New Technique Reduces Nicotine Levels, Harmful Compounds Simultaneously in Tobacco (Agriculture)

North Carolina State University researchers have developed a new technique that can alter plant metabolism. Tested in tobacco plants, the technique showed that it could reduce harmful chemical compounds, including some that are carcinogenic. The findings could be used to improve the health benefits of crops.

“A number of techniques can be used to successfully reduce specific chemical compounds, or alkaloids, in plants such as tobacco, but research has shown that some of these techniques can increase other harmful chemical compounds while reducing the target compound,” said De-Yu Xie, professor of plant and microbial biology at NC State and the corresponding author of a paper describing the research. “Our technology reduced a number of harmful compounds – including the addictive nicotine, the carcinogenic N-nitrosonornicotine (NNN), and other tobacco-specific nitrosamines (TSNAs) – simultaneously without detrimental effects to the plant.”

The technique uses transcription factors and regulatory elements as molecular tools for new regulation designs. Regulatory elements are short, non-coding DNA fragments that control the transcription of nearby coding genes. Transcription factors are proteins that help turn certain genes on or off by binding to regulatory elements. Xie hypothesized that these could be useful molecular tools to design new regulations for engineering new plant traits. Two Arabidopsis transcription factors in particular, PAP1 and TT8, are known to regulate the biosynthesis of anthocyanins, or classes of nutraceutical compounds with antioxidant properties. Xie further hypothesized that these proteins could be used as molecular tools to help repress a number of harmful chemical compound levels, such as nicotine.

“PAP1 regulates pigmentation, so tobacco plants with our overexpressed PAP1 genes are red,” Xie said. “We screened plant DNAs and found that tobacco has PAP1- and TT8-favored regulatory elements near JAZ genes, which repress nicotine biosynthesis. We then proposed that these elements were appropriate tools for a test. In all, we found four JAZ genes activated in red tobacco plants with a designed PAP1 and TT8 cassette overexpressed.”

Xie and his colleagues tested the hypothesis by examining tobacco plants in the greenhouse and in the field and showed the reductions of harmful chemical compounds and nicotine in both types of experiments. NNN levels were reduced from 63 to 79% in leaves from tobacco plants that had PAP1 and TT8 overexpressed, for example. Overall, four carcinogenic TSNAs were significantly reduced by the technique.

Xie believes that the technique holds the potential to be used in other crop plants to promote other beneficial traits and make some foods healthier.

The paper appears in Journal of Advanced Research. Research associate Mingzhu Li is a first author of the paper. Former postdoctoral fellows Xianzhi He and Christophe La Hovary are co-first authors. The research was supported by the R.J. Reynolds Tobacco Co.

Featured image: Overexpressed PAP1 and TT8 genes turn tobacco plants red, but also help reduce carcinogenic chemical compounds. Photo courtesy of De-Yu Xie


Reference:

  • Title: “A De Novo regulation design shows an effectiveness in altering plant secondary metabolism”
  • Authors: Mingzhuo Li, Xianzhi He, Christophe La Hovary, Yue Zhu, Yilun Dong, Shibiao Liu, Hucheng Xing, Yajun Liu, Yucheng Jie, Dongming Ma, Seyit Yuzuak and De-Yu Xie, NC State University
  • Published: June 20, 2021 in Journal of Advanced Research
  • DOI: 10.1016/j.jare.2021.06.017

Provided by NC State

Quantum Phase Transition Discovered in A Quasi-2D System Consisting Purely Of Spins (Quantum)

Pure quantum systems can undergo phase transitions analogous to the classical phase transition between the liquid and gaseous states of water. At the quantum level, however, the particle spins in states that emerge from phase transitions display collective entangled behavior. This unexpected observation offers a new avenue for the production of materials with topological properties that are useful in spintronics applications and quantum computing. 

The discovery was made by an international collaboration led by Julio Larrea, a professor at the University of São Paulo’s Physics Institute (IF-USP) in Brazil. Larrea is first author of an article on the study published in Nature. The research was supported by FAPESP

“We obtained the first experimental evidence of a first-order quantum phase transition in a quasi-two-dimensional system consisting entirely of spins. It was a groundbreaking study in terms of both experimental development and theoretical interpretation,” Larrea said.

To understand the significance of this discovery, it will help to examine the classical phase transition, which can be exemplified by the change in the state of water, and its quantum analogue, exemplified by the Mott metal-insulator transition.

“The change in the state of water, which occurs at 100 °C under standard atmospheric pressure, is what we call a first-order transition. It is characterized by a discontinuous jump in molecule density. In other words, the number of water molecules per unit volume varies drastically between one state and the other,” Larrea said. “This first-order discontinuous transition evolves in accordance with pressure and temperature until it is fully suppressed at the so-called critical point of water, which occurs at 374 °C and 221 bar. At the critical point, the transition is second-order, i.e. continuous.”

In the vicinity of the critical point, the properties of water behave anomalously, because the density fluctuations are infinitely correlated on the atomic length scale. As a result, the material manifests a unique state that differs both from a gas and a liquid (see Figure 1).

