TAG: "Infectious disease"

Forecasting the flu better


Combination of ‘big’ and traditional data improves power of prediction.

By Inga Kiderra, UC San Diego

Three UC San Diego researchers say they can predict the spread of flu a week into the future with as much accuracy as Google Flu Trends can display levels of infection right now.

The study – appearing in Scientific Reports, an online journal from the publishers of Nature – uses social network analysis and combines the power of Google Flu Trends’ “big data” with traditional flu monitoring data from the U.S. Centers for Disease Control and Prevention (CDC).

“Our innovation,” said corresponding author Michael Davidson, a doctoral student in political science at UC San Diego, “is to construct a network of ties between different U.S. health regions based on information from the CDC. We asked: Which places in years past got the flu at about the same time? That told us which regions of the country have the strongest ties, or connections, and gave us the analytic power to improve Google’s predictions.”

Google Flu Trends (GFT) is very good, Davidson said, at showing where in the U.S. people are searching for information on flu and flu-like symptoms. And these data are valuable because they come in real time, he said, about two weeks ahead of when the CDC can issue its reports. But GFT has also made some infamous errors – errors that probably reflect widespread public concerns about flu more than actual confirmed illness.

By weighting GFT predictions with a social network derived from CDC reports on laboratory-tested cases of flu, the researchers were able to refine and improve GFT’s predictions.

The researchers are optimistic their work will soon be put to public use. “We hope our method will be implemented by epidemiologists and data scientists,” Davidson said, “to better target prevention and treatment efforts, especially during epidemics.”

Davidson’s co-authors are Dotan A. Haim, who is also a political science graduate student at UC San Diego, and Jennifer M. Radin, of the UC San Diego/San Diego State University Joint Doctoral Program in Public Health.

The study was funded in part by the Robert Wood Johnson Foundation and the James S. McDonnell Foundation.

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Scientists ID important mechanism involved in production of mosquito eggs


Research could lead to innovative strategies for controlling mosquito populations.

Alexander Raikhel, UC Riverside (Photo by Lonnie Duka)

By Iqbal Pittalwala, UC Riverside

Diseases transmitted by mosquitoes have contributed to the death and suffering of millions throughout human history, earning the mosquito the title as the world’s most dangerous animal. Even today, several devastating mosquito-borne diseases (such as malaria, dengue fever and West Nile virus) continue to rage.

The urgent need to better control mosquito numbers and interfere with disease transmission has guided much mosquito research in laboratories worldwide. Female mosquitoes rely on a blood-meal as a source of nutrients required for reproduction.  The thinking is that if the mechanisms that govern mosquitoes’ egg production are better understood, novel approaches to controlling the reproduction and population of mosquitoes can be devised.

Now a team of scientists at UC Riverside has made a research breakthrough in understanding, at the molecular level, one such mechanism related to the mosquito reproductive process.  This mechanism includes small regulatory RNA molecules known as microRNAs or miRNAs.

The researchers report in this week’s issue of the Proceedings of the National Academy of Sciences that they have identified microRNA-8 (miR-8) as an essential regulator of mosquito reproductive events. They note that its depletion in the female mosquito results in severe defects related to egg development and deposition.

Using newly established genetic tools in mosquito biology and doing analysis that identifies microRNA targets, they were able to show that miR-8 plays an essential role in the female mosquito “fat body” (fatty tissue analogous to the mammalian liver) by regulating a molecule, called “swim,” that miR-8 directly targets.  High levels of this molecule are detrimental to egg development.

“To our knowledge, this is the first time a mosquito miRNA has been investigated in this specific manner,” said Alexander Raikhel, a distinguished professor of entomology, who has received wide acclaim for his research in the areas of insect reproductive biology. “In the lab, female transgenic mosquitoes with deficiency in miR-8 displayed severely compromised ovary development and reduced egg-laying.”

While the researchers focused in this study on only Aedes aegypti, the mosquito that spreads dengue and yellow fever, their research results can be applied also to other disease-spreading mosquitoes.

“Our work provides insight into the importance of miRNAs in adult mosquito development and how these small regulatory molecules have potential to serve as novel control approach to regulate mosquito numbers,” Raikhel said.

He explained that what his lab had set out to do was introduce birth control in mosquitoes.

“We were looking to find a way to disrupt the host-seeking behavior of mosquitoes by interrupting their egg development,” he said.  “With egg development halted, the population of mosquitoes would eventually collapse.”

At UC Riverside, Raikhel’s lab specializes in understanding the molecular basis of events in the mosquito reproduction cycle linked to a blood meal and pathogen transmission. His research focuses, too, on how pathogens of major human diseases, transmitted by mosquitoes, interact with their mosquito hosts.  A member of the National Academy of Sciences, he occupies the Mir S. Mulla Chair in Entomology at UCR, as well as the University of California President’s Chair.

To date, no effective vaccines for malaria, dengue fever or West Nile virus exist. This lack of vaccines, along with increasing pesticide resistance in mosquitoes, adds to the urgency of exploring alternative strategies for mosquito control.

