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Are You a Magnet for Mosquitoes? – Scientific American
Posted: June 24, 2017 at 1:52 pm
When it comes to attraction, the allure can begin even before she sets eyes on you. There seems to be something about the way youher dinnersmells from afar that makes you a desired target. While you are chatting with friends or overseeing the barbecue, that mosquito will go on the hunt and make you her next blood meal. But what makes you so attractive to tiny ankle biters?
This month a group of British researchers is launching a new investigation into the role of human genetics in this process. They are planning to collect smelly socks from 200 sets of identical and nonidentical twins, place the footwear in a wind tunnel with the bugs and see what happens next. The owners of the socks, the scientists hope, may naturally produce attractive or repellant chemicals that could become the basis for future mosquito control efforts. The researchers expect that studying the popularity of the garments the skeeters hone in onand analyzing both the odor compounds in them and the genetics of their ownerscould help.The study, which will include 100 twins each from the U.K. and from the Gambia, will start recruiting volunteers in the coming weeks.
We know very little about the genetics of what makes us attractive to mosquitoes, says James Logan, a medical entomologist at the London School of Hygiene and Tropical Medicine who is leading the work. Earlier studies suggest visual, olfactory and thermal (body heat) cues all help drive mosquito attraction. We hope this study will give us more insights into the mechanisms that help change our body odors to make us more or less attractive to mosquitos, he says. If we can identify important genes, perhaps we could develop a pill or medication that would allow the body to produce natural repellents to keep mosquitoes away. The findings, he adds, could also help epidemiologists improve their models for how vulnerable certain populations may be to disease-carrying mosquitoes.
Already scientists know there are differences among us that contribute to why some of us get bitten more. Those of us who exhale more carbon dioxide seem to be a natural beacon for mosquitoes, in particular. Researchers have also found a correlation with body size, with taller or larger people tending to attract more bitesperhaps because of their carbon dioxide output or body surface area. There is also some evidence women who are pregnant or at certain phases of the menstrual cycle are more attractive to mosquitoes. Other work has found that people infected with malaria are more attractive to malaria-carrying mosquitoes during their transmissible stage of infection.
But what of our individual genetics? Two years ago Logans team published a small study looking at 18 sets of identical twins and 19 sets of nonidentical twins and their attractiveness to mosquitoes. They found that identical twins were more similar in their desirability to the blood-sucking insects than the nonidentical twins. Because earlier work had found that identical twins smell more alike than nonidentical twins, the British researchers surmised genes may play a role in this mosquito attractiveness.
This new study aims to nail down some more concrete conclusions with its larger sample size and add another population into the mix. (Most research in this area has focused on European Caucasians whereas this study will also include twins from the Gambia). There are other differences that set this apart from their earlier work, too: The 2015 study had tested attractiveness among Aedes mosquitoesthose that carry dengue and Zikawhereas this study will test attractiveness among Anopheles mosquitoes, a species that can transmit malaria. The team suspects the different species will be attracted to the same volatile compounds in human odor but wants to explore this further.
This is novel work and its a good step. It will tell us if there are genetic differences or not but it wont be a complete answer about mosquito attraction because other factors like diet, wind, time of day and mosquito species can all influence that, says Zainulabeuddin Syed, a professor of biological sciences at the University of Notre Dame who studies the smell-influenced behavior and movement of insects and is not involved in the Logan project. Syeds work has found that people of various ethnic groups all seem to produce four major volatile compounds (although at varying levels) and there are some early hints that one compound in particular, called nonanal, may be particularly attractive, at least among certain species of mosquitoes.
Exactly what genes contribute to producing compounds that could possibly interest mosquitoes remains a vast unknown. Scientists that study human odors and genetics have previously suggested scent cues associated with genetics are likely controlled via the major histocompatibility complex (MHC) genes. Those genes appear to play a role in odor production and also in mammals mating choicesbecause humans and mice alike appear to prefer mates that smell less similar to themselves, which scientists have theorized may be a natural control against inbreeding. As a result, Logans team may target those odor-linked genes, but he says they are looking at all the options. In the next couple of years, he says, they hope to have some early answers. For now, and likely for many years to come, we can only slather on some bug repellant and hope for the best.
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Here We Go Again: Why They Are Wrong About The Aryan Migration Debate This Time As Well – Swarajya
Posted: at 1:52 pm
It is a 2001 deja vu moment in 2017, as we saw the 1901 deja vu moment in 2001.
