New Techniques Probe Vital And Elusive Proteins (Biology)

The number of proteins in the human body, collectively known as the proteome, is vast. Somewhere between 80,000 and 400,000 proteins circulate in our cells, tissues and organs, carrying out a broad range of duties essential for life. When proteins go awry, they are responsible for a myriad of serious diseases.

New methods of determining the structure of membrane proteins using lipidic cubic phase (LCP) microcrystals and microcrystal electron diffraction (MicroED) are described in the new study appearing on the cover of the Cell Press journal, Structure. ©Graphic by Jason Drees for the Biodesign Institute at Arizona State University

Now, researchers at the Biodesign Center for Applied Structural Discovery and ASU’s School of Molecular Sciences, along with their colleagues, investigate a critically important class of proteins, which adorn the outer membranes of cells. Such membrane proteins often act as receptors for binding molecules, initiating signals that can alter cell behavior in a variety of ways.

A new approach to acquiring structural data of membrane proteins in startling detail is described in the new study. Cryogenic electron microscopy (or cryo-EM) methods, a groundbreaking suite of tools, is used. Further, use of so-called LCP crystallization and Microcrystal electron diffraction (MicroED) help unveil structural details of proteins that have been largely inaccessible through conventional approaches like X-ray crystallography.

The findings describe the first use of LCP-embedded microcrystals to reveal high-resolution protein structural details using MicroED. The new research graces the cover of the current issue of the Cell Press journal Structure.

“LCP was a great success in membrane protein crystallization, according to Wei Liu, a corresponding author of the new study. “The new extensive application of LCP-MicroED offers promise for improved approaches for structural determination from challenging protein targets. These structural blueprints can be used to facilitate new therapeutic drug design from more precise insights.”

One class of membrane proteins of particular interest are the G-protein-coupled receptors (GPCRs), which form the largest and most varied group of membrane receptors found in eukaryotic organisms, including humans.

The physiological activities of GPCRs are so important that they are a major target for a wide range of therapeutic drugs. This is where problems arise however, as determining the detailed structure of membrane proteins–an essential precursor to accurate drug design– often poses enormous challenges.

The technique of X-ray crystallography has been used to investigate the atomic-scale structures and even dynamic behavior of many proteins. Here, crystallized samples of the protein under study are struck with an X-ray beam, causing diffraction patterns, which appear on a screen. Assembling thousands of diffraction snapshots allows a high-resolution 3D structural image to be assembled with the aid of computers.

Yet many membrane proteins, including GPCRs, don’t form large, well-ordered crystals appropriate for X-ray crystallography. Further, such proteins are delicate and easily damaged by X-radiation. Getting around the problem has required the use of special devices known as X-ray free electron lasers or XFELS, which can deliver a brilliant burst of X-ray light lasting mere femtoseconds, (a femtosecond is equal to one quadrillionth of a second or about the time it takes a light ray to traverse the diamere of a virus). The technique of serial femtosecond X-ray crystallography allows researchers to obtain a refraction image before the crystalized sample is destroyed.

Nevertheless, crystallization of many membrane proteins remains an extremely difficult and imprecise art and only a handful of these gargantuan XFEL machines exist in the world.

Enter cryogenic electron microscopy and MicroED. This ground-breaking technique involves flash-freezing protein crystals in a thin veneer of ice, then subjecting them to a beam of electrons. As in the case of X-ray crystallography, the method uses diffraction patterns, this time from electrons rather than X-rays, to assemble final detailed structures.

MicroED excels in collecting data from crystals too small and irregular to be used for conventional X-ray crystallography. In the new study, researchers used two advanced techniques in tandem in order to produce high-resolution diffraction images of two important model proteins: Proteinase K and the A2A adenosine receptor, whose functions include modulation of neurotransmitters in the brain, cardiac vasodilation and T-cell immune response.

The proteins were embedded in a special type of crystal known as a lipidic cubic phase or LCP crystal, which mimics the native environment such proteins naturally occur in. The LCP samples were then subjected to electron microscopy, using the MicroED method, which permits the imaging of extremely thin, sub-micron-sized crystals. Further, continuous rotation of LCP crystals under the electron microscope allows multiple diffraction patterns to be acquired from a single crystal with an extremely low, damage-free electron dose.

The ability to examine proteins that can only form micro- or nanocrystals opens the door to the structural determination of many vitally important membrane proteins that have eluded conventional means of investigation, particularly GPCRs.