Figure 1: Water phase diagram, showing start of first-order transition and coexistence of liquid and gaseous states along the black line. The transition ends at the critical point, marked with a star (figure produced by researcher Julio Larrea, adapted from image published in Nature)

“In quantum matter, the Mott metal-insulator transition is a rare example of a first-order transition. Unlike ordinary metals and insulators, which have free electrons that don’t interact, a Mott state involves strong interaction between electron charges, configuring collective behavior,” Larrea explained. “The energy scales of these interactions are very low, so a first-order quantum phase transition between a metal and an insulator can happen at absolute zero, which is the lowest possible temperature. The interaction between charges varies with temperature and pressure until it is suppressed at the critical point. As the critical point approaches, volume charge density, which is the quantity of charge per unit volume, undergoes such an abrupt change that it can induce new states of matter such as superconductivity.”

In the two examples mentioned, the phenomena involve massive particles such as water molecules and electrons. The question posed by the researchers was whether the concept of phase transition could be extended to massless quantum systems, such as a system made up solely of spins (understood as a quantum manifestation of matter associated with magnetic states). A situation of this kind had never been observed before.

“The material we used was a frustrated quantum antiferromagnet SrCu2(BO3)2,” Larrea said. “We measured the specific heat of small samples under simultaneously extreme conditions of temperature [to 0.1 kelvin], pressure [to 27 kilobar] and magnetic field [to 9 tesla]. Specific heat is a physical property that gives us a measure of the internal energy in the system, and from this, we can infer different types of orderly or disorderly quantum state, and possible electronic states or entangled spin states.”

Obtaining these measurements with the precision required to reveal correlated quantum states, using samples submitted to extremely low temperatures, high pressures and strong magnetic fields, was a formidable experimental challenge, according to Larrea. The experiments were performed in Lausanne, Switzerland, at the Laboratory for Quantum Magnetism of the Federal Polytechnic School of Lausanne (LQM-EPFL), headed by Henrik Rønnow. The precision of the measurements motivated the theoretical collaborators, led by Frédéric Mila (EPFL) and Philippe Corboz (University of Amsterdam), to develop state-of-the-art computational methods with which to interpret the different anomalies observed.

“Our results showed unexpected manifestations of quantum phase transitions in pure spin systems,” Larrea said. “First, we observed a quantum phase transition between two different kinds of entangled spin state, the dimer state [spins correlated at two atomic sites] and the plaquette state [spins correlated at four atomic sites]. This first-order transition ends at the critical point, at a temperature of 3.3 kelvin and pressure of 20 kilobar. Although the critical points of water and the SrCu2(BO3)2 spin system have similar characteristics, the states that emerge near the critical point of the spin system comply with a different description of physics, of the Ising type.” The term Ising refers to a model of statistical mechanics named for German physicist Ernst Ising (1900-98).

“We also observed that this critical point has a discontinuity in magnetic particle density, with triplets or states correlated in different configurations of spin orientation, leading to the emergence of a purely quantum antiferromagnetic state,” Larrea said (see Figure 2).

Figure 2: SrCu2(BO3)2 spin system phase diagram, showing start of first-order transition at absolute zero. The first-order transition ends at the critical point, analogously to the water diagram. However, unlike what happens with water, in the spin system a new orderly state emerges that is purely quantum and strongly correlated: the antiferromagnetic state (figure produced by researcher Julio Larrea, adapted from image published in Nature)

The next step for Larrea is to find out more about the criticality and entangled spin states that emerge in the vicinity of the critical point, the nature of the discontinuous and continuous quantum phase transitions, and the energy scales that represent the interactions and correlations between electron spins and charges leading to quantum states such as superconductivity. “To this end, we plan to conduct a study with pressures around the critical point and higher pressures,” he said. A new facility, the Laboratory for Quantum Matter under Extreme Conditions (LQMEC), is being set up for this purpose in collaboration with Valentina Martelli, a professor in IF-USP’s Department of Experimental Physics.

The article “A quantum magnetic analogue to the critical point of water” can be retrieved from: www.nature.com/articles/s41586-021-03411-8.

Featured image: The study could have applications in spintronics and quantum computing. It was conducted by an international collaboration and published in Nature. Its first author is a researcher at the University of São Paulo (figure: Julio Larrea/IF-USP)


Provided by FAPESP

Daily Practice Of Three-step Breathing Exercise Associated With A Lower Percentage of COVID-19 (Physiology)

Apurvakumar Pandya and colleagues in their recent paper, assess the prevalence of Covid-19 infection among people practicing threestep rhythmic breathing (3SRB) exercise and those who were not practising. Their study indicated that the prevalence of Covid-19 is lower among people practicing 3SRB compared to those who are not practicing 3SRB. Their study recently appeared in medRxiv.

Three-Step Breathing exercise is a breathing pattern that aids an individual breathe in rhythm with nature. It is a slow and deep breathing technique founded by Yogi Sri Soli Tavaria. It is also known as refining exercises and is believed to cleanse impurities from the mind and the body. Studies on the effect of Three Step Rhythmic Breathing (3SRB) on COVID-19 remain unknown. There are many claims that breathing exercises can strengthen the lungs and may be beneficial for reducing the impact of COVID-19 before, during, and after it strikes. Now, Apurvakumar Pandya and colleagues attempted to determine the prevalence of COVID-19 among people practicing 3SRB exercise and those who are not practicing 3SRB exercise in India.