Michael Bamshad Does A Herbert Risley
In 2001, population geneticist Michael Bamshad of the Institute of Human Genetics, University of Utah, studied the genetic makeup of caste groups from Visakhapatnam district in Andhra Pradesh and compared them with various castes and regional groups of India as well as those in Africa, Asia and Europe. Then in his paper, he announced how the 'genetic distances' between castes correlated with social rank. The 'upper castes' were 'significantly more similar to Europeans' than the 'lower castes', he concluded.
Exactly a century before Bamshad, there was Sir Herbert Risley, commissioner for the 1901 census of India and honorary director of the Ethnological Survey of the Indian Empire, who had applied the nasal index to the castes. He had proved how Indian castes belonged to several racial categories from dark skinned, snubbed nose Dravidians to fair skinned Aryans with pronounced proboscis.
Doubts were raised from the Indian side, when Swami Vivekanandas brother B N Dutta challenged Risleys notion that higher castes had European noses. He simply used more data than Risley.
Later, in a detailed work on the origins of untouchability, Dr B R Ambedkar, the chief architect of the Constitution of India, questioned the methodology and conclusions of Western ethnography. Considering the colonial thesis that the so-called untouchables belonged to a different race from the caste Hindus, Dr Ambedkar made a profound statement. Even if one were to consider anthropometry as a science by which the race of a person could be established, he said, the data obtained "disprove that scheduled communities belonged to a race different from the rest of Hindu communities. The measurements prove that the Brahmin and the Untouchables belong to the same race."
So, did Bamshad in 2001, with Single Nucleotide Polymorphism in the place of nasal index, prove Risleys colonial ethnographic project of 1901 right and Dr Ambedkar wrong?
Interestingly, the story was immediately grabbed by popular science magazines as well as local media. Popular Tamil newspaper Dinamani wrote an article approvingly quoting Bamshads paper as Aryan invasion/migration theory being finally proved by science.
UK-based popular science magazine New Scientist presented the Bamshad paper with the sensational heading 'Written in blood'. It then quoted a pro-missionary scholar Robert Hardgrave as saying that there are 'some historical and archeological evidence' that the "Aryans came in, they intermarried with indigenous people and also absorbed many of them into their social system of ranking".
The Times of India newspaper reported the study with the prominent heading in its international section: 'Upper caste Indian male more European, says study'.
Frontline, the magazine from the Left-leaning The Hindu family of publications, in reporting the Bamshad paper announced sensationally: "New genetic evidence for the origins of castes indicates that the upper castes are more European than Asian. It took a potshot at 'strident nationalism' in the form of 'Hindutva' ideology, which rejects the premise that Aryans were outsiders." While conceding that the archeological evidence of marauding or migrating Aryans was wanting, the article declared "modern population genetics, based on analyses of the variations in the DNA in population sets, has tools" that could provide "a more authoritative answer". And that answer was that the Y-chromosomes of the 'upper caste' men had markers closer to Eastern Europeans than to the Asians.
One lone media voice that questioned the study was India Today. Labelling the Bamshad study 'controversial', an article in the publication drew parallel with the pseudoscientific racial study of Risley a century ago. The magazine quoted the famous archeologist Dilip Chakravarti, questioning the terminology used by the papers. The article cautioned readers against taking the paper as the final say on the matter. Soon, the Bamshad study was followed by another study in 2004. A team of six scientists, including Richard Cordaux of Max Planck Institute for Evolutionary Anthropology, studying the origin of the 'Hindu caste system' concluded that 'paternal lineages of Indian caste groups are primarily descended from Indo-European speakers who migrated from central Asia 3,500 years ago'.
Subsequent Studies Reject The Authoritative Answer
In 2003, Dr Toomas Kivisild and 17 other scientists published a paper, which studied both tribal and 'caste' populations. The paper reported that the "Haplogroup R1a, previously associated with the putative Indo-Aryan invasion, was found at its highest frequency in Punjab but also at a relatively high frequency (26 per cent) in the Chenchu tribe". This suggested that southern and western Asia might be the source of this haplogroup.
This study did not receive the media spotlight that Bamshad paper received. However, it did prove to be a turning point. Dr Gyaneshwer Chaubey, of Estonian Biocenter, who is an expert in the field of biological anthropology and evolutionary biology, says, "the paper is still true and that is the one which has enlightened me to move to population genetics from Drosophila genetics!" Dr Chaubey since then has been at the forefront of research work related to the peopling of South Asia and is co-author of almost all the important papers dealing with the subject.