References: Lan Zhu, Guanhong Bu, Liang Jing, Tamir Gonen, Wei Liu, Brent L. Nannenga, “Structure Determination from Lipidic Cubic Phase Embedded Microcrystals by MicroED”, 28(10), pp. 1149-59, 2020, DOI: https://doi.org/10.1016/j.str.2020.07.006

Provided by Arizona State University

There’s A Reason Bacteria Stay In Shape (Biology)

Rice University theorists show how random processes cancel out to ensure microbial health.

A simple theoretical model by Rice University scientists seeks to explain why bacteria remain roughly the same size and shape. The model shows the random processes of growth and division are linked, essentially canceling each other out. ©Kolomeisky Research Group/Rice University

Fat bacteria? Skinny bacteria? From our perspective on high, they all seem to be about the same size. In fact, they are.

Precisely why has been an open question, according to Rice University chemist Anatoly Kolomeisky, who now has a theory.

A primal mechanism in bacteria that keeps them in their personal Goldilocks zones — that is, just right — appears to depend on two random means of regulation, growth and division, that cancel each other out. The same mechanism may give researchers a new perspective on disease, including cancer.

The “minimal model” by Kolomeisky, Rice postdoctoral researcher and lead author Hamid Teimouri and Rupsha Mukherjee, a former research assistant at Rice now at the Indian Institute of Technology Gandhinagar, appears in the American Chemical Society’s Journal of Physical Chemistry Letters.

“Everywhere we see bacteria, they more or less have the same sizes and shapes,” Kolomeisky said. “It’s the same for the cells in our tissues. This is a signature of homeostasis, where a system tries to have physiological parameters that are almost the same, like body temperature or our blood pressure or the sugar level in our blood.

“Nature likes to have these parameters in a very narrow range so that living systems can work the most efficiently,” he said. “Deviations from these parameters are a signature of disease.”

Bacteria are models of homeostasis, sticking to a narrow distribution of sizes and shape. “But the explanations we have so far are not good,” Kolomeisky said. “As we know, science does not like magic. But something like magic — thresholds — is proposed to explain it.”

For bacteria, he said, there is no threshold. “Essentially, there’s no need for one,” he said. “There are a lot of underlying biochemical processes, but they can be roughly divided into two stochastic chemical processes: growth and division. Both are random, so our problem was to explain why these random phenomenon lead to a very deterministic outcome.”

The Rice lab specializes in theoretical modeling that explains biological phenomena including genome editing, antibiotic resistance and cancer proliferation. Teimouri said the highly efficient chemical coupling between growth and division in bacteria was far easier to model.

“We assumed that, at typical proliferation conditions, the number of division and growth protein precursors are always proportional to the cell size,” he said. The model predicts when bacteria will divide, allowing them to optimize their function. The researchers said it agrees nicely with experimental observations and noted manipulating the formula to knock bacteria out of homeostasis proved their point. Increasing the theoretical length of post-division bacteria, they said, simply leads to faster rates of division, keeping their sizes in check.

“For short lengths, growth dominates, again keeping the bacteria to the right size,” Kolomeisky said.

The same theory doesn’t necessarily apply to larger organisms, he said. “We know that in humans, there are many other biochemical pathways that might regulate homeostasis, so the problem is more complex.”

However, the work may give researchers new perspective on the proliferation of diseased cells and the mechanism that forces, for instance, cancer cells to take on different shapes and sizes.

“One of the ways to determine cancer is to see a deviation from the norm,” Kolomeisky said. “Is there a mutation that leads to faster growth or faster division of cells? This mechanism that helps maintain the sizes and shapes of bacteria may help us understand what’s happening there as well.”

References: Hamid Teimouri, Rupsha Mukherjee, and Anatoly B. Kolomeisky, “Stochastic Mechanisms of Cell-Size Regulation in Bacteria”, J. Phys. Chem. Lett. 2020, 11, XXX, 8777–8782, 2020, doi:
https://doi.org/10.1021/acs.jpclett.0c02627

Provided by Rice University

Energy-Harvesting Plastics Pass The Acid Test (Material Science)

A polymer previously used to protect solar cells may find new applications in consumer electronics, reveals a KAUST team studying thin films capable of converting thermal energy into electricity.

