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January 15th

Possible Breakthrough in Producing Large Quantities of Potential Therapeutic Drug Compound (FR) Originally Found in Bacterium Colonizing Coralberry Plant; Compound Inhibits Gq Proteins and Has Shown Suggestive Effectiveness in Asthma and Certain Cancers

For some years, an active substance from the leaves of an ornamental plant has been regarded as a possible forerunner of a new group of potent drugs. So far, however, it has been very laborious to manufacture this substance in large quantities. That could now change as researchers at the University of Bonn (Germany) have identified a bacterium that produces the substance and can also be easily cultivated in the laboratory. The results were published online on January 8, 2021 in Nature Communications. The open-access article is titled “Thioesterase-Mediated Side Chain Transesterification Generates Potent Gq Signaling Inhibitor FR900359.” The coralberry (photo) currently once again adorns many living rooms. In winter, it bears bright red fruits, which make it a popular ornamental plant at this time of year in the Northern hemisphere. For pharmacists, however, it is interesting for a different reason: it contains an active substance that has emerged in recent years as a beacon of hope against asthma and certain types of cancer. Unfortunately, obtaining this substance, with the cryptic name FR900359 (abbreviated: FR), in larger quantities is rather laborious. Cultivating the plants in greenhouses takes many weeks; moreover, the yield can vary enormously depending on the specimen. Incidentally, the plants do not produce the active ingredient themselves, but have bacteria in their leaves that do it for them. "However, these only grow in the coralberry and cannot be cultivated in the laboratory," explains Max Crüsemann PhD, of the Institute of Pharmaceutical Biology at the University of Bonn. Manufacturing FR is a complex undertaking. The bacteria have a special assembly line for this purpose, in which a number of enzymes work hand in hand. The bacterial genetic makeup specifies how this assembly line must be set up.

January 14th

How Plants Produce Defensive Toxins Without Harming Themselves; Researchers Elucidate Biosynthesis & Mode of Action of Diterpene Glycosides in Wild Tobacco

Plants produce toxic substances to defend themselves against herbivores. In a new study, scientists from the Max Planck Institute for Chemical Ecology in Jena and the University of Münster, both in Germany, were able to describe in detail the biosynthesis and exact mode of action of an important group of defensive substances, the diterpene glycosides, in wild tobacco plants. Diterpene glycosides allow plants to fend off herbivores. The study shows that these plant chemicals attack certain parts of the cell membrane. To protect themselves from their own toxins and to prevent their cell membranes from being damaged, tobacco plants store these substances in a non-toxic form, which is synthesized in a very particular way. Autotoxicity and the protection against it seem to play a greater role in the evolution of plant defenses than previously thought according to results published in the January 15, 2021 issue of Science (https://science.sciencemag.org/content/371/6526/255). The article is titled “Controlled Hydroxylations of Diterpenoids Allow for Plant Chemical Defense Without Autotoxicity.” Many plants produce chemical defenses to protect themselves against being eaten. Still little is known about what makes these substances toxic to their consumers. Researchers at the Max Planck Institute for Chemical Ecology and the University of Münster have now investigated how plants produce toxins and store them in their tissues without harming themselves. In particular, they wanted to know whether the mechanisms of autotoxicity and its prevention share similar mechanisms as the toxic characteristics that provide defense against herbivores. For their experiments, the scientists chose diterpene glycosides from Nicotiana attenuata plants, a wild tobacco species. "These substances occur at very high concentrations in the leaves of tobacco plants.

