Cell Biology

Investigational drugs block bone loss in mice receiving chemotherapy – Mirage News

Bone loss that can lead to osteoporosis and fractures is a major problem for cancer patients who receive chemotherapy and radiation. Since the hormone estrogen plays an important role in maintaining bone health, bone loss is especially pronounced among postmenopausal women with breast cancer who are treated using therapies aimed at eliminating estrogen.

Men and children treated for other cancers also experience bone loss, suggesting that eliminating estrogen is not the only trigger leading to bone degeneration.

Studying mice, researchers from Washington University School of Medicine in St. Louis have found a driver of bone loss related to cancer treatment. They have shown that radiation and chemotherapy can halt cell division in bone, which results in a stress response referred to as senescence. According to the new study, cell senescence drives bone loss in female mice beyond that seen from the absence of estrogen alone. The researchers further found that this process occurs in males and females and is independent of cancer type. And perhaps most importantly, the researchers showed that such bone loss can be stopped by treating the mice with either of two investigational drugs already being evaluated in clinical trials.

The study appears Jan. 13 in Cancer Research, a journal of the American Association for Cancer Research.

Researchers have understood that this bone loss has to be due to more than just hormone loss, said senior author Sheila A. Stewart, professor of cell biology & physiology. Cancer patients who receive chemotherapy and radiation lose a lot more bone than women with breast cancer treated with aromatase inhibitors, which eliminate estrogen. And children who have not yet gone through puberty, and arent making much estrogen, also lose bone. We wanted to understand what causes bone loss beyond a lack of estrogen and whether we can do anything to stop it.

Stopping bone loss could improve quality of life for cancer patients. Bone loss leads to an increased risk of fractures that continues many years after treatment. This loss of bone density makes it much more likely that patients will develop fractures in the pelvis, hips and spine, which affect mobility and increase the risk of death.

The researchers studied bone loss in mice treated with two common chemotherapy drugs doxorubicin and paclitaxel as well as in mice that received radiation to one limb, to understand whether the bone loss effects were similar in different types of cancer therapies. In all situations, the treatments induced the process of cellular senescence.

Senescence is a chronic stress response in a cell that stops it from dividing and also results in the release of many molecules, some of which we showed drive bone loss, said Stewart, who is also the associate director for basic sciences at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

The cells in mouse bones that were most affected by the cancer therapies included those responsible for bone remodeling. These are sets of cells that strike a vital balance between dismantling old bone and building new bone in its place. This balance is disturbed in conditions such as osteoporosis, in which the bone-building cells can no longer keep up with the bone-dismantling cells. The new study suggests that the balance is even more off-kilter following cancer therapy: Bone-building cell activity slows down, and the activity of cells that remove old bone actually accelerates.

The researchers showed they could prevent bone loss in the mice if they took steps to remove the cells that are no longer dividing, thus eliminating the molecular signals that the cells produce that drive bone loss. Toward possible therapies, Stewart and her colleagues then showed they could achieve a similar effect with two different types of compounds that block these molecular signals.

The investigational drugs, a p38MAPK inhibitor and a MK2 inhibitor, block different parts of the same pathway leading to bone loss. Stewart and her colleagues also published a study in 2018 showing that the two inhibitors slowed the growth of metastatic breast cancer in mice. The p38MAPK inhibitor is being tested in U.S. clinical trials for inflammatory diseases, such as chronic obstructive pulmonary disease (COPD). And the MK2 inhibitor is about to be evaluated as a therapy for rheumatoid arthritis.

Cancer patients at risk of bone loss often are treated with drugs for osteoporosis, including bisphosphonates and denosumab. Both have some undesirable side effects, such as muscle and bone pain and, because of the way they work, they may be less desirable for children whose bones are still growing.

The inhibitors we studied have extremely low toxicity, so we are interested in exploring whether they could be an improved option to stop bone loss in children receiving cancer therapy, Stewart said. Were also interested in pursuing a clinical trial to evaluate these drugs in women with metastatic breast cancer to see if we can slow metastatic growth and also preserve bone health in these patients.