They conducted a community-based cross-sectional observational study and collected data using a self-constructed online google survey tool from July 2020 to August 2020.

Out of a total 1083 sample, a higher proportion of the participants (41.3%) belonged to the 34-49 years age group, followed by the age group of 50-65 (32.5%). The sample was almost equally distributed; about 51.9% of the population was male, and 48.4% were female.

They found that, COVID-19 positivity was recorded almost double (3.1%) in groups not practicing 3SRB exercises compared to a group (1.3%) practicing 3SRB exercises. Furthermore, the practice of 3SRB was significantly associated with a lower percentage of COVID-19 infection (p=0.046).

Their study is the first to show that the daily practice of 3SRB, associated with a lower percentage of COVID-19 infection. However, future study with a robust methodology is required to validate the findings of this study and determine the effects of 3SRB on physiological and biological markers.


Reference: Apurvakumar Pandya, Dileep Mavalankar, Pravin Maithia, “Three-step rhythmic breathing exercise and COVID-19: A cross-sectional study”, medRxiv 2021.07.07.21259527; doi: https://doi.org/10.1101/2021.07.07.21259527


Note for editors of other websites: To reuse this article fully or partially kindly give credit either to our author/editor S. Aman or provide a link of our article

How Brain Regions Interact And Properly Represent Memory? (Neuroscience)

Recall a phone number or directions just recited and your brain will be actively communicating across many regions. It is thought that working memory relies on interactions between these regions, but how these brain areas interact and properly represent memory has remained a mystery.

At Baylor College of Medicine, Dr. Nuo Li, assistant professor of neuroscience and a McNair Scholar, and his colleagues investigated the nature of the communication between brain regions involved in working memory and found evidence that a modular network organization is critical for persistent neural activity.

Dr. Li Nuo © BCM

How brain regions interact

Li and his colleagues were able to see that each hemisphere of the brain has a separate representation of a memory. However, the hemispheres are tightly coordinated on a moment-to-moment basis, resulting in highly coherent information flow across them during working memory.

In their study, the researchers engaged mice in a simple behavior that would require them to store specific information. They were trained to delay an instructed action for a few seconds. This time delay gave researchers the chance to look at brain activity during the memory process.

“We saw many neurons simultaneously firing from both hemispheres of the cortex in a coordinated fashion. If activity went up in one region, the other region followed closely. We hypothesized that the interactions between brain hemispheres is what was responsible for this memory,” Li said.

Li and his colleagues recorded activity in each hemisphere, showing that each one made its own copy of information during the memory process. So how are the two hemispheres communicating?

Li explained that through the use of optogenetics they were able to corrupt information in a single hemisphere, affecting thousands of neurons during the memory period. What they found was unexpected.

When we disrupted one hemisphere, the other area turned off communication, basically preventing the corruption from spreading and affecting activity in other regions,” Li said. “This is similar to modern networks such as electricity grids. They are connected to allow for the flow of electricity but also monitor for faults, shutting down connections when necessary so the entire electrical grid doesn’t fail.”

In collaboration with Dr. Shaul Druckmann and Ph.D. student Byungwoo Kang at Stanford University, the researchers developed theoretical analyses and network simulations of this process, showing that this modular organization in the brain is critical for the robustness of persistent neural activity. This robustness could be responsible for the brain being able to withstand certain injuries, protecting cognitive function from distractions.

“Understanding redundant modular organization of the brain will be important for designing neural modulation and repair strategies that are compatible with the brain’s natural processing of information,” Li said.

Read the paper in the journal Cell.

Others who took part in the study include the lead author Guang Chen with Baylor and Jack Lindsey with Stanford University.

Funding for this study was supported by the NIH NINDS and BRAIN Initiative grants (NS112312, NS104781, NS113110, EB02871), the Simons Collaboration on the Global Brain and the Robert and Janice McNair Foundation. Further support was provided by the Whitehall Foundation, Alfred P. Sloan Foundation, Searle Scholars Program, Pew Scholars Program and McKnight Foundation.

DOI: https://doi.org/10.1016/j.cell.2021.05.026


Provided by Baylor College of Medicine

Sensing “Junk” RNA After Chemotherapy Enhances Blood Regeneration (Biology)

Hematopoietic stem cells take advantage of RNA from pathogenic remnants integrated in the genome to replenish the blood system

Chemotherapy kills cycling blood cells thus sending signals to hematopoietic stem cells (HSCs) in the bone marrow to produce more differentiated blood cells. Scientists from the MPI of Immunobiology and Epigenetics in Freiburg reveal that during hematopoietic regeneration, RNA expressed from a part of the genome considered as “junk DNA” is used by hematopoietic stem cells to get activated and proliferate. The study published in the scientific journal Nature Cell Biology shows that these so-called transposable elements make RNA after chemotherapy and activate an immune receptor which induces inflammatory signals enhancing hematopoietic stem cell cycling and thus participating in the regeneration of the hematopoietic system.