Nearly 2.5 billion people are at risk for contracting dengue fever.  Each year, there are 100 million cases of dengue in the world.  Yellow fever results in 30,000 deaths per year; about 200,000 cases are reported each year. Malaria alone causes over a million deaths annually. Dengue fever is emerging across the globe at an alarming rate; more than three billion people are now at risk of contracting this serious and debilitating viral disease. West Nile virus has invaded and spread throughout North America in just one decade; thousands in the United States are afflicted with this mosquito-borne virus every year.

Raikhel was joined in the research by Keira J. Lucas, the research paper’s first author and a fifth-year Ph.D. graduate student in the Graduate Program in Genetics, Genomics and Bioinformatics; Sourav Roy, Jisu Ha, Amanda L. Gervaise and Vladimir A. Kokoza.  Ha is a fourth-year Ph.D. student in the Graduate Program in Genetics, Genomics and Bioinformatics.

The research was supported by a grant to Raikhel from the National Institutes of Health.

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Common human protein linked to adverse parasitic worm infections


UC Riverside-led research could lead to new therapies for parasitic worm infections.

Hookworms infect the lung and cause severe inflammation. This image shows immunofluorescent staining of infected mouse lung tissue for worm antigen (green), worm and macrophage bound lectin (red) and cell nuclei (blue). (Credit: Nair Lab, UC Riverside)

By Kathy Barton, UC Riverside

Worm infections represent a major global public health problem, leading to a variety of debilitating diseases and conditions, such as anemia, elephantiasis, growth retardation and dysentery. Several drugs are available to treat worm infections, but reinfection is high especially in developing countries.

Now, scientists at UC Riverside and colleagues around the world have made a discovery, reported in this month’s issue of PLOS Pathogens, that could lead to more effective diagnostic and treatment strategies for worm infections and their symptoms. The researchers found that resistin, an immune protein commonly found in human serum, instigates an inappropriate inflammatory response to worm infections, impairing the clearance of the worm.

“Targeting this inflammatory pathway with drugs or antibodies could be a new therapeutic strategy to treat worm infections and the associated pathology,” said Meera Nair, an assistant professor of biomedical sciences in the UC Riverside School of Medicine, whose laboratory made the discovery.  “Additionally, our data point to the diagnostic potential for resistin as a new biomarker for impaired immune responses to worms.”

Jessica Jang, the lead author of the research paper and a third-year UCR graduate student in microbiology, explained that resistin regulates the recruitment of innate immune cells called monocytes to the site of infection to produce inflammatory cytokines (small proteins that are important in cell signaling).

“Future work in my Ph.D. research will focus on further investigating the activation of monocytes so we can clinically exploit this immune pathway,” she said.

Parasitic worms, known scientifically as helminths, include filarial worms and hookworms. They cause diseases such as elephantiasis, which produces extreme swelling of extremities, and necatoriasis, which causes abdominal pain, diarrhea and weight loss. The infections are often associated with life-long morbidity, including malnutrition, growth retardation and organ failure.

In many developing countries where parasitic worms are prevalent due to substandard sanitation facilities, infections in humans are common, as are reinfections. Some infected patients develop immunity, but others remain susceptible to infections when they are re-exposed or develop chronic infections. Currently, no vaccine is available against human worm pathogens.

The research directed by Nair’s lab combined mouse studies with human data to demonstrate that resistin is actually detrimental, causing excessive inflammation that impedes the body’s ability to clear parasitic worms.

In the animal studies, mice containing the gene expressing human resistin and infected with a parasitic worm similar to the human hookworm experienced excessive inflammation, leading to increased weight loss and other symptoms. Clinical samples from two groups of individuals from the south Pacific island of Mauke and from Ecuador – one group infected with filarial worms causing lymphatic filariasis and a second group infected with intestinal roundworms Ascaris – revealed increased levels of resistin in the infected individuals compared to those who were uninfected or immune.

A better understanding of human resistin may also reveal new knowledge about obesity and diabetes. Resistin has been mapped to the pathway of immune-mediated inflammation that promotes diabetes and other obesity-related disorders and Nair hopes to combine her lab’s basic science expertise with the developing clinical research enterprise in the UCR medical school as a future avenue to research new diagnostic or treatment strategies.

Collaborating in the study were scientists from: the Malaghan Institute of Medical Research in New Zealand; Pontificia Universidad Católica del Ecuador in Quito, Ecuador; St. George’s University of London; the Laboratory of Parasitic Diseases at the National Institutes of Health; and the Perelman School of Medicine at the University of Pennsylvania.

Funding for the research at UCR was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Division of Biomedical Sciences (UCR School of Medicine) and a UCR Academic Senate Regents Faculty Fellowship.

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Study rules out spiders as common cause of bacterial infections in humans


Spiders shouldn’t be scapegoated for bacterial infections, UC Riverside spider expert advises.

By Iqbal Pittalwala, UC Riverside

Can spiders be carriers of human pathogens?  Can they provoke an infection through a break in the skin?

A team of scientists, led by an entomologist at the University of California, Riverside, has data-mined the history of publications on spider envenomations to conclude that the evidence for spider-vectored infection is scanty.  Further, the researchers note that the mere presence of bacteria on spider fangs or mouthparts does not establish spiders as vectors for these bacteria.

Study results appear as a letter to the editor in the January 2015 issue of Toxicon.