Diego Rosas-Villalva explained that the team was surprised that such an extremely thin polymer was so effective in improving the lifetime of the device. © 2020 KAUST

When two sides of a semiconductor are at different temperatures, electron migration from hot to cool areas can generate a current. This phenomenon, known as the thermoelectric effect, typically requires semiconductors with rigid ceramic structures to maintain the heat difference between the two sides. But the recent discovery that polymers also exhibit thermoelectric behavior has prompted a rethink of how to exploit this method for improved energy harvesting, including incorporation into wearable devices.

Derya Baran and her team at KAUST are helping to engineer self-powered devices using a conducting polymer containing a blend of poly(3,4-ethylenedioxythiophene) and polystyrenesulfonate (PEDOT:PSS) chains. Relatively inexpensive and easy to process for applications, including inkjet printing, PEDOT:PSS is one of the top-performing thermoelectric polymers thanks to its ability to take in efficiency-boosting additives known as dopants.

Diego Rosas-Villalva, a researcher in Baran’s group, explains that thermoelectric PEDOT:PSS thin films are often exposed to dopants in the form of strong acids. This process washes away loose PSS chains to improve polymer crystallinity and leaves behind particles that oxidize PEDOT chains to boost electrical conductivity.

A polymer-based thin film developed at KAUST can perform thermoelectric power conversions with less chance of premature failure. © 2020 Diego Villalva

“We use nitric acid because it’s one of the best dopants for PEDOT,” says Rosas-Villalva. “However, it evaporates rather easily, and this decreases the performance of the thermoelectric over time.”

After the doping step is completed, the PEDOT:PSS film has to undergo a reverse procedure to neutralize or “dedope” some conductive particles to improve thermoelectric power generation.

Typical dedopants include short hydrocarbons containing positively charged amine groups. The KAUST researchers were studying a polymerized version of these amine chains, known as ethoxylated polyethylenimine, when they noticed a remarkable effect–PEDOT:PSS films dedoped with polyethylenimine retained twice as much thermoelectric power after one week compared with untreated specimens.

The team’s investigations revealed that polyethylenimine was effective at encapsulating PEDOT:PSS films to prevent nitric acid escape. In addition, this coating modified the electronic properties of the thermoelectric polymer to make it easier to harvest energy from sources, including body heat.

“We were not expecting that this polymer would improve the lifetime of the device, especially because it’s such a thin film–less than 5 nanometers,” says Villalva. “It’s been incorporated into other organic electronics before, but barely explored for thermoelectrics.”

References: Diego Rosas Villalva, Md Azimul Haque, Mohamad Insan Nugraha, and Derya Baran, “Enhanced Thermoelectric Performance and Lifetime in Acid-Doped PEDOT:PSS Films Via Work Function Modification”, ACS Appl. Energy Mater. 2020, 3, 9, 9126–9132, 2020 doi:
https://doi.org/10.1021/acsaem.0c01511

Provided by King Abdullah University Of Science And Technology

How Immune Cells Can Recognise – And Control – HIV When Therapy Is Interrupted? (Medicine)

New findings reveal how HIV-1-specific immune cells can recognise viral particles that have the capacity to rebound following interruptions to antiretroviral therapy, with implications for new treatment strategies.

©wallpaperflare

Immune cells that can recognise residual HIV-infected cells in people living with HIV (PLWH) who take antiretroviral therapy (ART) remain active for years, says a new study published today in eLife.

The findings also suggest the majority of these immune cells, called CD8+ T cells, should have the capacity to detect the HIV-infected cells that drive HIV-1 rebound following interruptions to treatment. This insight could contribute to the development of new curative strategies against HIV infection.

ART has transformed HIV-1 from a fatal disease to a chronic condition in PLWH. However, it must be taken by those with the infection for the rest of their lives, as interrupting treatment often allows the virus to rebound within weeks. This rebound results from cells harbouring HIV-1 DNA that is integrated into the human genome.

“While more than 95% of proviral DNA is unable to replicate and reactivate HIV-1, the remaining fraction that we define in our study as the ‘HIV-1 reservoir’ maintains its ability to produce infectious virus particles and cause viral rebound,” explains lead author Joanna Warren, Postdoctoral Investigator at the Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, US. “The largest and most well-characterised HIV-1 reservoir resides in ‘resting’ CD4+ T cells, which circulate in the blood and are long-lived.”