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Investigational drugs block bone loss in mice receiving chemotherapy - Mirage News

Cell Biology

Clever Decoy That Neutralizes Viruses Points Way to Treat Viruses That Cross From Animals to Humans – SciTechDaily

The active part of Arenacept is shown as a rainbow-colored ribbon bound to the receptor-binding domain of Macho virus (grey surface representation). Credit: Weizmann Institute of Science

A host of disease-causing viruses called arenaviruses lurk in animal populations in various parts of the world, sometimes crossing over into humans. When they do cross over, they can be lethal, and only very few treatments exist. Researchers led by scientists at the Weizmann Institute of Science have now devised a clever decoy for these viruses that may keep them from spreading in the body.

Two disease-causing arenaviruses, known as Junn and Machupo, circulate through rodent populations, mainly in South America, and they can infect humans when people come in contact with affected rodents. Similar to Ebola, these diseases can cause the body to bleed out, and the only treatments, to date, are risky and complex, as they are taken from the blood of survivors.

The present study, which was reported in the journal Nature Communications on January 3, 2020, arose from an earlier research question in the group of Dr. Ron Diskin of the Institutes Structural Biology Department: how are certain arenaviruses able to move from rodents or other animals into humans? Comparing these viruses with members of the arenavirus family that are not infectious to humans, the researchers noted that the non-infectious viruses did not completely fit a particular receptor a protein complex on the cell membrane that serves as a viral entry point into human cells. But curiously, those that do infect humans were also not a perfect fit. They were just good enough to get by.

This observation led to another insight: Maybe the rodent cell receptors, which were a much better fit to the entry proteins on the viruses, could be used to intercept the viruses and lure them away from the human cells. There had been earlier attempts to develop such decoys sticky molecules designed to attract virus proteins explains Diskin, but these were based on the structures of human receptors, so they were identical to the ones on the bodys cells and thus unable to compete effectively. In contrast, a molecule based on a rodent receptor, he and his team reasoned, could far outcompete the human ones for binding to the virus.

Dr. Hadas Cohen-Dvashi, in Diskins group, led the next stage of the research, in which she surgically removed the very tip of the rodent receptor to which the virus binds and engineered it onto part of an antibody. The newly resulting molecule was called Arenacept.

Then the group began testing this molecule at first against pseudoviruses, engineered virus-like complexes which carry the entry proteins but that are not dangerous. Already at this stage, and in collaboration with the group of Dr. Vered Paler-Karavani of Tel Aviv University, the researchers noted that Arenacept not only bound strongly to the viruses, it recruited parts of the immune system to mount an attack against the viral invasion.

The next stages of testing took place in labs in the University of Texas, Galveston, USA, and in the Pasteur Institute, Lyon, France, which are equipped to test pathogens at the highest safety levels (BSL-4). Here, Arenacept was pitted against human receptors in lab tests simulating attacks by two of the real pathogenic viruses the Junn and Machupo viruses.

The researchers found Arenacept to be highly effective at sticking strongly to the viruses before these viruses could bind to the human receptors, and as with the pseudoviruses, they noted the activation of the immune response.

Because Arenacept is based on the entry point shared by all viruses in a given family, rather than on individual characteristics of each virus (as is the case with vaccines or antibodies), it should be equally effective against all the viruses in this family that cross to humans from animals and for that utilize the same receptor. It might even be effective against viruses from the same family that have not yet been discovered or newly-emergent ones, says Diskin.

All signs suggest Arenacept is non-toxic, and that it is also heat-resistant and stable, meaning it could be delivered to the remote areas where these diseases are endemic, he says. And the idea of creating decoys from mammal receptors might be applied to all sorts of other diseases that cross to humans from animals. Yeda Research and Development, the technology transfer arm of the Weizmann Institute of Science, has received a patent for Arenacept and is working with Diskin to advance clinical research.