Then in 2006, a major genetic study of the Indian population was taken up by a team of 12 scientists. The study produced results that contradicted the 2001 study of Bamshad et al. However, this too did not receive the media attention it deserved. The paper had concluded:
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Here We Go Again: Why They Are Wrong About The Aryan Migration Debate This Time As Well - Swarajya
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DNA: Definition, Structure & Discovery | What Is DNA?
Posted: at 1:51 pm
The structure of DNA and RNA. DNA is a double helix, while RNA is a single helix. Both have sets of nucleotides that contain genetic information.
Deoxyribonucleic acid or DNA is a molecule that contains the instructions an organism needs to develop, live and reproduce. These instructions are found inside every cell, and are passed down from parents to their children.
DNA is made up of molecules called nucleotides. Each nucleotide contains a phosphate group, a sugar group and a nitrogen base. The four types of nitrogen bases are adenine (A), thymine (T), guanine (G) and cytosine (C). The order of these bases is what determines DNA's instructions, or genetic code. Similar to the way the order of letters in the alphabet can be used to form a word, the order of nitrogen bases in a DNA sequence forms genes, which in the language of the cell, tells cells how to make proteins. Another type of nucleic acid, ribonucleic acid, or RNA, translates genetic information from DNA into proteins.
The entire human genome contains about3 billion bases and about 20,000 genes.
Nucleotides are attached together to form two long strands that spiral to create a structure called a double helix. If you think of the double helix structure as a ladder, the phosphate and sugar molecules would be the sides, while the bases would be the rungs. The bases on one strand pair with the bases on another strand: adenine pairs with thymine, and guanine pairs with cytosine.
DNA molecules are long so long, in fact, that they can't fit into cells without the right packaging. To fit inside cells, DNA is coiled tightly to form structures we call chromosomes. Each chromosome contains a single DNA molecule. Humans have 23 pairs of chromosomes, which are found inside the cell's nucleus.
DNA was first observed by a German biochemist named Frederich Miescher in 1869. But for many years, researchers did not realize the importance of this molecule. It was not until 1953 that James Watson, Francis Crick, Maurice Wilkins and Rosalind Franklin figured out the structure of DNA a double helix which they realized could carry biological information. Watson, Crick and Wilkins were awarded the Nobel Prize in Medicine in 1962 "for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material." [Related: Unraveling the Human Genome: 6 Molecular Milestones]
DNA sequencing is technology that allows researchers to determine the order of bases in a DNA sequence. The technology can be used to determine the order of bases in genes, chromosomes, or an entire genome. In 2000, researchers completed the first full sequence of the human genome.
Your DNA contains information about your heritage, and can sometimes reveal whether you're at risk for certain diseases. DNA tests, or genetic tests, are used for a variety of reasons, including to diagnose genetic disorders, to determine whether a person is a carrier of a genetic mutation that they could pass on to their children, and to examine whether a person is at risk for a genetic disease. For instance, mutations in the BRCA1 and BRCA2 genes are known to increase the risk of breast and ovarian cancer, and analysis of these genes in a genetic test can reveal whether a person has these mutations.
Genetic test results can have implications for a person's health, and the tests are often provided along with genetic counseling to help individuals understand the results and consequences of the test.
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DNA: Definition, Structure & Discovery | What Is DNA?
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What are DNA and Genes?
Posted: at 1:51 pm
DNA is all the same chemical
The stringy stuff in the test tube is DNA. But you can't tell which one of these organisms it came from just by looking at it. That's because DNA looks exactly the same in every organism on Earth.
All living things have DNA. And whether it comes from you, a pea plant, or your pet rat, it's all the same molecule. It's the order of the letters in the code that makes each organism different.
The order of building blocks in a strand of DNA makes up a "sequence." We can read a DNA sequence like letters in a book. In fact, we know the sequence of the entire human genomeall 3 billion letters. That's enough information to fill roughly 1,000 200-page books!
Contained within the 3 billion letters of the human genome are about 21,000 genes. Most of our known genes code for proteins, but some code for RNA molecules.
All humans have the same genes arranged in the same order. And more than 99.9% of our DNA sequence is the same. But the few differences between us (all 1.4 million of them!) are enough to make each one of us unique. On average, a human gene will have 1-3 bases that differ from person to person. These differences can change the shape and function of a protein, or they can change how much protein is made, when it's made, or where it's made.
