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Study suggests new way to help the immune system fight off sleeping sickness parasite

Jul 30, 2016

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Infectious diseases that have the ability to evade the immune system are quite difficult to treat. One such disease is the African sleeping sickness. It is caused by the parasite Trypanosoma brucei and is transmitted by the tsetse fly. The parasite gets transmitted to mammals through fly bites. If left untreated for prolonged period the disease can get fatal as it invades major organs such as the brain, disrupting the sleep cycle, among other symptoms.

There are different forms of trypanosomes. When they house themselves in a fly, they are covered with proteins called procyclins. Once they enter the bloodstream of a mammal, they acquire a dense layer of glycoproteins that continually change, which enables the parasite to dodge an attack from the host’s immune system.

Postdoctoral scientists Danae Schulz and Erik Debler, working in Nina Papavasiliou’s and Günter Blobel’s labs at Rockefeller University have innovated a method to manipulate trypanosomes in the mammalian bloodstream to acquire fly stage characteristics, a state that makes it easier for the host immune system to eliminate the invader. The details of the study were published recently in PLOS Biology. Their findings suggest that by inhibiting specific proteins that interact with chromatin�the mass of DNA and proteins that packages a cell’s genetic information�can trick the parasite into differentiating to a different stage of its lifecycle.

Nina Papavasiliou, head of the Laboratory of Lymphocyte Biology said that when these chromatin-interacting proteins are blocked, the parasite becomes visible to the immune system. �Since, the bloodstream form of the parasite constantly switches protein coats to evade the immune, this new method works as it makes the parasite think it’s in the fly, where it doesn’t need to worry about the immune system attacking it.

Regulatory proteins interact with chromatin to either package it more tightly or unwind it, which affects the genes that are expressed. Some of these regulatory proteins contain a region called the bromodomain, which recognizes a specific signal on chromatin and induces changes in gene expression. It is known that in mice bromodomains are involved in cell differentiation, which led the researchers to hypothesize that such epigenetic mechanisms may drive the trypanosome to change from one form to another.

Schulz, the lead author of the study remarked that to investigate if chromatin-altering mechanisms might be important for differentiation, the researchers inhibited bromodomain proteins in cells by introducing genetic mutations in their DNA or by exposing the cells to a small-molecule drug called I-BET151 known to block bromodomains in mammals.

When these changes were introduced the investigators observed changes in gene expression levels that resembled those seen in cells differentiating from the bloodstream form to the fly form. Also a procyclin coat normally found on the fly form developed on it. The results of the study made the researchers believe bromodomains could serve as a potential therapeutic target to treat African sleeping sickness.

The researchers then used drug-treated trypanosomes to infect mice to find if I-BET151 could be used to combat the disease. The results revealed that the parasite's ability to invade the host was diminished in the presence of I-BET151.

I-BET151 is not effective enough to be used in the clinic, but a crystal structure determined by Debler and published as part of this study provides direct clues for how an optimized drug could be designed to bind parasite bromodomains in a highly specific manner, limiting side effects.

Papavasiliou said that since the current treatments for this disease are limited and they have substantial side effects, including very high mortality rates, this study offers a promising new avenue to develop therapeutics. She also remarked that this could the findings will be helpful for not only African sleeping sickness, but also a number of related parasitic diseases like Chagas or malaria.

References:

https://newswire.rockefeller.edu/2015/12/08/study-suggests-new-way-to-help-the-immune-system-fight-off-sleeping-sickness-parasite/

https://medicalxpress.com/news/2015-12-immune-sickness-parasite.html

Study shows high frequency of spontaneous mutation in Ebola virus

Jul 29, 2016

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Ebola is a deadly form of viral hemorrhagic fever occurring in humans and other primates and is caused by Ebola viruses. It is understood that this virus transmitted to humans from wild animals and eventually spread in the human population through human-to-human transmission. The disease has an average fatality rate of 50%. Once the virus is contracted the symptoms appear between two days to three weeks. The typical symptoms include fever, sore throat, muscular pain, and headaches followed by vomiting, diarrhea along with decreased function of the liver and kidneys.

Ebola

The latest and perhaps the biggest outbreak of this epidemic happened in March 2014 in West Africa. Almost after two years since the epidemic began, the World Health Organization has declared the African country of Guinea to be free of Ebola virus infections. However, the race to find a cure and therapies to combat the disease are on, as officials are of the opinion that inattention could lead to another deadly epidemic.