Chemotherapy is widely used to treat cancer patients. During the treatment, chemotherapeutic agents affect various biochemical processes to kill or reduce the growth of cancer cells, which divide uncontrollably in patients. However, chemotherapy’s cell-damaging effect affects cancer cells and, in principle, many other cell types, including cycling blood cells. This puts the hematopoietic system under severe stress and pushes hematopoietic stem cells (HSCs) in the bone marrow to produce fresh cells and replenish the stable pool of differentiated blood cells in the body.

Researchers from the MPI of Immunobiology and Epigenetics, together with colleagues from the University of Freiburg, Lyon, Oxford, and St Jude Children’s Research Hospital in Memphis, now discovered that hematopoietic stem cells make use of RNA molecules from junk DNA sections to enhance their activation after chemotherapy.

Wake-up inflammation for HSC

Hematopoietic stem cells lie on the top of the hematopoietic hierarchy and give rise to most blood cells, including immune cells. Under normal conditions, HSCs kept dormant in the bone marrow to preserve their long-term self-renewal potential and prevent stem cell exhaustion. However, upon chemotherapy, they are “forced” to exit quiescence and start cycling. “Hematopoietic stem cells respond to chemotherapy by starting proliferating. We know that inflammatory signaling is pivotal for HSC activation. However, we still don’t understand completely how this happens”, says Eirini Trompouki, group leader at the MPI of Immunobiology and Epigenetics in Freiburg.

A link between chemotherapy-induced inflammation and junk RNA

Interestingly, she and her team observed that other RNA molecules besides the RNAs of “classic” coding genes are transcribed in HSCs after chemotherapy. A part of these RNAs stems from active or inactive transposable elements. Transposable elements are remnants of pathogens such as viruses or bacteria that have been integrated into the genome through millions of years of evolution. Researchers often considered these extensive strands of genetic material that dominate the human and mouse genome by more than one-third but seem to lack specific functions as “junk DNA.”

Once the team noticed that RNA from these elements is increased after chemotherapy, the question then became: “Is there a link between transposable element RNA and the increased inflammatory signals observed after chemotherapy?” explains Thomas Clapes, lead author in the study. Indeed, HSCs express some receptors that could induce inflammation, but they are primarily associated with immune cells, and their role is to sense viral RNA. “We hypothesized that these receptors could also bind to transposable element RNA,” says Aikaterini Polyzou. The data of the scientists show that transposable element RNA can bind to the immune receptor MDA5 and trigger an inflammatory response that results in HSCs exiting dormancy and starting to proliferate. “Without these interactions, HSC activation becomes slower and less efficient. This indicates that RNA sensing is probably not necessary for hematopoietic regeneration but helps to enhance blood regeneration after chemotherapy,” say Thomas Clapes, Aikaterini Polyzou, and Pia Prater.

Mechanism or adaptation?

These findings help to better understand the molecular underpinnings of hematopoietic regeneration, especially after chemotherapy. However, the results also pinpoint that transposable element RNA is used by the cells during developmental transitions. The transition of a cell from an inactive-quiescent to an active proliferative state means a massive reorganization of the genome. For example, the cell needs to switch off genes responsible for the energy-saving mode and turns on genes essential for increased metabolism or cell cycling. “It is interesting to think that cells make use of transposable elements or other repetitive RNAs to finetune and adapt whenever they need to change their state, for example after stress, like chemotherapy or even after physiological stress signals like development or aging,” says Eirini Trompouki. The scientists assume that the usage of RNA is a way for the cell to sense and buffer transcription. “We have many more things to find out to be able to understand if RNA sensing is an evolutionary adaptation used in cases of high cellular plasticity to finetune cell fate decisions,” says Eirini Trompouki.

Featured image: Under homeostatic conditions HSCs are quiescent in the bone marrow. Upon chemotherapy transposable element (TE) RNA is increased and activates the innate immune receptor MDA5. This leads to induction of inflammatory signals that are aiding HSCs to exit quiescence and start proliferating in order to replenish the differentiated blood cells that were eliminated by chemotherapy. © Created with BioRender.com


Reference:

Clapes T, Polyzou A, Prater P, Sagar, Morales-Hernández A, Galvao Ferrarini M, Kehrer N, Lefkopoulos S, Bergo V, Hummel B, Obier N, Maticzka D, Bridgeman A, Herman JS, Ilik I, Klaeylé L, Rehwinkel J, McKinney-Freeman S, Backofen R, Akhtar A, Cabezas-Wallscheid N, Sawarkar R, Rebollo R, Grün D and Trompouki E (2021), Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration, Nature Cell Biology 12 July 2021 DOI: 10.1038/s41556-021-00707-9


Provided by MPIIE

Microbiome-altering Diet Reduces Inflammation (Food)

Stanford researchers discover that a 10-week diet high in fermented foods boosts microbiome diversity and improves immune responses.

A diet rich in fermented foods enhances the diversity of gut microbes and decreases molecular signs of inflammation, according to researchers at the Stanford School of Medicine.

In a clinical trial, 36 healthy adults were randomly assigned to a 10-week diet that included either fermented or high-fiber foods. The two diets resulted in different effects on the gut microbiome and the immune system.