Cancer Research Reveals How Mutations in a Specific Gene (RUNX1) Cause Different Types of Cancers

Leading cancer experts at the University of Birmingham (UK) have solved a long-standing question of how various types of mutations in just one gene cause different types of diseases. A team of scientists at the University's Institute of Cancer and Genomic Sciences, led by Professor Constanze Bonifer, PhD, studied a gene known as RUNX1 (https://en.wikipedia.org/wiki/RUNX1) (image here is graphic reprentation of the RUNX1 protein), which is responsible for providing instructions for the development of all blood cells and is frequently mutated in blood cancers. The results of the team’s research has shown that the balance of cells types in the blood is affected much earlier than previously thought, which is particularly important for families that carry the mutant gene. The research, published online on January 4, 2021 in Life Science Alliance, opens up the possibility of identifying early changes in cells of patients carrying the mutation even before any disease manifests itself--increasing their chances of survival. The study, the culmination of four years of research, showed that while some types of RUNX1 mutations directly changed how other genes behaved in blood cells, not all did. In particular, the mutations that are inherited through families do not immediately affect the cells but instead change the roadmap (differentiation trajectory) they follow to become other cell types, such as platelets and white blood cells.

Researchers Reveal Mechanism That May Underlie Irritable Bowel Syndrome

KU Leuven (Belgium) researchers have identified a biological mechanism that explains why some people experience abdominal pain when they eat certain foods. The finding paves the way for more efficient treatment of irritable bowel syndrome (IBS) and other food intolerances. The study, carried out in mice and humans, was published online on January 13, 2021 in Nature. The article is titled “Local Immune Response to Food Antigens Drives Meal-Induced Abdominal Pain.” Up to 20% of the world's population suffers from IBS, which causes stomach pain or severe discomfort after eating. This affects their quality of life. Gluten-free and other diets can provide some relief, but why this works is a mystery, because the patients are not allergic to the foods in question, nor do they have known conditions such as celiac disease. "Very often these patients are not taken seriously by physicians, and the lack of an allergic response is used as an argument that this is all in the mind, and that they don't have a problem with their gut physiology," says Professor Guy Boeckxstaens (photo), MD, PhD, a gastroenterologist at KU Leuven and lead author of the new research. “With these new insights, we provide further evidence that we are dealing with a real disease.” His team’s laboratory and clinical studies reveal a mechanism that connects certain foods with activation of the cells that release histamine (called mast cells), and subsequent pain and discomfort. Earlier work by Professor Boeckxstaens and his colleagues showed that blocking histamine, an important component of the immune system, improves the condition of people with IBS.

Scientists Find Antibody That Blocks Dengue Virus in Mouse Model

A team of researchers led by scientists at the University of California, Berkeley and the University of Michigan has discovered an antibody that blocks the spread within the body of the dengue virus, a mosquito-borne pathogen that infects between 50 and 100 million people a year. The virus causes what is known as dengue fever, symptoms of which include fever, vomiting, and muscle aches, and can lead to more serious illnesses, and even death. Currently, there are no effective treatments or vaccines for the dengue virus. Because there are four different strains of the virus, building up antibodies against one strain can actually leave people more vulnerable to subsequent infection from another strain, which makes finding an effective therapeutic more difficult. Scientists using the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility located at the DOE's Argonne National Laboratory, outside of Chicago, Illinois, have reported success. The dengue virus uses a particular protein, called non-structural protein 1 (NS1), to latch onto the protective cells around organs. It weakens the protective barrier, allowing the virus to infect the cell, and may cause the rupture of blood vessels. The research team's antibody, called 2B7, physically blocks the NS1 protein, preventing it from attaching itself to cells and slowing the spread of the virus. Moreover, because it attacks the protein directly and not the virus particle itself, 2B7 is effective against all four strains of the dengue virus. The research team used X-ray diffraction techniques to determine structures of the NS1 protein with a bound antibody (2B7) and showed how the antibody provides protection against the virus. These diffraction images were obtained at the General Medical Sciences and Cancer Institutes Structural Biology Facility (GM/CA) at the APS.

