Synthetic molecule 'kicks and kills' some persistent HIV in mice

Scientists have designed a synthetic molecule that can reactivate dormant human immunodeficiency virus (HIV) in mice and lead to the death of some of the infected cells, according to a study published in PLOS Pathogens.

The new findings address a long-standing challenge in HIV treatment: While antiretroviral therapy can successfully stave off disease progression, the virus can silently persist in some cells for many years, so an infected person must be vigilantly treated for the rest of their life.
Previous studies have explored potential ways to eliminate latently infected cells, such as by stimulating them to produce some viral particles ("kick"), followed by cell death via the immune system or the virus itself ("kill"). A molecule called bryostatin 1 holds the potential to trigger a "kick and kill" response, but it is costly to obtain from its source, a marine animal known as Bugula neritina.
To address this challenge, Matthew Marsden and Jerome Zack of UCLA and Wender Group colleagues at Stanford have designed synthetic molecules capable of imitating the activity of bryostatin 1 and perhaps even improving on its function. In the new study, the team tested SUW133, one of their more promising synthetic bryostatin 1 analogs.
The researchers first demonstrated that SUW133, like bryostatin 1, is capable of activating latent HIV infection in cells removed from infected patients. Then, they tested SUW133 in mice of a strain commonly used for HIV research, in which the mouse immune system is modified to be similar to that of humans.
Molecular analysis revealed that SUW133 stimulated HIV protein production in latently infected cells in the mice. Within 24 hours, up to 25% of these cells then died. SUW133 was also better tolerated by the mice than was bryostatin 1.
These results support the potential for SUW133 to be used in a "kick and kill" treatment for HIV. Further research is needed to explore this potential and answer questions such as whether a greater percentage of cells could be killed over longer periods of time or with repeated dosing, whether similar effects might be seen in humans, and what the long-term effects of SUW133 may be.

Journal Reference:

1. Matthew D. Marsden, Brian A. Loy, Xiaomeng Wu, Christina M. Ramirez, Adam J. Schrier, Danielle Murray, Akira Shimizu, Steven M. Ryckbosch, Katherine E. Near, Tae-Wook Chun, Paul A. Wender, Jerome A. Zack. In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell "kick" and "kill" in strategy for virus eradication. PLOS Pathogens, 2017; 13 (9): e1006575 DOI: 10.1371/journal.ppat.1006575 

Courtesy: ScienceDaily

Alternative splicing, an important mechanism for cancer

Cancer, which is one of the leading causes of death worldwide, arises from the disruption of essential mechanisms of the normal cell life cycle, such as replication control, DNA repair and cell death. Thanks to the advances in genome sequencing techniques, biomedical researchers have been able to identify many of the genetic alterations that occur in patients that are common among and between tumor types. But until recently, only mutations in DNA were thought to cause cancer. In a new study published in the journal Cell Reports, researchers show that alterations in a process known as alternative splicing may also trigger the disease.

Although DNA is the instruction manual for cell growth, maturation, division, and even death, it's proteins that actually carry out the work. The production of proteins is a highly regulated and complex mechanism: cellular machinery reads the DNA fragment that makes up a gene, transcribes it into RNA and, from the RNA, makes proteins. However, each gene can lead to several RNA molecules through alternative splicing, an essential mechanism for multiple biological processes that can be altered in disease conditions.
Using data for more than 4,000 cancer patients from The Cancer Genome Atlas (TCGA project), a team led by Eduardo Eyras, ICREA research professor at the Department for Experimental and Health Sciences of the Pompeu Fabra University (DCEXS-UPF), has analyzed the changes in alternative splicing that occur in each tumor patient and studied how these changes could impact the function of genes. The results of the study show that alternative splicing changes lead to a general loss of functional protein domains, and particularly those domains related to functions that are also affected by genetic mutations in cancer patients.
"Thanks to our previous research, we know that tumor type and stage can be predicted by observing alterations in alternative splicing," says Eyras, head of the research group in Computational RNA Biology from the Research Programme on Biomedical Informatics (GRIB), a joint research unit of the Hospital del Mar Medical Research Institute (IMIM) and the DCEXS-UPF. "With this new study, we have discovered that changes in alternative splicing that occur in cancer impact protein functions in a way that is similar to that previously described for genetic mutations," he adds.
All of these alterations in protein functions would cause changes in cells morphology and function, giving them the characteristics of tumor cells, such as a high proliferative potential or the ability to avoid programmed cell death.
According to Adam Godzik, professor at Sanford Burnham Prebys Medical Discovery Institute (SBP) and co-author of the study, "These changes potentially have oncogenic power in cells, which means, the ability to turn a healthy cell into a cancer cell." A novel aspect of the study is that these changes tend to occur in genes other than those often mutated in cancer, and in patients with a low number of mutated genes.
"Changes in alternative splicing provide cancer with new ways in which it can escape fine cellular regulation. Therefore, the study of alternative splicing opens new doors in the research to cure cancer and may provide new alternatives to the treatment of this disease."
 