Eating foods such as yogurt, kefir, fermented cottage cheese, kimchi and other fermented vegetables, vegetable brine drinks, and kombucha tea led to an increase in overall microbial diversity, with stronger effects from larger servings. “This is a stunning finding,” said Justin Sonnenburg, PhD, an associate professor of microbiology and immunology. “It provides one of the first examples of how a simple change in diet can reproducibly remodel the microbiota across a cohort of healthy adults.”

In addition, four types of immune cells showed less activation in the fermented-food group. The levels of 19 inflammatory proteins measured in blood samples also decreased. One of these proteins, interleukin 6, has been linked to conditions such as rheumatoid arthritis, Type 2 diabetes and chronic stress.

“Microbiota-targeted diets can change immune status, providing a promising avenue for decreasing inflammation in healthy adults,” said Christopher Gardner, PhD, the Rehnborg Farquhar Professor and director of nutrition studies at the Stanford Prevention Research Center. “This finding was consistent across all participants in the study who were assigned to the higher fermented food group.”

Justin Sonnenburg © Stanford University

Microbe diversity stable in fiber-rich diet

By contrast, none of these 19 inflammatory proteins decreased in participants assigned to a high-fiber diet rich in legumes, seeds, whole grains, nuts, vegetables and fruits. On average, the diversity of their gut microbes also remained stable. “We expected high fiber to have a more universally beneficial effect and increase microbiota diversity,” said Erica Sonnenburg, PhD, a senior research scientist in basic life sciences, microbiology and immunology. “The data suggest that increased fiber intake alone over a short time period is insufficient to increase microbiota diversity.”

The study published online July 12 in Cell. Justin and Erica Sonnenburg and Christopher Gardner are co-senior authors. The lead authors are Hannah Wastyk, a PhD student in bioengineering, and former postdoctoral scholar Gabriela Fragiadakis, PhD, who is now an assistant professor of medicine at UC-San Francisco.

A wide body of evidence has demonstrated that diet shapes the gut microbiome, which can affect the immune system and overall health. According to Gardner, low microbiome diversity has been linked to obesity and diabetes.

“We wanted to conduct a proof-of-concept study that could test whether microbiota-targeted food could be an avenue for combatting the overwhelming rise in chronic inflammatory diseases,” Gardner said.

The researchers focused on fiber and fermented foods due to previous reports of their potential health benefits. While high-fiber diets have been associated with lower rates of mortality, the consumption of fermented foods can help with weight maintenance and may decrease the risk of diabetes, cancer and cardiovascular disease.

Erica Sonnenburg © Stanford University

The researchers analyzed blood and stool samples collected during a three-week pre-trial period, the 10 weeks of the diet, and a four-week period after the diet when the participants ate as they chose.

The findings paint a nuanced picture of the influence of diet on gut microbes and immune status. On one hand, those who increased their consumption of fermented foods showed similar effects on their microbiome diversity and inflammatory markers, consistent with prior research showing that short-term changes in diet can rapidly alter the gut microbiome. On the other hand, the limited change in the microbiome within the high-fiber group dovetails with the researchers’ previous reports of a general resilience of the human microbiome over short time periods.

Designing a suite of dietary and microbial strategies

The results also showed that greater fiber intake led to more carbohydrates in stool samples, pointing to incomplete fiber degradation by gut microbes. These findings are consistent with other research suggesting that the microbiome of people living in the industrialized world is depleted of fiber-degrading microbes.

“It is possible that a longer intervention would have allowed for the microbiota to adequately adapt to the increase in fiber consumption,” Erica Sonnenburg said. “Alternatively, the deliberate introduction of fiber-consuming microbes may be required to increase the microbiota’s capacity to break down the carbohydrates.”

In addition to exploring these possibilities, the researchers plan to conduct studies in mice to investigate the molecular mechanisms by which diets alter the microbiome and reduce inflammatory proteins. They also aim to test whether high-fiber and fermented foods synergize to influence the microbiome and immune system of humans. Another goal is to examine whether the consumption of fermented food decreases inflammation or improves other health markers in patients with immunological and metabolic diseases, and in pregnant women and older individuals.

Christopher Gardner © Stanford University

“There are many more ways to target the microbiome with food and supplements, and we hope to continue to investigate how different diets, probiotics and prebiotics impact the microbiome and health in different groups,” Justin Sonnenburg said.

Other Stanford co-authors are Dalia Perelman, health educator; former graduate students Dylan Dahan, PhD, and Carlos Gonzalez, PhD; graduate student Bryan Merrill; former research assistant Madeline Topf; postdoctoral scholars William Van Treuren, PhD, and Shuo Han, PhD; Jennifer Robinson, PhD, administrative director of the Community Health and Prevention Research Master’s Program and program manager of the Nutrition Studies Group; and Joshua Elias, PhD.

Researchers from Chan-Zuckerberg Biohub also contributed to the study.

The work was supported by donations to the Center for Human Microbiome Research; Paul and Kathy Klingenstein; the Hand Foundation; Heather Buhr and Jon Feiber; Meredith and John Pasquesi; the National Institutes of Health (grant T32 AI 7328-29); a Stanford Dean’s Postdoctoral Fellowship; a National Science Foundation Graduate Student Fellowship; and seed funding from the Institute for Immunity, Transplantation and Infection and from the Sean N. Parker Center for Allergy and Asthma Research.