Reference: Rational design of universal immunotherapy for TfR1-tropic arenaviruses by Hadas Cohen-Dvashi, Ron Amon, Krystle N. Agans, Robert W. Cross, Aliza Borenstein-Katz, Mathieu Mateo, Sylvain Baize, Vered Padler-Karavani, Thomas W. Geisbert and Ron Diskin, 3 January 2020, Nature Communications.DOI: 10.1038/s41467-019-13924-6

Also participating in this research were Aliza Borenstein-Katz of the Weizmann Institute of Science; Ron Amon of Tel Aviv University; Krystle N. Agans, Robert W. Cross and Thomas W. Geisbert of the University of Texas; and Mathieu Mateo, Sylvain Baize of the Pasteur Institute.

Dr. Ron Diskins research is supported by theMoross Integrated Cancer Center; theDr. Barry Sherman Institute for Medicinal Chemistry; theJeanne and Joseph Nissim Center for Life Sciences Research; and the estate of Emile Mimran.

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Cell Biology

Douglas Hanahan Appointed Distinguished Scholar of the Ludwig Institute for Cancer Research – Newswise

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Newswise JANUARY 14, 2020, New York Ludwig Cancer Research is pleased to announce the appointment of Douglas Hanahan as a Distinguished Scholar at the Lausanne Branch of the Ludwig Institute for Cancer Research. A pioneering molecular biologist and renowned cancer researcher, Hanahan has made several seminal discoveries in cancer biology and immunology over the course of his career.

Everybody working in cancer research today knows of Dougs iconic work, since much of it has had a profound influence on the field, said Chi Van Dang, scientific director of the Ludwig Institute. He continues to do outstanding, multidisciplinary research, providing significant insights into mechanisms of cancer progression and the tumor microenvironment. Ludwig researchers will benefit enormously from the insights and mentorship of such an accomplished scientist. We couldnt be happier to have him on board.

While still a Harvard graduate student working at the Cold Spring Harbor Laboratory in New York in the 1970s, Hanahan developed new and more efficient methods for gene cloning and bacterial genetic engineering. After earning his PhD, Hanahan stayed on at Cold Spring Harbor and by the late 1980s had developed among the first mouse models engineered to develop cancers in specific organs. He went on to use these models to examine the stages by which precancerous cells progress to invasive malignancies, the role cancer genes play in this transformation and the immune systems response to cells bearing novel mutations associated with cancers.

In collaboration with the late Judah Folkman, Hanahan identified in these mouse models the angiogenic switcha defined step in which the new blood vessels absolutely required for solid tumor growth are induced in the early stages of tumorigenesis. He and Folkman subsequently explored the pharmacological inhibition of that step, work that ultimately contributed to the development of anti-angiogenic drugs for cancer therapy.

Hanahan is also noted for his co-authorship with Ludwig MIT Director Robert Weinberg of The Hallmarks of Cancer, a landmark perspective on cancer biology published in Cell in 2000, as well as an update the pair published in the journal in 2011. Their essay drew from all corners of the sprawling field of cancer biology to create a unifying conceptual framework for understanding tumor initiation and progression, identifying a handful of capabilities cells must acquire to become malignant. The papers, which remain among the most influential publications in modern cancer biology, have shaped efforts to develop new cancer therapies.

Hanahans lab today continues to unravel the stages and drivers of tumor progression and investigate pharmacologic strategies to disrupt each step of the process. It also explores how the tumor microenvironment contributes to drug resistance, with a focus on its role in thwarting immune clearancea phenomenon that is being investigated from multiple angles by researchers at Ludwig Lausanne.

Working with me over the past seven years, Doug played an important part in making the Swiss Cancer Center in the Lemanic region a reality, and he is more than familiar with our goals and plans at the Lausanne Ludwig Branch, said Ludwig Lausanne Director George Coukos. His experience and scientific creativity will be of immeasurable value to the researchers here and, I expect, across the Ludwig organization.

Hanahan, who earned his bachelors degree in physics from MIT and his PhD in biophysics from Harvard in 1983, has been widely recognized for his contributions to cancer biology. He received the Lifetime Achievement Award from the American Association for Cancer Research (AACR) in 2014 and is an elected member of the American Academy of Arts & Sciences, the U.S. National Academies of Science and of Medicine, the AACR Academy and the European Molecular Biology Organization.

