ReportWire

Tag: Nature (journal)

  • A win, win, win for dairy production in East Africa

    A win, win, win for dairy production in East Africa

    [ad_1]

    Newswise — Adopting high yield dairy cattle breeds and improving feed would allow Tanzania to increase milk production, while reducing planet warming greenhouse gas (GHG) emissions and alleviating poverty, a new study reveals.

    Tanzania has the second largest dairy herd in East Africa with 28 million cows. However, its dairy sector is poorly developed with mainly small-scale farms stocked with low-yielding breeds, using poor quality feeds. This, along with other supply chain problems around handling and refrigeration, results in poor productivity and the need to import processed dairy products leading to a $23 million trade deficit.

    A new research paper from an international team of researchers led by Lancaster University scientists and published in Nature Food is the first to find evidence that breeding higher yielding dairy cattle offers significant potential to help Tanzania to reduce its dependency on foreign food imports and at the same time help meet its climate commitments.

    The findings show that two key targets of Tanzanian government policy – becoming self-sufficient in milk and cutting GHG emissions by a third – can be achieved simultaneously while increasing income in farming communities.

    Researchers carried out a household survey of 1,200 dairy farmers in Tanzania which was used as a baseline for a sectoral modelling analysis. The survey, which extended across four districts and two agro-ecological zones, was used to estimate milk production, yields from different cattle breeds and how the cattle are managed – for instance what they are fed and how disease is managed.

    Tanzania’s local cattle cope well with high temperatures but produce little milk. New breeds, which cross local cattle with high yielding European cows, produce three times as much milk, while still coping well with heat.

    The study takes as its starting point the Tanzanian Dairy Development Roadmap (DDR), a Government plan which, with support from stakeholders, aims to achieve dairy self-sufficiency by 2030. Currently, Tanzania’s low cost-competitiveness with trading partners results in the import of roughly 23 Million USD per year in dairy, and the DDR aims to replace these imports with domestic production. The researchers model how the Roadmap could be delivered through farmers changing from local to improved breeds of cattle, and feeding their cattle more nutritious, locally produced feed. Crucially, it assumes land that is already used in agriculture, mainly local pasture, is converted to grow feed crops, so farmers do not rely on imported feed and no forest needs to be cut down to grow it.

    “The idea was to model the Tanzanian Government’s planned interventions to increase milk production and also their targets for improved dairy breeds and feeding practices,” said Dr James Hawkins, an environmental economist from the Lancaster Environment Centre, and lead author of the study.

    “What is very important is understanding the interactions between cattle management and productivity because the carbon footprint is strongly related to the productivity of dairy cows.”

    The combination of more nutritious feed and more productive cattle means that production can be increased while reducing herd size, and cutting the amount of land needed to support the cattle, the study found. Better feed can increase the milk yield for local cows by up to 179% and for the higher yielding breeds by up to 130%. 

    The study modelled a series of scenarios, with different levels of milk production and adoption of new breeds and feeds. All the scenarios showed increases in production and a decrease in GHG emissions. The analysis showed that fulfilling the DDR targets for adopting improved breeds would enable Tanzania to meet 70% of the target milk production level while also fulfilling the country’s ambition to reduce GHG emissions from dairy by a third. The main driver of emissions reductions was from avoided land use change. While the model showed improving feed requires more cropland, a much larger decline in grasslands would reduce carbon dioxide emissions from forest clearance.

    “This is a win, win, win for Tanzania,” said Professor Mariana Rufino, from the Lancaster Environment Centre, principal investigator in the study, who has been researching dairy production in Africa for almost twenty years.

    “There have been a lot of studies showing how to mitigate emissions from the livestock sector that tell low-income countries what they should do, that they shouldn’t have livestock etc.  This study is special because we take Tanzania’s own ambitions, a country level target, and work out how they can achieve it, and more.

    “This Tanzanian policy only aims for food security, we find a way they can also improve incomes and meet their climate target at the same time.

    “Dairy is very good for poor communities. It generates daily cash, instead of farmers having to wait for a crop to be harvested once a year. There is a market for feed and lots of small businesses develop around dairy, so it generates income and alleviates poverty. Drinking milk can make a big difference to children in poor communities, providing a little bit of protein and concentrated micronutrients which they cannot get in other foods. So dairy can have a very important societal impact.”

    The income benefits are not equally distributed, the study shows, with farmers who do not have the resources to invest in, feed and care for higher yielding cattle losing out. The authors warn that while overall incomes increase, these farmers’ incomes could fall, especially if increasing production lowers the price they can charge for milk. Support policies should create safeguards for this key food sector, the researchers say.

    Dr Amos Omore, Tanzania country representative for the International Livestock Research Institute, said: “The findings of this paper have huge implications. The same quantity of milk being produced in smallholder dairy farms that dominate in eastern Africa can easily be produced with less than a quarter the number of animals currently, given the large yield gaps. What is required is more investment in sustainable animal productivity in smallholder farms – a clear win-win for better lives and greener planet.”

    The findings are outlined in the paper ‘High yield dairy cattle breeds improve farmer incomes, curtail greenhouse gas emissions and reduce dairy import dependency in Tanzania’

    Partners in the study include the Center for International Forestry Research (CIFOR) and the International Livestock Research Institute (ILRI), both in Kenya, and the Universities of Reading, Queensland and Wisconsin-Madison.

    [ad_2]

    Lancaster University

    Source link

  • Scientists uncover potential ‘electrical language’ of breast cancer cells

    Scientists uncover potential ‘electrical language’ of breast cancer cells

    [ad_1]

    Newswise — New research has found variable voltages in the membranes of breast cancer cells, revealing clues about how they grow and spread.

    The research, led by Imperial College London and The Institute of Cancer Research, London, could help us better understand how cancer cells ‘decide’ when to multiply and where to spread to.

    When cells become cancerous, they undergo a series of bioelectric changes. For example, the layer surrounding cells, called the cell membrane, becomes more positively charged than healthy cell membranes.

    This new research, published today in Communications Biology, found that as well as the membrane voltage being higher than in healthy cells, it also fluctuates over time – with breast cancer cells behaving much like neurons. The researchers believe this could indicate an electrical communications network between cancer cells that could in future be a target for disruption, creating possible new treatments.

    Co-lead author Dr Amanda Foust, from Imperial’s Department of Bioengineering, said: “When healthy cells become cancerous, the changes they undergo can help them to grow and spread. We know, for example, that certain genes that control cell multiplication can switch off, causing uncontrolled cell growth.

    “We don’t yet know why the voltage of membranes fluctuates in cancer cells – but our discovery and technology, enabled by the exciting collaboration of engineers and biologists, opens doors to further work that could help us better understand cancer signalling networks and growth.”

    Testing the network

    To test the voltages, the researchers grew cells from eight breast cancer cell lines and one healthy breast cell line. They then recorded the voltages of their cell membranes with a microscope originally engineered to film electrical activity in brain cells, before using machine learning to categorise and characterise the signals.

    Unexpectedly, they found fluctuations in the voltage of the cancer cell membranes. Though more research is needed, the researchers suspect the ‘blinking’ and ‘waving’ electrical signals might be a form of communication between cells.

    They added tetrodotoxin, a potent neurotoxin that blocks sodium channels to prevent the generation of electrical charge in nerve cells. Previous studies had shown that cancer cells rely on these sodium channels to become more invasive.

    They found that, similarly to its effect on nerve cells, tetrodotoxin suppressed the voltage fluctuations in cancer cells. The researchers say this could potentially indicate new treatment avenues for blocking cancer cell communication and behaviour.

    Co-lead author Professor Chris Bakal, Professor of Cancer Morphodynamics at The Institute of Cancer Research, London, said: “This is the first time we’ve observed such rapid fluctuations in electrical activity within breast cancer cells. It looks like breast cancer cells have established a type of electrical language. We still don’t know how complex the language is, but it could allow cancer cells to relay information about nearby nutrients or hostile environments across large distances, and ultimately promote tumour survival.”

    To further test their findings, they induced cancer in the healthy cell line before recording them again. They found that once these cells had become cancerous, the voltage of their membranes was also fluctuating.

    The level of electrical signals varied across cancer types. The more aggressive and untreatable cancer cell lines featured more frequent fluctuations, with signals sometimes appearing as a wave traveling from cell to cell.

    Co-author Emeritus Professor Mustafa Djamgoz at Imperial’s Department of Life Sciences said: “Of all the cells in the body, we usually associate ‘excitable’ brain or heart cells with electrical activity. Our research suggests a hidden electrical signalling network among cancer cells that might play a key role in cancer cell behaviour including communication with each other and other cells within the tumour. We know already that the spreading of cancer, the main cause of death from cancer, is facilitated by electrical activity.”

    Professor Bakal added: “We think these networks may even allow cancer cells to form brain-like structures that allow cancer cells to act together as a single machine, rather than as individual units.”

    Connecting the clues

    The researchers are now working to identify and unpick the potential links between cell membrane voltage and the behaviour of cancer cells, to see if they can be cut. Professor Bakal said: “If you can stop cancer cells communicating with one another, they could become easier to treat. It’s not so dissimilar from a war. If you can stop a commander from relaying information to soldiers at the front, the battle becomes easier to win.”

    Dr Foust said: “We are now investigating the role of voltage in cancer cell behaviour. Do cancer cells clone themselves and multiply as their voltage fluctuates in a certain pattern, or break off to invade other body parts? Can we use this knowledge to interject at a particular stage of fluctuation to prevent cancer spread? These are key questions we hope to answer with our ongoing work.”

    This study was funded by Integrated Biological Imaging Network, the Royal Academy of Engineering, the Biotechnology and Biology Research Council (BBRC, part of UKRI), Wellcome Trust, Engineering and Physical Sciences Research Council (EPSRC, part of UKRI), Cancer Research UK and Stand Up to Cancer UK.

    [ad_2]

    Imperial College London

    Source link

  • Truly chiral phonons observed in three-dimensional materials for the first time

    Truly chiral phonons observed in three-dimensional materials for the first time

    [ad_1]

    Newswise — Chirality is the breaking of reflection and inversion symmetries. Simply put, it is when an object’s mirror images cannot be superimposed over each other. A common example are your two hands—while mirror images of each other, they can never overlap. Chirality appears at all levels in nature and is ubiquitous. In addition to static chirality, chirality can also occur due to dynamic motion including rotation. With this in mind, we can distinguish true and false chirality. A system is truly chiral if, when translating, space inversion does not equate to time reversal combined with a proper spatial rotation.

    Phonons are quanta (or small packets) of energy associated with the vibration of atoms in a crystal lattice. Recently, phonons with chiral properties have been theorized and experimentally discovered in two-dimensional (2D) materials such as tungsten diselenide. The discovered chiral phonons are rotating—yet not propagating—atomic motions. But, truly chiral phonons would be atomic motions that are both rotating and propagating, and these have never been observed in three-dimensional (3D) bulk systems.