“Although spider bite may be an attractive and tenable causative agent of a bacterial infection, the data show this is highly improbable,” said Richard S. Vetter, the lead author of the study and a former staff research associate in the UC Riverside Department of Entomology, now retired. “Any implied causative association between skin infections and spider bites should be considered suspect.  The medical community should not scapegoat spiders for bacterial infections. When examining reports of thousands of spider bites of many species worldwide, we found almost no mention of infection associated with the arachnid-inflicted injury.”

Vetter explained that an important advancement in spider bite diagnosis in recent years is the realization that bacterial infections have been commonly misattributed as spider envenomation by both physicians and patients.

“‘Spider bite’ is used as a default diagnosis despite lack of supporting evidence,” he said. “In a study published three years ago, of 182 Southern Californian patients presenting with complaint of spider bite, less than 4 percent had spider envenomations, while about 86 percent had skin infections.”

He mentioned that the only credible report of spider bite leading to infection that his research team is aware of is an episode involving an Australian golden silk spider, a very large orbweaver.

“It resulted in colonization by a bacterium rarely found in humans,” he said.  “The bite led to a pus-filled lesion that persisted more than two months.”

Vetter’s advice to people concerned with skin infections is that both the medical community and the general public should stop blaming spiders as the cause of bacterial infections.

“This medical platitude is not supported by the history of spider bite data and could lead to misdiagnosed patients who then have an overzealous reaction that could, in turn, lead to the unwarranted development of arachnophobia in bite victims, possibly then requiring psychological desensitization to spiders or excessive use of pesticides in living spaces,” he said.

Vetter was joined in the study by David L. Swanson, Mayo Clinic, Scottsdale, Ariz.; and Scott A. Weinstein and Julian White at the Women’s and Children’s Hospital, North Adelaide, Australia.

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A sense for biosensors


UC Irvine’s Weian Zhao has created a device that improves detection of bacterial, viral invaders in blood samples.

The Integrated Comprehensive Droplet Digital Detection system invented by Weian Zhao of UC Irvine converts blood samples directly into billions of very small droplets. (Photo by Steve Zylius, UC Irvine)

By Tom Vasich, UC Irvine

As a doctoral student at McMaster University in Hamilton, Ontario, Weian Zhao took part in a Canada-wide research effort to develop bioactive paper that would detect, capture and deactivate waterborne and airborne pathogens.

As part of this project, he helped invent gold nanoparticle-coated paper that could detect common pathogens, such as E. coli, but ultimately, the product didn’t meet his exacting standards of diagnostic speed and sensitivity. With a freshly minted Ph.D. in chemistry, Zhao moved on to a joint postdoctoral fellowship at both the Massachusetts Institute of Technology and Harvard, where he dove into stem cell research, his biosensor work seemingly left north of the border.

But the challenge of creating a technology that could rapidly and selectively identify bacterial and viral invaders in blood samples nagged at the young scientist, even as he joined UC Irvine in 2011 as an assistant professor of pharmaceutical sciences with state-of-the-art lab space in the Sue & Bill Gross Stem Cell Research Center.

And then he met Enrico Gratton. In his Laboratory for Fluorescence Dynamics, the UCI biomedical engineer and colleagues have been developing imaging tools for biomedical applications. Among them is a three-dimensional particle counter that tags low-concentration fluorescent particles in large volumes of solution within several minutes, which drew Zhao’s attention. He knew he was back in the biosensor game.

Employing this particle counter, Zhao created a bloodstream infection test that speeds up diagnosis times with unprecedented accuracy – allowing physicians to treat patients with potentially deadly ailments more promptly and effectively.

Zhao says that the Integrated Comprehensive Droplet Digital Detection system can, in as little as 90 minutes, detect bacteria in milliliters of blood with single-cell sensitivity; no cell culture is needed. He published his latest results in the November issue of Nature Communications.

“We are extremely excited about this technology because it addresses a long-standing unmet medical need in the field,” says Zhao, who also holds a faculty appointment in biomedical engineering. “As a platform technology, it may have many applications in detecting extremely low-abundance biomarkers in other areas, such as cancers, HIV and, most notably, Ebola.”

Bloodstream infections are a major cause of illness and death. In particular, infections associated with antimicrobial-resistant pathogens are a growing health problem in the U.S. and worldwide. According to the Centers for Disease Control & Prevention, more than 2 million people a year globally get antibiotic-resistant blood infections, with about 23,000 deaths. The high mortality rate for blood infections is due, in part, to the inability to rapidly diagnose and treat patients in the early stages.

Recent molecular diagnosis methods, including polymerase chain reaction, can reduce the assay time to hours but are often not sensitive enough to detect bacteria that occur at low concentrations in blood, as is common in patients with incipient blood infections.

The Integrated Comprehensive Droplet Digital Detection technology differs from other diagnostic techniques in that it converts blood samples directly into billions of very small droplets. Fluorescent DNA sensor solution infused into the droplets detects those with bacterial markers, lighting them up with an intense fluorescent signal. Zhao says that separating the samples into so many small drops minimizes the interference of other components in blood, making it possible to directly identify target bacteria without the purification typically required in conventional assays.