In addition to his Ludwig Distinguished Scholar appointment, Hanahan is currently Professor and Director of the Swiss Institute for Experimental Cancer Research within the School of Life Sciences at EPFL, the Swiss Federal Institute of Technology Lausanne and Co-director of the new multi-institutional Swiss Cancer Center Leman.

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for 48 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www.ludwigcancerresearch.org.

For further information please contact Rachel Reinhardt, rreinhardt@lcr.org or +1-212-450-1582

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Douglas Hanahan Appointed Distinguished Scholar of the Ludwig Institute for Cancer Research - Newswise

Biochemistry

Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells | DDDT – Dove Medical Press

Ziqian Wang, 1, 2 Tuo Tang, 1, 2 Shengnan Wang, 1, 2 Tianyu Cai, 1, 2 Hong Tao, 1, 2 Qing Zhang, 1, 2 Shimei Qi, 1, 2 Zhilin Qi 1, 2

1Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu, Anhui 241002, Peoples Republic of China; 2Anhui Province Key Laboratory of Active Biological Macro-Molecules, Wannan Medical College, Wuhu, Anhui 241002, Peoples Republic of China

Correspondence: Zhilin QiDepartment of Biochemistry and Molecular Biology, Wannan Medical College, 22 Wenchang West Road, Wuhu, Anhui 241002, Peoples Republic of ChinaEmail 422627721@qq.com

Background: Aloin has been reported to have many pharmacological effects including anti-inflammatory, anti-oxidant and anti-tumour activities. However, the precise molecular mechanisms underlying the anti-tumour properties of aloin are yet to be elucidated.Methods: HGC-27 and BGC-823 gastric cancer cells were treated with aloin. EdU and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using wound healing and transwell assays. Western blotting was used to detect the levels of cyclinD1, cyclin E1, MMPs, N-cadherin, E-cadherin and NOX2. The phosphorylation of Akt, mTOR, P70S6K, S6, Src, stat3 and IB were also detected by Western blotting. Flow cytometry was used to detect the cell cycle distribution.The location of p65 in cells was determined by using a confocal microscopy assay. The total amounts of ROS present in cells were measured using an ROS assay kit.Results: Here, we found that aloin inhibited the proliferation and migration of HGC-27 and BGC-823 gastric cancer cells using a combination of EdU, colony formation, wound healing and transwell assays. Further investigations revealed that aloin decreased the protein expression levels of cyclin D1, N-cadherin, and the matrix metalloproteinases (MMP)-2 and MMP-9; increased E-cadherin expression in a dose-dependent manner; inhibited reactive oxygen species (ROS) generation; and mediated the activation of Akt-mTOR, signal transducer and activator of transcription-3 (Stat3), and NF-B signalling pathways. Our results also indicated that aloin is able to attenuate the expression levels of the two regulatory proteins of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), p47phox and p22phox, but had no effect on the level of gp91phox. N-acetylcysteine treatment of gastric cancer cells inhibited ROS production and Akt-mTOR, Stat3, and IB phosphorylation. Taken together, our data suggest that aloin inhibits the proliferation and migration of gastric cancer cells by downregulating NOX2ROS-mediated activation of the Akt-mTOR, Stat3, and NF-B signalling pathways.Conclusion: Our findings suggest a potential role for aloin in the prevention of gastric cancer cell proliferation and migration and provide novel insights into the anti-cancer properties of aloin.

Keywords: aloin, gastric cancer, proliferation, migration, nicotinamide adenine dinucleotide phosphate oxidase 2, reactive oxygen species

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells | DDDT - Dove Medical Press

Biochemistry

Antibiotics Could Be Promising Treatment for Form of Dementia – UKNow

LEXINGTON, Ky. (Jan. 10, 2020)Researchers at the University of Kentuckys College of Medicine have found that a class of antibiotics called aminoglycosides could be a promising treatment for frontotemporal dementia.

Results of their proof of concept study, which was a collaborative effort between UKs Department of Molecular and Cellular Biochemistry and the University of California San Franciscos Department of Pathology, were recently published in the journal,Human Molecular Genetics.