Featured image: Stanford researchers found that eating a diet high in fermented foods such as kimchi increases the diversity of gut microbes, which is associated with improved health.
Nungning20/Shutterstock


Provided by Stanford Medicine

How Cells Infected With Tuberculosis Bacteria Can Die? (Medicine)

Boosting the body’s own disease-fighting immune pathway could provide answers in the desperate search for new treatments for tuberculosis.

Tuberculosis still represents an enormous global disease burden and is one of the top 10 causes of death worldwide.

Led by WEHI’s Dr Michael Stutz and Professor Marc Pellegrini and published in Immunity, the study uncovered how cells infected with tuberculosis bacteria can die, and that using new medicines to enhance particular forms of cell death decreased the severity of the disease in a preclinical model.

At a glance

  • Researchers were able to demonstrate that cells infected with tuberculosis bacteria have functional apoptosis cell death pathways, and showed their importance in combatting severe disease.
  • Using preclinical models, researchers were able to pinpoint the critical apoptotic pathways as targets for new therapies, whereby infected cells can be killed by drugs called IAP inhibitors.
  • The study demonstrated that host-directed therapies were viable for infections such as tuberculosis, which is important in the era of extensive antibiotic resistance.

Fighting antibiotic resistance

Tuberculosis is caused by bacteria that infect the lungs, spreading from person to person through the air. A challenge in the fight against tuberculosis is that the bacteria that cause the disease have developed resistance to most antibiotic treatments, leading to a need for new treatment approaches.

Tuberculosis bacteria grow within immune cells in the lungs. One of the ways that cells protect against these ‘intracellular’ pathogens is to undergo a form of cell death called apoptosis – destroying the cell as well as the microbes within it.

Using preclinical models, researchers sequentially deleted key apoptosis effectors, to demonstrate their roles in controlling tuberculosis infections. This demonstrated that a proportion of tuberculosis-infected cells could die by apoptosis – opening up new opportunities for controlling the disease.

Using host-directed therapies to reduce disease burden

Dr Stutz said researchers then tested new drugs that force cells to die. This revealed that a drug-like compound that inhibits cell death-regulatory proteins called IAPs could promote death of the infected cells.

“When we treated our infection models with this compound, we were able to significantly reduce the amount of tuberculosis disease,” he said.

“The longer the treatment was used, the greater the reduction of disease.”

The research team was able to replicate these results using various different IAP inhibitors.

“Excitingly, many of these compounds are already in clinical trials for other types of diseases and have proven to be safe and well-tolerated by patients,” Dr Stutz said.

“We predict that if these compounds were progressed for treating tuberculosis, they would be most effective if used alongside existing antibiotic treatments.”

Opening the door to new treatment methods

Professor Marc Pellegrini said until now, antibiotics were the only treatment for tuberculosis, which were limited in their application due to increasing antibiotic resistance.

“Unlike antibiotics, which directly kill bacteria, IAP inhibitors kill the cells that the tuberculosis bacteria need to survive,” he said.

“The beauty of using a host-directed therapy is that it doesn’t directly target the microbe, it targets a host process. By targeting the host rather than the microbe, the chances of resistance developing are incredibly low.”

The team hope the research will lead to better treatments for tuberculosis.

“This research increases our understanding of the types of immune responses that are beneficial to us, and this is an important step towards new treatments for tuberculosis, very few of which have been developed in the last 40 years,” Dr Stutz said.

“We have demonstrated that host-directed therapies are viable for infections such as tuberculosis, which is particularly important in the era of extensive antibiotic resistance.”

This work was made possible with funding from the National Health and Medical Research Council, the Sylvia and Charles Viertel Charitable Foundation, The Harry Secomb Trust and the Victorian Government.

Featured image: Neutrophil Extracellular Traps (NETs) are released by a type of white blood cell (neutrophils) when infected with mycobacterium tuberculosis, the bacterium responsible for causing tuberculosis. © WEHI


Reference: Michael Stutz et al., “Macrophage and neutrophil death programs differentially confer resistance to tuberculosis”, Immunity, 2021. DOI: https://doi.org/10.1016/j.immuni.2021.06.009


Provided by WEHI

Biologists Identify Venom Peptide From Ants That Can Activate Pseudo Allergic Pathway Unravelling A Pathway Of MRGPRX2 (Biology)

HKU biologists identify and demonstrate a naturally abundant venom peptide from ants that activates a previously unknown pseudo allergic pathway, unravelling a novel immunomodulatory pathway of MRGPRX2

Ants are omnipresent, and we often get blisters after an ant bite. But do you know the molecular mechanism behind it? A research team led by Professor Billy K C CHOW from the Research Division for Molecular and Cell Biology, Faculty of Science, the University of Hong Kong (HKU), in collaboration with Dr Jerome LEPRINCE from The Institut national de la santé et de la recherche médicale (INSERM) and Professor Michel TREILHOU from the Institut National Universitaire Champollion in France, have identified and demonstrated a novel small peptide isolated from the ant venom can initiate an immune pathway via a pseudo-allergic receptor MRGPRX2. The study has recently been published in a top journal in Allergy – The Journal of Allergy and Clinical Immunology.