“The IC 3D instrument is designed to read a large volume in each measurement, to speed up diagnosis,” Gratton says. “Importantly, using this technique, we can detect a positive hit from hundreds of millions of measurement samples with very high confidence.”

But invention was only the first step. Zhao wants to commercialize IC 3D. At UCI, faculty researchers with an entrepreneurial bent can work with the Institute for Innovation, an interdisciplinary and campuswide center focused on integrating research, entrepreneurship and technology to create real-world applications that benefit the public and drive the economy. The Office of Technology Alliances, part of the institute, helped Zhao patent-protect the IC 3D technology and establish a spin-off company, Velox Biosystems, to test and manufacture a commercial IC 3D device.

Currently, Zhao is focusing on applying IC 3D to cancer treatments – an extension of the research he’s been advancing since joining UCI.

Zhao has been developing stem cell messengers that selectively migrate to cancer sites to deliver tumor-fighting drugs or probes for contrast-enhanced medical imaging. This could, potentially, enable the identification of cancer micro-metastases at their early stages and increase the effectiveness of chemotherapeutic treatments for metastatic cancer while mitigating the symptoms associated with systemic chemotherapy.

For this work, Zhao was included in the MIT Technology Review’s 2012 list of the world’s top innovators under the age of 35, and this year he earned a prestigious National Institutes of Health Director’s New Innovator Award to further his efforts to create stem cell-based detection methods and treatments for cancer.

He’s also collaborating with Dr. Jason Zell, an assistant professor of medicine and co-leader of the Colon Cancer Disease-Oriented Team at UCI’s Chao Family Comprehensive Cancer Center, to use IC 3D to identify biomarkers in colon cancers. This could enable oncologists to gauge the effectiveness of treatment during the cancer’s early stages more accurately than with current methods, which Zell says are not reliable.

Zhao is now seeking business partners to accelerate Velox Biosystems’ growth and hopes to conduct clinical studies of IC 3D’s utility in patient diagnosis and treatment.

“That’s what’s so important about this project,” he says. “We’ve created a multi-platform tool that has the potential to work with a variety of infections and diseases. I’m very excited about its future.”

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Typhoid Mary, not Typhoid Mouse


Lack of enzyme explains why typhoid fever is a human-specific disease.

By Heather Buschman, UC San Diego

The bacterium Salmonella Typhi causes typhoid fever in humans, but leaves other mammals unaffected.  Researchers at UC San Diego and Yale University schools of medicine now offer one explanation — CMAH, an enzyme that humans lack. Without this enzyme, a toxin deployed by the bacteria is much better able to bind and enter human cells, making us sick. The study is published in today’s (Dec. 4) issue of Cell.

In most mammals (including our closest evolutionary cousins, the great apes), the CMAH enzyme reconfigures the sugar molecules found on these animals’ cell surfaces into a form that the typhoid toxin cannot bind. Humans don’t produce CMAH, meaning our cell surface sugars are left unchanged — and as this study shows, in a state just right for typhoid toxin attachment.

“We started this project looking at something completely different in relation to cancer, but serendipity instead helped us solve the mystery of what the typhoid toxin binds,” said co-senior author Ajit Varki, M.D., Distinguished Professor in the departments of medicine and cellular and molecular medicine at UC San Diego. “That’s the beauty of basic research — though we didn’t set out with the intent, these findings may now spur the development of new therapies for typhoid fever.” Varki co-directed the study with Jorge E. Galán, Ph.D., D.V.M., professor and department chair at Yale University School of Medicine.

All mammals decorate their cell surfaces with a type of sialic acid sugar called Neu5Ac. In most mammals, the enzyme CMAH coverts Neu5Ac to Neu5Gc, a subtle but important distinction involving a single oxygen atom. Varki, Galán and their teams are the first to discover that typhoid toxin binding is exquisitely specific for Neu5Ac (the human type). The toxin damages cells expressing Neu5Ac sugars on their surface, but not those with Neu5Gc (the non-human type). In fact, when the researchers added Neu5Gc to cultured human cells, they became resistant to typhoid toxin. The findings were confirmed in a mouse model.

“We have previously shown that typhoid toxin can cause typhoid fever in experimental animals and that to intoxicate cells, the toxin must bind specific surface glycoproteins. The discovery that a single oxygen atom could make such a difference in toxin binding is remarkable and has implications for the design of potential toxin inhibitors,” said Galán.

Typhoid is typically transmitted through food or water contaminated by infected people. While hand washing and other sanitary measures have minimized occurrences of typhoid fever in the U.S.,  roughly 21 million cases of typhoid fever and 200,000 deaths occur worldwide each year, according to the Centers for Disease Control and Prevention.

Co-authors include Lingquan Deng, Nissi Varki, Yuko Naito-Matsui, UC San Diego School of Medicine; Jeongmin Song, Xiang Gao, Yale University School of Medicine; Jiawei Wang, Tsinghua University; Hai Yu, Xi Chen, University of California, Davis.

This research was funded, in part, by the National Cancer Institute (grant CA38701) and the National Institute of Allergy and Infectious Diseases (grant AI079022), both part of the U.S. National Institutes of Health.

