting the study were the Departamento de Ciência e Tecnologia do Ministério da Saúde do Brasil; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES/ 88887.116627/2016-01,) and the National Institute of Allergy and Infectious Diseases/National Institutes of Health grant AI AI28697.

See the full article here .

YOU CAN HELP FIND A CURE FOR THE ZIKA VIRUS.

There is a new project at World Community Grid [WCG] called OpenZika.
Zika
Zika depiction. Image copyright John Liebler, www.ArtoftheCell.com
Rutgers Open Zika

WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the OpenZika project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

This project is directed by Dr. Alexander Perryman a senior researcher in the Freundlich lab, with extensive training in developing and applying computational methods in drug discovery and in the biochemical mechanisms of multi-drug-resistance in infectious diseases. He is a member of the Center for Emerging & Re-emerging Pathogens, in the Department of Pharmacology, Physiology, and Neuroscience, at the Rutgers University, New Jersey Medical School. Previously, he was a Research Associate in Prof. Arthur J. Olson’s lab at The Scripps Research Institute (TSRI), where he ran the day-to-day operations of the FightAIDS@Home project, the largest computational drug discovery project devoted to HIV/AIDS, which also runs on WCG. While in the Olson lab, he also designed, led, and ran the largest computational drug discovery project ever performed against malaria, the GO Fight Against Malaria project, also on WCG.

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UC LA Campus

For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

#applied-research-technology, #medicine, #openzika-project-at-world-community-grid, #ucla, #zika

From NYT: “Colombia Reports Major Rise in Birth Defect Amid Zika Crisis”

New York Times

The New York Times

DEC. 10, 2016
DONALD G. McNEIL Jr.

Colombia, which suffered a Zika epidemic that peaked in February, has reported four times as many cases of babies born with microcephaly this year as it did in 2015, providing more proof that the Zika virus causes brain damage in infants.

Because births of microcephalic infants peaked five months after the epidemic did, at about nine times the numbers of the previous July, scientists feel sure that the greatest risk is to babies whose mothers were infected during their first trimesters or early in their second.

The numbers were reported in a study released Friday by the Centers for Disease Control and Prevention and conducted jointly by scientists from the C.D.C. and Colombia’s national health institute.

With 105,000 suspected Zika cases, Colombia has had the second-largest Zika epidemic after Brazil. Brazil has had proportionally many more cases of microcephaly, and the reason has remained a mystery, although its population is four times larger than Colombia’s and it experienced a much longer, more intense epidemic in 2014 and 2015, especially in the northeast.

As of Thursday, Brazil had reported 2,211 cases of microcephaly in which Zika infection had been confirmed to the World Health Organization, while Colombia had reported only 60.

W.H.O. reports of confirmed cases have sometimes lagged weeks behind local reports. The study released by the C.D.C. found 476 cases of microcephaly in Colombia between January and mid-November. Of those, only 147 — about 30 percent — had laboratory evidence of Zika virus infection. But many others were not tested, and the virus is not always detectable months after it damages a fetus, so the true numbers may be higher.

About 4 percent of the fetuses tested had evidence of other infections that can cause microcephaly, such as toxoplasmosis, herpes, cytomegalovirus or syphilis. Many other fetuses were not tested or their microcephaly had no clear cause.

Of the total, 432 of the microcephaly cases were in babies born alive, and 44 were in fetuses that were stillborn, miscarried or aborted. One theory — still unproven — is that Colombia had fewer microcephaly cases than expected because many fearful women aborted their pregnancies, legally or illegally. Abortion is much more restricted in Brazil than in Colombia.

The number of confirmed cases of microcephaly is in line with predictions made by health officials after they declared an end to the Zika epidemic in Colombia in July. Early in the year, based on Brazil’s experience, Dr. Fernando Ruiz, the vice minister for public health, estimated that Colombia would have 700 cases of Zika-related microcephaly this year. In August, he changed that estimate to between 100 and 250.

Although Colombia is widely believed to have a better disease-surveillance system than Brazil, it still relies on doctors to voluntarily report birth defects. They may have been underreported in 2015, before microcephaly was in the news.