APA format:
Genetic Science Learning Center. (2016, March 1) What are DNA and Genes?. Retrieved June 22, 2017, from http://learn.genetics.utah.edu/content/basics/dna
CSE format:
What are DNA and Genes? [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2016 [cited 2017 Jun 22] Available from http://learn.genetics.utah.edu/content/basics/dna
Chicago format:
Genetic Science Learning Center. "What are DNA and Genes?." Learn.Genetics.March 1, 2016. Accessed June 22, 2017. http://learn.genetics.utah.edu/content/basics/dna.
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What are DNA and Genes?
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Jellyfish fluorescence shines new light on DNA copying – Phys.Org
Posted: at 1:51 pm
June 23, 2017 The jellyfish glow helped focus laser beams on proteins. Credit: University of York
Scientists at the University of York have used florescent proteins from jellyfish to help shed new light on how DNA replicates.
Using these proteins, originally found in jellyfish to make them glow, the team where able to focus laser beams on the brightly lit proteins and track them inside a bacteria that normally lives inside the human gut.
This allowed scientists to watch the molecular machinery of DNA as it replicated inside a cell one molecule at a time. It revealed for the first time that only one component of this process, called DnaB helicase, remains stable - like a molecular anchor to the process.
In most cells, whether human or bacterial, a new cell is created after an existing cell divides in two. This means that a copy of the original sequence of genes coded in its DNA must be precisely copied and placed into the new cell.
This is thought to be a process that occurs slowly and methodically at set points in time. New research at the University of York, in collaboration with the University of Oxford and McGill University Canada, however, has now tracked this replication process in real-time and shown that it is far more dynamic than the textbooks suggest, occurring instead through a 'stuttering-like process' in short bursts.
Pioneering
Professor Mark Leake, Chair of Biological Physics at the University of York, said: "We pioneered a new method of light microscopy which allowed us to see this fascinating replication process occur molecule-by-molecule.
"We were surprised to find, however, that rather than the organised and methodical way that we expected this process to unfold, it instead happened in a 'stuttering' action, much like driving too slowly in high gear of a car. The big question, of course, was why the cell performs an essential process in such an unstable way?
"The stuttering action provide 'checkpoints' at various stages of the DNA copying process to make sure there is no errors made and, if there is, correct them before it is too late. This means that the cells can pause to fix an error in a small fragment of the DNA rather than attempt an unmanageable correction in one complete and huge strand of it.
"Although the process looks inelegant and almost random, it is actually highly efficient."
Human health
The process of DNA replication is fundamental to all life and the way errors in the process are resolved is especially important to human health. Errors can give rise to forms of cancer and become more prevalent in an ageing population.
This work will help scientists not only understand more fully the basic building blocks of life but potentially also provides new insights into a range of health conditions as well as even shedding new light on how human ageing can give rise to diseases associated with errors in copying the DNA from cell to cell.
Research was conducted using the DNA of Escherichia coli cell, bacteria, but However, the next stage of this research will investigate the same process in more complex cells, ultimately including those from humans.
The research, 'Frequent exchange of DNA polymerase during bacterial chromosome replication', was supported by the BBSRC and is published in the journal,eLife.
Explore further: Excessive DNA replication and its potential use against cancer
More information: Thomas R Beattie et al. Frequent exchange of the DNA polymerase during bacterial chromosome replication, eLife (2017). DOI: 10.7554/eLife.21763
Journal reference: eLife
Provided by: University of York
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Jellyfish fluorescence shines new light on DNA copying - Phys.Org
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From strands to dropletsnew insights into DNA control – Phys.Org
Posted: at 1:51 pm
June 23, 2017 by Bennett Mcintosh A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Credit: NHGRI
A host of proteins and other molecules sit on the strands of our DNA, controlling which genes are read out and used by cells and which remain silent. This aggregation of genetic material and controlling molecules, called chromatin, makes up the chromosomes in our cell nuclei; its control over which genes are expressed or not is what determines the difference between a skin cell and a neuron, and often between a healthy cell and a cancerous one.
Parts of the genome are only loosely coiled in the nucleus, allowing cells to access the genes inside, but large sections are compacted very densely, preventing the genes form being read until their region of the genome is unfolded again. These compacted regions, known as heterochromatin, are formed by a protein known as HP1 and similar proteins, but exactly how HP1 segregates this off-limits DNA from the rest of the nucleus has been largely a mystery, until now.
In a new study by UC San Francisco researchers published in the journal Nature on June 22, 2017, what looked at first like a failed experiment instead revealed the intriguing possibility that HP1 binds to stretches of DNA and pulls it into droplets that shield the genetic material inside from the molecular machinery of the nucleus that reads and translates the genome.
"This provides a very simple explanation for how cells prevent access to genes," said Geeta Narlikar, PhD, professor of biochemistry and biophysics and senior author of the study.