    Now, a team of researchers led by scientists from Tokyo Institute of Technology (Tokyo Tech) have identified truly chiral phonons, both theoretically and experimentally. The team, led by Professor Takuya Satoh of the Department of Physics at Tokyo Tech, observed the chiral phonons in cinnabar (α-HgS). This was achieved using a combination of first-principles calculations and an experimental technique called circularly polarized Raman scattering. “Chiral structures can be probed using chiral techniques. So, using circularly polarized light, which has its own handedness (i.e., right-handed or left-handedness), is critical. Dynamic chiral structures can be mapped using pseudo-angular momentum (PAM). Pseudo-momentum and PAM originate from the phase factors acquired by discrete translation and rotation symmetry operations, respectively,” explains Professor Satoh.

    The researchers’ novel experimental approach also allowed them to probe the fundamental traits of PAM. They found that the law of the conservation of PAM—one of the key laws of physics—holds between circularly polarized photons and chiral phonons. “Our work also provides an optical method to identify the handedness of chiral materials using PAM. Namely, we can determine the handedness of materials with better resolution than x-ray diffraction (XRD) can achieve. Moreover, XRD requires a large-enough crystal, is invasive, and can be destructive. Circularly polarized Raman scattering, on the other hand, allowed us to determine the chirality of structures XRD could not, in a non-contact and non-destructive manner,” concludes Professor Satoh.

    This study is the first to identify truly chiral phonons in 3D materials, which are clearly distinct from those seen previously in 2D hexagonal systems. The learnings gained here could drive new research into developing ways for transferring the PAM from photons to electron spins via propagating chiral phonons in future devices. Furthermore, this approach enables the determination of the true chirality of a crystal in an improved manner, providing a new critical tool for experimentalists’ and researchers.

    [ad_2]

    Tokyo Institute of Technology

    Source link

  • Observation of a self-generated current to self-confine fusion plasmas

    Observation of a self-generated current to self-confine fusion plasmas

    [ad_1]

    Newswise — Nuclear fusion has drawn more attention in the era of carbon neutrality because of no carbon dioxide production during power generation and no generation of high-level radioactive wastes.

    A tokamak, a torus-shaped nuclear fusion device, needs an electric current in the plasma to produce magnetic field around the torus for confining fusion plasmas. Plasma current is conventionally generated by electromagnetic induction.

    However, for a steady-state fusion reactor, minimizing the inductive current is essential to extend the tokamak operating duration. Several non-inductive current drive schemes have been developed for steady-state operations such as radio-frequency waves and neutral beams. However, commercial reactors require minimal use of these external sources to maximize the fusion gain, Q, the ratio of the fusion power to the external power. Apart from these external current drives, a self-generated current, so-called bootstrap current, was predicted theoretically and demonstrated experimentally.

    The research team led by Prof. Yong-Su Na in the Department of Nuclear Engineering at Seoul National University and Dr. Jaemin Seo at Princeton University have revealed that another type of self-generated current can exist in a tokamak which can not yet been explained by present theories. They discovered this in the experiments on the KSTAR tokamak in collaboration with Korea Institute of Fusion Energy, Princeton Plasma Physics Laboratory, and General Atomics.

    While conducting an experiment on plasma turbulence, it was discovered by chance that an un-identified plasma current that could not be explained by existing theories and simulations occurred. As a result of the analysis, it was found that this comprises a significant amount up to 30% of the total plasma current, and appears when the turbulence was relatively low.

    The discovery of a new plasma current generated by itself without magnetic induction shows a new possibility that the plasma confines by itself and continues the fusion reaction in long-pulse operations for a fusion reactor.

    The new current source in this experiment was unusually observed only when the fuel was injected into the plasma and the exact cause is still unknown, so follow-up studies are planned to proceed actively in the future.

    Prof. Yong-Su Na, the co-first author and corresponding author of the study, said, “This result was obtained from a unfamiliar experiment to the extent that the experiment proposal was not selected at KSTAR. If we had tried to look at it from a conventional point of view, we would not have found it. “We were able to discover new things by approaching with an open perspective rather than being confined to what we wanted to see or get.” Another co-first author, Dr. Seo Jae-min, said, “Big science such as the nuclear fusion research is being devoted to small steps that put an apple on the shoulders of giants. I hope that future scientists who can step forward together will be interested in and support the nuclear fusion research.”

    Once the physics mechanism is found, this new discovery is expected to significantly contribute to the long continuous operation of ITER and commercial reactors, which are exploring current drive ways that do not reoly on inductive current.

     

    This work was supported by National R&D Program through the National Research Foundation of Korea (NRF) funded by the Korean government (Ministry of Science and ICT) (NRF-2021M1A7A4091135 and 2021M3F7A1084419). This work was also supported by the Ministry of Science and ICT under the KFE R&D Program of “KSTAR Experimental Collaboration and Fusion Plasma Research (KFE-EN2201-12)”.

    [ad_2]

    Seoul National University

    Source link

  • DNA barcoding reveals cancer cells’ ability to evade the immune system

    DNA barcoding reveals cancer cells’ ability to evade the immune system

    [ad_1]

    Newswise — Some cancer cells can deploy parallel mechanisms to evade the immune system’s defences as well as resist immunotherapy treatment, according to a new study from the Garvan Institute of Medical Research.  

    By suppressing the action of killer T-cells and hindering the ability of the immune system to flag tumour cells for destruction, breast cancer cells are able to replicate and metastasise, the researchers found.  

    “We know that breast cancer typically doesn’t respond well to immunotherapy, and we wondered if there’s an intrinsic mechanism enabling breast cancer cells to escape the immune system,” says first author Ms Louise Baldwin, who is a PhD student in Associate Professor Alex Swarbrick’s lab at Garvan. 

    The researchers used a technique called DNA barcoding, which tags cells with a known sequence and tracks the progression of tumour cells through time. 

    “We showed that there are rare cancer cells capable of escaping the immune system and escaping treatment with immunotherapy,” Ms Baldwin says. 

    The mechanisms could be used as potential targets for therapies, to stop tumorous cells from adapting and spreading. Another future application could be in prognosis, where a high number of cells could indicate which patients might not respond to immunotherapy. 

    The new study is published in Nature Communications.  

    While immunotherapy is an effective treatment in many cancers, in some people their cancer cells evolve to outplay the immune system defences. This process is known as immunoediting, where interaction between tumour cells and immune cells results in many cancerous cells being destroyed by the immune system, but leaving some undetected, which continue to grow and spread. 

    The researchers used mouse breast cancer cells tagged with a known DNA ‘barcode’, a sequence that was passed on from one generation of cells to the next.  

    The barcoding allowed the team to see where more aggressive, resistant cells came from, as they could trace it back to the original cell to see if it had grown or shrunk.  

    “Lead author Dr Simon Junankar wanted to understand whether resistance was adaptive – whether cancer cells duck and weave – or are they pre-programmed to evade the immune system,” says Associate Professor Alex Swarbrick, a laboratory head and Co-Lead of the Dynamic Cellular Ecosystems in Cancer Program at Garvan. 

    The team found that even before treatment, the cancer cells had diversified. “Some cells had already acquired the ability to evade immunity, meaning they have an innate ability to escape the immune system,” he says.  

    The cells seem to do this with parallel approaches. One way is to suppress the action of killer T-cells, which would usually destroy harmful cells. The other is to reduce the expression of MHC1 on cells, which act as a flag for the immune system to recognise harmful cells. 

    “Most tumour cells vanish when the immune system gets switched on, but a small proportion keep growing and expanding,” says Associate Professor Swarbrick. 

    “Tumours keep evolving and diversifying, and action by the immune system or treatment like chemotherapy is like pruning a tree – cancer cells get wiped out but the remaining branches on the tree continue to grow.” 

    The researchers also looked at the genetics of the cells, but there were no genes found to be associated, suggesting epigenetics might be at play.  

     

    –ENDS– 

     

    This research was supported by research grants from the National Breast Cancer Foundation (NBCF). Louise Baldwin is supported by an Australian Government research training (RTP) stipend and Associate Professor Swarbrick is the recipient of a research fellowship from the NHMRC. 

    Associate Professor Swarbrick is a Conjoint Associate Professor at St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney.  

    [ad_2]

    Garvan Institute of Medical Research

    Source link

  • Personalising whole genome sequencing doubles diagnosis of rare diseases

    Personalising whole genome sequencing doubles diagnosis of rare diseases

    [ad_1]

    Newswise — Tailoring the analysis of whole genome sequencing to individual patients could double the diagnostic rates of rare diseases, finds a new study led by UCL researchers.

    In 2018, the UK’s department of health announced an NHS Genomic Medicine Service, which allows patients with rare diseases to have their entire genetic code read in the hope of providing a much-needed diagnosis.

    However, the interpretation of this data can be extremely challenging and many people with complex, rare genetic diseases still do not receive a molecular answer to the cause of their problems.

    In the study, published in Nature Communications, researchers at The London Mitochondrial Centre at UCL Queen Square Institute of Neurology and UCL Great Ormond Street Institute of Child Health sought to offer such patients an improved chance of receiving a genetic diagnosis.

    To do so, they tested how using a genomic medicine team of specialist doctors, bioinformaticians, and scientists could boost the capabilities of NHS diagnostic laboratories beyond the standard semi-automated analysis of data. The UCL team re-evaluated undiagnosed cases to identify clues that might help direct further, more personalised analysis. They subsequently applied additional bioinformatic approaches, using advanced computer technologies to identify genetic alterations in a patients’ DNA which may be causing disease but had been overlooked during routine testing.

    The work included 102 undiagnosed patients, suspected of having a primary mitochondrial disease (a large group of incurable genetic disorders that affect children and adults, associated with a broad spectrum of medical problems, severe disabilities, and reduced lifespan), who had undergone whole genome sequencing via the NHS’s 100,000 Genomes Project.

    This personalised approach increased the diagnostic rate from 16.7% to 31.4%. It also detected potential disease-causing variants in a further 3.9% of patients.

    Lead author, Dr Robert Pitceathly (co-lead for the London NHS Highly Specialised Service for Rare Mitochondrial Disorders and a research group leader at UCL Queen Square Institute of Neurology), said: “The NHS has invested heavily in advanced genetic technologies. Consequently, the UK has established itself at the forefront of diagnostic whole genome sequencing. That said, some people with rare genetic diseases remain without a molecular diagnosis after their genome is analysed.

    “We believe investing in specialist genomic medicine teams is crucial, ensuring equitable access to dedicated multidisciplinary expertise and maximising diagnoses. On average, patients in our study waited over 30 years for a diagnosis – we now have the capability to solve such cases but need adequate workforce planning to support NHS diagnostic genetic laboratories in achieving this goal.”

    Receiving a genetic diagnosis is important as it allows patients to receive access to family planning, specialised IVF, and drugs trials. It can also permit targeted screening of known disease complications and access to drug studies.

    Dr Pitceathly said: “In this study, every new genetic diagnosis had a direct impact on patient care. This included additional check-ups for heart problems, hearing loss, and diabetes, and access to clinical trials.”

    Professor Michael Hanna, Director of UCL Queen Square Institute of Neurology said: “This work is a significant step forward in developing the best ways to maximise the benefits of genome analysis for patients. It clearly demonstrates that by combining automated approaches to genome analysis with data interpretation by a skilled multidisciplinary team the diagnostic rates doubles. This is an important finding that will influence how genomic medicine diagnostic services should evolve world-wide.”