Scientists Discover “Spectacular” Bat from West Africa

A group of scientists led by researchers at the American Museum of Natural History and Bat Conservation International have discovered a new species of a striking orange and black bat in a mountain range in West Africa. The species, which the researchers expect is likely critically endangered, underscores the importance of sub-Saharan "sky islands" to bat diversity. The species was described in an article published on January 13, 2021 in the journal American Museum Novitates. The open-access article is titled “A New Dichromatic Species of Myotis (Chiroptera: vespertilionidae) from the Nimba Mountains, Guinea” (American Museum Novitates, no. 3963). "In an age of extinction, a discovery like this offers a glimmer of hope," said Winifred Frick, PhD, Chief Scientist at Bat Conservation International and an Associate Research Professor at the University of California, Santa Cruz. "It's a spectacular animal. It has this bright-orange fur, and because it was so distinct, that led us to realize it was not described before. Discovering a new mammal is rare. It has been a dream of mine since I was a child." In 2018, Dr. Frick and her colleagues at Bat Conservation International and the University of Maroua in Cameroon were in the Nimba Mountains in Guinea (Africa) conducting field surveys in natural caves and mining tunnels, known as adits, that were built in the 1970s and 1980s and have since been colonized by bats. In collaboration with the local mining company, Société des Mines de Fer de Guinée (SMFG), the scientists are trying to understand which bat species use which adits and at what times of the year. Of particular interest is Lamotte's roundleaf bat, Hipposideros lamottei, which is listed by the International Union for Conservation of Nature (IUCN) as critically endangered and has only ever been recorded in the Nimba Mountains.

January 13th

CRISPR/Cas9 Gene-Editing Produces Tenfold Increase in Superbug-Slaying Antibiotics (Formicamycins) Found in Bacteria Living in Nests of a Certain African Ant (Tetraponera penzigi)

Scientists have used gene-editing advances to achieve a ten-fold increase in the production of super-bug-targeting formicamycin antibiotics. The John Innes Centre (UK) researchers used the technology to create a new strain of Streptomyces formicae bacteria which over-produces the medically promising molecules. The results were reported in an article published on January 12, 2021 in Cell Chemical Biology. The open-access article is titled “Re-Wiring the Regulation of the Formicamycin Biosynthetic Gene Cluster to Enable the Development of Promising Antibacterial Compounds.” Discovered within the last ten years, formicamycins have great potential because, under laboratory conditions, superbugs like methicillin-resistant Staphylococcus aureus (MRSA) do not become resistant to them. However, Streptomyces formicae only produce the antibiotics in small quantities. This has made it difficult to scale up purification for further study and is an obstacle to the molecules being taken forward for clinical trials. In a new study, researchers used CRISPR/Cas9 genome editing to make an S. formicae strain which produces ten times more formicamycins on agar plates and even more in liquid cultures. Using DNA sequencing the researchers found that the formicamycin biosynthetic gene cluster consists of 24 genes and is controlled by the activity of three key regulators inside the cluster. The scientists used CRISPR/Cas9 to make changes in regulatory genes and measured how much of the antibiotics were produced. CRISPR/Cas9 involves using part of a microbial immune system to make targeted changes in DNA. Through uncovering the roles of the three important regulators, the team was able to combine mutations to maximise production.

Breakthrough Against Antibiotic-Resistance of World’ Leading Superbug Actinobacter baumannii Achieved Using Bacteriophage in Mouse Model

A major risk of being hospitalized is catching a bacterial infection. Hospitals, especially areas including intensive care units and surgical wards, are teeming with bacteria, some of which are resistant to antibiotics--they are infamously known as “superbugs.” Superbug infections are difficult and expensive to treat, and can often lead to dire consequences for the patient. Now, new research published online on January 11, 2021 in Nature Microbiology has discovered how to revert antibiotic-resistance in one of the most dangerous superbugs. The article is titled “Bacteriophage-Resistant Acinetobacter Baumannii Are Resensitized to Antimicrobials.” The strategy involves the use of bacteriophages (also known as 'phages'). "Phages are viruses, but they cannot harm humans," said lead study author Fernando Gordillo Altamirano, MD, from the Monash University School of Biological Sciences. "They only kill bacteria." The research team investigated phages that can kill the world's leading superbug, Acinetobacter baumannii (image), which is responsible for up to 20 per cent of infections in intensive care units. "We have a large panel of phages that are able to kill antibiotic-resistant A. baumannii," said Jeremy Barr, PhD, senior author of the study and Group Leader at the School of Biological Sciences and part of the Centre to Impact AMR (antimicrobial resistance) (https://www.monash.edu/impact-amr). "But this superbug is smart, and in the same way it becomes resistant to antibiotics, it also quickly becomes resistant to our phages," Dr Barr said. The study pinpoints how the superbug becomes resistant to attack from phages, and in doing so, the superbug loses its resistance to antibiotics. "A. baumannii produces a capsule, a viscous and sticky outer layer that protects it and stops the entry of antibiotics," said Dr. Altamirano.