'Bad News' Led to New Discovery
Narlikar's graduate student Adam Larson was trying to purify HP1, and noticed that the liquid in his samples was growing cloudy. For protein scientists, this is typically bad news, said Narlikar: it suggests that proteins that should dissolve in water are instead clumping together into a useless mass.
But Larson thought the clumps might actually be useful. After all, previous work had shown that the role of HP1 is to sequester long strands of DNA into very small volumes. What if this was exactly the sort of clumping he was seeing in the tube?
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Larson took his samples to the lab across the hall from Narlikar's, where Roger Cooke, PhD, professor emeritus of biochemistry and biophysics, helped him examine under the microscope what could have been just a tangled molecular mess. Instead, Larson and Cooke saw clouds of delicate droplets floating around in the water, like a freshly shaken mix of oil and vinegar.
HP1 had a reputation as a difficult protein to work with get any solution too concentrated, and the protein would clump out. But if the protein was supposed to clump, said Narlikar, "a lot of things we couldn't explain started to make sense."
Narlikar speculates that other scientists may have seen the same cloudiness before, but thinking it was simply a ruined sample, never pursued it like Larson did. "It demonstrates the power of curiosity-driven research," she said.
Rapidly Compacting DNA
To see how and why the HP1 formed droplets, the team produced different mutant versions of the protein, watching which separated out. By watching which parts of the protein were important for forming droplets, and using X-rays to monitor changes in the protein's shape, the team found that the protein nearly doubles in length when small phosphate residues are added in cetain locations. "The molecule literally opens up," said Narlikar. "I was surprised at the size of the change."
This opening-up exposes electrically charged regions of the protein, which stick together, turning dissolved pairs of proteins into long chains that clump together into droplets. Just as balsamic vinegar's dark and flavorful molecules don't seep into the oil of a salad dressing without some extra effort by the chef, the molecules for reading DNA don't seep into the HP1 droplets.
The fact that such a drastic change in shape comes from such a small modification may allow the cell to tightly regulate where and when HP1 silences genes, said Narlikar. The changes come quickly and robustly too using a technology employed by Sy Redding, PhD a Sandler Fellow, the team created a "curtain" of DNA molecules pulled straight by fluid flowing around them, then added HP1 and watched the protein compress the DNA into tiny droplets, folding it up against the flow.
"People have been seeing for over a hundred years that you get these dense regions of DNA in the nucleus," said Madeline Keenen, the Ph.D. student who ran the curtain experiment. "Now we're seeing the actual mechanism."
Explore further: Researchers find new mechanism for genome regulation
More information: Adam G. Larson et al. Liquid droplet formation by HP1 suggests a role for phase separation in heterochromatin, Nature (2017). DOI: 10.1038/nature22822
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From strands to dropletsnew insights into DNA control - Phys.Org
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Dead Wilmington woman’s DNA found in Bradley’s truck – News … – StarNewsOnline.com
Posted: at 1:51 pm
James Opelton Bradley is charged with first-degree murder in the presumed death of his missing coworker, Shannon Rippy Van Newkirk, who vanished April 5, 2014.
WILMINGTON -- DNA, computer searches and letters written from jail by the defendant were presented to the jury in the ninth day of testimony Friday in the murder trial of James Opelton Bradley.
Bradley, 54, of Wilmington is charged with first-degree murder in the presumed death of his missing coworker Shannon Rippy Van Newkirk, 53, of Wilmington, who vanished April 5, 2014.
Investigators testified Bradley told police three different stories in the days after Van Newkirk went missing -- initially denying he saw her on the day she was last seen and then ultimately saying he'd picked her up from her house that day. When a discussion they were having became "heated," she ran from his truck near Greenfield Lake, investigators said Bradley told them.
Three weeks later, when police searched land in Hampstead owned by Bradleys employer, they unearthed the body of Elisha Tucker, 33, another missing Wilmington woman whod last been seen in August 2013. Despite the fact that Van Newkirks body was never been found, Bradley is being tried in her presumed death.
A trial in Tuckers killing has yet to be set, but prosecutors said they will seek the death penalty in that case. Bradley has a previous murder conviction for killing his 8-year-old stepdaughter in 1988. The jury learned of that prior conviction after the prosecution successfully argued it be admissible.
On Friday, Sharon Hinton, a DNA analyst with the N.C. State Crime Laboratory, told the jury that she was unable to locate Van Newkirks DNA on any of the items she tested from Bradleys apartment or vehicle.