    Co-author, Dr James Davison (Metabolic Medicine Department at Great Ormond Street Hospital and chair of the British Inherited Metabolic Diseases Group), said: “The journey to reaching a diagnosis for children and adults with rare, complex, medical conditions can be a very long process, and genomic medicine provides a transformative and powerful tool in helping reach that goal.

    “This study highlights the importance of the collaboration between specialist clinicians and genetic scientists in interpreting the results of genome sequencing to maximise the opportunity of reaching a diagnosis which can then help guide medical management and treatment options.”

    The researchers involved in this study are funded by the Medical Research Council.

    Patient story

    Rachel North was one of the patients involved in the trial and described getting a diagnosis as “life changing”. It has since allowed her to be screened for disease complications such as osteopenia, and these have been treated.

    She said: “I had attended so many hospitals over the past 20 years and had been searching so long, I never thought I’d get a diagnosis.

    “Wondering about it took up so much energy, and I was worried about my 12-year-old son, and if my condition would affect him. So, getting a rare recessive diagnosis was a relief and takes away fear of the unknown.

    “Having a diagnosis allows me to research my condition and be very proactive in managing it.

    “Anything that helps me understand and make sense of what is happening to my body helps me come to terms with it and gives me confidence that I am managing it as well as possible.”

    Notes to Editors

     

    William L. Macken, Micol Falabella, Caroline McKittrick, Chiara Pizzamiglio, Rebecca Ellmers, Kelly Eggleton, Cathy E. Woodward, Yogan Patel, Robyn Labrum, Genomics England Research Consortium, Rahul Phadke, Mary M. Reilly, Catherine DeVile, Anna Sarkozy, Emma Footitt, James Davison, Shamima Rahman, Henry Houlden, Enrico Bugiardini, Rosaline Quinlivan, Michael G. Hanna, Jana Vandrovcova, Robert D. S. Pitceathly. Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing, will be published in Nature Communications, on 7th November 2022 at 10:00 GMT / 05:00 ET.

     

    The DOI for this paper will be: 10.1038/s41467-022-32908-7

    [ad_2]

    University College London

    Source link

  • Research team discovers central functions of innate immune cells

    Research team discovers central functions of innate immune cells

    [ad_1]

    Newswise — Inflammation and increased mucus production are typical symptoms of worm infections and allergies. This immune response involves our innate immune cells, but their exact functions are not yet fully understood. A research team from Charité – Universitätsmedizin Berlin has now shed light on the key tasks that these cells perform. In the study, which has been published in the journal Nature*, the researchers also identify potential therapeutic approaches for the treatment of allergies.

    The human immune system is made up of two interconnected branches: the adaptive immune system, which learns something new with every infection and constantly develops over the course of a lifetime, and the innate immune system, which is less specialized but reacts particularly quickly and effectively. The cells of the innate immune system are located in the mucous membranes of the respiratory tract and the intestine, where they form a first line of defense at the point of entry for pathogens. These cells include group 2 innate lymphoid cells (ILC2s for short), which are active in the intestine in the case of parasitic diseases, and in the respiratory tract in the case of allergies.

    “Innate lymphoid cells were discovered a decade or so ago and we already know a lot about them, but their exact function in the machinery of the immune system is not yet completely understood,” explains Dr. Christoph Klose, who heads the Emmy Noether Independent Junior Research Group on the regulation of type 2 immune responses by neuropeptides and neurotransmitters at the Institute of Microbiology, Infectious Diseases and Immunology at Charité. “There is a group of adaptive immune cells – namely the T cells – that carry out some similar functions as part of the type 2 immune response, so it was previously thought that the role of ILC2s may be redundant and could be easily taken over by the T cells.”

    However, the recently published study has now disproved this theory. Using an animal model and state-of-the-art molecular methods such as single-cell sequencing, which allows scientists to zoom into individual cells and analyze their molecular state, they have shed light on the central functions of ILC2s. “A certain type of immune cells called eosinophils were not able to develop properly when ILC2s were absent,” explains Dr. Klose. “This relationship was previously unknown and came as a big surprise.” Eosinophils are involved in inflammatory processes in the tissue. The scientists also found that ILC2s have a major effect on the ability of epithelial cells to promote mucus production and expel parasites, such as worms, from the body. “The absence of ILC2s was clearly noticeable in our tests examining the immune response to worm infections. There was only limited mucus production in the tissue and the parasites could no longer be combated effectively,” says Dr. Klose, summarizing the results of the study.

    In further experiments, the researchers examined the symptoms of allergic asthma and found that these improved when ILC2s were absent. “This could be a starting point for future studies aimed at developing potential allergy therapies,” says Dr. Klose. “With our study, we were able to show that group 2 innate lymphoid cells are essential cogs in the machinery of the immune system and cannot be replaced without compromising the immune response.” In future research projects, Dr. Klose and his team would like to investigate whether the innate lymphoid cells regulate other aspects of the immune response.

    [ad_2]

    Charite – Universitatsmedizin Berlin

    Source link

  • Cancer cells exposed to high viscosity move better and their metastatic potential increases

    Cancer cells exposed to high viscosity move better and their metastatic potential increases

    [ad_1]

    Newswise — The human body is made up of more than a billion cells that join to form the tissues and organs of our bodies. However, cells are dynamic structures that, using different techniques, move through the body to fulfil various functions, such as close wounds or carry nutrients to other tissues.

    Understanding how cancer cells move and make decisions in these confined environments is important as 90% of cancer-related deaths involve metastases

    The labs of Dr. Konstantinos Konstantopoulos of Johns Hopkins University and of Dr. Miguel A. Valverde of UPF, together with teams from the USA and Canada have been working together over the past six years to unravel how cancer cells use ion movement through mechanically activated ion channels -stimuli that deform cell membranes- to adapt their movement to different mechanical stresses and environments. The results of this research have been published in two studies in the journals Nature and Nature Communications.

    In these two new studies, the scientists asked themselves:

    1) how cancer cells polarize ion transport mechanisms in the leading edge and trailing edge of the cells to move through narrow spaces; and

    2) how cancer cells optimize movement when fluid viscosity is high.

    To address these important questions, they studied the movement of cells in three-dimensional media generated using bioengineering techniques, which resemble the pathways along which cells normally move in our bodies. Key proteins were located within the cell using high-resolution microscopy, cell volume, ion movements and electrical activity were recorded, and they evaluated how the expression of different genes that are important for the progression of cancer changes.

    First study: using water as propulsion

    In the first study, published in Nature Communications, the international team found that cancer cells can move in confined spaces by simply taking in water at the leading edge of the cell and releasing it at the trailing edge. They do so without the need to establish molecular interactions with the walls of the surrounding tissue. “It works like a hydraulic propeller, similar to the device that Tom Clancy fictionalized to propel a submarine in his novel The Hunt for Red October”, Dr. Miguel Valverde explains.

    “Cancer cells can move in confined spaces by simply transferring water from the leading edge to the trailing edge of the cell”                                                       

    In real life, this is possible because in their leading edge, the cells accumulate an ion transport system, the sodium/proton exchanger (NHE1), which charges the cell with sodium which increases osmotic pressure and favours the entry of water into the cell.

    At the same time, cancer cells concentrate the SWELL1 protein in their trailing edge. SWELL1 (also known as LRRC8A) is a chloride channel activated by increases in cellular water content that facilitates the exit of chloride and water.

    The end result of the coordinated action of these two ion transport systems on the leading and trailing edges enables cell movement. More importantly, the study shows that the activity of these two systems is essential for the movement of cancer cells outside of blood vessels and in the development of metastasis. 

    Second Study: moving through viscosity using muscles and cell skeleton

    In the second study, published in Nature, the scientists questioned how changes in viscosity in the cellular environment can condition the way cancer cells move and behave.

    Viscosity measures the resistance that a fluid exerts on anything that moves in or with it. As such, common sense and fundamental engineering indicate that inert particles move more slowly in high viscosity media.

    The scientists have now demonstrated an effect that a priori may seem counterintuitive: high viscosity promotes the migration, invasion, as well as the extravasation of tumour cells – exiting from blood vessels – and lung colonization.

    “Unlike inert particles, cells exposed to high viscosity move faster”

    “The cells of our body are constantly exposed to fluids of varying viscosities”, Valverde continues. “In some pathological situations such as tumour growth, the local viscosity surrounding the initial tumour increases due to abnormal protein degradation or compression of the normal drainage pathways -the lymphatic vessels. In addition, as the cancer spreads to other parts of the body, cells have to travel through spaces filled with interstitial fluids and blood, which are more viscose than water”.

    In previous studies, Valverde’s team demonstrated that cells adapt to high viscosity situations by activating a protein called TRPV4, an ion channel that facilitates the entry of calcium into the cell, otherwise impossible due to the lipid membrane that delimits the cell and is impermeable to ions. Calcium is an element that, when increased inside the cell, controls various cell functions.

    With this background in mind, the international team of scientists posited that cancer cells exposed to high viscosity may use a similar mechanism to enhance their motility and dissemination. And they were right… but with interesting surprises!!!

    By exposing cancer cells to high viscosity, they observed that the first cellular element that responded to this stimulus was the protein actin, which is part of the cytoskeleton and shapes the body of the cell. This initiates a cascade of molecular events that ends with the activation of the TRPV4 channel, which in turn activates a cascade of intracellular events that result in the reinforcement of the cell cytoskeleton and the activation of motor proteins.

    Interestingly, by means of all these changes the cells modify their means of migration and no longer employ the movement of water. In these conditions, they use their cellular “skeleton and muscles”, as well as interactions with surrounding walls to propel themselves faster. In the words of Dr.Selma Serra of UPF, co-author of the study, “it is as if the cells had gone to the gym to train hard -under high viscous loads- and perform better when they are physically challenged on their journey from the primary tumour to their final destination in distant metastasis”.

    The study authors also found that cells not only move faster when surrounded by high viscosity fluids, but also when they have been previously exposed to such fluids and then removed. In other words, cells can not only detect and respond to elevated viscosity, but can also develop a memory of their exposure to this condition.

    “Cells develop mechanobiological memory to enhance the spread of cancer”

    How important is the discovery?

    The vast majority of cell biology research is conducted in cell culture media with viscosities close to that of water. “In our work, we define for the first time how cells detect and respond to the physiologically relevant levels of fluid viscosity in which they are commonly found in the body of healthy and sick patients”, explains study coordinator, Dr. Konstantopoulos. “The definition of the molecular mechanism used by cells to adapt to changes in the viscosity of the medium was a tour de force in which we had to change our preconceived idea of which cellular elements are the first to respond to this type of mechanical stimulus”.

    The great coordination between the structural elements of the cells -their actin and myosin cytoskeleton- with the mechanisms of ion transport and water that regulate cell volume marks a major breakthrough in our understanding of cell mechanobiology.

    Dr. Valverde explains the major breakthrough represented by demonstrating that cancer cells have the ability to form memory in response to pre-exposure/pre-conditioning in high viscosities, and highlights the importance of teamwork. “Our papers are also a good example of the need for multidisciplinary collaboration -bioengineers, geneticists, theoretical biophysicists, cell biologists and physiologists- each with a different but complementary approach, which allows us to seek answers to complex problems”, he concludes.