January 11th

Enhanced Oral Administration of Exosomes with Milk Protein Casein Shows Possible Effectiveness in Treating Muscular Dystrophy and Heart Failure in Mouse Model

Cell-derived exosomes are effective in treating disease when mixed with the dominant protein (casein) in breast milk and given orally, a new Smidt Heart Institute (https://www.cedars-sinai.org/programs/heart.html) of Cedars-Sinai study of laboratory mice shows. The findings, published online on January 11, 2021 in the Journal of Extracellular Vesicles, could establish a basis for developing new oral medications for treating patients with muscular dystrophy and heart failure. The open-access article is titled “Casein‐enhanced uptake and disease‐modifying bioactivity of ingested extracellular vesicles.” The study builds on more than a decade of research led by Eduardo Marbán, MD, PhD (https://bio.cedars-sinai.org/marbane/index.html?_ga=2.237266880.17442914...), Executive Director of the Smidt Heart Institute and Cedars-Sinai Professor of Cardiology. The research has focused on human cardiosphere-derived cells (CDCs) and a type of extracellular vesicle, called an exosome, that is secreted by those cells and travels throughout the body. Exosomes contain various biomolecules. "When we started our first human trial in 2009, we were injecting the cells into the hearts of patients, and we thought the cells themselves were the therapeutic answer," Dr. Marbán said. "Now, we know it's really the exosomes that do the heavy lifting, and our recent work shows that they could be just as effective when administered orally." Since that first study concluded in 2010, Dr. Marbán has led several studies that have each produced new insights and new methods of delivering the cells to patients and an expansion of the type of patients the cells could potentially help. The first studies led by Dr.

January 10th

Severe Sepsis May Be Predicted by Detected Release of Common Protein (Galectin-1), UConn-Led Study Suggests

A sugar-binding protein (galectin-1) could fuel terrible inflammation and worsen sepsis, a disease that kills more than 270,000 people every year in the US alone, reports a team of researchers led by University of Connecticut (UConn) Health in an article published online on January 4, 2021 in Nature Immunology. The article is titled “Intracellular Immune Sensing Promotes Inflammation Via Gasdermin D–Driven Release of a Lectin Alarmin” (https://www.nature.com/articles/s41590-020-00844-7). Sepsis is caused mostly by bacterial infections. The immune system runs out of controls and triggers a cytokine storm, a condition in which inflammation-causing proteins flood the blood. Organs may break down, and death often follows. Other diseases can also cause cytokine storms; medical historians believe cytokine storms were behind the lethality of the 1918-1919 flu epidemic, as well as the Black Death. Cytokine storms are also observed in patients with severe COVID-19 and are believed to be involved in death in COVID-19. A main trigger for the cytokine storms during sepsis is the overreaction of the body when it detects an infection inside the cells. When a cell detects bacteria or pieces of bacteria inside itself, it immediately activates enzymes that in turn activate a protein that pokes holes on the cell membrane from within, eventually causing the cell to burst open and spill cytokines into the bloodstream. Cytokines are alarm signals, calling in the immune system to fight the bacteria. Cytokines also make other cells more likely to burst open and sound the alarm. Usually, the system damps itself after a while and calms down, but in sepsis it spins out of control, causing more and more cells to burst and die and release even more cytokines into the bloodstream.