Scientists at Texas Biomedical Research Institute have been working on therapies, diagnostics and vaccines for years before the 2014 epidemic. Finally, they seem to have discovered a promising mechanism for attacking the virus reveals a recent study by Dr. Anthony Griffiths. This study is scheduled to be published in the Journal of Virology – Issue 5 March 2016 print edition. However, it can be accessed online already.

Dr. Griffiths, in his paper titled Determination and Therapeutic Exploitation of Ebola Virus Spontaneous Mutation Frequency, explains how typically RNA viruses have high spontaneous mutation rates, which permit rapid evolution and the ability to adapt to new selection pressures. These selection pressures can include antiviral drugs, the immune system, or even new animal hosts. But, it was unknown whether filoviruses exhibit high mutation frequencies. He added that when the work on this study was at its initial stage, there was not an appreciation that Ebola virus had any capacity to evolve and if those changes would be well tolerated.

Kendra Alfson, a graduate student in Griffiths' team along with his mentor used ultra-deep sequencing to find that the spontaneous mutation frequency for Ebola virus was high and similar to other RNA viruses. But, it was also found that Ebola virus had very limited ability to tolerate spontaneous changes in the genome. That is why it was reasoned that chemically increasing the mutation frequency may decrease the number of viable virions released from a cell. Typically, it was understood that Ebola virus has the potential to evolve rapidly however, the genetic changes result in viruses that are weakened or not viable. But, since the latest outbreak had an unprecedented numbers of individuals infected, it is now evident that Ebola virus does evolve in humans. Hence, to have better diagnostics and potential therapies for the condition, a better understanding of the capacity of the virus to evolve is essential.

Griffiths explains that any change in a genome can be neutral, negative, or positive to a virus. It may seem that viruses have evolved to have an optimal mutation rate. But, increasing the mutation rate could produce a negative effect on the virus and serve as a valuable therapeutic tool. In order to determine whether Ebola virus was sensitive to increasing mutation rate, Griffiths’ team tested a drug called ribavirin. The preliminary experiments with mice suggest ribavirin could be a potential therapy as it did cause the desired effect of increasing the mutation frequency enough to make the virus non-viable. When further tests were carried out in monkeys, it was seen that ribavirin reduced production of infectious Ebola virus; however results were not strong enough to recommend ribavirin as a treatment protocol.

Griffith opined that since modifying mutation rate as a therapeutic tool for Ebola virus infections seems promising, the future course of action is to test other drugs in the hope of improving the efficacy observed using ribavirin.

References:

https://www.txbiomed.org/news-press/detail/news/2016/01/05/ebola-mutation-frequency

https://medicalxpress.com/news/2016-01-high-frequency-spontaneous-mutation-ebola.html

Study reveals environment and behavior contribute to 80 percent of cancers

Jul 28, 2016

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Environmental exposures and behaviors have a huge role to play in the development of a vast majority of cancers. Quantitative evidence proving the same has been found by a team of researchers from Stony Brook University, led by Yusuf Hannun, MD, the Joel Strum Kenny Professor in Cancer Research and Director of the Stony Brook University Cancer Center. The findings were published in a recent online issue of Nature. The study is significant as its findings may be important for strategizing cancer prevention, research and public health.

The study was inspired by a January 2015 research paper published in Science, which said that the majority of the variation in cancer risk among tissues is due to “bad luck”. The researchers at Stony Brook used the same data to determine what increases the risk of developing cancer. The team of researchers which had people from the Departments of Applied Mathematics and Statistics, Medicine, Pathology and Biochemistry, came to a very different conclusion � that most cancers are the result of external risk factors.

Dr. Hannun, senior author of the paper remarked that development of cancer is a complex issue and that is the reason why solid analytical models are needed to investigate what intrinsic and extrinsic factors cause certain forms of cancer.

Song Wu, PhD, lead author of the paper, and Assistant Professor in the Department of Applied Mathematics and Statistics, Stony Brook University in order to argue against the ‘bad luck’ or ‘random mutation’ theory of cancer, an alternative analysis to quantify the contribution of external risk factors is a must. This study does exactly that � it provides an alternative analysis by applying four distinct analytic approaches.