    What’s next? Implications for drug development

    It will be very informative to examine how primary tumours and cancer cells that spread from primary tumours respond to local changes in the viscosity of extracellular fluid found in the body during disease progression and during invasion into the tissue microenvironment. The development and optimization of biosensors that allow real-time measurement of extracellular fluid viscosity along with imaging of cancer cells in live animals will be crucial to address this point. “At this stage, we cannot propose a specific molecular intervention to combat cancer metastasis, but we believe that the molecules and pathway we identified in our study can be used as pharmacological targets for possible cancer therapies”, Valverde explains. 

    Reference articles:

    Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis

    Yuqi Zhang, Yizeng Li, Keyata N. Thompson, Konstantin Stoletov, Qinling Yuan, Kaustav Bera, Se Jong Lee, Runchen Zhao, Alexander Kiepas, Yao Wang, Panagiotis Mistriotis, Selma A. Serra, John D. Lewis, Miguel A. Valverde, Stuart S. Martin, Sean X. Sun & Konstantinos Konstantopoulos. Nature Communications volume 13, Article number: 6128 (2022) https://doi.org/10.1038/s41467-022-33683-1

    Extracellular fluid viscosity enhances cell migration and cancer dissemination.

    Kaustav Bera, Alex Kiepas, Inês Godet, Yizeng Li,  Pranav Mehta,  Brent Ifemembi, Colin D. Paul, Anindya Sen,  Selma A. Serra, Konstantin Stoletov, Jiaxiang Tao, Gabriel Shatkin, Se Jong Lee, Yuqi Zhang, Adrianna Boen, Panagiotis Mistriotis, Daniele M. Gilkes, John D. Lewis, Chen-Ming Fan, Andrew P. Feinberg, Miguel A. Valverde, Sean X. Sun, Konstantinos Konstantopoulos.  Nature (2022) www.nature.com/articles/s41586-022-05394-6

    [ad_2]

    Universitat Pompeu Fabra- Barcelona

    Source link

  • DNA ‘Nanotransporters’ to treat cancer

    DNA ‘Nanotransporters’ to treat cancer

    [ad_1]

    Newswise — A team of Canadian researchers from Université de Montréal has designed and validated a new class of drug transporters made of DNA that are 20,000 times smaller than a human hair and that could improve how cancers and other diseases are treated

    Reported in a new study in Nature Communications, these molecular transporters can be chemically programmed to deliver optimal concentration of drugs, making them more efficient than current methods.

    Optimal dosing at all times: a medical challenge

    One of the key ways to successfully treat disease is to provide and maintain a therapeutic drug dosage throughout treatment. Sub-optimal therapeutic exposure reduces efficiency and typically leads to drug resistance, while overexposure increases side effects.

    Maintaining an optimal concentration of drugs in the blood remains a major challenge in modern medicine. Since most drugs undergo rapid degradation, patients are forced to (and often forget) to take multiple doses at regular intervals. And because each patient has a distinct pharmacokinetic profile, the drugs concentration in their blood varies significantly.

    Observing that only about 50 per cent of cancer patients get an optimal drug dosage during certain chemotherapy, UdeM Chemistry associate professor Alexis Vallée-Bélisle, an expert in bio-inspired nanotechnologies, started to explore how biological systems control and maintain the concentration of biomolecules.

    “We have found that living organisms employ protein transporters that are programmed to maintain precise concentration of key molecules such as thyroid hormones, and that the strength of the interaction between these transporters and their molecules dictates the precise concentration of the free molecule,” he said.

    This simple idea led Valléé-Belisle – who holds a Canada Research Chair in bioengineering and bionanotechnology – and his research team to start developing artificial drug transporters that mimic the natural effect of maintaining a precise concentration of a drug during treatment.

    UdeM PhD student Arnaud Desrosiers, the first author of the study, initially identified and developed two DNA transporters: one for quinine, an antimalarial, and the other for doxorubicin, a commonly used drug for treating breast cancer and leukemia.

    He then demonstrated that these artificial transporters could be readily programmed to deliver and maintain any specific concentration of drug.

    “More interestingly, we also found that these nanotransporters could also be employed as a drug reservoir to prolong the effect of the drug and minimize its dosage during treatment,” said  Desrosiers.

    “Another impressive feature of these nanotransporters,” he added, “is that they can be directed to specific parts of the body where the drug is most needed – and that, in principle, should reduce most side effects.”

    Nanotreated mice: reduced cardiotoxicity

    To demonstrate the effectiveness of these nanotransporters, the researchers teamed up with Jeanne Leblond-Chain, a pharmacist at Université de Bordeaux, in France; Luc DesGroseillers, a biochemist at UdeM; Jérémie Berdugo, a pathologist at UdeM; Céline Fiset, a pharmacist at the Montreal Heart Institute; and Vincent De Guire, a clinical biochemist at the UdeM-affiliated Maisonneuve-Rosemont Hospital.

    Using the new drug transporter developed for doxorubicin, the team demonstrated that a specific drug-transporter formulation allows doxorubicin to be maintained in the blood and drastically reduces its diffusion towards key organs such as the heart, lungs and pancreas.

    In mice treated with this formulation, doxorubicin was maintained 18 times longer in the blood and cardiotoxicity was reduced as well, keeping the mice more healthy as evidenced by their normal weight gain. 

    “Another great property of our nanotransporters is their high versatility,” said Vallée-Bélisle.

    “For now, we have demonstrated the working principle of these nanotransporters for two different drugs. But thanks to the high programmability of DNA and protein chemistries, one can now design these transporters to precisely deliver a wide range of threrapeutic molecules.”

    And, he added, “additionally, these transporters could also be combined with human-designed liposomic transporters that are now being employed to deliver drugs at various rates.”

    A clinical study for blood cancers?

    The researchers are now eager to validate the clinical efficiency of their discovery. Since their doxorubicin nanotransporter is programmed to optimally maintain the drug in blood circulation, it could be deal to treat blood cancers, they believe.

    “We envision that similar nanotransporters may also be developed to deliver drugs to other specific locations in the body and maximize the presence of the drug at tumor sites,” said Vallée-Bélisle. “This would drastically improve the efficiency of drugs as well as decrease their side effects.”

    [ad_2]

    Universite de Montreal

    Source link

  • Flood Modeling Framework Reveals Heightened Risk and Disparities in Los Angeles

    Flood Modeling Framework Reveals Heightened Risk and Disparities in Los Angeles

    [ad_1]

    Newswise — Irvine, Calif., Oct. 31, 2022 – Flood risk in Los Angeles is vastly larger than previously indicated by federally defined flood maps, and low-income and marginalized communities face a significantly higher threat, according to a study led by researchers at the University of California, Irvine.

    The findings are the product of a recently developed high-resolution flood modeling platform that can assess risk every 10 feet across the 2,700-square-mile expanse of the Greater Los Angeles basin. The framework, described in a paper published today in Nature Sustainability, connects hazards from rainfall, stream flow and storm tides with demographic data including population density, ethnicity, race and economic disadvantage.

    “We have developed an innovative, new flood risk modeling platform that, for the first time, enables household exposure and inequalities to be systematically quantified across major metro regions,” said lead author Brett Sanders, UCI professor of civil and environmental engineering. “This platform could, in principle, be applied everywhere to not only assess risks but measure the efficacy and equity of proposed solutions. And because the modeling is at a very fine resolution, anyone can immediately visualize the risk and contemplate how it might impact them.”

    A 100-year flood event in Los Angeles would expose more than 400,000 people to danger, and property damage could exceed $50 billion. According to the UCI researchers, losses would be comparable to those felt in severe hurricanes such as Katrina in 2005, Sandy in 2012, and Irma and Harvey in 2017, each of which incurred tens of billions of dollars in damages and displaced hundreds of thousands of people.

    Los Angeles is less at risk of impact from a tropical cyclone – the most common source of flooding in the southeastern United States – but Southern California is subject to occasionally catastrophic levels of precipitation from climate change-driven atmospheric river events.

    “The impacts of a severe flood would not be evenly distributed across Angelinos,” Sanders said. “Disadvantaged communities are disproportionately affected, and they’re less well protected. Recovery from floods is often prolonged and incomplete in these areas due to unequal government responses, which further exacerbate the inequities.”

    A sizeable portion of the risk – and the inequality in possible outcomes – in Greater Los Angeles comes from the region’s built environment, according to the researchers.

    “The impacts of a severe flood would not be evenly distributed across Angelinos. Disadvantaged communities are disproportionately affected, and they’re less well protected,” says Brett Sanders, UCI professor of civil and environmental engineering, here walking in the Santa Ana River channel. Jo Kwon / Spectrum News

    “Recent flooding disasters across the U.S. have demonstrated that cities are underprepared and that infrastructure is undersized,” said co-author Richard Matthew, UCI professor of urban planning and public policy. “As we saw in Texas and Florida recently, areas exposed to flood risk have been underestimated by previous mapping, especially among disadvantaged communities, and this is the case here in Los Angeles and Orange County too.”

    Matthew noted that the drivers of disaster differ from inland to coastal areas. Poorer regions are more affected by intense rainfall, causing runoff to collect in streets and overwhelm flood channels, while more affluent communities along the coast are more vulnerable to flooding from storm tides and waves. Each set of hazards requires different mitigation measures, he stressed.

    “The development of this modeling framework is especially timely given that the U.S. is increasingly focused on climate change, committed to infrastructure investments, concerned about social justice, and in need of tools that facilitate community participation in infrastructure planning and design,” Sanders said.

    The project received financial support from the National Science Foundation, high-performance computing assistance from the National Center for Atmospheric Research’s Computational and Information Systems Laboratory in Wyoming, and data from Los Angeles County and Orange County. Additional researchers included Amir AghaKouchak, Steven Davis, Daniel Kahl, Jochen Schubert and Nicola Ulibarri of UCI; Katharine Mach of the University of Miami; David Brady of UC Riverside; and Fonna Forman of UC San Diego.

    About the University of California, Irvine: Founded in 1965, UCI is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit www.uci.edu.

    Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

    NOTE TO EDITORS: PHOTO AVAILABLE AT
    https://news.uci.edu/2022/10/31/uci-flood-modeling-framework-reveals-heightened-risk-and-disparities-in-los-angeles

    [ad_2]

    University of California, Irvine

    Source link

  • Reward for Cooperative Behavior

    Reward for Cooperative Behavior

    [ad_1]

    Newswise — Researchers at the Max Planck Institute in Plön show that reputation plays a key role in determining which rewarding policies people adopt. Using game theory, they explain why individuals learn to use rewards to specifically promote good behaviour.

    Often, we use positive incentives like rewards to promote cooperative behaviour. But why do we predominantly reward cooperation? Why is defection rarely rewarded? Or more generally, why do we bother to engage in any form of rewarding in the first place? Theoretical work done by researchers Saptarshi Pal and Christian Hilbe at the Max Planck Research Group ‘Dynamics of Social Behaviour’ suggests that reputation effects can explain why individuals learn to reward socially.