Frontotemporal dementia isthe most common type of early onset dementia. It typically begins between ages 40 and 65 and affects the frontal and temporal lobes of the brain, which leads to behavior changes, difficulty speaking and writing, andmemory deterioration.

A subgroup of patients with frontotemporal dementia have a specific genetic mutation that prevents brain cells from making a protein called progranulin. Although progranulin is not widely understood, its absence is linked to the disease.

A group led by Haining Zhu, a professor in UKs Department of Molecular and Cellular Biochemistry, discovered that after aminoglycoside antibiotics were added to neuronal cells with this mutation, the cells started making the full-length progranulin protein by skipping the mutation.

These patients brain cells have a mutation that prevents progranulin from being made. The team found that by adding a small antibiotic molecule to the cells, they could trick the cellular machinery into making it, said Matthew Gentry, a co-author of the study and the Antonio S. Turco Endowed Professor in the Department of Molecular and Cellular Biochemistry.

The researchers found two specific aminoglycoside antibiotics - Gentamicin and G418 - were both effective in fixing the mutation and making the functional progranulin protein. After adding Gentamicin or G418 molecules to the affected cells, the progranulin protein level was recovered up to about 50 to 60%.

These results could be promising to drug development. Currently, there are no effective therapies for any type of dementia.

After this preclinical proof of concept study, the next step is to study the antibiotics effects on mice with the mutation that causes frontotemporal dementia, Zhu says. Another focus is to possibly develop new compounds from Gentamicin and G418 that could be safer and more effective. Although Gentamicin is an FDA-approved medication, its clinical usage is limited as it is associated with a number of adverse side effects.

If we can get the right resources and physician to work with, we could potentially repurpose this drug. This is an early stage of the study, but it provides an important proof of concept that these aminoglycoside antibiotics or their derivatives can be a therapeutic avenue for frontotemporal dementia, said Zhu.

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Antibiotics Could Be Promising Treatment for Form of Dementia - UKNow

Biochemistry

Phage therapy: A new old… – ScienceBlog.com

The fight against drug-resistant pathogens remains an intense one. While the Centers for Disease Controls (CDC) 2019 biggest threats report reveals an overall decrease in drug-resistant microbe-related deaths as compared to its previous report (2013) the agency also cautions that new forms of drug-resistant pathogens are still emerging.

Meanwhile, the options for treating infections by these germs are diminishing, confirming doctors and scientists worries about the end of the age of antibiotics.

We knew it was going to be a problem early on, said UC Santa Barbara chemistry and biochemistry professorIrene Chen. Basically as soon as penicillin was discovered, a few years later it was reported that there was a resistant organism. Thanks to factors such as horizontal gene transfer and rapid reproduction, organisms such as Gram-negative bacteria are able to evolve faster than we can produce antibiotics to control them.

So Chen and her research group are seeking alternatives to antibiotics, in a growing effort to head off the tide of incurable bacterial infections. In their work, the group has turned to bacteriophages, a naturally occurring group of viruses that colonize on bacteria.

Thats their natural function, really, to grow on and kill bacteria, said Chen, author of apaperthat appears in the Proceedings of the National Academy of Sciences. By taking advantage of the bacteriophages ability to home in on specific bacteria without damaging the rest of the microbiome, the researchers were able to use a combination of gold nanorods and near-infrared light to destroy even multidrug-resistant bacteria without antibiotics.

Phage therapy isnt new, Chen said. In fact, it has been used in the former Soviet Union and Europe for about a century, though they are seen largely as last-resort alternatives to antibiotics. Among the unresolved issues of phage therapy is the incomplete characterization of the phages biology a biology that could allow for unintended consequences due to the phages own rapid evolution and reproduction, as well as potential toxins the viruses may carry. Another issue is the all-or-nothing aspect of phage therapy, Chen added.

Its difficult to analyze the effect of a phage treatment, she said. You might see it completely work or you might see it completely fail, but you dont have the kind of dose response you want.

To surmount these challenges, the Chen lab developed a method of controlled phage therapy.

What we did was to conjugate the phages to gold nanorods, she explained. These phanorods were applied to bacteria on in-vitro cultures of mammalian cells and then exposed to near-infrared light.