There are a couple of strategies to allow people with HIV-1 to stop ART without viral rebound. Both approaches may harness HIV-1-specific CD8+ T cells to achieve the reduction or elimination of the HIV-1 reservoir. However, variations (or mutations) in viral particles that exist in the HIV-1 reservoir may limit the capacity of these T cells to recognise and clear virus-infected cells, meaning the cells can escape detection and go on to cause viral rebound. “In our study, we wanted to determine the frequency and patterns of T-cell escape mutations in the HIV-1 reservoir of people who are on ART,” Warren says.

To do this, the team measured HIV-1-specific T-cell responses and isolated reservoir virus in 25 PLWH who are on ART. Of these participants, four started on ART during acute HIV-1 infection, which means virus levels were controlled early, while the other 21 started on ART during chronic HIV-1 infection, which means considerable virus mutation occurred before virus levels were controlled.

In the HIV-1 proteome (the entire set of proteins expressed by the virus) for each participant, the team identified T-cell epitopes (regions of proteins that trigger an immune response). They sequenced HIV-1 ‘outgrowth’ viruses from resting CD4+ T cells and tested mutations in T-cell epitopes for their effect on the size of the T-cell response. These strategies revealed that the majority (68%) of T-cell epitopes did not harbour any detectable escape mutations, meaning they could be recognised by circulating T cells.

“Our findings show that the majority of HIV-1-specific T cells in people on ART can detect HIV viruses that have the capacity to rebound following treatment interruption,” concludes senior author Nilu Goonetilleke, a faculty member at the Department of Microbiology and Immunology, University of North Carolina at Chapel Hill. “This suggests that T cells likely help to control viral rebound and could be leveraged in future treatment strategies against HIV.”

References: Joanna A Warren, Shuntai Zhou, Yinyan Xu, Matthew J Moeser, Daniel R MacMillan, Olivia Council, Jennifer Kirchherr, Julia M Sung, Nadia Roan, Adaora A Adimora, Sarah Joseph, JoAnn D Kuruc, Cynthia L Gay, David M Margolis, Nancie Archin, Zabrina L Brumme, Ronald Swanstrom, Nilu Goonetilleke, “The HIV-1 latent reservoir is largely sensitive to circulating T cells”, Immunology and Inflammation, 2020 doi:https://doi.org/10.7554/eLife.57246 link: https://elifesciences.org/articles/57246

Provided by ELIFE

Liquid Gel In COVID Patients Lungs Makes Way For New Treatment (Medicine)

In some patients who died with severe COVID-19 and respiratory failure, a jelly was formed in the lungs. Researchers have now established what the active agent in the jelly is and thanks to that, this new discovery can now be the key to new effective therapies. This according to a new study at Umeå University, Sweden.

Urban Hellman, researcher at Department of Public Health and Clinical Medicine, Umeå University, Sweden. CREDIT: Lena Mustonen

“There are already therapies that either slow down the body’s production of this jelly or breaks down the jelly through an enzyme. Our findings can also explain why cortisone seems to have an effect on COVID-19,” says Urban Hellman, researcher at Umeå University.

When performing lung scans on critically ill patients with COVID-19 infection, medical professionals have been able to see white patches. Additionally, the autopsies of some deceased COVID-19 patients have shown that the lungs were filled with a clear liquid jelly, much resembling the lungs of someone who has drowned. It was previously unknown where this jelly originated from.

Now though, a group of researchers at the Translational Research Centre at Umeå University have shown that the jelly consists of the substance hyaluronan, which is a polysaccharide in the glycosaminoglycan group.

The presence of hyaluronan is normal in the human body, with various functions in different tissues, but it generally acts as a useful characteristic in the connective tissue. Not least, hyaluronan is involved in the early stages of wound healing. Hyaluronan is also produced synthetically in the beauty industry for lip augmentation and anti-wrinkle treatments.

Since hyaluronan can bind large amounts of water in its web of long molecules, it forms a jelly-like substance. And it is this process that runs riot in the alveoli of COVID-19 patients’ lungs resulting in the patient needing ventilator care and, in worst case, dies from respiratory failure.

Currently, a drug called Hymecromone is used to slow down the production of hyaluronan in other diseases such as gallbladder attacks. There is also an enzyme that can effectively break down hyaluronan. As an example, this enzyme can be used in the event that an unsuccessful beauty treatment needs to be terminated abruptly.