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UC Davis awarded $100M to lead program to predict, prevent pandemic threats


Second phase of program will help attack problems like Ebola before they start.

The PREDICT program helps detect emerging viruses that move among people, livestock and wildlife, such as this macaque in Nepal. (Photo by One Health Institute, UC Davis)

The U.S. Agency for International Development has awarded up to $100 million for the second phase of the PREDICT project based at the UC Davis School of Veterinary Medicine. PREDICT is part of the Emerging Pandemic Threats, or EPT, program — an unprecedented international campaign to rapidly detect and respond to emerging viruses such as Ebola and SARS that move among people, wildlife and livestock.

PREDICT is managed by the school’s One Health Institute. The new award is one of the largest extramurally funded projects in UC Davis history.

“PREDICT and its partners have enabled a platform for effective collaboration across disciplines and geographic borders to promote global health problem solving,” said Jonna Mazet, director of the One Health Institute and principal investigator of the new award. “We can now attack problems, like Ebola, before they start — reducing fear and improving response and control.”

The award for the PREDICT project opens a second phase for the EPT program. Building on its long-standing efforts in disease surveillance and response, USAID is developing multiple initiatives to help prepare the world for emerging infectious diseases like pandemic influenza, SARS and Ebola. Other partners within USAID’s EPT program include the PREPAREDNESS & RESPONSE and ONE HEALTH WORKFORCE projects, the U.S. Centers for Disease Control and Prevention, the Food and Agriculture Organization, and the World Health Organization.

Building on success

For the past five years, the One Health Institute has led a global consortium of implementing partners in conducting pathogen surveillance, viral discovery and global health capacity strengthening in more than 20 countries. In that time, the PREDICT team:

  • Equipped, supplied and trained staff in 32 diagnostic laboratories around the world to safely and properly process and test wildlife samples for viruses of pathogenic potential.
  • Trained 2,500 government personnel, physicians, veterinarians, resource managers, laboratory technicians, hunters and students in biosafety, surveillance, laboratory techniques and outbreak investigations.
  • Discovered more than 800 novel viruses at high-risk pathogen transmission interfaces.
  • Responded to 24 disease outbreaks, including multiple Ebola outbreaks in central Africa.

The new award will build on the success of the first phase of PREDICT, funded in 2009. In collaboration with other U.S. government, international and host country partners, it will continue to strengthen health capacity and to intensify pathogen surveillance and risk assessment activities in geographic areas and animal-human interfaces identified as high-risk for the emergence and spread of disease.

Ebola response

Tragically, the world is currently responding to the worst Ebola outbreak in history. The extreme challenges faced in this response are amplified by the lack of public knowledge on the virus and its potential hosts and transmission. Unfortunately, the countries in West Africa were not expecting or prepared for this epidemic, primarily because there was previously no evidence that the Ebola virus was present in that region of Africa.

In contrast, during a separate Ebola outbreak in this same time period in the Democratic Republic of Congo, where the PREDICT team and other partners were actively engaged with the government and inserted into the public health infrastructure, sick individuals were detected much more quickly. Samples were tested and control measures implemented all within just days of the first signs of illness. The rapid response and significantly reduced death toll in DRC illustrate what can be achieved when a One Health workforce is trained, employed and able to be activated in the face of extreme health challenges.

In this second and new phase, PREDICT will continue to focus surveillance on viral families of epidemic and pandemic potential. These include coronaviruses, the viral family to which SARS and MERS belong, influenza viruses, and filoviruses, such as Ebola.

This second phase also will increase focus on the effects of human behavior and other drivers for disease emergence and spread, with a focus on livestock and people living in high-risk areas for disease spillover and transmission. By working with social and behavioral scientists in a transdisciplinary approach, PREDICT will integrate virus detection with investigations of human-animal interactions and the social and cultural reasons for those interactions. This One Health approach is designed to improve our understanding of the dynamics of zoonotic disease spillover, evolution, amplification and spread in order to inform future prevention and control measures.

Identifying and controlling emerging diseases

The One Health Institute will execute the project in a coordinated consortium with EcoHealth Alliance, Metabiota, Smithsonian Institution and the Wildlife Conservation Society, along with valued technical partners at Columbia University’s Center for Infection and Immunity, HealthMap at Boston Children’s Hospital, International Society for Infectious Disease, and UC San Francisco’s Viral Diagnostics and Discovery Center.

“Our work has shown that emerging diseases are on the rise and represent a growing threat to our health, our economies, and our global security,’ said Peter Daszak, president of EcoHealth Alliance, a partner in the PREDICT consortium. “This next phase of funding allows us to identify the activities that cause diseases to emerge in high-risk disease ‘hotspots’ so that we can minimize the impacts of a new virus spilling over and infecting people.”

The consortium will continue to work closely with partner organizations in each country, as well as with a network of laboratories, universities, government ministries and agencies in these global hotspots. PREDICT is engaged in the Africa, South Asia, and Southeast Asia regions, working in Bangladesh, Cambodia, Cameroon, China, Democratic Republic of Congo, Gabon, Indonesia, Laos, Malaysia, Myanmar, Nepal, Republic of Congo, Rwanda, Tanzania, Thailand, Uganda and Vietnam, along with a new focus in West Africa in response to the Ebola outbreak.