Journal Reference:

1. Héctor Climente-González, Eduard Porta-Pardo, Adam Godzik, Eduardo Eyras. The Functional Impact of Alternative Splicing in Cancer. Cell Reports, 2017; 20 (9): 2215 DOI: 10.1016/j.celrep.2017.08.012 

Courtesy: ScienceDaily
 

Zika virus kills brain cancer stem cells

Brain cancer stem cells (left) are killed by Zika virus infection (image at right shows cells after Zika treatment). A new study shows that the virus, known for killing cells in the brains of developing fetuses, could be redirected to destroy the kind of brain cancer cells that are most likely to be resistant to treatment.

Credit: Zhe Zhu

 

While Zika virus causes devastating damage to the brains of developing fetuses, it one day may be an effective treatment for glioblastoma, a deadly form of brain cancer. New research from Washington University School of Medicine in St. Louis and the University of California San Diego School of Medicine shows that the virus kills brain cancer stem cells, the kind of cells most resistant to standard treatments.

The findings suggest that the lethal power of the virus -- known for infecting and killing cells in the brains of fetuses, causing babies to be born with tiny, misshapen heads -- could be directed at malignant cells in the brain. Doing so potentially could improve people's chances against a brain cancer -- glioblastoma -- that is most often fatal within a year of diagnosis.
"We showed that Zika virus can kill the kind of glioblastoma cells that tend to be resistant to current treatments and lead to death," said Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine at Washington University School of Medicine and the study's co-senior author.
The findings are published Sept. 5 in The Journal of Experimental Medicine.
Each year in the United States, about 12,000 people are diagnosed with glioblastoma, the most common form of brain cancer. Among them is U.S. Sen. John McCain, who announced his diagnosis in July.
The standard treatment is aggressive -- surgery, followed by chemotherapy and radiation -- yet most tumors recur within six months. A small population of cells, known as glioblastoma stem cells, often survives the onslaught and continues to divide, producing new tumor cells to replace the ones killed by the cancer drugs.
In their neurological origins and near-limitless ability to create new cells, glioblastoma stem cells reminded postdoctoral researcher Zhe Zhu, PhD, of neuroprogenitor cells, which generate cells for the growing brain. Zika virus specifically targets and kills neuroprogenitor cells.
In collaboration with co-senior authors Diamond and Milan G. Chheda, MD, of Washington University School of Medicine, and Jeremy N. Rich, MD, of UC San Diego, Zhu tested whether the virus could kill stem cells in glioblastomas removed from patients at diagnosis. They infected tumors with one of two strains of Zika virus. Both strains spread through the tumors, infecting and killing the cancer stem cells while largely avoiding other tumor cells.
The findings suggest that Zika infection and chemotherapy-radiation treatment have complementary effects. The standard treatment kills the bulk of the tumor cells but often leaves the stem cells intact to regenerate the tumor. Zika virus attacks the stem cells but bypasses the greater part of the tumor.
"We see Zika one day being used in combination with current therapies to eradicate the whole tumor," said Chheda, an assistant professor of medicine and of neurology.
To find out whether the virus could help treat cancer in a living animal, the researchers injected either Zika virus or saltwater (a placebo) directly into the brain tumors of 18 and 15 mice, respectively. Tumors were significantly smaller in the Zika-treated mice two weeks after injection, and those mice survived significantly longer than the ones given saltwater.
If Zika were used in people, it would have to be injected into the brain, most likely during surgery to remove the primary tumor. If introduced through another part of the body, the person's immune system would sweep it away before it could reach the brain.
The idea of injecting a virus notorious for causing brain damage into people's brains seems alarming, but Zika may be safer for use in adults because its primary targets -- neuroprogenitor cells -- are rare in the adult brain. The fetal brain, on the other hand, is loaded with such cells, which is part of the reason why Zika infection before birth produces widespread and severe brain damage, while natural infection in adulthood causes mild symptoms.
The researchers conducted additional studies of the virus using brain tissue from epilepsy patients and showed that the virus does not infect noncancerous brain cells.
As an additional safety feature, the researchers introduced two mutations that weakened the virus's ability to combat the cell's defenses against infection, reasoning that the mutated virus still would be able to grow in tumor cells -- which have a poor antiviral defense system -- but would be eliminated quickly in healthy cells with a robust antiviral response.
When they tested the mutant viral strain and the original parental strain in glioblastoma stem cells, they found that the original strain was more potent, but that the mutant strain also succeeded in killing the cancerous cells.
"We're going to introduce additional mutations to sensitize the virus even more to the innate immune response and prevent the infection from spreading," said Diamond, who also is a professor of molecular microbiology, and of pathology and immunology. "Once we add a few more changes, I think it's going to be impossible for the virus to overcome them and cause disease."