Even cortisone reduces the production of hyaluronan. In a British study, preliminary data shows positive effects on treatments with the cortisone drug Dexamethasone in severely ill COVID-19 patients.

“It has previously been assumed that the promising preliminary results would be linked to the general anti-inflammatory properties of cortisone, but in addition to those beliefs, cortisone may also reduce the production of hyaluronan, which may reduce the amount of jelly in the lungs,” says Urban Hellman.

References: Urban Hellman, Mats G Karlsson, Anna Engström-Laurent, Sara Cajander, Luiza Dorofte, Clas Ahlm, Claude Laurent and Anders Blomberg, ‘Presence of hyaluronan in lung alveoli in severe Covid-19 – an opening for new treatment options?”, Journal Of Biological chemistry, 2020 link: http://m.jbc.org/content/early/2020/09/25/jbc.AC120.015967 doi: http://dx.doi.org/10.1074/jbc.AC120.015967

Provided by Umea University

Imaging Technique Could Replace Tissue Biopsies In Assessing Drug Resistance In Cancer (Medicine)

Imaging techniques could replace the need for invasive tissue biopsies in helping rapidly determine whether cancer treatments are working effectively, according to researchers at the University of Cambridge.

False colour image of a breast tumour (outlined) pre- and post-treatment with a PI3Ka inhibitor. Weaker colours post-treatment indicate that the drug is working. ©Brindle Lab, University of Cambridge

In a study published in the journal Cancer Cell, researchers at the Cancer Research UK (CRUK) Cambridge Institute have shown how a new technique known as hyperpolarisation – which involves effectively magnetising molecules in a strong magnetic field – can be used to monitor how effective cancer drugs are at slowing a tumour’s growth.

In healthy tissue, cell proliferation is a tightly controlled process. When this process goes wrong, cell proliferation can run away with itself, leading to unchecked growth and the development of tumours.

All tissue needs to be ‘fed’. As part of this process – known as metabolism – our cells break down glucose and other sugars to produce pyruvate, which is in turn converted into lactate. This is important for producing energy and the building blocks for making new cells.

Tumours have a different metabolism to healthy cells, and often produce more lactate. This metabolic pathway is affected by the presence of a protein known as FOXM1, which controls the production of a metabolic enzyme that converts pyruvate into lactate. FOXM1 also controls the production of many other proteins involved in cell growth and proliferation.

Around 70% of all cases of breast cancer are of a type known as estrogen-receptor (ER) positive. In many ER-positive breast cancer cases, an enzyme known as PI3K? is activated. This leads to an abundance of FOXM1, enabling the cancer cells to grow uncontrollably – the characteristic sign of a tumour cell.

Drugs that inhibit PI3K? are currently being tested in breast cancer patients. Such drugs should be able to decrease the amount of FOXM1 and check the tumour’s growth. However, a patient’s tumour may have an innate resistance to PI3K? inhibitors, or can acquire resistance over time, making the drugs increasingly less effective.

Dr Susana Ros, first author from the CRUK Cambridge Institute, said: “Thanks to advances in cancer treatments, our medicines are becoming more and more targeted, but not all drugs will work in every case – some tumours are resistant to particular drugs. What we need are biomarkers – biological signatures – that tell us whether a drug is working or not.”

The researchers took breast cancer cells from patients and grew them in mouse ‘avatars’ to allow them to study the tumours in detail. They found that in tumours resistant to PI3K? inhibitors, cancer cells continue to produce FOXM1 – meaning that this molecule could be used as a biomarker for drug resistance in patients with ER-positive breast cancer.

Checking whether a tumour is continuing to produce FOXM1 – and hence whether the PI3K? inhibitor is still working – would usually involve an invasive tissue biopsy. However, researchers have used a new imaging technique to monitor this in real time and non-invasively.

The technique developed and used by the team is known as hyperpolarisation. First, the team produces a form of pyruvate whose carbon atoms are slightly heavier than normal carbon atoms (they carry an additional neutron and are hence known as carbon-13 molecules). The researchers then ‘hyperpolarise’ – or magnetise – the carbon-13 pyruvate by cooling it to around one degree above absolute zero (-272°C) and exposing it to extremely strong magnetic fields and microwave radiation. The frozen material is then thawed and dissolved into an injectable solution.