Conjugated to phages,gold nanorods find their target: a bacterial cell wall

Photo Credit:COURTESY IMAGE

When these nanorods are photo-excited, they translate the energy from light to heat, Chen said, and that creates very high local temperatures.

The heat is enough to kill the bacteria, and it also kills the phages, preventing any unwanted further evolutions. The result is a guided missile of targeted phage therapy that also allows for dosage control. The lab found success in destroyingE. coli,P. aeruginosaandV. cholerae human pathogens that cause acute symptoms if left unchecked. They also were able to successfully destroyX. campestris, a bacteria that causes rot in plants.

In a collaboration with UC Santa Barbara mechanical engineerBeth Pruitt, the lab determined that while the heat successfully destroyed bacteria and phage, more than 80% of the mammalian cell culture underneath the bacteria biofilm survived.

Bacteria under fire: Green bacteria are alive, while the red ones are dead

Photo Credit:COURTESY IMAGE

This issue of whether it damages mammalian tissues is very important, Chen said. Work in nanotechnology and nanomedicine treating bacterial infections indicates that when its non-targeted, it really does burden the surrounding tissues.

The lab plans to investigate other possible phages to counter other bacteria, possibly engineering a photothermal method that could treat multiple bacterial infections.

Research on this study was conducted also by UCSB postdoctoral fellow Huan Peng (lead author), Raymond E. Borg and Liam P. Dow.

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Phage therapy: A new old... - ScienceBlog.com

Biochemistry

Dr. Lisak honored with Healthcare Professional Champion Award for efforts against MS – The South End

Wayne State University School of Medicine Professor of Neurology Robert Lisak, M.D., FRCP, FAAN, received the Healthcare Professional Champion Award from the Michigan Chapter of the National Multiple Sclerosis Society.

The award is presented to an individual who has demonstrated their commitment to helping people meet the challenges of Multiple Sclerosis, including improving access to and quality of MS clinical care. Recipients must have demonstrated leadership in establishing relationships with other health care providers and professional organizations, increasing referrals to the society and improving MS knowledge in the health care workforce.

It is nice to be recognized for doing things that you enjoy doing for others, said Dr. Lisak, who received the honor Jan. 11 at the chapters annual Breakthroughs in MS meeting in Novi. Mich.

Mirela Cerghet, M.D., Ph.D., a neurologist with the Henry Ford Health System, presented Dr. Lisak, also a professor of Biochemistry, Microbiology and Immunology, and former chair of WSU Neurology, with the award on behalf of the chapter.

Dr. Lisak, said Dr. Cerghet, has been a champion for patients living with MS for the entire span of his distinguished career. His involvement with the National MS Society spans decades, and over the years of his service great strides have been made toward creating a world free of MS, including the development of all the disease-modifying medications.

A member of the societys Board of Trustees and chair of the Healthcare Provider Council, Dr. Lisak has played a critical role in attracting new talent to the field through his involvement in MS professional education, medical student mentoring, clinical training programs and engagement with clinical fellows, Dr. Cerghet said.

Most recently, Dr. Lisak, representing both WSU and the Consortium of Multiple Sclerosis Centers in his role on the AAN Guideline Development, Dissemination and Implementation Subcommittee, helped develop new guidelines for disease-modifying therapy for multiple sclerosis. The Consortium of Multiple Sclerosis Centers is a professional organization of MS centers and health care providers and researchers in the United States and Canada committed to a comprehensive multidisciplinary approach to treatment and care, education and research and advocacy for MS so that the centers can provide the best care and outcomes for patients and their families. The consortium also is an international clearinghouse for research results, the latest treatments, clinical trials and patient education programs.

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Dr. Lisak honored with Healthcare Professional Champion Award for efforts against MS - The South End

Biochemistry

January: smoking cessation | News – University of Bristol

As smokers know all too well, nicotine is highly addictive. Its hard to quit smoking, a habit that claims the lives of more than seven million people each year.

Smoking tobacco delivers nicotine to the neuroreceptors responsible for addiction, affecting the nervous system and causing addiction.

A new study, led by scientists from the University of Bristol, into the molecular interactions involved has revealed how these neuroreceptors respond to nicotine.