Allergy is a common undesirable immune response for most people, and are often caused by allergens such as food, pollen, drugs, mites, bites and stings from venomous insects etc. When an allergic reaction happens, mast cells that line the body surfaces alert the immune system by releasing cytokines. Thus, other immune cells are recruited to the infected area to clear the allergens.

There are two kinds of allergic reaction: allergic and pseudo allergic reactions. Allergic reactions are triggered when allergens bind to the high-affinity IgE receptor on mast cells, whereas the pseudo allergic reactions are majorly triggered when allergens bind to MRGPRX2 on mast cells. Therefore, different medical treatments are required to contain them.

Schematic diagram depicting the overall pathway involved in MRGPRX2 mediated monocyte recruitment and differentiation © University of Hong Kong

Recently, the discovery of IgE and MRGPRX2 expressed receptors in mast cells has helped us to understand the root cause of most allergic and pseudo allergic reactions. However, functional characterisation of MRGPRX2 is very limited since it has not got much attention in the allergic field as a pseudo allergic receptor until recently, whereas the former is very well studied. The function of MRGPRX2, other than being a pseudo allergic receptor, is largely unknown and yet to be explored.

For instance, pseudo allergic reactions can be induced by various FDA approved drugs. So, understanding this pseudo allergic mechanisms will help in developing drugs without side effects. In addition, understanding of pseudo allergic reactions will also help in developing antagonists that would minimise clinically relevant MRGPRX2 mediated allergic reactions such as rosacea or red man syndrome.

Through concerted efforts, our research team identifies and demonstrates a naturally abundant venom peptide from ants that activates a previously unknown pseudo allergic pathway, which in turn, help to discover other function of MRGPRX2, sheding light on the non-pseudo allergic function of MRGPRX2.

Research background

Insect venoms are biochemical arsenals developed by animals to defend themselves. Interestingly, arthropods contain the maximum number of species capable of making venoms that can produce biological effects in our body. Particularly, ants are the most dominant and diversified species with more than 14,700 known species and the biggest biomass in most territorial ecosystems. Therefore, Insect venoms are very important resources for us containing a treasure of biologically active chemicals, peptides and proteins. For instance, Purotoxin-1 (PT1), Apamin and Bicarinalin are bioactive peptides isolated from various insect venoms that are known to play a role in inflammatory pain, antimicrobial effects and cytotoxic effects against cancer cells.

P17 is a short host defence peptide isolated from the venom of an ant Tetramorium bicarinatum. We have recently demonstrated its involvement in our body defence system via interacting with an unknown receptor to activate the immune system to kill the fungal infection in mice lungs. P17, therefore can be exploited as a therapeutic peptide for inflammatory disorders or cancer and pseudo allergic reactions. In this study, after screening almost the entire human G protein-coupled receptor repertoire, we have successfully identified a specific human receptor or Mas-related G protein–coupled receptor-X2 (MRGPRX2) that is responsible for interacting with P17 to carry out its activity.

Key findings

The research team has extensively worked on identifying a lock (GPCR) for a key (P17) by trying about 400 locks for a single key and eventually identified the GPCR for P17. In addition, we also demonstrated the molecular pathways of P17-MRGPRX2 mediated activation of mast cells, an immune cell that is responsible for the allergic reaction. Upon deorphanising of P17, we then used computational approaches to find the important amino acids (ridges in the key) that are important for the binding of the venom peptide with its receptor – like a key ridge in the key for a lock.

Professor Billy K C CHOW and Dr Karthi DURAISAMY (from right to left). © University of Hong Kong

Our team then uncovered a novel pathway for this receptor. We showed P17 induces infiltration of monocytes at the injected site by activating MRGPRX2. The effect is quite similar to an ant bite in humans. Once the ant bites you, you will have blisters/swelling, which indicates the immune cell infiltration at the bite site to remove the ant venom. Usually, our body detects the external substances (arrows in the diagram) via receptors (targets) and act upon those external substances to clear them out. In this scenario, P17 is the arrow detected by MRGPRX2 of mast cells to recruit monocytes and differentiates them into macrophages to engulf and clear the pathogens. To the best of our knowledge, we demonstrated for the first time that MRGPRX2 mediated activation of mast cell could recruit human monocyte and differentiate them into macrophages. This study shows a novel immunomodulatory effect of MRGPRX2 and suggests that it is a vital receptor in innate immunity.

Societal impact of the findings

Firstly, a novel immunomodulatory pathway of MRGPRX2 has been demonstrated, which could enhance the overall understanding of the receptor function among the scientific community. Additionally, Macrophages are specialised cells involved in the detection, phagocytosis and destruction of bacteria and other harmful organisms. Thus, using this novel information, we can design new analogues that are agonists or antagonists of MRGPRX2 to modify our immune response to deal with host defence, allergic or other immune diseases.