Patients are injected with the solution and then receive a regular MRI scan. The signal strength from the hyperpolarised carbon-13 pyruvate molecules is 10,000 times stronger than that from normal pyruvate, making the molecules visible on the scan. The researchers can use the scan to see how fast pyruvate is being converted into lactate – only the continued presence of FOXM1 would allow this to happen, and this would be a sign that the drugs are not working properly.

Dr Ros added: “We’ve been able to detect the presence of FOXM1, our biomarker, by using this new imaging technique in breast cancer models to look for a proxy – that is, how quickly pyruvate is converted to lactate.”

Professor Kevin Brindle, senior author of the study, commented: “In the future, this could provide us with a rapid assessment of how a breast cancer patient is responding to treatment without the need for invasive biopsies. This information could help put an end to giving treatments that are not working and the side effects that accompany them. Currently, patients can wait a long time to find out if a treatment is working. This technique could shorten this time, and help to tailor treatment for individual patients.”

References: Ros, S et al. Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer. Cancer Cell; 24 Sept 2020; DOI: 10.1016/j.ccell.2020.08.016

Provided by University Of Cambridge

Colorectal Cancer Treatment: The Winning Combinations (Medicine)

A technique developed by scientists from UNIGE and HUG has made it possible to identify in vitro and validate in vivo, an optimised combination of anticancer drugs that are more effective than chemotherapy and that do not have side effects.

A schematic drawing of colon and colorectal carcinoma.©@UNIGE/Nowak-Sliwinska

Chemotherapy-based cancer treatment has distressing side effects for patients and increases the risk of developing resistance to the treatment. In an attempt to solve these problems, scientists from the University of Geneva (UNIGE) have developed a technique for quickly identifying from a large number of existing drugs the optimal synergistic combination and dose of products that can kill the tumour cells without affecting healthy cells. In partnership with the University Hospital of Geneva (HUG) and the University Medical Center in Amsterdam, they have demonstrated the effectiveness of this approach in colorectal cancer. The results are published in an article in the journal Molecular Oncology. The best drug combinations identified were assessed using in vitro tests and, for the first time, in vivo on mouse models. All the combinations were shown to be more effective than chemotherapy and did not cause any apparent toxicity in the healthy cells or in the animals. This study further paves the way for personalised, effective and safe cancer treatment.

“The technique we’ve designed and patented is called TGMO, which stands for phenotypically-driven therapeutically guided multidrug optimisation. It combines testing and highly-advanced statistical analysis,” begins Patrycja Nowak-Sliwinska, professor at the School of Pharmaceutical Sciences of UNIGE’s Faculty of Science. “It can be used to rapidly perform – in a few steps – simultaneous tests on cancerous and healthy cells (from the same patient), and evaluate all the possible combinations of drugs that we selected for the purpose. The positive synergies are preserved, while the antagonisms are rejected.”

The experiment incorporated 12 drugs, all recently approved for commercialization or in the final phase of clinical trials. Colorectal cancer cell lines that had been perfectly characterised for the requirements of scientific studies were submitted to the TGMO-based “machinery”. The aim of the search was to determine the combination of products closest to the desired outcome: the death of cancer cell together with an absence of effect on the healthy cell – and all using the lowest possible drug doses. The procedure resulted in multidrug combinations of three or four drugs, all slightly different from each other.

80% reduction of tumour growth

The activity of the combinations was then verified under somewhat more complex conditions than a single cell: first on a three-dimensional model of a human tumour containing cancer cells and other types, as is the case in reality, and finally on mice serving as an experimental model for colorectal cancer. The drug combinations reduced tumour growth by about 80% and consistently outperformed the effectiveness of chemotherapy. They revealed a total absence of toxicity in the healthy cells – unlike with chemotherapy – and significant activity on cancer cells freshly taken from current patients in Switzerland.

“It’s the first time that in vivo tests have been carried out with drug combinations derived from our TGMO technology,” enthuses Patrycja Nowak-Sliwinska. “The study shows that it is possible to efficiently identify low-dose synergistic and selective optimized drug combinations, regardless of the mutation status of the tumour, and which are more effective than conventional chemotherapy. We are currently discussing setting up a clinical study on patients so we can take things a stage further. But this stage, financing of which depends very much on the interest that a private sector might have in our approach, is first and foremost the work of clinical physicians.”