Journal Reference:

1. Zhe Zhu, Matthew J. Gorman, Lisa D. McKenzie, Jiani N. Chai, Christopher G. Hubert, Briana C. Prager, Estefania Fernandez, Justin M. Richner, Rong Zhang, Chao Shan, Xiuxing Wang, Pei-Yong Shi, Michael S. Diamond, Jeremy N. Rich, Milan G. Chheda. Zika virus has oncolytic activity against glioblastoma stem cells. The Journal of Experimental Medicine, Sept. 5, 2017 DOI: 10.1084/jem.20171093 

Courtesy: ScienceDaily 

 

Human skin cells transformed directly into motor neurons

Scientists have discovered a new way to convert human skin cells directly into motor neurons (above). The technique, developed at Washington University School of Medicine in St. Louis, could help researchers better understand diseases of motor neurons, such as amyotrophic lateral sclerosis. Human motor neurons are difficult to study since they can't be taken from living patients. The motor neurons pictured were converted from skin cells sampled from a healthy 42-year-old woman.

Credit: Daniel Abernathy

Scientists working to develop new treatments for neurodegenerative diseases have been stymied by the inability to grow human motor neurons in the lab. Motor neurons drive muscle contractions, and their damage underlies devastating diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy, both of which ultimately lead to paralysis and early death.