But, Hinton said, she was able to extract a full DNA profile for Elisha Tucker from at least one stain from the carpet padding in Bradleys Chevy Tahoe. The probability of it being anyone else's DNA other than Tucker's was 1 in 359 trillion, she said. That stain, however, did not test positive for blood.
FBI computer examiner Rich Novelli testified that on April 20, 2014 -- four days after his last interview with police -- Bradley searched online for information on cellphone pinging and visited a webpage that explained how cellphones are tracked. Novelli said Bradley also searched for the StarNews.
Additionally, Jurors each read a copy of two letters. One was addressed to a relative's daughter and the other was to a friend. The contents of the letters were not discussed before court took an early recess.
Testimony in the case resumes Monday.
Reporter F.T. Norton can be reached at 910-343-2070 or Fran.Norton@StarNewsOnline.com.
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Whole-Genome Study Shows IGF1R Inhibitors May Help Some Osteosarcoma Patients – Genetic Engineering & Biotechnology News
Posted: at 1:50 pm
Researchers report in Nature Communications (Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma) that a genetic sequencing study has revealed that some patients with osteosarcoma could be helped by an existing drug.
The team, from the Wellcome Trust Sanger Institute, University College London Cancer Institute, and the Royal National Orthopedic Hospital NHS Trust, that 10% of patients with a genetic mutation in particular growth-factor-signaling genes may benefit from IGF1R inhibitors.
The results, the scientists say,suggest a re-trial of IGF1R inhibitors for the subset of patients with osteosarcoma who are likely to respond based on their genetic profile.
The current treatment for osteosarcoma is chemotherapy followed by surgery, where the bone tumors are removed. There has not been a new treatment for osteosarcoma in almost 40 years.
In the study, investigators analyzed the genome of 112 childhood and adult tumorsdouble the number of tumors studied previously. In 10% of cases, the team discovered cancer-causing mutations in insulin-like growth factor (IGF) signaling genes.IGF signaling plays a major role in bone growth and development during puberty. Researchers believe that IGF signaling is also implicated in the uncontrolled bone growth that is characteristic of osteosarcoma.
IGF signaling genes are the target of IGF1R inhibitors. Past clinical trials of IGF1R inhibitors as a treatment for osteosarcoma yielded mixed results, although occasionally patients responded to therapy. IGF1R inhibitors have not been further tested in osteosarcoma, as it had been unclear which patients would benefit from the treatment.
"Osteosarcoma is difficult to treat, notes Sam Behjati, Ph.D., first author from the Wellcome Trust Sanger Institute and University of Cambridge. Despite extensive research over the past 40 years, no new treatment options have been found. In this study, we reveal a clear biological target for osteosarcoma that can be reached with existing drugs."
In the study, scientists looked for mutations in the tumors to understand the mechanism of osteosarcoma development. The genetic information revealed a specific process for rearranging the chromosomes that results in several cancer-driving mutations at once.
In a whole-genome study of osteosarcoma, structural variants were identified as a major source of driver mutation. Some of these variants occurred in the context of chromothripsis, the shattering of chromosomes resulting in copy number oscillations, wrote the researchers. Using whole-exome sequencing combined with copy number arrays, Kovac et al. described genomic alterations in osteosarcoma indicative of compromised homology-directed DNA repair.
"We have unpicked the mechanism behind osteosarcoma for the first time, adds Adrienne Flanagan, Ph.D., senior author from the Royal National Orthopedic Hospital NHS Trust and University College London Cancer Institute. We discovered a new processchromothripsis amplificationin which the chromosome is shattered, multiplied, and rejigged to generate multiple cancer-driving mutations at the same time. We believe this is why we see very similar osteosarcoma tumors in children and adults, which are not the result of aging."
"Currently, there are no new osteosarcoma treatments on the horizon, says Peter Campbell, M.D., Ph.D., lead author from the Wellcome Trust Sanger Institute. Genomic sequencing has provided the evidence needed to revisit clinical trials of IGF1R inhibitors for the subset of patients that responded in the past. The mutations of patients' tumors may enable clinicians to predict who will, and will not respond to these drugs, resulting in more efficient clinical trials.
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‘Scandal’ actress Katie Lowes opens up about psoriasis – WATE 6 On Your Side
Posted: at 1:49 pm
KNOXVILLE (WATE) Quinn Perkins, played by Actress Katie Lowes is one tough cookie on the show Scandal, but she is also tough in real life.
Lowes has lived with a chronic autoimmune disease known as psoriasis for the past eight years. She says she was diagnosed with psoriasis eight years ago but finally decided to go public with her experiences in the hopes of helping others.