With the four approaches, the researchers found collectively and individually that most cancers are attributed largely to external risk factors – just 10-to-30 percent are caused due to random mutations, or intrinsic factors.

The researchers applied a data driven approach and examined extrinsic risks by tissue cell turnover. They re-examined the quantitative relationship between observed lifetime risk of cancer for lung, pancreatic, colorectal and other tissues and division of the normal tissue stem cells in those groups reported in the Science paper. The researchers argued that if intrinsic risk factors played a major role, the tissue with the similar stem cell divisions would show similar observed lifetime cancer risk. But, their study revealed that such a pattern was rare which led them to conclude that intrinsic factors played a vital role in only about 10 percent of cancers. That explains why immigrants moving from countries with lower cancer incidence to countries with higher rates of cancer incidence acquire the higher risk in their new country.

The researchers also mathematically surveyed and analyzed some 30 distinct signatures among various cancers. They signatures were analysed and categorized as having intrinsic or extrinsic origins. It was found that a few forms of cancer had a greater than 50 percent of intrinsic mutations but a majority of them like colorectal, lung, bladder and thyroid cancers were most likely caused by extrinsic factors.

Next, the team analyzed the SEER (Surveillance, Epidemiologic and End Results Program) data, which revealed that the incidences and mortality of many cancers have been increasing, suggesting that external factors contribute heavily to these cancers.

Computational modeling was also applied by the researchers to dissect the contribution of the intrinsic processes in the development of cancer. It was found that when three or more mutations are required for cancer onset, intrinsic factors are far from sufficient to account for the observed risks. This indicated that there is a small percentage of intrinsic cancer risk in many cancers.

Dr. Hannun is of the opinion that their study will have important consequences for strategizing cancer prevention, research and public health by providing a new framework to quantify the lifetime cancer risks from both intrinsic and extrinsic factors.

References:

https://medicalxpress.com/news/2015-12-reveals-environment-behavior-contribute-percent.html

https://www.sciencedaily.com/releases/2015/12/151216144831.htm

Stereotypes around aging can negatively impact memory and hearing

Jul 27, 2016

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Old age is typically associated with the loss of mental capabilities. But, a new research led by researchers at the University of Toronto has revealed that there is a different aspect to this occurrence. The study shows that when older adults feel negatively about aging, they tend to lose confidence in their abilities to hear and remember things, and perform poorly at both. �The results of the study were published recently in Psychology and Aging.

Alison Chasteen, lead author of the study and a professor in U of T’s Department of Psychology remarked that people’s feelings about getting older have an influence on their sensory and cognitive functions. Ironically, these feelings drop from stereotypes about getting older and comments made by those around them that their hearing and memory are failing. �Hence, there is a need to take a deeper approach to understanding the factors that influence their daily lives.

The study was coauthored by researchers at the University of Toronto, Baycrest Health Sciences, the James H.Quillen VA Medical Center, and Phonak AG. The research was supported by a Catalyst Grant from the Canadian Institutes for Health Research

Three variables were examined as a part of the study – views on aging, self-perceptions of one’s abilities to hear and remember, and one’s actual performance of both functions. The idea was to uncover connections between them. 301 adults between the ages of 56 and 96 were chosen as participants of the study. They completed standard hearing tests to determine their ability to hear which were followed by a series of recall tasks to test their memory. A third test needed them to listen to and repeat a list of five words, and then recall them after a five-minute delay. These tests provided an accurate measurement of each participant’s performance in both functions.

Later the participants were made to respond to a series of questions and statements relating to their own perceptions of their hearing and memory abilities. They were asked to agree or disagree with statements like – “I am good at remembering names,” or “I can easily have a conversation on the telephone. In order to assess their views on aging, the participants were asked to imagine 15 scenarios and rate their concerns about each based on age. Each scenario asked them about their opinion about how they felt about being old, losing their independence, becoming more forgetful, etc.

Chasteen remarked that it was found that those who held negative views about getting older and about the challenges old age brings to their abilities to hear and remember things, also did poorly on the hearing and memory tests. Well, the reverse doesn't hold good in all cases � that is to say that all older adults who demonstrate poor capacities for hearing and memory have negative views of aging. The crux of the findings is a negative view impacts an individual’s confidence in the ability to function.