    With tools from evolutionary game theory, the researchers construct a model where individuals in a population (the players) can adopt different strategies of cooperation and rewarding over time. In this model, the players’ reputation is a key element. The players know, with a degree of certainty (characterized by the information transmissibility of the population), how their interaction partners are going to react to their behaviour (that is, which behaviours they deem worthy of rewards). If the information transmissibility is sufficiently high, players learn to reward cooperation. In contrast, without sufficient information about peers, players refrain from using rewards. The researchers show that these effects of reputation also play out in a similar way when individuals interact in groups with more than two individuals.

    Antisocial rewarding

    In addition to highlighting the role of reputation in catalyzing cooperation and social rewarding, the scientists identify a couple of scenarios where antisocial rewarding may evolve. Antisocial rewarding either requires populations to be assorted or rewards to be mutually beneficial for both the recipient and the provider of the reward. “These conditions under which people may learn to reward defection are however a bit restrictive since they additionally require information to be scarce” adds Saptarshi Pal.

    The results from this study suggest that rewards are only effective in promoting cooperation when they can sway individuals to act opportunistically. These opportunistic players only cooperate when they anticipate a reward for their cooperation. A higher information transmissibility increases both, the incentive to reward others for cooperating, and the incentive to cooperate in the first place. Overall, the model suggests that when people reward cooperation in an environment where information transmissibility is high, they ultimately benefit themselves. This interpretation takes the altruism out of social rewarding – people may not use rewards to enhance others’ welfare, but to help themselves.

    [ad_2]

    Max Planck Society (Max-Planck-Gesellschaft)

    Source link

  • The Origin-of-Life Molecule, a Key to Cancer Research

    The Origin-of-Life Molecule, a Key to Cancer Research

    [ad_1]

    Newswise — RNA, the molecule that gave rise to life, has been shown to be essential for repairing human genetic material and preventing mutations that might lead to developing cancer. Recent advances in research, such as those published by the research team of Daniel Gómez Cabello at the University of Seville, propose this compound as a therapeutic target for developing tailored strategies for treating cancer.

    The RNA polymerase enzyme, the RNA production machine in cells, is essential for repairing breakages in human DNA safely and reliably. RNA production is essential for healthy cells but especially for tumour cells, which require much more activity by this enzyme to grow uncontrolled.

    The study revealed that RNA synthesis inhibition with the THZ1 compound and analogues after therapies that cause DNA breakages, such as radiation therapy, greatly increases tumour cells’ sensitivity to death. “This study provides clues on how to improve conventional therapies and achieve a higher success rate with treatments. Although there is still a long way to go to be able to use these RNA polymerase inhibitors in the clinical setting, clinical trials are currently underway based on this enzyme for treating cancer”, explained the Principal Investigator, Daniel Gómez-Cabello. “Increasing the knowledge on how to use these compounds in a safer and more tailored manner allows us to address as best as possible the treatment of cancer”, added the researcher Diana Aguilar-Morante, the study’s co-author.

    This research by the Biomedical Institute of Seville and the University of Seville, in collaboration with the Danish Cancer Society, has been published in the prestigious journal Nature Communications. Both researchers return to Spain from Denmark and have been able to continue their research thanks to contracts funded by the Government of Andalusia and the Spanish Association against Cancer (AECC). “Thanks to the AECC, we have been able to continue with these studies and move this project forward”, explained the author.

    Currently, these researchers are working on the mechanisms of how RNA, the original molecule that enables life, can serve as a tool for treating diseases. “Once we have observed that selectively inhibiting RNA production boosts the utility of radiation therapy in cancer cells and does not drastically affect the rest of the cells, we will start researching it in various types of cancer, such as glioblastoma and paediatric neuroblastoma”, commented Diana Aguilar-Morante. “At this point, our challenge will be to improve the efficiency of these new RNA production inhibitors and reduce the side effects that can occur in patients with cancer”, stated Gómez-Cabello.

    RNA, the molecule that gave rise to life, has been shown to be essential for repairing human genetic material and preventing mutations that might lead to developing cancer. Recent advances in research, such as those published by the research team of Daniel Gómez Cabello at the University of Seville, propose this compound as a therapeutic target for developing tailored strategies for treating cancer.

    The RNA polymerase enzyme, the RNA production machine in cells, is essential for repairing breakages in human DNA safely and reliably. RNA production is essential for healthy cells but especially for tumour cells, which require much more activity by this enzyme to grow uncontrolled.

    The study revealed that RNA synthesis inhibition with the THZ1 compound and analogues after therapies that cause DNA breakages, such as radiation therapy, greatly increases tumour cells’ sensitivity to death. “This study provides clues on how to improve conventional therapies and achieve a higher success rate with treatments. Although there is still a long way to go to be able to use these RNA polymerase inhibitors in the clinical setting, clinical trials are currently underway based on this enzyme for treating cancer”, explained the Principal Investigator, Daniel Gómez-Cabello. “Increasing the knowledge on how to use these compounds in a safer and more tailored manner allows us to address as best as possible the treatment of cancer”, added the researcher Diana Aguilar-Morante, the study’s co-author.

     

    This research by the Biomedical Institute of Seville and the University of Seville, in collaboration with the Danish Cancer Society, has been published in the prestigious journal Nature Communications. Both researchers return to Spain from Denmark and have been able to continue their research thanks to contracts funded by the Government of Andalusia and the Spanish Association against Cancer (AECC). “Thanks to the AECC, we have been able to continue with these studies and move this project forward”, explained the author.

    Currently, these researchers are working on the mechanisms of how RNA, the original molecule that enables life, can serve as a tool for treating diseases. “Once we have observed that selectively inhibiting RNA production boosts the utility of radiation therapy in cancer cells and does not drastically affect the rest of the cells, we will start researching it in various types of cancer, such as glioblastoma and paediatric neuroblastoma”, commented Diana Aguilar-Morante. “At this point, our challenge will be to improve the efficiency of these new RNA production inhibitors and reduce the side effects that can occur in patients with cancer”, stated Gómez-Cabello.

    [ad_2]

    University of Seville

    Source link

  • New Scottish Fossil Sheds Light on the Origins of Lizards

    New Scottish Fossil Sheds Light on the Origins of Lizards

    [ad_1]

    Newswise — A fossil discovery from Scotland has provided new information on the early evolution of lizards, during the time of the dinosaurs.

    The tiny skeleton discovered on the Isle of Skye, called Bellairsia gracilis, is only 6 cm long and dates from the Middle Jurassic, 166 million years ago. The exceptional new fossil comprises a near-complete skeleton in life-like articulation, missing only the snout and tail. This makes it the most complete fossil lizard of this age anywhere in the world.

    Bellairsia has a mixture of ancestral and modern features in its skeleton, providing evidence of what the ancestor of today’s lizards (which are part of the wider animal group known as ‘squamates’) might have looked like.

    The research, a joint project between researchers at the universities of Warsaw, Oxford and UCL, is reported in the journal Nature. First author Dr Mateusz Tałanda (University of Warsaw and UCL) said: ‘This little fossil lets us see evolution in action. In palaeontology you rarely have the opportunity to work with such complete, well-preserved fossils coming from a time about which we know so little.’

    The fossil was found in 2016 by a team led by Oxford University and National Museums Scotland. It is one of several new fossil discoveries from the island, including early amphibians and mammals, which are revealing evolution of important animal groups that persist to the present day.

    Dr Tałanda commented: ‘Bellairsia has some modern lizard features, like traits related to cranial kinesis – that’s the movement of the skull bones in relation to one another. This is an important functional feature of many living squamates.’

    Co-author Dr Elsa Panciroli (Oxford University Museum of Natural History and National Museums Scotland) who discovered the fossil, said: ‘It was one of the first fossils I found when I began working on Skye. The little black skull was poking out from the pale limestone, but it was so small I was lucky to spot it. Looking closer I saw the tiny teeth, and realised I’d found something important, but we had no idea until later that almost the whole skeleton was in there.’

    Squamates are the living group that includes lizards and snakes, and comprises more than 10,000 species today, making them one of the most species-rich living vertebrate animal groups. They include animals as diverse as snakes, chameleons, and geckos, found around the world. The group is characterised by numerous specialised features of the skull and rest of the skeleton.

    Although we know the earliest origins of squamates lie 240 million years ago in the Triassic, a lack of fossils from the Triassic and Jurassic has made their early evolution and anatomy difficult to trace.

    Analysing the new fossil alongside living and extinct fossil squamates confirms Bellairsia belongs to the ‘stem’ of the squamate family tree. This means that it split from other lizards just before the origin of modern groups. The research also supports the finding that geckos are a very early branching lineage, and that the enigmatic fossil Oculudentavis, previously suggested to be a dinosaur, is also a stem squamate.

    To study the specimen, the team used X-ray computed tomography (CT) which, like medical CT, allows for non-invasive 3D imaging. This allowed the researchers to image the entire fossil, even though most of the specimen is still hidden by surrounding rock. Whereas medical scanners work at the millimetre scale, the Oxford University CT scanner revealed details down to a few tens of micrometres.

    Parts of the skeleton were then imaged in even greater detail, including the skull, hindlimbs and pelvis, at the European Synchrotron (ESRF, Grenoble, France). The intensity of the synchrotron beam permits a resolution of 4 micrometres, revealing details of the smallest bones in the skeleton.

    Co-author Professor Roger Benson (Department of Earth Sciences, University of Oxford), said: ‘Fossils like this Bellairsia specimen have huge value in filling gaps in our understanding of evolution and the history of life on Earth. It used to be almost impossible to study such tiny fossils like this, but this study shows the power of new techniques including CT scanning to image these non-destructively and in great detail.’

    Co-author Professor Susan Evans (UCL), who first described and named Bellairsia from a few jaw and skull bones from Oxfordshire 25 years ago, added: ‘It is wonderful to have a complete specimen of this tantalising little lizard, and to see where it fits in the evolutionary tree. Through fossils like Bellairsia we are gaining a better understanding of early lizard anatomy. Angus Bellairs, the lizard embryologist after which Bellairsia was originally named, would have been delighted.’

    The study was led by Dr Mateusz Tałanda (University of Warsaw) and involved researchers from the University of Oxford’s Earth Sciences Department, Oxford University Museum of Natural History, UCL (University College London), the European Synchrotron Radiation Facility, the Natural History Museum in London and National Museums of Scotland.

    Funding was provided by the Ministry of Science and Higher Education, Poland. The John Muir Trust provided access to the Elgol Coast Site of Special Scientific Interest, and NatureScot granted permits for fossil collection.

     

    Notes to Editors

    The study will be published in Nature. The DOI number for this paper will be 10.1038/s41586-022-05332-6. Once the paper has been published online, it will be available at the following URL: https://www.nature.com/articles/s41586-022-05332-6

     

    About the University of Oxford

    Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the seventh year running, and ​number 2 in the QS World Rankings 2022. At the heart of this success are the twin-pillars of our ground-breaking research and innovation and our distinctive educational offer.

    Oxford is world-famous for research and teaching excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research alongside our personalised approach to teaching sparks imaginative and inventive insights and solutions.