The researchers used new computational simulation methods to discover how receptors in the brain respond to nicotine.

One of the key features of the study is the speed at which the discovery was made, thanks to the use of Oracle Cloud Infrastructure, which allowed the researchers to run a large number of simulations in unprecedentedly short time.

The work brought together computational chemists, biochemists and research software engineers, working together to deploy large numbers of simulations of nicotine receptors in the cloud.

Reducing the time to results to just five days using Oracles high-performance cloud infrastructure is transformational from a research perspective. Calculations that might otherwise have taken months to complete were completed in a matter of days.

The study, carried out by researchers from Bristol in partnership with Oracle, whose cloud technologies were a key part of the investigation, is reported in the Journal of the American Chemical Society, the flagship publication of the American Chemical Society, the worlds largest scientific society and a global leader in providing access to chemistry-related research. The project was supported by funding from EPSRC.

Co-author of the study, Professor Adrian Mulholland, from Bristols Centre for Computational Chemistry, part of Bristols School of Chemistry, said: Nicotine is highly addictive: its very hard to give up smoking. To understand why it is so addictive, and to make molecules to help people quit, we need to understand how it affects the nervous system.

We have used simulations to model and understand how nicotine affects receptors in the brain. Using the power of cloud computing, we were able to show how nicotine exerts its effects, at the molecular level, the first stage of signaling in the brain. This information, and the methods we have developing, will help in developing new smoking cessation aids.

Researchers are now working with Achieve Life Sciences to design and develop molecules that mimic nicotine, and computer simulations that will help test their potential effectiveness. This work builds on previous studies using chemical synthetic approaches to develop new smoking cessation aids, which will be investigated and tested in simulation scenarios.

Smoking is the second most common cause of death worldwide, but most current anti-smoking drugs are only moderately effective in reducing symptoms of withdrawal and may cause undesirable side effects. New, specific and effective smoking cessation aids are needed.

Nicotine is the major psychoactive agent in tobacco and causes addiction by binding to specific receptors in the brain. Understanding how nicotine binds to these receptors and creates the nicotine hit and subsequent craving is a key focus for public health research.

The study saw researchers perform 450 individual molecular dynamics simulations of the biochemistry associated with the binding of nicotine to a subtype (7) of nicotinic acetylcholine receptors in the brain. They were able to compare with other types nicotine receptor and identify common features of receptor activation.

The study also showed how cloud computing can be combined effectively with more traditional high-performance computing.

This work shows how rigorous simulations can be used to predict effects on drug targets in a matter of days.

On this quick timescale, calculations help to plan and interpret experiments, and will help design and develop effective drugs. More broadly, the agility and other benefits of using cloud computing for research offers the potential to accelerate the pace of discovery dramatically.

Paper:

A general mechanism for signal propagation in the nicotinic acetylcholine receptor family by A. Oliveria, C. Edsall, C. Woods, P. Bates, G. Viedma-Nunez, S. Wonnacott, I. Bermudez, G. Ciccotti, T. Gallagher, R. Sessions and A. Mulholland in Journal of the American Chemical Society

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January: smoking cessation | News - University of Bristol

Biochemistry

An Astrobiologist Seeks to Explain Whether There Are Other ‘Beings’ Amongst Us – Qrius

Samantha Rolfe, University of Hertfordshire

Life is pretty easy to recognise. It moves, it grows, it eats, it excretes, it reproduces. Simple. In biology, researchers often use the acronym MRSGREN to describe it. It stands for movement, respiration, sensitivity, growth, reproduction, excretion and nutrition.

But Helen Sharman, Britains first astronaut and a chemist at Imperial College London, recently said that alien lifeforms that are impossible to spot may be living among us. How could that be possible?

While life may be easy to recognise, its actually notoriously difficult to define and has had scientists and philosophers in debate for centuries if not millennia. For example, a 3D printer can reproduce itself, but we wouldnt call it alive. On the other hand, a mule is famously sterile, but we would never say it doesnt live.