When I was first diagnosed I was so embarrassed and ashamed. You know, being an actress in Hollywood, there is such a pressure to look a certain way and after living with it for eight years, says Lowes, Im really living my best life and I thought there are 7.5 million other Americans living with this disease and if I can help even one of them feel inspired to be there own best advocate to get to a place where they are living their fullest life and theyre not limiting themselves because of psoriasis, then that would just be a huge win.
The actress is partnering with Jansen and the National Psoriasis Foundation on a campaign called Inside Story. She shares her story about living with psoriasis and encourages others to do the same.
While on the set of Scandal, Lowes said there were times when she had flare-ups. She said there were times when she couldnt wear a certain red carpet look or wear a bathing suit on vacation.
There are all these limitations placed on your life and I know from personal experience it can be so upsetting and you can feel so alone, but with 7.5 million people living with this disease, you are not, said Lowes. This site is a wonderful tool that people struggling with psoriasis can use to their benefit because I want people to feel, you know, that we are a large community that we support each other. I want to encourage people to find a doctor they can trust, to find a treatment that works for them and I just want people to know that it is possible to get to a place where youre not limiting fashion and style and being with our family and things like that.
Lowes appears on the final season of Scandal which airs Thursdays on WATE 6 On Your Side. When asked if she knows how the show will end, Lowes said she is under lock-and-key.
We are not allowed to say anything, but I can assure you that this will be the final season of Scandal and the writers are leaving it all on the dance floor and it is going to be a wild and crazy ride for sure.
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ALS/FTD Genes Reveal Pathways to Pathology – Alzforum
Posted: at 1:48 pm
24 Jun 2017
Two new papers show how rare genetic mutations are helping scientists understand more about the processes that go wrong in the amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum. A hallmark of these diverse conditions is the abnormal clumping of the nuclear protein TDP-43 in the cytoplasm. In the June 6 Nature Communications, researchers led by David Kang, University of South Florida, Tampa, reported that mutations in the mitochondrial protein CHCHD10 induced TDP-43 translocation from the nucleus to the cytoplasm and poisoned mitochondria and synapses. In a second paper, Yongchao Ma and colleagues from Northwestern University Feinberg School of Medicine, Chicago, debut a new ALS gene, UBQLN4, identifying a variant in a woman with familial ALS. Their paper, published May 2 in eLIFE, shows that the D90A substitution in the ubiquilin impairs proteasome function and causes abnormal sprouting and branching of motor axons in model systems. The results further highlight the role of protein homeostasis in neuronal health and disease.
Kangs intriguing work suggests that wild-type CHCHD10 maintains TDP-43 nuclear localization and protects against TDP-43 toxicity, while disease-related mutations of CHCHD10 have opposite, damaging effects, said Ronald Klein, Louisiana State University Health in Shreveport. The work also adds significantly to the importance of mitochondrial function in neurodegenerative diseases, Klein wrote in an email toAlzforum.
The discovery, just over two years ago, of mutations in the mitochondrial protein CHCHD10 (short for coiled-coil-helix-coiled-coil-helix domain containing protein 10) in several families with amyotrophic lateral sclerosis/ frontotemporal dementia (ALS-FTD) suggested for the first time that dysfunction in the organelles, the cells power plants, could cause motor neuron disease (see Jun 2014 newsand Oct 2014 news).Scientists know little about the function of CHCHD10, which sits inside the mitochondria as part of a protein complex that stabilizes cristae, the organelles membrane folds. In patients with ALS-associated CHCHD10 mutations, mitochondria appear disorganized and dysfunctional (Genin et al., 2015).
Kang set out to understand how CHCHD10 mutations affect protein function, and whether they also impact TDP-43 accumulation and toxicity. To get at those issues, the researchers first turned to the roundworm Caenorhabditis elegans, whose single CHCHD10 homolog, har-1, includes both the arginine-15 (R15) and serine-59 (S59) residues that are mutated in ALS/FTD. Co-first author Courtney Trotter found that har-1 knockouts developed movement problems similar to those seen in worms overexpressing TDP-43. The animals crawled more slowly on an agar plate, and curled up when dropped in liquid, rather than thrashing about like wild-type worms. Their mitochondria appeared to be in poor health. They produced more superoxide than mitochondria from normal worms. Introducing a human CHCHD10 transgene into the har-1 knockouts completely normalized their behaviorthe transgenic worms crawled and swam normally, and their mitochondrial superoxide hovered at control levels. In contrast, human CHCHD10 bearing either the R15L or S59L mutation did not compensate at all, suggesting that the mutations caused a loss of CHCHD10function.