Chasteen is of the opinion that it is important to take into account the perceptions older people have about their abilities to function and how they feel about aging when determining their cognitive and sensory health. She opines that educating older people about ways in which they can influence their aging experience like providing them with training exercises to enhance their cognitive and physical performance, and disspelling stereotypes about aging can be really helpful

To sum up the results of the study – changing how older adults feel about themselves could improve their abilities to hear and remember and will enable the development of interventions to improve their quality of life.

Looking for ways to improve your memory? Try this.

References:

https://news.artsci.utoronto.ca/all-news/aging-hearing-memory/

https://medicalxpress.com/news/2015-12-stereotypes-aging-negatively-impact-memory.html

Stem cells likely to be safe for use in regeneration medicine, study confirms

Jul 26, 2016

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In a study published recently in the journal Cell Stem Cell, it has been revealed that Cambridge researchers have found the strongest evidence to date that human pluripotent stem cells will develop normally once transplanted into an embryo. Human pluripotent stem cells are cells that can give rise to all tissues of the body and the findings of this study could have significant implications for regenerative medicine.

These stem cells have promising therapeutic uses in regenerative medicine to treat devastating conditions that affect various organs and tissues, particularly those that have poor regenerative capacity, such as the heart, brain and pancreas. The human pluripotent stem cells used in regenerative medicine or biomedical research typically come from two sources – and induced pluripotent stem cells, where skin cells are ‘reset’ to their original, pluripotent form and embryonic stem cells, derived from fertilised egg cells discarded from IVF procedures.

There have been doubts and concerns by many scientists that it might give rise to tumors in case the cells are not incorporated properly into the body � they might not distribute themselves. The present study dispels the doubts and suggests that when the stem cells are transplanted appropriately, they are likely to be safe for use in regenerative medicine. The research is funded by the British Heart Foundation.

This study provides strong evidence to suggest that human stem cells will develop in a normal�and importantly, safe way commented Professor Roger Pedersen from the Anne McLaren Laboratory for Regenerative Medicine at the University of Cambridge.

Since, it is unethical to carry out the transplantation into an early-stage human embryo, researchers use mouse embryos. The gold standard test, developed in Cambridge in the 1980s, involves putting the stem cells into a mouse blastocyst, a very early stage embryo after fertilization, then assessing stem cell contribution to the various tissues of the body. In previous researches scientists were not successful in getting human pluripotent stem cells incorporated into mouse embryos. However, in this study Professor Pedersen and co-author Victoria Mascetti and have shown that it is possible to successfully transplant human pluripotent stem cells into the mouse embryo and that they then develop and grow normally.

The reason why stem cell research is so significant is because it holds great promise for treating serious conditions like heart disease and Parkinson’s disease. Till now, the big question mark on such research has been how safe and effective they will be. Through this research, Mascetti has been able to demonstrate that human pluripotent stem cells are equivalent to an embryonic counterpart.

The reason why previous attempts to incorporate human pluripotent stem cells failed is that the stem cells had not been matched to the correct stage of embryo development. Previously, the cells were transplanted into the mouse embryo earlier than ideal. But, when they were transplanted at the right stage (gastrulation stage of embryonic development), the stem cells went on to grow and proliferate normally, to integrate into the embryo and to distribute themselves correctly across relevant tissues.

These results substantially strengthen the view that induced pluripotent stem cells from adult tissue are suitable for use in regenerative medicine�like in attempts to repair damaged heart muscle after a heart attack opined Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation.

Mascetti was excited about the study's finding and said that their finding that human stem cells integrate and develop normally in the mouse embryo will allow them to study aspects of human development during a window in time that would otherwise be inaccessible.

References:

https://www.cam.ac.uk/research/news/stem-cells-likely-to-be-safe-for-use-in-regenerative-medicine-study-confirms

https://medicalxpress.com/news/2015-12-stem-cells-safe-regeneration-medicine.html

Scientists reveal new phase of HIV infection

Jul 25, 2016

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A new life cycle stage of HIV infection has been identified by researchers at the University Of Massachusetts Medical School with the help of a novel technique they developed that enables then to take images of intact infected cells. This staged is named as intra-nuclear migration and it relies on the human protein CPSF6 to guide the virus through the host cell’s nucleus and position it at active genes where it prefers to make its home explained principal investigator Abraham L. Brass, MD, PhD.