The consortium is united by its belief in the One Health approach, which employs the knowledge that the health of animals, people and the environment are inextricably linked to solve global health problems.

“The new funding for PREDICT will allow our One Health Institute investigators and their partners to continue to identify pandemic threats and build capacity in developing regions worldwide,” said Mazet. “The UC Davis School of Veterinary Medicine has an extensive history of excellence in public health programs that address societal needs. This new funding will ensure our research teams’ continued contributions to enhance capabilities to prevent future pandemics.”

“Attempts to date to control deadly viruses have been almost entirely reactionary due to structural and technological limitations,” Mazet said. “The world is now poised to be able to identify the key processes influencing the evolution, spillover, amplification and spread of pathogen threats in order to halt them at their source.”

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Breakthrough in managing yellow fever disease


UC Riverside-led research could lead to antiviral therapeutics, better diagnostics.

Ilhem Messaoudi (right) is an associate professor of biomedical sciences in the UC Riverside School of Medicine. (Photo by L. Duka)

By Iqbal Pittalwala, UC Riverside

Yellow fever is a disease that can result in symptoms ranging from fever to severe liver damage. Found in South America and sub-Saharan Africa, each year the disease results in 200,000 new cases and kills 30,000 people.  About 900 million people are at risk of contracting the disease.

Now a research team led by a biomedical scientist at UC Riverside has determined that the yellow fever virus, a hemorrhagic fever virus, replicates primarily in the liver. Therefore, other organ failures that often follow in people with the disease are due to secondary effects.

When the virus targets the liver, it replicates rapidly causing significant damage to liver cells. In the process, inflammatory cytokines – proteins secreted by cells especially of the immune system – are made in massive amounts, which soon gain access to the blood stream.  These cytokines are most likely responsible for the damage to distant organs, the research team’s findings suggest.

The research team also identified a clinical parameter that could greatly help in managing yellow fever cases.

“Yellow fever causes severe loss of lymphocytes,” said Ilhem Messaoudi, an associate professor of biomedical sciences in the UC Riverside School of Medicine, who led the research project. “This process, called lymphopenia, occurs before any measurable changes in liver enzymes can be detected – that is, about a day or so before we see changes in the liver. It could provide an earlier clinical outcome measure of subsequent disease severity, giving doctors a good prognostic tool for offering more aggressive supportive care for these patients.”

Study results appear today (Nov. 20) in PLOS Neglected Tropical Diseases.

The research, performed on rhesus macaques (currently, the best model for studying human yellow fever infection) at Oregon National Primate Research Center, is the first study on yellow fever in non-human primates in more than 20 years.

“Yellow fever is truly a neglected tropical disease,” Messaoudi said. “Even though it continues to cause fatality, it remains understudied. While it is true there is a highly effective vaccine, it remains extremely challenging to get comprehensive vaccine coverage in sub-Saharan Africa and Latin America.  Moreover, the vaccine works well if you are between one and 55 years old.  It is not safe for babies or the elderly, who could develop yellow fever from the vaccine.”

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New test rapidly diagnoses bloodstream infection


New technology can detect bacterial invaders with unprecedented speed, sensitivity.

UCI project scientist Don-Ku Kang observes the IC 3D technology, which can rapidly detect bacteria in blood samples. (Photo by Steve Zylius, UC Irvine)

A new bloodstream infection test created by UC Irvine researchers can speed up diagnosis times with unprecedented accuracy, allowing physicians to treat patients with potentially deadly ailments more promptly and effectively.

The UCI team, led by Weian Zhao, assistant professor of pharmaceutical sciences, developed a new technology called Integrated Comprehensive Droplet Digital Detection. In as little as 90 minutes, IC 3D can detect bacteria in milliliters of blood with single-cell sensitivity; no cell culture is needed.

The work appears online today (Nov. 13) in Nature Communications.

“We are extremely excited about this technology because it addresses a long-standing unmet medical need in the field,” Zhao said. “As a platform technology, it may have many applications in detecting extremely low-abundance biomarkers in other areas, such as cancers, HIV and, most notably, Ebola.”

Bloodstream infections are a major cause of illness and death. In particular, infections associated with antimicrobial-resistant pathogens are a growing health problem in the U.S. and worldwide. According to the Centers for Disease Control & Prevention, more than 2 million people a year globally get antibiotic-resistant blood infections, with about 23,000 deaths. The extremely high mortality rate for blood infections is due, in part, to the inability to rapidly diagnose and treat patients in the early stages.

Recent molecular diagnosis methods, including polymerase chain reaction, can reduce the assay time to hours but are often not sensitive enough to detect bacteria that occur at low concentrations in blood, as is common in patients with blood infections.

The IC 3D technology differs from other diagnostic techniques in that it converts blood samples directly into billions of very small droplets. Fluorescent DNA sensor solution infused into the droplets detects those with bacterial markers, lighting them up with an intense fluorescent signal. Zhao said that separating the samples into so many small drops minimizes the interference of other components in blood, making it possible to directly detect target bacteria without the purification typically required in conventional assays.