As nobody can agree, there are more than 100 definitions of what life is. An alternative (but imperfect) approach is describing life as a self-sustaining chemical system capable of Darwinian evolution, which works for many cases we want to describe.

The lack of definition is a huge problem when it comes to searching for life in space. Not being able to define life other than well know it when we see it means we are truly limiting ourselves to geocentric, possibly even anthropocentric, ideas of what life looks like. When we think about aliens, we often picture a humanoid creature. But the intelligent life we are searching for doesnt have to be humanoid.

Sharman says she believes aliens exist and theres no two ways about it. Furthermore, she wonders: Will they be like you and me, made up of carbon and nitrogen? Maybe not. Its possible theyre here right now and we simply cant see them.

Such life would exist in a shadow biosphere. By that, I dont mean a ghost realm, but undiscovered creatures probably with a different biochemistry. This means we cant study or even notice them because they are outside of our comprehension. Assuming it exists, such a shadow biosphere would probably be microscopic.

So why havent we found it? We have limited ways of studying the microscopic world as only a small percentage of microbes can be cultured in a lab. This may mean that there could indeed be many lifeforms we havent yet spotted. We do now have the ability to sequence the DNA of unculturable strains of microbes, but this can only detect life as we know it that contain DNA.

If we find such a biosphere, however, it is unclear whether we should call it alien. That depends on whether we mean of extraterrestrial origin or simply unfamiliar.

A popular suggestion for an alternative biochemistry is one based on silicon rather than carbon. It makes sense, even from a geocentric point of view. Around 90% of the Earth is made up of silicon, iron, magnesium and oxygen, which means theres lots to go around for building potential life.

Silicon is similar to carbon, it has four electrons available for creating bonds with other atoms. But silicon is heavier, with 14 protons (protons make up the atomic nucleus with neutrons) compared to the six in the carbon nucleus. While carbon can create strong double and triple bonds to form long chains useful for many functions, such as building cell walls, it is much harder for silicon. It struggles to create strong bonds, so long-chain molecules are much less stable.

Whats more, common silicon compounds, such as silicon dioxide (or silica), are generally solid at terrestrial temperatures and insoluble in water. Compare this to highly soluble carbon dioxide, for example, and we see that carbon is more flexible and provides many more molecular possibilities.

Life on Earth is fundamentally different from the bulk composition of the Earth. Another argument against a silicon-based shadow biosphere is that too much silicon is locked up in rocks. In fact, the chemical composition of life on Earth has an approximate correlation with the chemical composition of the sun, with 98% of atoms in biology consisting of hydrogen, oxygen and carbon. So if there were viable silicon lifeforms here, they may have evolved elsewhere.

That said, there are arguments in favour of silicon-based life on Earth. Nature is adaptable. A few years ago, scientists at Caltech managed to breed a bacterial protein that created bonds with silicon essentially bringing silicon to life. So even though silicon is inflexible compared with carbon, it could perhaps find ways to assemble into living organisms, potentially including carbon.

And when it comes to other places in space, such as Saturns moon Titan or planets orbiting other stars, we certainly cant rule out the possibility of silicon-based life.

To find it, we have to somehow think outside of the terrestrial biology box and figure out ways of recognising lifeforms that are fundamentally different from the carbon-based form. There are plenty of experiments testing out these alternative biochemistries, such as the one from Caltech.

Regardless of the belief held by many that life exists elsewhere in the universe, we have no evidence for that. So it is important to consider all life as precious, no matter its size, quantity or location. The Earth supports the only known life in the universe. So no matter what form life elsewhere in the solar system or universe may take, we have to make sure we protect it from harmful contamination whether it is terrestrial life or alien lifeforms.

So could aliens be among us? I dont believe that we have been visited by a life form with the technology to travel across the vast distances of space. But we do have evidence for life-forming, carbon-based molecules having arrived on Earth on meteorites, so the evidence certainly doesnt rule out the same possibility for more unfamiliar life forms.

Samantha Rolfe, Lecturer in Astrobiology and Principal Technical Officer at Bayfordbury Observatory, University of Hertfordshire

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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An Astrobiologist Seeks to Explain Whether There Are Other 'Beings' Amongst Us - Qrius

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