HIV, DNA

Dr. Brass who is also an assistant professor of microbiology & physiological systems said that the findings of the study are significant as it reveals an important stage and mechanism in HIV infection that was previously unappreciated. The details of the finding and imaging techniques used were published in Cell Reports.

ViewHIV is the technique vital to this finding; it was developed by Brass and his colleagues, Jill Perreira and Chris Chin, both research associates at UMMS; and Eric Feeley, a PhD candidate at Duke University. Using this technique, close monitoring of the migration of HIV was possible. HIV is made up of a protein capsule that contains the virus’s DNA, as it passes through the nuclear membrane and moves around inside the nucleus. Scientists have been unable to generate good images of HIV inside the nucleus using standard techniques.

Perreira, a co-lead author on the study opined that there are certain characteristics of a virus that can be learnt by keeping it intact and seeing it in action in single cells. Even though researchers have been studying HIV for 30 years, there is no good way to look inside infected cells. The aim of the research has been to find a way to see what’s going on inside which in turn will help in getting a better idea of what the virus is doing and how to stop it.

ViewHIV developed by the research team, is capable of generating images of both the viral genome and protein capsid simultaneously inside an infected host cell. ViewHIV pairs a very sensitive type of fluorescence in situ hybridization (FISH) with a monoclonal antibody that binds to the viral capsid. This allowed the capsid, tagged with a fluorescent antibody, to be seen in the images of the nucleus. This technique enabled scientists to visualize the movement and fate of the viral capsid, DNA and RNA inside the cell. Standard confocal microscopy is then used to take both horizontal and vertical photos of the cell that are re-assembled into detailed three-dimensional images of the cell.

With the help of the images produced by ViewHIV, Perreira and Chin, were able to track the virus and its capsid as it moved through the cytoplasm, across the nuclear membrane and finally into the nucleus where it permanently integrates into the host cell’s DNA. By knocking down certain host proteins, the researchers were able to observe what impact these proteins had on the virus’ ability to enter the nucleus and integrate into the host genome.

The viral capsid seemed to have a vital role to play in the virus’s ability to enter and navigate through the nucleus. The images clearly show that a portion of the capsid is still present and associated with the viral DNA after nuclear entry, with the final shedding of capsid occurring when the virus reaches its final destination. The capsid’s uses the host proteins CPSF6 and TNPO3 to enter and navigate through the nucleus. Typically, the CPSF6 protein works to modify the cells newly made messenger RNAs and its aim is to find active genes once it gets into the nucleus. This study reveals that when a cell is infected with HIV, the virus takes a ride on the protein, which is transported across the nuclear membrane by the nuclear importer, TNPO3. Once inside the nucleus, it is carried to active gene areas where it prefers to integrate.

This stage in HIV’s life cycle taking place between the time the virus enters the nucleus and the time its DNA is integrated into our genome, has been discovered thanks to the development of ViewHIV. When we have knowledge about these early infection events, new ways can be designed to stop the HIV virus from becoming a part of our DNA and infecting us for life.

References:

https://www.umassmed.edu/news/news-archives/2015/12/umms-scientists-reveal-new-phase-of-hiv-infection/

https://www.ibtimes.com.au/viewhiv-reveals-new-phase-hiv-infection-1494542

Scientists identify molecule that appears to fuel deadly genetic illness, Fanconi anemia

Life Style

Jul 24, 2016

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Fanconi anemia is a complex genetic disorder that is responsible for birth anomalies, organ damage, anemia and cancer. Researchers working on this condition have identified a molecular target and experimental treatment strategy for DNA repair defects responsible for it. The findings of the study were published recently in Stem Cell Reports.

The findings of the study have created a bit of molecular intrigue. The cells with Fanconi anemia (FA) DNA repair defect used in the study were given targeted treatment and post treatment they were able to recover and grow normally.

Susanne Wells, PhD, director of the Epithelial Carcinogenesis and Stem Cell Program in the Cincinnati Children’s Hospital Medical Center (Cancer and Blood Diseases Institute) and lead investigator of the study said that this study provides an experimental platform to test new therapies that could prevent pre- and post-natal Fanconi anemia conditions, which have no cure and limited treatment options. Our findings are just the tip of the iceberg as there are plenty of questions that still need to be answered.