    Through its research commercialisation arm, Oxford University Innovation, Oxford is the highest university patent filer in the UK and is ranked first in the UK for university spinouts, having created more than 200 new companies since 1988. Over a third of these companies have been created in the past three years. The university is a catalyst for prosperity in Oxfordshire and the United Kingdom, contributing £15.7 billion to the UK economy in 2018/19, and supports more than 28,000 full time jobs.

    About UCL – London’s Global University

    UCL is a diverse global community of world-class academics, students, industry links, external partners, and alumni. Our powerful collective of individuals and institutions work together to explore new possibilities.

    Since 1826, we have championed independent thought by attracting and nurturing the world’s best minds. Our community of more than 43,800 students from 150 countries and over 14,300 staff pursues academic excellence, breaks boundaries and makes a positive impact on real world problems.

    We are consistently ranked among the top 10 universities in the world and are one of only a handful of institutions rated as having the strongest academic reputation and the broadest research impact.

    We have a progressive and integrated approach to our teaching and research – championing innovation, creativity and cross-disciplinary working. We teach our students how to think, not what to think, and see them as partners, collaborators and contributors.  

    For almost 200 years, we are proud to have opened higher education to students from a wide range of backgrounds and to change the way we create and share knowledge.

    We were the first in England to welcome women to university education and that courageous attitude and disruptive spirit is still alive today. We are UCL.

    www.ucl.ac.uk | Follow @uclnews on Twitter | Read news at www.ucl.ac.uk/news/ | Listen to UCL podcasts on SoundCloud | Find out what’s on at UCL Minds

    About the Natural History Museum

    The Natural History Museum is both a world-leading science research centre and the most-visited indoor attraction in the UK last year. With a vision of a future in which both people and the planet thrive, it is uniquely positioned to be a powerful champion for balancing humanity’s needs with those of the natural world. It is custodian of one of the world’s most important scientific collections comprising over 80 million specimens accessed by researchers from all over the world both in person and via over 30 billion digital data downloads to date. The Museum’s 350 scientists are finding solutions to the planetary emergency from biodiversity loss through to the sustainable extraction of natural resources. The Museum uses its global reach and influence to meet its mission to create advocates for the planet – to inform, inspire and empower everyone to make a difference for nature. We welcome millions of visitors through our doors each year, our website has had 17 million visits in the last year and our touring exhibitions have been seen by around 20 million people in the last 10 years. 

    [ad_2]

    University of Oxford

    Source link

  • Engineers Record Neurons to Pinpoint Synaptic Links

    Engineers Record Neurons to Pinpoint Synaptic Links

    [ad_1]

    Newswise — HOUSTON – (Oct. 19, 2022) – It’s a mystery how human thoughts and dreams emerge from electrical pulses in the brain’s estimated 100 trillion synapses, and Rice University neuroengineer Chong Xie dreams of changing that by creating a system that can record all the electrical activity in a living brain.

    In a recently published study in Nature Biomedical Engineering, Xie and colleagues described their latest achievement toward that goal, a 3D electrode array that allows them to map the locations and activity of up to 1 million potential synaptic links in a living brain based on recordings of the millisecond-scale evolution of electrical pulses in tens of thousands of neurons in a cubic millimeter of brain tissue.

    “The thing that is novel about this work is the recording density,” said Xie, an associate professor of electrical and computer engineering at Rice and a core member of the Rice Neuroengineering Initiative. “Microcircuits in the brain are very mysterious. We don’t have many ways to map their activity, especially volumetrically. We want to deliver very dense recordings of the cortex because those are important, scientifically, for understanding how brain circuits work.”

    Xie collaborated on the study with colleagues from Rice and the University of California, San Francisco, including Loren Frank of UCSF and co-corresponding author Lan Luan of Rice.

    Neurons are small. Each cubic millimeter of brain tissue contains about 100,000. That density is roughly the same for humans and other mammals, including the rodents that are the subject of experiments in Xie’s lab. The processing power of the brain arises from synaptic connections between neurons. Synaptically linked neuron pairs are connected by narrow bridges of tissue called axons, which are just a few millionths of a meter in diameter.

    Xie’s team has spent years developing a material called nanoelectronic thread (NET) that is thin, ultraflexible and biocompatible, a trifecta of properties for making minimally invasive electrode implants. In previous studies, Xie’s team has demonstrated techniques for emplanting tightly packed NET arrays of up to 128 electrodes. The researchers also showed their arrays could stay in place for up to 10 months,  recording the pulsed spikes of electricity, or action potentials, in nearby neurons.

    “When neurons fire action potentials, there are very faint electrical signals coming out of them,” Xie said. “You have to place the electrodes very close to each neuron in order to capture that signal. Usually, that means a distance less than 100 microns.”

    Using electrodes to record neuronal spikes has been a primary technique in neuroscience for decades, but the evolution of electrode materials has gradually transformed the implantation of neural electrodes from highly invasive procedures that damaged the very brain tissue the electrodes were meant to measure to procedures that result in no measurable tissue damage.

    One of the primary focuses of Xie’s lab is scaling up the size of its implant arrays. In the new study, Xie and colleagues, including Hanlin Zhu, one of the lead graduate students on the project, implanted arrays of 1,024 NET electrodes in a 1 cubic millimeter volume of brain tissue. 

    “The primary signals we try to measure are the electrical spikes coming from neurons,” Xie said. “That’s how they communicate. And one thing we care a lot about and really want to understand is how neurons are connected.”

    Xie said there is no straightforward way to probe synaptic connections

    “Axons can be very long, and each neuron can be connected by many thousands of others,” he said. “It’s a very, very, very messy network. And probing it is an extremely challenging task, especially while the brain is working.”

    The density of the new electrode array, together with its ability to capture millisecond-by-millisecond changes in the electrical spikes of individual neurons allowed Xie and co-authors to decipher potential synaptic links between neuron pairs.

    “When the synapse works, you usually see a typical pattern when you look at the firing activity of the two neurons,” Xie said.

    It takes a bit of time for the electrical impulse that starts in the presynaptic neurons to propagate down the axon and activate the postsynaptic neuron, he said.

    “We record many, many spikes, and then we need to sort the spikes and attribute each of them to individual neurons,” he said. “We know the location of each electrode, or channel. And each channel records no more than a few neurons at a time. Each neuron is also typically recorded by more than one contact as well. So, you can do something akin to triangulation to identify the location of individual neurons.”

    Once the neurons are mapped, it’s relatively easy to calculate the distance between them and from that, the propagation time for synaptic activation. 

    The 1,024-electrode array gave Xie’s team a ratio of approximately one electrode per 100 neurons in the cubic millimeter volume of brain tissue under study. The lab is working to create denser arrays that pack more electrodes into the same volume.

    The vast majority of neurons in people’s brains are unused, despite the fact that our brains typically consume about as much energy as can be supplied by the body. Neuroscientists don’t fully understand why the brain has so many unused neurons, and Xie said that’s a factor his team considers in the design of their electrode arrays.

    “I want to capture as much of the interactivity as possible,” he said. “I would argue that we don’t need a 1-to-1 ratio of electrodes to neurons to capture all of it, and it is indeed my dream to capture all the interactivity.”

    The research was supported by the National Institute of Neurological Disorders and Stroke (R01NS102917, U01NS115588, R01NS109361, UF1NS107667), the National Heart, Lung and Blood Institute (K25HL140153), the Welch Foundation (F-1941-20170325) and the Howard Hughes Medical Institute.

    -30-

    [ad_2]

    Rice University

    Source link

  • Study reveals new insights into how fast-moving glaciers may contribute to sea level rise

    Study reveals new insights into how fast-moving glaciers may contribute to sea level rise

    [ad_1]

    Newswise — Climate change is resulting in sea level rise as ice on land melts and oceans expand. How much and how fast sea levels will rise in the near future will depend, in part, on the frequency of glacier calving events. These occur when large chunks of ice detach from glaciers that terminate in the ocean (known as tidewater glaciers), and fall into coastal fjords as icebergs. The faster these glaciers flow over the ground towards the ocean, the more ice enters the ocean, increasing the rate of sea level rise.

    During the warmer summer months, the surface of Greenland’s glaciers can melt and form large lakes that may then drain through to the base of the glacier. Studies on the inland Greenland ice sheet have shown that this reduces friction between the ice and ground, causing the ice to slide faster for a few days. Up to now, however, it has been unclear whether such drainage events affect the flow speed of tidewater glaciers, and hence the rate of calving events.

    To investigate this, a research team from Oxford University’s Earth Sciences department, the Oxford University Mathematical Institute, and Columbia University used Global Positioning System (GPS) observations of the flow speed of Helheim Glacier—the largest single-glacier contributor to sea level rise in Greenland. The GPS captured a near perfect natural experiment: high-temporal-resolution observations of the glacier’s flow response to lake drainage.

    The results found that Helheim Glacier behaved very differently to the inland ice sheet, which shows a fast, downhill movement during lake drainage events. In contrast, Helheim Glacier exhibited a relatively small ‘pulse’ of movement where the glacier sped up for a short amount of time and then moved slower, resulting in no net increase in movement.

    Using a numerical model of the subglacial drainage system, the researchers discovered that this observation was likely caused by Helheim glacier having an efficient system of channels and cavities along its bed. This allows the draining waters to be quickly evacuated from the glacier bed without causing an increase in the total net movement.

    Although this appears positive news in terms of sea level rise implications, the researchers suspected that a different effect may occur for glaciers without an efficient drainage system where surface melt is currently low but will increase in future due to climate change (such as in Antarctica).

    They ran a mathematical model based on the conditions of colder, Antarctic tidewater glaciers. The results indicated that lake drainages under these conditions would produce a net increase in glacier movement. This was largely due to the less efficient winter-time subglacial drainage system not being able to evacuate flood waters quickly. As of yet, however, there are no in situ observations of Antarctic tidewater glacier responses to lake drainage.

    The study calls into question some common approaches for inferring glacial drainage systems based on glacier velocities recorded using satellite observations (which are currently used in sea level rise models).

    Lead author Associate Professor Laura Stevens (Department of Earth Sciences, Oxford University) said: ‘What we’ve observed here at Helheim is that you can have a big input of meltwater into the drainage system during a lake drainage event, but that melt input doesn’t result in an appreciable change in glacier speed when you average over the week of the drainage event.’

    With the highest temporal resolution of satellite-derived glacier speeds currently available being roughly one week, lake drainage events like the one captured in the Helheim GPS data usually go unnoticed.

    ‘These tidewater glaciers are tricky,’ Associate Professor Stevens added. ‘We have a lot more to learn about how meltwater drainage operates and modulates tidewater-glacier speeds before we can confidently model their future response to atmospheric and oceanic warming.’

     

    About the University of Oxford

    Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the seventh year running, and ​number 2 in the QS World Rankings 2022. At the heart of this success are the twin-pillars of our ground-breaking research and innovation and our distinctive educational offer.

    Oxford is world-famous for research and teaching excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research alongside our personalised approach to teaching sparks imaginative and inventive insights and solutions.

    Through its research commercialisation arm, Oxford University Innovation, Oxford is the highest university patent filer in the UK and is ranked first in the UK for university spinouts, having created more than 200 new companies since 1988. Over a third of these companies have been created in the past three years. The university is a catalyst for prosperity in Oxfordshire and the United Kingdom, contributing £15.7 billion to the UK economy in 2018/19, and supports more than 28,000 full time jobs.