As the two other first authors, Jung-A. Woo and Tian Liu, worked their way through studies on mammalian cells, primary neurons, and finally mouse brains in vivo, they saw the same pattern. Loss of CHCHD10 function, either by knockdown or by overexpression of mutated protein, spelled trouble for mitochondria, disrupting their structure, increasing superoxide production, and causing expression of mitochondrial genes to decrease by half. In primary mouse hippocampal neurons, CHCHD10 mutant expression led to a 50 percent reduction in synaptic markers drebrin and synatophysin as visualized by confocal microscopy. All told, the results suggest the loss of CHCHD10 function in these models poisons mitochondria and zaps synapses.Does any of this affect TDP-43? In the primary neurons, TDP43 exclusively localized to the nucleus, but after knockdown of CHCHD10 or expression of the mutants, a fraction of the TDP-43 moved to the cytoplasm, reaching as far as neuritic processes. Expression of CHCHD10 mutants doubled the cytosol/nuclear ratio of TDP-43 over that seen in wild-type cells. Recent work suggests TDP-43s toxicity stems from its localization to mitochondria (Jul 2016 news). Indeed, under the influence of CHCHD10 mutants, nearly half of the cytosolic TDP-43 deposited inmitochondria.
TDP-43 (red) normally resides in the nucleus but in NIH3T3 mouse fibroblasts expressing R15L or S59L CHCHD10 mutations (second and third rows), it leaches into the cytoplasm, where it localizes with the mitochondrial outer membrane protein TOM20 (green). [Courtesy of DavidKang.]
The CHCHD10 variants also enhanced TDP43 toxicity. Adenovirus-mediated expression of TDP-43 in the brains of young mice caused synaptic markers to drop by 50 and 39 percent in the dentate gyrus and CA3 region of the hippocampus, respectively. Co-expression of CHCHD10 prevented the decline, and expression of either mutant exacerbated it. The results establish that CHCHD10 mutations influence toxicity of TDP43 in neurons, however, the researchers have yet to test this in motor neurons or cortical neurons, the cell types affected in ALS orFTD.
While the work connects CHCHD10 to TDP-43, many questions remain. How does CHCHD10 influence where TDP-43 localizes, and why do the mutations cause TDP-43 to appear in the cytoplasm? Co-immunoprecipitation hinted that CHCHD10 and TDP-43 physically associate, but that mutations do not disrupt this interaction. We have to work out the details, Kang said, noting that their next studies will focus on the mechanisms of CHCHD10 and TDP-43 translocations and theirregulation.
The second report details how a newly discovered ALS variant in UBQLN4 disrupts a different and equally fundamental homeostatic mechanismthe regulated recycling of proteins via the ubiquitin proteasome system. Ubiquilins deliver proteins to the proteasome. UBQLN1 and UBQLN2 are linked to Alzheimers disease and FTD/ALS, but this is the first time UBQLN4 variants have been linked to disease. Ma worked with coauthor Teepu Siddique, whose lab identified the variant through targeted gene sequencing in 267 familial and 411 sporadic ALS cases. One patient carried the single amino acid change, from aspartate to alanine at position 90. None of 332 in-house controls, or more than 60,000 people in a sequencing consortium database, had the change, suggesting it may be the pathogenicvariant.
To test this, first author Brittany Edens expressed wild-type or D90A UBQLN4 in cultured mouse spinal cord neurons, and found the mutant increased neurite number. In zebrafish embryos, the mutant induced abnormal motor neuron branching as well. These morphological effects accompanied inhibition of the proteasome and upregulation of -catenin, one of UBQLN4s target proteins and an important regulator of neuronal development. Treatment with the -catenin inhibitor quercetin reversed the mutant effects on morphology in neurons andzebrafish.
This is an interesting first report linking UBQLN4 to ALS, said Lihong Zhan of the University of California, San Francisco, who was not involved with the work. Zhan told Alzforum hed like to see how the mutation behaves in models more relevant to ALS, such as age-related neuron death. Ma agreed that the models are mainly developmental, but considers them still relevant for ALS, as early life events may render the neurons vulnerable later. The models used in the study were short-term expression systems; Ma told Alzforum they are now working on additional models that will enable a more thorough examination of the mutants impact across the lifespan. He hopes that -catenin, or other substrates of UBQNL4, could become useful therapeutic targets in ALS.Pat McCaffrey
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