To identify bacteria-containing droplets among billions of others in a timely fashion, the team incorporated a three-dimensional particle counter developed by UCI biomedical engineer Enrico Gratton and his colleagues that tags fluorescent particles within several minutes.

“The IC 3D instrument is designed to read a large volume in each measurement, to speed up diagnosis,” Gratton said. “Importantly, using this technique, we can detect a positive hit with very high confidence.”

A UCI spinoff, Velox Biosystems, is now further developing the IC 3D technology.

Dong-Ku Kang, M. Monsur Ali, Kaixiang Zhang, Dr. Susan Huang, Ellena Peterson and Michelle Digman of UCI contributed to the work, which received startup funding from UCI’s Department of Pharmaceutical Sciences, Sue & Bill Gross Stem Cell Research Center, and Chao Family Comprehensive Cancer Center. The National Institutes of Health (grants UL1 TR000153, P41 GM103540 and P50-GM076516) also provided support.

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Betting big on women, girls


Melinda Gates explains Gates Foundation’s strategy to lift countries out of poverty.

Melinda Gates talks with NPR’s Morning Edition co-anchor Renee Montagne about the source of her passion for improving conditions for people in undeveloped countries.

By Peggy McInerny, UCLA

The Bill and Melinda Gates Foundation is betting big on women and girls to help developing countries lift themselves out of poverty, foundation co-chair Melinda Gates told a UCLA audience that filled Korn Convocation Hall on Nov. 5.

Gates sat down to talk with NPR’s Morning Edition co-anchor Renee Montagne at the 2014-2015 Arnold C. Harberger Distinguished Lecture on Economic Development of the UCLA Burkle Center for International Relations. Co-sponsored this year by UCLA’s Center for World Health and the Health and Human Rights Law Project of the School of Law, the annual event is intended to bring economic policy experts to discuss their views with UCLA students and faculty.

UCLA Distinguished Professor Emeritus of Economics Harberger, who founded and supports the lecture series, was in attendance. A pioneer in the field of development economics, he has trained scores of Latin American economists over his 30 years at UCLA, where he continues to teach.

Gates has worked assiduously to restore contraception to a major place on the global health agenda. Her efforts in this direction led to the 2012 London Summit on Family Planning, which brought together donors, national governments and the development community from around the world. The summit adopted the goal of providing contraception to 120 million women in the developing world by 2020.

Today, 15 developing nations have created national family planning action plans. “We funnel our money through those action plans,” said Gates, which includes support at both the policy and the project levels.

Yet, said the speaker, she quickly realized that contraception alone could not resolve culturally ingrained gender inequality. Soon she began to advocate a holistic approach to cultivate the “other half” of the population of developing countries and, in the process, reduce poverty levels and promote economic growth.

Gates’ focus on gender inequality has led the Gates Foundation to “bet big” on three core areas: health, decision making power and economic empowerment. Saying she saw incredible opportunities in these areas to change things for the better for women and girls, she emphasized that the contributions of many individuals to these causes could create palpable change in our lifetimes.

Gates went even further, saying that development as a whole needs to be looked at through a gender lens. She explained, for example, that agricultural projects often do not take into account that the primary farmers in many countries are women, who frequently seek to avoid cash crops because they lose power over cash resources.

Longstanding development data show that investments in women’s health and education lead to smaller families with healthier, better-educated children. Where women have economic opportunity and decision-making power over resources, more of those resources are also invested in their families, promoting overall economic development.

“We need men and boys in the conversation on all of these issues,” said Gates. Only by educating men first about how contraception and women’s access to economic resources benefit the health and well-being of their children and their wives, she emphasized can these things become culturally acceptable. Moreover, the way in which health education is delivered must be culturally appropriate and respond to gender-specific circumstances.

Focusing on solving today’s problems

The Gates Foundation, which has an endowment of $42 billion and has already disbursed over $30 billion in grants, is focused on solving contemporary problems of the present generation — and perhaps the next — said the speaker.

The development aid provided by the foundation is not intended to endure indefinitely, noted Gates. Neither is the foundation itself. She and her husband do not expect it to have a shelf life much beyond their own — perhaps 15–20 years at most. “We want to spend our energy and our lives doing this work for the problems of today’s society,” she remarked.

“We are trying to build capacity now, so we can funnel more and more resources through those mechanisms,” she explained. “[And] as we learn what mechanisms work in one area, we take them and try to apply them to other areas.”

At present, the foundation is deeply engaged in the health sector in developing countries, supporting vaccination programs, building governmental and human capacity in health care, and developing ways to measure the impact of interventions, particularly those designed to improve gender inequality.

“The way that Bill and I think about this is that the only role [of] a foundation is to be a catalytic wedge,” said Gates. That is, foundations are able to take the risks needed to prove what does and doesn’t work. “But,” she added, “it takes government money to scale those things up.”

After helping create a global Vaccine Alliance (known as Gavi) and raising replenishment funds for it among wealthy nations, the Gates Foundation is now asking developing countries to make contributions to vaccination programs in their countries. Over time, these contributions are expected to increase until the programs become fully funded by those nations.

As a result of these programs, Gates noted that the governments of Ethiopia and Nigeria had built out basic-level primary health care systems in the form of “health posts.” (Ethiopia has built 15,000 such centers.)