     

    [ad_2]

    University of Oxford

    Source link

  • New insights into how serotonin regulates behavior

    New insights into how serotonin regulates behavior

    [ad_1]

    Newswise — Ithaca, NY – Rates of anxiety and depression have been increasing around the world for decades, a trend that has been sharply exacerbated by the COVID-19 pandemic. New research led by the Boyce Thompson Institute’s Frank Schroeder could ultimately lead to new therapeutics to help relieve this global mental health burden.

    First discovered in the 1930s, serotonin is a neurotransmitter produced in many animals that mediates myriad behaviors, such as feeding, sleep, mood and cognition. Drugs that alter serotonin levels are the main weapon to treat psychological conditions like anxiety and depression, as well as eating disorders.

    As a simple model for neurobiology research, the microscopic roundworm Caenorhabditis elegans has been used extensively to study serotonin’s role in regulating behavior and food intake. For many years, researchers thought that serotonin was made in C. elegans by one specific molecular pathway, and that serotonin was then quickly degraded. Schroeder’s team and colleagues at Columbia University now demonstrated that both of those assumptions were not quite correct.

    “We discovered a second, parallel biosynthetic pathway that accounts for about half of the total serotonin produced in our model system,” said Schroeder.

    The findings are described in a paper published in Nature Chemical Biology on October 10.

    The work began about three years ago, when the researchers unexpectedly discovered an enzyme that converts serotonin into derivative compounds.

    “Most people in the field thought serotonin is made and then quickly broken down, but we found that, instead, it is used as a building block for other compounds that are responsible for some of serotonin’s activity,” explained Schroeder. “So, we decided to start at the beginning and see how serotonin is made, and once it is made then how is it converted into these new molecules.”

    Jingfang Yu, a graduate student in Schroeder’s lab and first author on the paper, further showed that the new serotonin derivatives affect feeding behavior.

    “When the worms lack endogenous serotonin, they tend to move quickly across the bacteria food lawn on an agar plate, and turn infrequently to explore the food,” Yu said. “We found this behavior can be alleviated by treating the worms with serotonin derivatives, suggesting these newly identified compounds contribute to effects previously attributed to serotonin.”

    The worm C. elegans is an excellent model for studying serotonin because the compound’s molecular signaling pathways are highly conserved across species, including in humans. For example, the researchers showed that in C. elegans a large portion of serotonin is made in the gut, which is also the case in humans.

    Schroeder said there are hints that human serotonin is converted into metabolites similar to the ones identified in C. elegans.

    “This research opens up the door for many more avenues of research in humans,” said Schroeder, who is also a professor in the Department of Chemistry and Chemical Biology in the college of Arts and Sciences at Cornell University.

    “Are the analogous metabolites important in humans? What is the role of one manufacturing pathway versus the other? How are these manufacturing pathways and metabolites important for human behaviors, like mental health and feeding behaviors?” he asked.

    The researchers are currently exploring how the new serotonin derivatives affect behavior in C. elegans and whether similar serotonin metabolites exist in humans.

    About Boyce Thompson Institute:

    Opened in 1924, Boyce Thompson Institute is a premier life sciences research institution located in Ithaca, New York. BTI scientists conduct investigations into fundamental plant and life sciences research with the goals of increasing food security, improving environmental sustainability in agriculture, and making basic discoveries that will enhance human health. Throughout this work, BTI is committed to inspiring and educating students and to providing advanced training for the next generation of scientists. BTI is an independent nonprofit research institute that is also affiliated with Cornell University. For more information, please visit BTIscience.org.

    ###

    [ad_2]

    Boyce Thompson Institute

    Source link

  • Phage Trial to Treat CF Patients With Multi-Drug Resistant Bacterial Infections

    Phage Trial to Treat CF Patients With Multi-Drug Resistant Bacterial Infections

    [ad_1]

    Newswise — Cystic fibrosis (CF) is an inherited disorder that causes severe damage to the lungs and other organs in the body. Nearly 40,000 children and adults in the United States live with CF, an often difficult existence exacerbated by an opportunistic bacterium called Pseudomonas aeruginosa, which is a major cause of chronic, life-threatening lung infections.

    P. aeruginosa infections are not easily treated. The pathogen can be resistant to most current antibiotics. However, an early-stage clinical trial led by scientists at University of California San Diego School of Medicine, with collaborators across the country, has launched to assess the safety and efficacy of treating P. aeruginosa lung infections in CF patients with a different biological weapon: bacteriophages.

    Bacteriophages are viruses that have evolved to target and destroy specific bacterial species or strains. Phages are more abundant than all other life forms on Earth combined and are found wherever bacteria exist. Discovered in the early 20th century, they have long been investigated for their therapeutic potential, but increasingly so with the rise and spread of antibiotic-resistant bacteria.

    In 2016, scientists and physicians at UC San Diego School of Medicine and UC San Diego Health used an experimental intravenous phage therapy to successfully treat and cure colleague Tom Patterson, PhD, who was near death from a multidrug-resistant bacterial infection. Patterson’s was the first documented case in the U.S. to employ intravenous phages to eradicate a systemic bacterial infection. Subsequent successful cases helped lead to creation of the Center for Innovative Phage Applications and Therapeutics (IPATH) at UC San Diego, the first such center in North America.

    In 2020, IPATH researchers published data from 10 cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections, all at UC San Diego. In 7 of 10 cases, there was a successful outcome.

    The new phase 1b/2 clinical trial advances this work. The trial is co-led by Robert Schooley, MD, professor of medicine and an infectious disease expert at UC San Diego School of Medicine who is co-director of IPATH and helped lead the clinical team that treated and cured Patterson in 2016.

    It will consist of three elements, all intended to assess the safety and microbiological activity of a single dose of intravenous phage therapy in males and non-pregnant females 18 years and older, all residing in the United States.

    The dose is a cocktail of four phages that target P. aeruginosa, a bacterial species commonly found in the environment (soil and water) that can cause infections in the blood, lungs and other parts of the body after surgery.

    For persons with CF, P. aeruginosa is a familiar and sometimes fatal foe. The Cystic Fibrosis Foundation estimates that roughly half of all people with CF are infected by Pseudomonas. Previous studies have indicated that chronic P. aeruginosa lung infections negatively impact life expectancy of CF patients, who currently live, on average, to approximately 44 years.

    In the first stage of the trial, two “sentinel subjects” will receive one of three dosing strengths of the IV bacteriophage therapy. If, after 96 hours and no adverse effects, the second stage (2a) will enroll 32 participants into one of four arms: the three doses and a placebo.

    After multiple follow-up visits over 30 days and an analysis of which dosing strength exhibited the most favorable safety and microbiologic activity, i.e. most effective at reducing P. aeruginosa, stage 2b will recruit up to 72 participants to either receive that IV dose or a placebo.

    Enrollment will occur at 16 cystic fibrosis clinical research sites in the United States, including UC San Diego. It is randomized, double-blind and placebo-controlled. The trial is being conducted through the Antibacterial Resistance Leadership Group and funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, with additional support for the UC San Diego trial site from the Mallory Smith Legacy Fund.

    Mallory Smith was born with cystic fibrosis and died in 2017 at the age of 25 from a multidrug-resistant bacterial infection following a double lung transplant.

    “Mallory’s death was a preventable tragedy,” said her mother, Diane Shader Smith. “We are supporting the IPATH trial through Mallory’s Legacy Fund because Mark and I deeply believe in the promise of phage therapy to save lives by combatting multidrug-resistant bacteria.”

    In an article published in 2020 in Nature Microbiology, Schooley and Steffanie Strathdee, PhD, associate dean of global health sciences and Harold Simon Professor in the Department of Medicine and IPATH co-director, describe phages as “living antibiotics.”

    As such, said Schooley, researchers need to learn how to best use them to benefit patients through the same systematic clinical trials employed to evaluate traditional antibiotics.

    The primary objectives of the new trial are first to determine the safety of a single IV phage dose in clinically stable patients with CF who are also infected with P. aeruginosa, said Schooley.

    “Second, it’s to describe the microbiological activity of a single IV dose and third, to assess the benefit-to-risk profile for CF patients with P. aeruginosa infections. This is one study, with a distinct patient cohort and carefully prescribed goals. It’s a step, but an important one that can, if ultimately proven successful, help address the growing, global problem of antimicrobial resistance and measurably improve patients’ lives.”

    Estimated study completion date is early 2025.

    For more information on the clinical trial and participant eligibility criteria, visit clinicaltrials.gov or visit IPATH and click on the Contact Us button.

    # # #

    [ad_2]

    University of California San Diego

    Source link

  • Age vs. genetics: Which is more important for determining how we age?

    Age vs. genetics: Which is more important for determining how we age?

    [ad_1]

    Newswise — Amid much speculation and research about how our genetics affect the way we age, a University of California, Berkeley, study now shows that individual differences in our DNA matter less as we get older and become prone to diseases of aging, such as diabetes and cancer.

    In a study of the relative effects of genetics, aging and the environment on how some 20,000 human genes are expressed, the researchers found that aging and environment are far more important than genetic variation in affecting the expression profiles of many of our genes as we get older. The level at which genes are expressed — that is, ratcheted up or down in activity — determines everything from our hormone levels and metabolism to the mobilization of enzymes that repair the body.

    “How do your genetics — what you got from your sperm donor and your egg donor and your evolutionary history — influence who you are, your phenotype, such as your height, your weight, whether or not you have heart disease?” said Peter Sudmant, UC Berkeley assistant professor of integrative biology and a member of the campus’s Center for Computational Biology. “There’s been a huge amount of work done in human genetics to understand how genes are turned on and off by human genetic variation. Our project came about by asking, ‘How is that influenced by an individual’s age?’ And the first result we found was that your genetics actually matter less the older you get.”

    In other words, while our individual genetic makeup can help predict gene expression when we are younger, it is less useful in predicting which genes are ramped up or down when we’re older — in this study, older than 55 years. Identical twins, for example, have the same set of genes, but as they age, their gene expression profiles diverge, meaning that twins can age much differently from each other.

    The findings have implications for efforts to correlate diseases of aging with genetic variation in humans, Sudmant said. Such studies should perhaps focus less on genetic variants that impact gene expression when pursuing drug targets.

    “Almost all human common diseases are diseases of aging: Alzheimer’s, cancers, heart disease, diabetes. All of these diseases increase their prevalence with age,” he said. “Massive amounts of public resources have gone into identifying genetic variants that predispose you to these diseases. What our study is showing is that, well, actually, as you get older, genes kind of matter less for your gene expression. And so, perhaps, we need to be mindful of that when we’re trying to identify the causes of these diseases of aging.”

    Sudmant and his colleagues reported their results this week in the journal Nature Communications.

    Medawar’s hypothesis

    The findings are in line with Medawar’s hypothesis: Genes that are turned on when we are young are more constrained by evolution because they are critical to making sure we survive to reproduce, while genes expressed after we reach reproductive age are under less evolutionary pressure. So, one would expect a lot more variation in how genes are expressed later in life.