See the full article here .

YOU CAN HELP FIND A CURE FOR THE ZIKA VIRUS.

There is a new project at World Community Grid [WCG] called OpenZika.
Zika
Zika depiction. Image copyright John Liebler, www.ArtoftheCell.com
Rutgers Open Zika

WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the OpenZika project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

This project is directed by Dr. Alexander Perryman a senior researcher in the Freundlich lab, with extensive training in developing and applying computational methods in drug discovery and in the biochemical mechanisms of multi-drug-resistance in infectious diseases. He is a member of the Center for Emerging & Re-emerging Pathogens, in the Department of Pharmacology, Physiology, and Neuroscience, at the Rutgers University, New Jersey Medical School. Previously, he was a Research Associate in Prof. Arthur J. Olson’s lab at The Scripps Research Institute (TSRI), where he ran the day-to-day operations of the FightAIDS@Home project, the largest computational drug discovery project devoted to HIV/AIDS, which also runs on WCG. While in the Olson lab, he also designed, led, and ran the largest computational drug discovery project ever performed against malaria, the GO Fight Against Malaria project, also on WCG.

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From Harvard Medical School: “Zika’s Entry Points”

Harvard University
Harvard University

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Harvard Medical School

December 1, 2016
HANNAH ROBBINS
ERIC BENDER

Fast-spreading virus can take multiple routes into the growing brain.

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Zika virus (light blue) spreads through a three-dimensional model of a developing brain. Image: Max Salick and Nathaniel Kirkpatrick/Novartis

Around the world, hundreds of women infected with the Zika virus have given birth to children suffering from microcephaly or other brain defects, as the virus attacks key cells responsible for generating neurons and building the brain as the embryo develops.

Studies have suggested that Zika enters these cells, called neural progenitor cells or NPCs, by grabbing onto a specific protein called AXL on the cell surface. Now scientists at the Harvard Stem Cell Institute (HSCI) and Novartis have shown that this is not the only route of infection for NPCs.

The scientists demonstrated that the Zika virus infected NPCs even when the cells did not produce the AXL surface receptor protein that is widely thought to be the main vehicle of entry for the virus.

“Our finding really recalibrates this field of research, because it tells us we still have to go and find out how Zika is getting into these cells,” said Kevin Eggan, principal faculty member at HSCI, professor of stem cell and regenerative biology at Harvard University’s Faculty of Arts and Sciences and Harvard Medical School, and co-corresponding author on a paper reporting the research in Cell Stem Cell.

“It’s very important for the research community to learn that targeting the AXL protein alone will not defend against Zika,” agreed Ajamete Kaykas, co-corresponding author and a senior investigator in neuroscience at the Novartis Institutes for Biomedical Research (NIBR).

Previous studies have shown that blocking expression of the AXL receptor protein does defend against the virus in a number of human cell types. Given that the protein is highly expressed on the surface of NPCs, many labs have been working on the hypothesis that AXL is the entry point for Zika in the developing brain.

“We were thinking that the knocked-out NPCs devoid of AXL wouldn’t get infected,” said Max Salick, a NIBR postdoctoral researcher and co-first author on the paper. “But we saw these cells getting infected just as much as normal cells.”

Working in a facility dedicated to infectious disease research, the scientists exposed two-dimensional cell cultures of AXL-knockout human NPCs to the Zika virus. They followed up by exposing three-dimensional mini-brain “organoids” containing such NPCs to the virus. In both cases, cells clearly displayed Zika infection. This finding was supported by an earlier study that knocked out AXL in the brains of mice.

“We knew that organoids are great models for microcephaly and other conditions that show up very early in development and have a very pronounced effect,” said Kaykas. “For the first few months, the organoids do a really good job in recapitulating normal brain development.”

Historically, human NPCs have been difficult to study in the lab because it would be impossible to obtain samples without damaging brain tissue. With the advancements in induced pluripotent stem cell (iPS cell) technology, a cell reprogramming process that allows researchers to coax any cell in the body back into a stem cell-like state, researchers can now generate these previously inaccessible human tissues in a petri dish.