For the study induced pluripotent stem cells (iPSCs) were used the researchers as they can become any cell type in the body. These induced stem cells were created by reprogramming mature skin and connective tissue cells donated by Fanconi anemia patients. They cells had the defective (FA) DNA repair pathway, which typically helps protect the genome from mutations.

The stem cells were closely studied by scientists in laboratory cultures and cells injected into humanized mouse models monitoring their genetic, molecular and developmental progression. Even though the cells had defective FA DNA repair, the stem cells were capable of transforming into different tissues. In fact, humanized mice injected with the defective cells started to form teratomas�benign tumors that contain a haphazard mishmash of cells and tissues of different organ systems. However, it was observed by the researchers that due to the DNA repair defect the pluripotent stem cells were started to get killed by blocking cell division and causing programmed cell death.

It was observed that an enzyme that serves as a DNA regulatory checkpoint during cell division (CHK1) was hyperactive in the stem cells, which seemed to hasten their death. To block the hyperactive enzyme at a critical stage of the stem cell cycle, existing pharmacologic inhibitors of CHK1 were used by the researchers. This enabled them to override what usually are unfixable errors in the FA repair pathway. It was seen that after the targeted treatment, FA-pathway-deficient pluripotent stem cells resumed dividing and expanding normally. It was a surprise to the researchers that the cells resumed growth with chromosome abnormalities.

The researchers speculate that a compensating DNA repair process is engaged in the reinvigorated cells. Wells and colleagues are hopeful that study may point to an approach that treats all clinical manifestations of the disease like anemia and cancer.

Well remarked that an important question that need to be answered is what type of DNA repair kicks in under these conditions and if it is totally error free or prone to errors. He added that it is likely that a novel mode of emergency DNA repair might be discovered in the iPSC cells. �Since, human cells have other DNA repair processes besides the FA repair pathway researchers hope to closely monitor their upcoming experiments for one of these existing DNA repair pathways.

Timothy Chlon, PhD (a research associate in the Wells laboratory) and first author of the study stressed the current results are early and need extensive additional study before becoming clinically relevant. To further their study, the research team plan to follow up this study with additional testing in ‘humanized’ and genetic mouse models.

References:

https://medicalxpress.com/news/2016-01-scientists-molecule-fuel-deadly-genetic.html#nRlv

https://www.sciencenewsline.com/news/2016011217500005.html

Scientists identify a neural population highly selective for music

Jul 23, 2016

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For long scientists have wondered if there is some neural mechanism in the human brain that is specific to music perception. Finally, the neuroscientists at the MIT have identified a neural population in the human auditory cortex that responds selectively to sounds that is typically categorized as music, but not to speech or other environmental sounds.

Music

Josh McDermott, the Frederick A. and Carole J. Middleton Assistant Professor of Neuroscience in the Department of Brain and Cognitive Sciences at MIT said that this particular subject has received quite widespread speculation. There has been a lot of curiosity to know to what extent music has dedicated mechanisms in the brain and to what extent it piggybacks off of mechanisms that primarily serve other functions.

This finding has been possible due to the development of a novel method that can identify neural populations from functional magnetic resonance imaging (fMRI) data. Six neural populations with different functions have been identified by the researchers using this method � these include the music-selective population and another one that responds selectively to speech. The findings were published recently in an online edition of Neuron.

Sam Norman-Haignere, a postdoc at MIT’s McGovern Institute for Brain Research and lead author of the paper opined that this finding is notable because highly selective responses to music were not clearly seen before.

Nancy Kanwisher, the Walter A. Rosenblith Professor of Cognitive Neuroscience at MIT, a member of MIT’s McGovern Institute for Brain Research and study's senior author remarked that the findings of the study are hard to reconcile with the idea that music piggybacks entirely on neural machinery that is optimized for other functions, because the neural responses that have been seen in the study are highly specific to music.

The brains of 10 human subjects listening to 165 natural sounds which include various types of speech and music along with everyday sounds like phone ringing, footsteps, etc., were scanned.