“We demonstrated that peptides isolated from venoms can be used to modulate immune responses and these peptides are abundant in nature. One key message we should take from this finding is biodiversity is one of the greatest treasure we have and we just have to use them wisely,” said Professor Chow. “Our findings are evident that novel scientific innovations come from observing the nature. Ant bite leads to immune cell infiltration, so we just isolated the peptide that recruits the immune cells that can be beneficial,” said Dr Duraisamy.  Besides, the HKU team’s laboratory has established a platform for translating basic biology into novel drug discoveries as we already have filed a patent for the design and synthesis of a group of drugs with high efficacies to translate them into societal impact. Using this novel pathway we could eventually tweak it a bit to our benefit to kill off pathogens during infection.

Research Team
The research was conducted by the team led by Professor Billy KC CHOW from the Research Division for Molecular and Cell Biology. Dr Karthi DURAISAMY from Professor Chow’s group is the first author of the paper, while Dr Jérôme LEPRINCE is the co-corresponding author of the paper. Professor Michel TREILOU, Dr Elsa BONNAFÉ, Dr Kailash SINGH, Mr Benjamin LEFRANC and Mr Mukesh KUMAR contributed to the research.

The research has been supported by various grants from the Research Grants Council of Hong Kong and European Regional Development Fund. This work was supported by HK government RGC Grant GRF 1711320 and 17111421, NSFC/RGC and HKU seed fund for basic research 201910159222 to BKCC. Institut National de la Santé et de la Recherche Médicale (Inserm), the Normandy University (Rouen), the Region Normandy, the European Union (PHEDERCPG and 3R projects) and Europe gets involved in Normandy with European Regional Development Fund (ERDF) to JL.

About Professor Chow
Professor Billy KC Chow focuses on novel therapeutic molecules for the treatment of major critical diseases that involves GPCRs. Using his years of experience in basic research, he has founded a start-up company PhrmaSec Ltd, which aims to translate basic research into major societal impact.  His expertise lies in GPCRs in general with GPCR physiological functions, and target receptor identification and their molecular mechanisms of novel bioactive agents.

About the research paper: https://doi.org/10.1016/j.jaci.2021.04.040

Featured image: Cartoon depicting the overall pathway involved in MRGPRX2 mediated monocyte recruitment and differentiation. P17 activation of MRGPRX2, but not IgE receptor in mast cells resulting in cytokine releases (MCP-1, MIP1-α, GM-CSF and M-CSF) and subsequent monocyte recruitment and differentiation © University of Hong Kong

Hijacked Immune Activator Promotes Growth & Spread Of Colorectal Cancer (Biology)

Through a complex, self-reinforcing feedback mechanism, colorectal cancer cells make room for their own expansion by driving surrounding healthy intestinal cells to death – while simultaneously fueling their own growth. This feedback loop is driven by an activator of the innate immune system. Researchers from the German Cancer Research Center (DKFZ) and the University of Heidelberg discovered this mechanism in the intestinal tissue of fruit flies.

Maintaining the well-functioning state of an organ or tissue requires a balance of cell growth and differentiation on the one hand, and the elimination of defective cells on the other. The intestinal epithelium is a well-studied example of this balance, termed “tissue homeostasis”: Stem cells in the intestinal crypts constantly produce progenitor cells that further differentiate to replace the rapidly deteriorating mature cells of the intestinal mucosa.

Growth requires a constant dynamic reorganization of tissue architecture: Defective cells must be displaced from the tissue, also by mechanical forces. Tumor cells disrupt this finely balanced structure: They aggressively make room for their own expansion. Until now, it was not understood how exactly they do this.

Jun Zhou, Erica Valentini and Michael Boutros from the German Cancer Research Center and the University of Heidelberg have now investigated these processes in the intestinal epithelium of the fruit fly, which has a similar structure to the intestine of mammals. By blocking the important BMP signaling pathway, the researchers triggered numerous tumors in the fly intestine. Using this model, they uncovered how cancer cells accelerate their own growth through a sophisticated, self-reinforcing feedback effect.

First, tumor cells tear apart the tissue structure by acting on cell adhesion. The resulting altered mechanical adhesion of the intestinal cells activates a stress-sensitive signaling pathway in neighboring intestinal cells, which in turn causes the activation og genes that promote programmed cell death (apoptosis): The team was able to detect large amounts of proteins that initiate aopotosis in the intestinal cells surrounding individual tumor cells.

Presumably due to cytokines released by dying intestinal cells, the growth-promoting JAK/Stat signaling pathway is activated in tumor cells, leading to further tumor spread.

The team also found that the immune activator PGRP-LA is required for this process. When PGRP-LA is turned off, fewer colon cells die through apoptosis and tumor growth also slows down. “The colon cancer cells apparently hijack a signaling molecule of the innate immune system and misuse it for their own purposes. In this way, they kill two birds with one stone: they make room for their expansion by eliminating intestinal cells in their environment – and additionally fuel their own growth,” explains study leader Michael Boutros. Future studies will determine whether the same mechanisms also play a role in the spread of human intestinal tumors.

Featured image: Graphical abstract by Jun Zhou et al.


Reference: Jun Zhou, Erica Valentini und Michael Boutros: Microenvironmental innate immune signalling and cell mechanical responses promote tumor growth. Developmental Cell 2021, DOI: 10.1016/jdevcell.2021.06.007


Provided by DKFZ