The team was able to produce human iPS cells and then, using gene-editing technology, modify the cells to knock out AXL expression, said Michael Wells, a Harvard postdoctoral researcher in the Eggan Lab and co-first author. The scientists pushed the iPS cells to become NPCs, building the two-dimensional and three-dimensional models that were infected with Zika.

The Harvard and NIBR collaborators started working with the virus in mid-April 2016, only six months before they published their findings. This unusual speed of research reflects the urgency of Zika’s global challenge, as the virus has spread to more than 70 countries and territories.

“At the genesis of the project, my wife was pregnant,” Eggan remarked. “One can’t read the newspapers without being concerned.”

The collaboration grew out of interactions at the Broad Institute of Harvard and MIT’s Stanley Center for Psychiatric Research, where Eggan directs the stem cell program. His lab already had developed cell culture systems for studying NPCs in motor neuron and psychiatric diseases. The team at Novartis had created brain organoids for research on tuberous sclerosis complex and other genetic neural disorders.

“Zika seemed to be a big issue where we could have an impact, and we all shared that interest,” Eggan said. “It’s been great to have this public/private collaboration.”

The researchers are studying other receptor proteins that may be open to Zika infection in hopes that their basic research eventually will help in the quest to develop vaccines or other drugs that defend against the virus.

See the full article here .

YOU CAN HELP FIND A CURE FOR THE ZIKA VIRUS.

There is a new project at World Community Grid [WCG] called OpenZika.
Zika
Zika depiction. Image copyright John Liebler, www.ArtoftheCell.com
Rutgers Open Zika

WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the OpenZika project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

This project is directed by Dr. Alexander Perryman a senior researcher in the Freundlich lab, with extensive training in developing and applying computational methods in drug discovery and in the biochemical mechanisms of multi-drug-resistance in infectious diseases. He is a member of the Center for Emerging & Re-emerging Pathogens, in the Department of Pharmacology, Physiology, and Neuroscience, at the Rutgers University, New Jersey Medical School. Previously, he was a Research Associate in Prof. Arthur J. Olson’s lab at The Scripps Research Institute (TSRI), where he ran the day-to-day operations of the FightAIDS@Home project, the largest computational drug discovery project devoted to HIV/AIDS, which also runs on WCG. While in the Olson lab, he also designed, led, and ran the largest computational drug discovery project ever performed against malaria, the GO Fight Against Malaria project, also on WCG.

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Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

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From SLAC: “X-rays Reveal New Path In Battle Against Mosquito-borne Illness”


SLAC Lab

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The mosquito larvicide BinAB is composed of two proteins, BinA (yellow) and BinB (blue). Inside bacterial cells, BinAB naturally forms nanocrystals. Using these crystals and the intense X-ray pulses produced by SLAC’s Linac Coherent Light Source, scientists shed light on the three-dimensional structure of BinAB and its mode of action. (SLAC National Accelerator Laboratory)

September 28, 2016

SLAC’s X-ray Laser Provides Clues to Engineering a New Protein to Kill Mosquitos Carrying Dengue, Zika

Structural biology research conducted at the U.S. Department of Energy’s SLAC National Accelerator Laboratory has uncovered how small insecticidal protein crystals that are naturally produced by bacteria might be tailored to combat dengue fever and the Zika virus.

SLAC’s X-ray free-electron laser – the Linac Coherent Light Source (LCLS), a DOE Office of Science User Facility – offered unprecedented views of the toxin BinAB, used as a larvicide in public health efforts against mosquito-borne diseases such as malaria, West Nile virus and viral encephalitis.

SLAC/LCLS
SLAC/LCLS

The larvicide is currently ineffective against the Aedes mosquitos that transmit Zika and dengue fever, and therefore not used to combat these species of mosquitos at this time. The new information provides clues to how scientists could design a composite toxin that would work against a broader range of mosquito species, including Aedes.

Today, Nature published the study.

“A more detailed look at the proteins’ structure provides information fundamental to understanding how the crystals kill mosquito larvae,” said Jacques-Philippe Colletier, a scientist at the Institut de Biologie Structurale in Grenoble, France and lead author on the paper. “This is a prerequisite for modifying the toxin to adapt it to our needs.”