It is difficult to map brain's auditory system as the spatial resolution of fMRI is coarse � it measures blood flow as an index of neural activity. “Voxels”�the smallest unit of measurement in fMRI�reflect the response of hundreds of thousands of neurons. Norman-Haignere explains that when one goes by the raw voxel responses, it is reflection of a mixture of underlying neural responses. In order to overcome this shortcoming, the researchers made use of a technique that models each voxel as a mixture of multiple underlying neural responses. With the help of this method six neural populations each with a unique response pattern to sounds were identified. One population responded most to music, another to speech, and the other four to different acoustic properties such as pitch and frequency.

Josef Rauschecker, a professor of physiology and biophysics at Georgetown University remarked that the key to this advance is the researchers’ new approach to analyzing fMRI data. He added that this is a study of the highest caliber of data analysis.

The four acoustically responsive neural populations overlap with regions of “primary” auditory cortex, which performs the first stage of cortical processing of sound. Speech and music-selective neural populations lie beyond this primary region. Norman-Haignere opined that this provides evidence that there’s a hierarchy of processing where there are responses to relatively simple acoustic dimensions in this primary auditory area. It is followed by a second stage of processing that represents more abstract properties of sound related to speech and music.

McDermott said that it is not right to conclude that auditory cortex is the seat of music in the brain as there may be other brain regions involved in processing music, including its emotional components.

Kanwisher also notes that an important question for the future will be how this system arises in development like how early it is found in infancy or childhood, and how dependent it is on experience? The next step for the researchers is to investigate if the music-selective population identified in this study contains subpopulations of neurons that respond to different aspects of music, like rhythm, melody, and beat.

References:

https://medicalxpress.com/news/2015-12-scientists-neural-population-highly-music.html

https://news.mit.edu/2015/neural-population-music-brain-1216

Scientists Grow Functional Vocal Cord Tissue in the Lab

Jul 22, 2016

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In a report published recently in the journal Science Translational Medicine, it was revealed that scientists at the University of Wisconsin-Madison have succeeded in growing functional vocal cord tissue in the laboratory. This is a major breakthrough as it may go a long way restoring the voice to people who have lost their vocal cords to cancer surgery or other injuries. The report said that Dr. Nathan Welham, a UW speech-language pathologist, and colleagues from several disciplines were able to bioengineer vocal cord tissue that was able to transmit sound.

Statistics reveal that almost 20 million Americans suffer from voice impairments; many of these people may have damaged vocal cord mucosae, the specialized tissues that vibrate as air moves over them, giving rise to voice. For short term, injections of collagen and other materials can be helpful, but for people who have had larger areas of their vocal cords damaged or removed, there was no substantial treatment option.

Welham, an associate professor of surgery in the UW School of Medicine and Public Health opined that voice is something we do not realize the value of unless something goes wrong with it. Our vocal cords comprises of special tissue that need to be flexible enough to vibrate and also strong enough to bang together hundreds of times per second. It is an exquisite system and quite a hard thing to replicate.

For their experiment Welham and his fellow colleagues started with vocal cord tissue from a cadaver and four patients who had their larynxes removed but did not have cancer. Cells from the mucosa were isolated, purified and grown. A 3-D collagen scaffold was then applied to it – similar to a system used to grow artificial skin in the laboratory. It took two weeks for the cells to grow together and form a tissue with a pliable but strong connective tissue beneath, and layered epithelial cells on top. When proteomic analysis was carried out, it was found that the cells produced many of the same proteins as normal vocal cord cells. Physical testing also revealed that the epithelial cells had also begun to form an immature basement membrane that is instrumental in creating a barrier against pathogens and irritants in the airway.

Welham remarked that the lab-grown tissue was quite like vocal cord tissue and in materials testing it was found that it did have the qualities of viscosity and elasticity similar to normal tissue. In order to see if these bio-engineered tissues could transmit sound, the researchers transplanted the bioengineered tissue onto one side of larynges removed from cadaver dogs. The larynges were attached to artificial windpipes and warm, humidified air was blown through them. The tissue produced sound and high-speed digital imaging showed the engineered mucosa vibrating like the native tissue on the opposing side. Acoustic analysis also revealed that the two types of tissue had similar sound characteristics.

As a final leg of their experiment, the researchers decided to find out if the tissue would be rejected or accepted by mice that had been engineered to have human immune systems. The tissue grew and was not rejected in mice.