Results in under two weeks

TGMO technology is designed in such a way that it achieves results in under two weeks, which is the same as the time that doctors take to determine the treatment to be administered to a patient as soon as a diagnosis has been made. “This approach clearly represents the future for oncology patients,” continues Thibaud Koessler, head of Gastrointestinal Oncology in the HUG Oncology Department and one of the authors of the article. “The ability to test different drugs ex vivo and to select the combination for each patient that the cancer will be most sensitive to should increase the effectiveness of treatments while reducing the toxicity, two of the most problematic aspects in current therapies.”

References: Zoetemelk, M., Ramzy, G.M., Rausch, M., Koessler, T., van Beijnum, J.R., Weiss, A., Mieville, V., Piersma, S.R., de Haas, R.R., Delucinge‐Vivier, C., Andres, A., Toso, C., Henneman, A.A., Ragusa, S., Petrova, T.V., Docquier, M., McKee, T.A., Jimenez, C.R., Daali, Y., Griffioen, A.W., Rubbia‐Brandt, L., Dietrich, P.‐Y. and Nowak‐Sliwinska, P. (2020), Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment. Mol. Oncol.. doi:10.1002/1878-0261.12797

Provided by University Of Geneve

RUDN University Chemist Created A Niobium-Silica Catalyst To Boost Petrochemical Reactions (Chemistry)

Alkylation reactions are used in the petrochemical industry to obtain high-octane number components for gasolines. A chemist from RUDN University found a way to speed this process up to 24 times. To do so, he developed a catalyst based on silica and niobium. The results of his work were published in the Molecular Catalysis journal.

Alkylation reactions are used in the petrochemical industry to obtain high-octane number components of motor gasoline. A chemist from RUDN University found a way to speed this process up 24 times. To do so, he developed a catalyst based on silica and niobium. ©RUDN University

In the course of alkylation, an atom of hydrogen in an organic compound is replaced with other substances, the so-called alkylating agents. Alkylation is used in the chemical and petrochemical industries, for example, to obtain high-octane number components in gasolines. For the process to go on quickly and efficiently, it needs catalysts including mineral acids and zeolites–minerals that are capable of selectively releasing substances and then adsorbing them back. However, mineral (e.g. sulphuric or phosphoric) acids can be expensive and dangerous: in order to extract them from the reaction mix, one needs additional reagents that can be hard to handle. Unlike mineral acids, zeolites are safe and cheap to produce. The only problem lies in their microporous structure that limits the size of the molecules they can react with. A chemist from RUDN University created a catalyst that is free from these disadvantages and able to speed up the alkylation reaction up to 24 times. To do so, his team used niobium and SBA-15, a mesoporous ordered form of silica.

“SBA-15 materials are relevant as catalytic support due to their high surface area and pore volume in the mesopore range that convert it in an outstanding catalyst support. We aimed to evaluate the acidity of several Al-SBA-15 supported niobium oxide catalysts prepared by a mechanochemical protocol with different metal loadings,” said Rafael Luque PhD, the head of the Molecular Design and Synthesis of Innovative Compounds for Medicine Science Center at RUDN University.

The team paid attention to the reductive-oxidative and acidic properties of niobium-based compounds that are important for a catalyst and decided to test niobium in an alkylation reaction. To do so, they put niobium oxide nanoparticles (that had been mechanochemically ground down to several nanometers in size) on the support. The metal content in the new material varied from 0.5% to 1% and the size of the particles was controlled with a transmission electron microscope. The team used energy-dispersive X-ray spectroscopy to secure even distribution of particles across the surface of the support.

To analyze the catalytic properties of the new material, the chemists carried out the reaction of toluene alkylation with benzyl alcohol and benzyl chloride that acted as alkylating agents. As a result of the experiment, the team confirmed a positive effect of niobium particles on the reaction: its time of reaction reduced from 4 hours to 10 minutes. The catalyst with lower niobium content (0.5%) turned out to be more effective due to better dispersion. The team believes that when the catalyst was synthesized, niobium oxide deposited on the support, and the more niobium, the bigger the catalyst particles turned out to be. This reduced the effective contact area of the particles and therefore had a negative impact on the material’s catalytic activity.

“We managed to create a catalyst that reduces the time of alkylation reactions from several hours to just 10 minutes, is free from the chemical limitations of zeolites, and poses no danger unlike mineral acids,” added Rafael Luque.