    “We’re all aging in different ways,” Sudmant said. “While young individuals are closer together in terms of gene expression patterns, older individuals are further apart. It’s like a drift through time as gene expression patterns become more and more erratic.”

    This study is the first to look at both aging and gene expression across such a wide variety of tissues and individuals, Sudmant said. He and his colleagues built a statistical model to assess the relative roles of genetics and aging in 27 different human tissues from nearly 1,000 individuals and found that the impact of aging varies widely — more than twentyfold — among tissues.

    “Across all the tissues in your body, genetics matters about the same amount. It doesn’t seem like it plays more of a role in one tissue or another tissue,” he said. “But aging is vastly different between different tissues. In your blood, colon, arteries, esophagus, fat tissue, age plays a much stronger role than your genetics in driving your gene expression patterns.”

    Sudmant and colleagues also found that Medawar’s hypothesis does not hold true for all tissues. Surprisingly, in five types of tissues, evolutionary important genes were expressed at higher levels in older individuals.

    “From an evolutionary perspective, it is counterintuitive that these genes should be getting turned on, until you take a close look at these tissues,” Sudmant said. These five tissues happen to be the ones that constantly turn over throughout our lifespan and also produce the most cancers. Every time these tissues replace themselves, they risk creating a genetic mutation that can lead to disease.

    “I guess this tells us a little bit about the limits of evolution,” he said. “Your blood, for instance, always has to proliferate for you to live, and so these super-conserved, very important genes have to be turned on late in life. This is problematic because it means that those genes are going to be susceptible to getting somatic mutations and getting turned on forever in a bad, cancerous way. So, it kind of gives us a little bit of a perspective on what the limitations of living are like. It puts bounds on our ability to keep living.”

    Sudmant noted that the study indirectly indicates the effect on aging of one’s environment, which is the impact of everything other than age and genetics: the air we breathe, the water we drink, the food we eat, but also our levels of physical exercise. Environment amounts to up to a third of gene expression changes with age.

    Sudmant is conducting similar analyses of the expressed genes in several other organisms — bats and mice — to see how they differ and whether the differences are related to these animals’ different lifespans.

    UC Berkeley graduate students Ryo Yamamoto and Ryan Chung are co-first authors of the paper. Other co-authors are Juan Manuel Vazquez, Huanjie Sheng, Philippa Steinberg and Nilah Ioannidis. The work was supported by the National Institute of General Medical Sciences (R35GM142916) of the National Institutes of Health.

    [ad_2]

    University of California, Berkeley

    Source link

  • Mapping human brain development

    Mapping human brain development

    [ad_1]

    Newswise — The human brain is probably the most complex organ in the entire living world and has long been an object of fascination for researchers. However, studying the brain, and especially the genes and molecular switches that regulate and direct its development, is no easy task.

    To date, scientists have proceeded using animal models, primarily mice, but their findings cannot be transferred directly to humans. A mouse’s brain is structured differently and lacks the furrowed surface typical of the human brain. Cell cultures have thus far been of limited value in this field, as cells tend to spread over a large area when grown on a culture dish; this does not correspond to the natural three-dimensional structure of the brain.

    Mapping molecular fingerprints

    A group of researchers led by Barbara Treutlein, ETH Professor at the Department of Biosystems Science and Engineering in Basel, has now taken a new approach to studying the development of the human brain: they are growing and using organoids – millimetre-sized three-dimensional tissues that can be grown from what are known as pluripotent stem cells.

    Provided these stem cells receive the right stimulus, researchers can program them to become any kind of cell present in the body, including neurons. When the stem cells are aggregated into a small ball of tissue and then exposed to the appropriate stimulus, they can even self-organise and form a three-dimensional brain organoid with a complex tissue architecture.

    In a new study just published in Nature, Treutlein and her colleagues have now studied thousands of individual cells within a brain organoid at various points in time and in great detail. Their goal was to characterise the cells in molecular-genetic terms: in other words, the totality of all gene transcripts (transcriptome) as a measure of gene expression, but also the accessibility of the genome as a measure of regulatory activity. They have managed to represent this data as a kind of map showing the molecular fingerprint of each cell within the organoid.

    However, this procedure generates immense data sets: each cell in the organoid has 20,000 genes, and each organoid in turn consists of many thousands of cells. “This results in a gigantic matrix, and the only way we can solve it is with the help of suitable programs and machine learning,” explains Jonas Fleck, a doctoral student in Treutlein’s group and one of the study’s co-lead authors. To analyse all this data and predict gene regulation mechanisms, the researchers developed their own program. “We can use it to generate an entire interaction network for each individual gene and predict what will happen in real cells when that gene fails,” Fleck says.

    Identifying genetic switches

    The aim of this study was to systematically identify those genetic switches that have a significant impact on the development of neurons in the different regions of brain organoids.

    With the help of a CRISPR-Cas9 system, the ETH researchers selectively switched off one gene in each cell, altogether about two dozen genes simultaneously in the entire organoid. This enabled them to find out what role the respective genes played in the development of the brain organoid.

    “This technique can be used to screen genes involved in disease. In addition, we can look at the effect these genes have on how different cells within the organoid develop,” explains Sophie Jansen, also a doctoral student in Treutlein’s group and the second co-lead author of the study.

    Checking pattern formation in the forebrain

    To test their theory, the researchers chose the GLI3 gene as an example. This gene is the blueprint for the transcription factor of the same name, a protein that docks onto certain sites on DNA in order to regulate another gene. When GLI3 is switched off, the cellular machinery is prevented from reading this gene and transcribing it into an RNA molecule.

    In mice, mutations in the GLI3 gene can lead to malformations in the central nervous system. Its role in human neuronal development was previously unexplored, but it is known that mutations in the gene lead to diseases such as Greig cephalopolysyndactyly and Pallister Hall Syndromes.

    Silencing this GLI3 gene enabled the researchers both to verify their theoretical predictions and to determine directly in the cell culture how the loss of this gene affected the brain organoid’s further development. “We have shown for the first time that the GLI3 gene is involved in the formation of forebrain patterns in humans. This had previously been shown only in mice,” Treutlein says.

    Model systems reflect developmental biology

    “The exciting thing about this research is that it lets you use genome-wide data from so many individual cells to postulate what roles individual genes play,” she explains. “What’s equally exciting in my opinion is that these model systems made in a Petri dish really do reflect developmental biology as we know it from mice.”

    Treutlein also finds it fascinating how the culture medium can give rise to self-organised tissue with structures comparable to those of the human brain – not only at the morphological level but also (as the researchers have shown in their latest study) at the level of gene regulation and pattern formation. “Organoids like this are truly an excellent way to study human developmental biology,” she points out.

    Versatile brain organoids

    Research on organoids made up of human cell material has the advantage that the findings are transferable to humans. They can be used to study not only basic developmental biology but also the role of genes in diseases or developmental brain disorders. For example, Treutlein and her colleagues are working with organoids of this type to investigate the genetic cause of autism and of heterotopia; in the latter, neurons appear outside their usual anatomical location in the cerebral cortex. 

    Organoids may also be used for testing drugs, and possibly for culturing transplantable organs or organ parts. Treutlein confirms that the pharmaceutical industry is very interested in these cell cultures.

    However, growing organoids takes both time and effort. Moreover, each clump of cells develops individually rather than in a standardised way. That is why Treutlein and her team are working to improve the organoids and automate their manufacturing process.

    [ad_2]

    ETH Zurich

    Source link

  • 3D map reveals DNA organization within human retina cells

    3D map reveals DNA organization within human retina cells

    [ad_1]

    Newswise — National Eye Institute researchers mapped the organization of human retinal cell chromatin, the fibers that package 3 billion nucleotide-long DNA molecules into compact structures that fit into chromosomes within each cell’s nucleus. The resulting comprehensive gene regulatory network provides insights into regulation of gene expression in general, and in retinal function, in both rare and common eye diseases. The study published in Nature Communications.

     “This is the first detailed integration of retinal regulatory genome topology with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, two leading causes of vision loss and blindness,” said the study’s lead investigator, Anand Swaroop, Ph.D., senior investigator and chief of the Neurobiology Neurodegeneration and Repair Laboratory at the NEI, part of the National Institutes of Health.

    Adult human retinal cells are highly specialized sensory neurons that do not divide, and are therefore relatively stable for exploring how the chromatin’s three-dimensional structure contributes to the expression of genetic information.

    Chromatin fibers package long strands of DNA, which are spooled around histone proteins and then repeatedly looped to form highly compact structures. All those loops create multiple contact points where genetic sequences that code for proteins interact with gene regulatory sequences, such as super enhancers, promoters, and transcription factors. 

    Such non-coding sequences were long considered “junk DNA.” But more advanced studies demonstrate ways these sequences control which genes get transcribed and when, shedding light on the specific mechanisms by which non-coding regulatory elements exert control even when their location on a DNA strand is remote from the genes they regulate.

    Using deep Hi-C sequencing, a tool used for studying 3D genome organization, the researchers created a high-resolution map that included 704 million contact points within retinal cell chromatin. Maps were constructed using post-mortem retinal samples from four human donors.

    The researchers then integrated that chromatin topology map with datasets on retinal genes and regulatory elements. What emerged was a dynamic picture of interactions within chromatin over time, including gene activity hot spots and areas with varying degrees of insulation from other regions of DNA.

    They found distinct patterns of interaction at retinal genes suggesting how chromatin’s 3D organization plays an important role in tissue-specific gene regulation.

    “Having such a high-resolution picture of genomic architecture will continue to provide insights into the genetic control of tissue-specific functions,” Swaroop said. 

    Furthermore, similarities between mice and human chromatin organization suggest conservation across species, underscoring the relevance of chromatin organizational patterns for retinal gene regulation. More than a third (35.7%) of gene pairs interacting through a chromatin loop in mice also did so in human retina.

    The researchers integrated the chromatin topology map with data on genetic variants identified from genome-wide association studies for their involvement in AMD and glaucoma, two leading causes of vision loss and blindness. The findings point to specific candidate causal genes involved in those diseases.

    The integrated genome regulatory map will also assist in evaluating genes associated with other common retina-associated diseases such as diabetic retinopathy, determining missing heritability and understanding genotype-phenotype correlations in inherited retinal and macular diseases. 

    The study was supported by the NEI Intramural Research Program, grants ZIAEY000450 and ZIAEY000546. 

    Reference: Marchal C, Singh N, Batz Z, Advani J, Jaeger C, Corso-Diaz X, and Swaroop A. “High-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci.” Published October 7, 2022, Nature Communications. DOI:10.1038/s41467-022-33427-1

     

    ##

    This press release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process— each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research. To learn more about basic research, visit https://www.nih.gov/news-events/basic-research-digital-media-kit.

    NEI leads the federal government’s efforts to eliminate vision loss and improve quality of life through vision research…driving innovation, fostering collaboration, expanding the vision workforce, and educating the public and key stakeholders. NEI supports basic and clinical science programs to develop sight-saving treatments and to broaden opportunities for people with vision impairment. For more information, visit https://www.nei.nih.gov.

    About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov/.

    NIH…Turning Discovery Into Health®

     

    [ad_2]

    NIH, National Eye Institute (NEI)

    Source link