“With basic supplies to help people and with basic trained health workers, usually two women, you can get unbelievable changes in maternal and child mortality,” observed Gates. The big lesson of the Ebola crisis is that investing in this primary level of health care provides an institutional bulwark against contagious diseases, which she predicted would continue to arise in perhaps more virulent form, she noted.

Nigeria, for example, was able to contain Ebola because after the first cases were reported, one of its polio clinics (supported by the Gates Foundation and the Centers for Disease Control and Prevention) was transformed into an Ebola emergency response clinic. Not only was the clinic able to trace the origin and spread of the disease in the country, the government was able to distribute appropriate behavior change messages throughout the system of health posts. In contrast, Liberia’s health system rapidly collapsed in the face of the Ebola crisis, having been greatly weakened by two decades of civil war.

Participating as an interlocutor, not an observer

Gates reflected that it was a great privilege to be able to travel for the foundation and learn firsthand about the concerns of men and women in the developing world. She traced her passion to making a difference in the world to the values of her parents, who encouraged all four of their children to attend college despite the serious financial burden this goal would impose.

A practicing Catholic, Gates said she attended a Catholic high school, but sought to transfer to an academically superior school in order to get into a good college. It took a while, she said, to understand that her parents sent her to the Catholic school because they believed in its values. “I was out serving in the courthouse … in the hospital, in a school two miles down the road,” she remarked. “These very liberal nuns showed us that we could make a change in the world.”

Asked if she had gotten pushback from Catholics about her support for contraception in developing nations, Gates said she had received surprisingly little criticism from people of faith. On the other hand, she noted, push back from Rome had been expected.

Whenever she travels to a development conference, the speaker said she makes a point to stop somewhere in Africa and meet people on the ground to remind herself what the work is about. Similarly, she takes a day or two to decompress after long stays in developing countries to let the stories she has heard wash through her, experience the grief sparked by them and decide what she wants to do.

“You don’t go to these countries and not let your heart break,” she said.

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Surviving sepsis


UC Santa Barbara scientist receives $3.5M NIH grant to expand his research on sepsis.

The enzyme neuraminidase remodels the surface of platelets and glycoproteins, triggering an inherent protective mechanism that can reverse the coagulation factors that make sepsis lethal. (Photo by Sanford-Burnham Medical Research Institute)

It’s the most common cause of death in American hospitals and among the top five killers worldwide, but sepsis remains largely under the radar in conversations about public health — and in promising treatments.

A biomedical scientist at UC Santa Barbara may have a hand in reversing both those trends, thanks to his novel therapeutic approach and a big new grant from the National Institutes of Health.

Jamey Marth, director of UCSB’s Center for Nanomedicine (CNM) and a professor of the Sanford-Burnham Medical Research Institute, has been awarded $3.5 million from the NIH Heart, Lung and Blood Institute for his continued work to boost survival rates in sepsis.

“This research funding award represents recognition by the NIH and scientific colleagues throughout the nation of the leading research in sepsis going on at CNM focused on understanding and thwarting the pathogenesis of sepsis, a common syndrome that remains one of the most difficult to detect and treat effectively,” said Marth, who is also the Carbon Professor of Biochemistry and Molecular Biology and the Mellichamp Professor of Systems Biology at UCSB. “With this grant, we will be able to more rapidly and more effectively follow up on our earlier discoveries of a completely new approach to the treatment of sepsis that once in the clinic may save millions of lives.”

The new grant supports an ongoing collaboration of UCSB, the Sanford-Burnham Medical Research Institute, the Santa Barbara Cottage Hospital and UC San Diego that is focusing on advancing these discoveries to the point of clinical trials. His team has already shown the method increases, by twofold, sepsis survival rates in models of bacterial infection.

Now, using Cottage’s robust data registry of septic patients, including blood samples from consenting participants, the research will accelerate to further translate the approach for human patients.

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Scientists discover exact receptor for DEET that repels mosquitoes


Discovery could pave the way for better, more affordable insect repellents.

UC Davis biochemist Walter Leal has discovered which receptor on mosquito antennae detects DEET, making it an effective repellant. (Photo by Kathy Keatley Garvey, UC Davis)

DEET has been the gold standard of insect repellents for more than six decades, and now researchers led by a UC Davis scientist have discovered the exact odorant receptor that repels them.

They also have identified a plant defensive compound that might mimic DEET, a discovery that could pave the way for better and more affordable insect repellents. Findings from the study appear today (Oct. 27) in the journal Proceedings of the National Academy of Sciences.

More than 200 million people worldwide use DEET, developed by scientists at the U.S. Department of Agriculture and patented by the U.S. Army in 1946.

“Mosquitoes are considered the most deadly animals on the planet, but unfortunately, not everyone who needs this repellent can afford to use it, and not all who can afford it can use it due to its undesirable properties such as an unpleasant odor,” said lead author professor Walter Leal of the Department of Molecular and Cellular Biology.

“Vector-borne diseases are major health problems for travelers and people living in endemic regions,” Leal said. “Among the most notorious vectors are mosquitoes that transmit the protozoan parasites causing malaria and viruses that cause infections, such as dengue, yellow fever, chikungunya and encephalitis.”

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