References: Antonio Pineda, Noelia Lázaro, Alina M.Balu, Angel Garcia, Antonio A. Romero, Rafael Luque, “Evaluation of acid properties of mechanochemically synthesized supported niobium oxide catalysts in the alkylation of toluene”, Molecular Catalysis, Volume 493, September 2020, 111092, doi: https://doi.org/10.1016/j.mcat.2020.111092 link: https://www.sciencedirect.com/science/article/abs/pii/S2468823120303552?via%3Dihub#!

Provided by RUDN University

Astronomers Turn Up The Heavy Metal To Shed Light On Star Formation (Astronomy)

Astronomers from The University of Western Australia’s node of the International Centre for Radio Astronomy Research (ICRAR) have developed a new way to study star formation in galaxies from the dawn of time to today.

A selection of the 7,000 galaxies used by the researchers in this work. Credit: GAMA Survey Team, ICRAR/UWA.

“Stars can be thought of as enormous nuclear-powered processing plants,” said lead researcher Dr Sabine Bellstedt, from ICRAR.

“They take lighter elements like hydrogen and helium, and, over billions of years, produce the heavier elements of the periodic table that we find scattered throughout the Universe today.

“The carbon, calcium and iron in your body, the oxygen in the air you breathe, and the silicon in your computer all exist because a star created these heavier elements and left them behind,” Bellstedt said.

Artist’s impression of a galaxy. Credit: ICRAR.

“Stars are the ultimate element factories in the Universe.”

Understanding how galaxies formed stars billions of years ago requires the very difficult task of using powerful telescopes to observe galaxies many billions of light-years away in the distant Universe.

However, nearby galaxies are much easier to observe. Using the light from these local galaxies, astronomers can forensically piece together the history of their lives (called their star-formation history). This allows researchers to determine how and when they formed stars in their infancy, billions of years ago, without struggling to observe galaxies in the distant Universe.

Traditionally, astronomers studying star formation histories assumed the overall metallicity–or amount of heavy elements–in a galaxy doesn’t change over time.

But when they used these models to pinpoint when stars in the Universe should have formed, the results didn’t match up with what they were seeing through their telescopes.

Annotated graph showing the history of star formation from the Big Bang to now. Credit: ICRAR / UWA

“The results not matching up with our observations is a big problem,” Bellstedt said. “It tells us we’re missing something.”

“That missing ingredient, it turns out, is the gradual build-up of heavy metals within galaxies over time.”

Using a new algorithm to model the energy and wavelengths of light coming from almost 7000 nearby galaxies, the researchers succeeded in reconstructing when most of the stars in the Universe formed–in agreement with telescope observations for the first time.

The designer of the new code–known as ProSpect–is Associate Professor Aaron Robotham from ICRAR’s University of Western Australia node.

“This is the first time we’ve been able to constrain how the heavier elements in galaxies change over time based on our analysis of these 7000 nearby galaxies,” Robotham said.

“Using this galactic laboratory on our own doorstep gives us lots of observations to test this new approach, and we’re very excited that it works.

“With this tool, we can now dissect nearby galaxies to determine the state of the Universe and the rate at which stars form and mass grows at any stage over the past 13 billion years.

“It’s absolutely mind-blowing stuff.”

This work also confirms an important theory about when most of the stars in the Universe formed.

“Most of the stars in the Universe were born in extremely massive galaxies early on in cosmic history–around three to four billion years after the Big Bang,” Bellstedt said.

“Today, the Universe is almost 14 billion years old, and most new stars are being formed in much smaller galaxies.”

Based on this research, the next challenge for the team will be to expand the sample of galaxies being studied using this technique, in an effort to understand when, where and why galaxies die and stop forming new stars.

Bellstedt and Robotham, along with colleagues from Australia, the UK and the United States, are reporting their results in the scientific journal the Monthly Notices of the Royal Astronomical Society.

References: Sabine Bellstedt, Aaron S G Robotham, Simon P Driver, Jessica E Thorne, Luke J M Davies, Claudia del P Lagos, Adam R H Stevens, Edward N Taylor, Ivan K Baldry, Amanda J Moffett, Andrew M Hopkins, Steven Phillipps, Galaxy And Mass Assembly (GAMA): a forensic SED reconstruction of the cosmic star formation history and metallicity evolution by galaxy type, Monthly Notices of the Royal Astronomical Society, Volume 498, Issue 4, November 2020, Pages 5581–5603, https://doi.org/10.1093/mnras/staa2620

Provided by International Center For Radio astronomy Research