Selective Mosquito Control, Courtesy of Bacteria

The BinAB crystals are produced by Lysinibacillus sphaericus bacteria, which release the crystals along with spores at the end of their life cycle. Mosquito larvae eat the crystals along with the spores, and then die.

BinAB is inactive in the crystalline state and does not work on contact. For the crystals to dissolve, they must be exposed to alkaline conditions, such as those in a mosquito larva’s gut. The binary protein is then activated, recognized by a specific receptor at the surface of cells and internalized.

Because Aedes larvae can evade one of these steps of intoxication, they are resistant to BinAB. These larvae do not express the correct receptors at the surface of their intestinal cells. Many other insect species, small crustaceans and humans also lack these receptors, as well as alkaline digestive systems.

“Part of the appeal is that the larvicide’s safe because it’s so specific, but that’s also part of its limitation,” said Michael Sawaya, a scientist at the University of California, Los Angeles-DOE Molecular Biology Institute and co-author on the paper.

For public health officials who want to prevent mosquito-borne disease, BinAB could also offer an alternative for controlling certain species of mosquitos that have begun to show resistance to other forms of chemical control.

Creating a Tailored Insecticide

The research team already knew the larvicide is composed of a pair of proteins, BinA and BinB, that pair together in crystals and are later activated by larval digestive enzymes.

In the LCLS experiments, they learned the molecular basis for how the two proteins paired with each other – each performing an important, unique function. Previous research had determined that BinA is the toxic part of the complex, while BinB is responsible for binding the toxin to the mosquito’s intestine. BinB ushers BinA into the cells; once inside, BinA kills the cell.

The scientists also identified four “hot spots” on the proteins that are activated by the alkaline conditions in the larval gut. All together, they trigger a change from a nontoxic form of the protein to a version that is lethal to mosquito larvae.

Using the information gathered during the crystallography study, the research team has already begun to engineer a form of the BinAB proteins that will work against more species of mosquitos. This is ongoing work at Institut de Biologie Structurale, UCLA, University of California, Riverside and SLAC.

Solving the Structure

Only coarse details were known about the unique three-dimensional structure and biological behavior of BinAB prior to the experiment at LCLS.

“We chose to look at the BinAB larvicide because it is so widely used, yet the structural details were a mystery,” said Brian Federici, professor of entomology at UC Riverside.

The small size of the crystals made them difficult to study at conventional X-ray sources. So the research team used genetic engineering techniques to increase the size of the crystals, and the bright, fast pulses of light at LCLS allowed the scientists to collect detailed structural data from the tiny crystals before X-rays damaged their samples.

The researchers used a crystallography technique called de novo phasing. This involves tagging the crystals with heavy metal markers, collecting tens of thousands of X-ray diffraction patterns, and combining the information collected to obtain a three-dimensional map of the electron density of the protein.

“This is the first time we’ve used de novo phasing on a crystal of great interest at an X-ray free-electron laser,” said Sebastien Boutet, SLAC scientist.

The technique had so far only been used on test samples where the structure was already known, in order to prove that it would work.

“The most immediate need is to now expand the spectrum of action of the BinAB toxin to counter the progression of Zika, in particular,” said Colletier. “BinAB is already effective against Culex [carrier of West Nile encephalitis] and Anopheles [carrier of malaria] mosquitos. With the results of the study, we now feel more confident that we can design the protein to target Aedes mosquitos.”

Additional contributors to the research include scientists from the Howard Hughes Medical Institutes at UCLA, Lawrence Berkeley National Laboratory, and Stanford University. The Institut de Biologie Structurale is a research center for integrated structural biology funded by the Commissariat à l’Énergie Atomique, the Centre National de la Recherche Scientifique and the Université Grenoble Alpes. The Collaborative Innovation Award program of Howard Hughes Medical Institute (HCIA-HHMI), W.M Keck Foundation, National Institutes of Health, National Science Foundation, France Alzheimer Foundation, Agence Nationale de la Recherche, and DOE Office of Science supported the research.

See the full article here .

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SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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