Of course, these lab made tissues were not as good as the real thing � human vocal cords keep developing till at least 13 years after birth. So, the similar complexing in its fiber structure cannot be expected.

Clinical applications of this study are still years away, but Welham is of the opinion that this proof-of-principle study is a robust benchmark along the route to replacement vocal cord tissue. Of course, further promising work need more testing of safety and long-term function.

References:

https://medicalxpress.com/news/2015-11-scientists-functional-vocal-cord-tissue.html

https://www.nlm.nih.gov/medlineplus/news/fullstory_155789.html

Scientists find key driver for treatment of deadly brain cancer

Jul 21, 2016

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Glioblastoma multiforme is a quite a deadly form of brain cancer. Typically, the maximum lifespan of person with this form of brain cancer after diagnosis is 15 months, if given the best care. Researchers at the Salk Institute have discovered a crucial key to how these tumor cells proliferate so fast and also how to use the finding into a target for cancer treatment. The details of the study finding were published recently in the journal Science Advances.

Inder Verma, professor in the Salk Institute’s Laboratory of Genetics and senior author of the paper remarked that there has been practically no improvement in treatment outcome for this disease for years. Years of study have confirmed the fact that even if a surgeon removes 99.99 percent of a glioblastoma multiforme tumor, what is left grows again into more tumor.

Verma’s team focused on a transcription factor called nuclear factor kB (or NF-kB) to study how glioblastoma multiforme spreads. The function of a transcription factor which is a protein is to bind to DNA and control the gene expression for a particular set of genes. NF-kB activity in a cell can be triggered due to ultraviolet and ionizing radiation, immune proteins (cytokines) and DNA damage. A number of tests were carried out by Verma and his team to show how overzealous NF-kB activity pushed the cancer cells to proliferate, and how stopping NF-kB slowed cancer growth and increased survival.

Dinorah Friedmann-Morvinski, currently a researcher in the department of biochemistry and molecular biology at Tel Aviv University in Israel and first author of the paper said that their experiments confirmed that NF-kB is required for the cancer cell to proliferate. We have also found a way to ameliorate the tumor to increase lifespan.

The team of researchers began their experiments on a mouse model of glioblastoma multiforme and used genetic tools to manipulate cells into shutting down NF-kB activity in two ways. One was to ramp up the presence of a protein called IkBaM, which inhibits NF-kB activity and second was to eliminate an enzyme that increases NF-kB activity. When the NF-kB activity was reduced, the tumor growth slowed and mice lived significantly longer. These genetic experiments however aren’t a feasible treatment in humans.

Verma said that they thought of manipulating the system using pharmacology rather than genetics. The tumor microenvironment is one reason why glioblastoma multiforme comes back so quickly after surgery. It seems the tumor changes the environment of its nearby tissues to help cancer cells thrive. So, Verma and colleagues decided to treat the brain tumors in a way that also changed the tumor microenvironment. The scientists fed mice a peptide (called NBD) that is known to block NF-kB activity when NF-kB is triggered by cytokines (proteins produced by the immune system). The NBD peptide can travel across the central nervous system, and successfully penetrate glioblastoma tumor cells. Treating mice with the NBD peptide doubled their typical survival time compared to mice that didn’t get the NBD peptide.

Verma remarked that they could increase survival time from one month without treatment to three months with treatment and that achievement is something significant. However, this step is not a complete solution as peptide treatment eventually causes toxicity, particularly in the liver. So, another way to slow NF-kB activity needs to be explored. Reducing NF-kB activity is tricky because as it has many important roles like regulate cell survival, inflammation and immunity, etc.

Verma said that in order to be more selective in the treatment, our aim is to find the handful of genes that directly affect tumor growth. On further experimentation, the researchers found that the gene Timp1 is influenced by NF-kB activity. When this gene is targeted in treatment, it also slowed tumor growth and increased survival time in mice by a few months.

Friedmann-Morvinski remarked that in the future they would focus on ways to reduce the toxicity of anti-NF-kB drug. Also, they would work to identify treatments that target NF-kB activity in a safe and effective way.

References:

https://medicalxpress.com/news/2016-01-scientists-key-driver-treatment-deadly.html

https://www.salk.edu/news-release/scientists-find-key-driver-for-treatment-of-deadly-brain-cancer/

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