In new research, scientists at Washington University School of Medicine in St. Louis have converted skin cells from healthy adults directly into motor neurons without going through a stem cell state.
The technique makes it possible to study motor neurons of the human central nervous system in the lab. Unlike commonly studied mouse motor neurons, human motor neurons growing in the lab would be a new tool since researchers can't take samples of these neurons from living people but can easily take skin samples.
The study is published Sept. 7 in the journal Cell Stem Cell.
Avoiding the stem cell phase eliminates ethical concerns raised when producing what are called pluripotent stem cells, which are similar to embryonic stem cells in their ability to become all adult cell types. And importantly, avoiding a stem cell state allows the resulting motor neurons to retain the age of the original skin cells and, therefore, the age of the patient. Maintaining the chronological age of these cells is vital when studying neurodegenerative diseases that develop in people at different ages and worsen over decades.
"In this study, we only used skin cells from healthy adults ranging in age from early 20s to late 60s," said senior author Andrew S. Yoo, PhD, an assistant professor of developmental biology. "Our research revealed how small RNA molecules can work with other cell signals called transcription factors to generate specific types of neurons, in this case motor neurons. In the future, we would like to study skin cells from patients with disorders of motor neurons. Our conversion process should model late-onset aspects of the disease using neurons derived from patients with the condition."
"Going back through a pluripotent stem cell phase is a bit like demolishing a house and building a new one from the ground up," Yoo said. "What we're doing is more like renovation. We change the interior but leave the original structure, which retains the characteristics of the aging adult neurons that we want to study."
The ability of scientists to convert human skin cells into other cell types, such as neurons, has the potential to enhance understanding of disease and lead to finding new ways to heal damaged tissues and organs, a field called regenerative medicine.
To convert skin cells into motor neurons, the researchers exposed the skin cells to molecular signals that are usually present at high levels in the brain. Past work by Yoo and his colleagues -- then at Stanford University -- showed that exposure to two short snippets of RNA turned human skin cells into neurons. These two microRNAs -- called miR-9 and miR-124 -- are involved with repackaging the genetic instructions of the cell.
In the new study, the researchers extensively characterized this repackaging process, detailing how skin cells reprogrammed into generic neurons then can be guided into specific types of neurons. They found that genes involved in this process become poised for expression but remain inactive until the correct combination of molecules is provided. After much experimentation with multiple combinations, the researchers found that adding two more signals to the mix -- transcription factors called ISL1 and LHX3 -- turned the skin cells into spinal cord motor neurons in about 30 days.
The combination of signals -- microRNAs miR-9 and miR-124 plus transcription factors ISL1 and LHX3 -- tells the cell to fold up the genetic instructions for making skin and unfurl the instructions for making motor neurons, according to Yoo and the study's co-first authors, Daniel G. Abernathy and Matthew J. McCoy, doctoral students in Yoo's lab; and Woo Kyung Kim, PhD, a postdoctoral research associate.
Another past study from Yoo's team showed that exposure to the same two microRNAs, miR-9 and miR-124, plus a different mix of transcription factors could turn skin cells into a different type of neuron. In that case, the skin cells became striatal medium spiny neurons, which are affected in Huntington's disease -- an inherited, eventually fatal genetic disorder that causes involuntary muscle movements and cognitive decline beginning in middle adulthood.
In the new study, the researchers said the converted motor neurons compared favorably to normal mouse motor neurons, in terms of the genes that are turned on and off and how they function. But the scientists can't be certain these cells are perfect matches for native human motor neurons since it's difficult to obtain samples of cultured motor neurons from adult individuals. Future work studying neuron samples donated from patients after death is required to determine how precisely these cells mimic native human motor neurons.

Journal Reference:

1. Andrew S. Yoo et al. MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts. Cell Stem Cell, September 2017 DOI: 10.1016/j.stem.2017.08.002 

Courtesy: ScienceDaily

Nutrition has benefits for brain network organization

Nutrition has been linked to cognitive performance, but researchers have not pinpointed what underlies the connection. A new study by University of Illinois researchers found that monounsaturated fatty acids -- a class of nutrients found in olive oils, nuts and avocados -- are linked to general intelligence, and that this relationship is driven by the correlation between MUFAs and the organization of the brain's attention network.

The study of 99 healthy older adults, recruited through Carle Foundation Hospital in Urbana, compared patterns of fatty acid nutrients found in blood samples, functional MRI data that measured the efficiency of brain networks, and results of a general intelligence test. The study was published in the journal NeuroImage.
"Our goal is to understand how nutrition might be used to support cognitive performance and to study the ways in which nutrition may influence the functional organization of the human brain," said study leader Aron Barbey, a professor of psychology. "This is important because if we want to develop nutritional interventions that are effective at enhancing cognitive performance, we need to understand the ways that these nutrients influence brain function."
"In this study, we examined the relationship between groups of fatty acids and brain networks that underlie general intelligence. In doing so, we sought to understand if brain network organization mediated the relationship between fatty acids and general intelligence," said Marta Zamroziewicz, a recent Ph.D. graduate of the neuroscience program at Illinois and lead author of the study.
Studies suggesting cognitive benefits of the Mediterranean diet, which is rich in MUFAs, inspired the researchers to focus on this group of fatty acids. They examined nutrients in participants' blood and found that the fatty acids clustered into two patterns: saturated fatty acids and MUFAs.
"Historically, the approach has been to focus on individual nutrients. But we know that dietary intake doesn't depend on any one specific nutrient; rather, it reflects broader dietary patterns," said Barbey, who also is affiliated with the Beckman Institute for Advanced Science and Technology at Illinois.
The researchers found that general intelligence was associated with the brain's dorsal attention network, which plays a central role in attention-demanding tasks and everyday problem solving. In particular, the researchers found that general intelligence was associated with how efficiently the dorsal attention network is functionally organized used a measure called small-world propensity, which describes how well the neural network is connected within locally clustered regions as well as across globally integrated systems.
In turn, they found that those with higher levels of MUFAs in their blood had greater small-world propensity in their dorsal attention network. Taken together with an observed correlation between higher levels of MUFAs and greater general intelligence, these findings suggest a pathway by which MUFAs affect cognition.
"Our findings provide novel evidence that MUFAs are related to a very specific brain network, the dorsal attentional network, and how optimal this network is functionally organized," Barbey said. "Our results suggest that if we want to understand the relationship between MUFAs and general intelligence, we need to take the dorsal attention network into account. It's part of the underlying mechanism that contributes to their relationship."
Barbey hopes these findings will guide further research into how nutrition affects cognition and intelligence. In particular, the next step is to run an interventional study over time to see whether long-term MUFA intake influences brain network organization and intelligence.
"Our ability to relate those beneficial cognitive effects to specific properties of brain networks is exciting," Barbey said. "This gives us evidence of the mechanisms by which nutrition affects intelligence and motivates promising new directions for future research in nutritional cognitive neuroscience."

Journal Reference:

1. Marta K. Zamroziewicz, M. Tanveer Talukdar, Chris E. Zwilling, Aron K. Barbey. Nutritional status, brain network organization, and general intelligence. NeuroImage, 2017; 161: 241 DOI: 10.1016/j.neuroimage.2017.08.043 

Courtesy: ScienceDaily

Medical camera makes light work of seeing through the body

The camera is designed to help doctors track medical tools known as endoscopes that are used to investigate a range of internal conditions.

The new device is able to detect sources of light inside the body, such as the illuminated tip of the endoscope's long flexible tube.

Until now, it has not been possible to track where an endoscope is located in the body in order to guide it to the right place without using X-rays or other expensive methods

Light from the endoscope can pass through the body, but it usually scatters or bounces off tissues and organs rather than travelling straight through. This makes it nearly impossible to get a clear picture of where the endoscope is.

The new camera takes advantage of advanced technology that can detect individual particles of light, called photons.

Experts have integrated thousands of single photon detectors onto a silicon chip, similar to that found in a digital camera.

The technology is so sensitive that it can detect the tiny traces of light that pass through the body's tissue from the light of the endoscope.

It can also record the time taken for light to pass through the body, allowing the device to also detect the scattered light.

By taking into account both the scattered light and the light that travels straight to the camera, the device is able to work out exactly where the endoscope is located in the body.

Researchers have developed the new camera so that it can be used at the patient's bedside.

Early tests have demonstrated that the prototype device can track the location of a point light source through 20 centimetres of tissue under normal light conditions.

The project -- led by the University of Edinburgh and Heriot-Watt University -- is part of the Proteus Interdisciplinary Research Collaboration, which is developing a range of revolutionary new technologies for diagnosing and treating lung diseases.

Proteus is funded by the Engineering and Physical Sciences Research Council.

The research is published in the journal Biomedical Optics Express.

Professor Kev Dhaliwal, of the University of Edinburgh, said: "This is an enabling technology that allows us to see through the human body. It has immense potential for diverse applications such as the one described in this work. The ability to see a device's location is crucial for many applications in healthcare, as we move forwards with minimally invasive approaches to treating disease."

Dr Michael Tanner, of Heriot-Watt University, said: "My favourite element of this work was the ability to work with clinicians to understand a practical healthcare challenge, then tailor advanced technologies and principles that would not normally make it out of a physics lab to solve real problems. I hope we can continue this interdisciplinary approach to make a real difference in healthcare technology."

 

Journal Reference:

1. M. G. Tanner, T. R. Choudhary, T. H. Craven, B. Mills, M. Bradley, R. K. Henderson, K. Dhaliwal, R. R. Thomson. Ballistic and snake photon imaging for locating optical endomicroscopy fibres. Biomedical Optics Express, 2017; 8 (9): 4077 DOI: 10.1364/BOE.8.004077 

Courtesy: ScienceDaily