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Researchers Gain Insights Into How Ultrasmall Bacteria From the Environment Have Adapted to Live Inside Humans

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The microbes that live inside our mouths, collectively known as the oral microbiome, impact our overall health in many ways that are not yet fully understood. Some bacteria cause inflammation, leading to periodontitis and other systemic diseases, such as cardiovascular disease and diabetes. Other oral organisms have been associated with certain types of cancer. Scientists are working to understand how these microbes interact with one another and our bodies to tease out their individual roles in health and disease.

Credit: Dr. Jing “Janet” Tian, Pediatric Dentist, Peking University Hospital of Stomatology, visiting scholar, The Forsyth Institute.

The microbes that live inside our mouths, collectively known as the oral microbiome, impact our overall health in many ways that are not yet fully understood. Some bacteria cause inflammation, leading to periodontitis and other systemic diseases, such as cardiovascular disease and diabetes. Other oral organisms have been associated with certain types of cancer. Scientists are working to understand how these microbes interact with one another and our bodies to tease out their individual roles in health and disease.

Among the diverse bacterial species living within our mouths is a group belonging to the Candidate Phyla Radiation (CPR). These bugs are especially mysterious because they are ultra-small, adopt a unique symbiotic lifestyle with their host bacteria, and most have yet to be cultured by scientists and studied in the lab. The only bacteria within the CPR to be examined in-depth are a group called TM7, which were cultivated for the first time by Forsyth Institute researcher Dr. Xuesong He in 2014.

In an important step toward better understanding these elusive bacteria, Dr. He and his collaborator, Dr. Jeffrey S. McLean at the University of Washington, have developed a new model system using the first isolated human oral TM7 strain, TM7x, and its host bacterium, Actinomyces odontolyticus. Researchers used the model system to experimentally study these tiny bacteria, testing a hypothesis for how TM7 adapted to live inside humans, and providing empirical data to confirm previous genomic studies. Their findings were published today in the journal Proceedings of the National Academy of Sciences (PNAS).

Scientists have found TM7 in many different environments, including soil, groundwater, and the bodies of other mammals. Studies have shown that while maintaining a remarkably similar genome overall, the TM7 found in human mouths are unique from those in other environments because they have acquired a gene cluster encoding the arginine deiminase system, or ADS.

“This was intriguing to us since there seem to be very few genomic changes that occurred in this group of tiny bacteria with already small genomes as they transitioned from the environment to mammals,” said Dr. McLean.

Researchers hypothesized that TM7 acquired ADS as an evolutionary advantage to help them adapt and survive in the human oral cavity. To test this hypothesis, Dr. Jing “Janet” Tian, first author of the study, used the model system to experimentally investigate the function and impact of ADS on TM7x and its host bacterium. She found that ADS helped TM7x break down arginine, a process that produces the compounds Adenosine triphosphate (ATP) and ammonia. The increased abundance of ATP and ammonia benefitted TM7x by increasing its infectivity, or ability to multiply. It also protected TM7x and its host bacterium from acid stress, a condition that microbes frequently encounter in the human oral cavity due to the acid created when bacteria feed on and metabolize dietary carbohydrates.

Ultimately, the experiment showed TM7x were able to survive in the experimental environment for longer than they could without the addition of arginine, thanks to ADS.

“Most of the current studies on CPR bacteria are based on a culture-independent genomic approach. Using this TM7 bacterial model system, we are able to directly test a hypothesis generated from genome analysis, which helps move the CPR research field from genome-focused studies toward hypothesis-driven studies to better understand their biology,” said Dr. He.

“The production of ammonia through TM7-encoded ADS raises the pH level in the human oral microenvironment, which poses an intriguing question about the role of TM7 in the development of dental caries,” said Dr. Tian, a Pediatric Dentist at Peking University Hospital of Stomatology and visiting scholar at Forsyth. In a previous study of dental caries in children, Dr. Tian found that the abundance of TM7 increased significantly after treatment of the caries. “We think this indicates that TM7 may be more associated with a caries-free state, and we are planning to do more research in this area,” Dr. Tian said.

This study also adds to a growing body of evidence that TM7 bacteria may play a more protective role in oral health than researchers initially thought. For example, abundance of TM7 is found to increase drastically in the mouths of patients with periodontal disease, which led scientists to assume the bacteria contributed to the disease. But a recent study by led by Dr. Batbileg Bor at Forsyth showed the opposite effect—TM7 decreased periodontal inflammation and bone loss in a mouse model.

“We are still in the early stages of understanding how each of the many different types of these ultrasmall parasitic bacteria, which we basically just uncovered within humans, are impacting health and disease,” said Dr. McLean.

“That’s why it’s so important to have a bacterial model system to not only achieve better understanding of the unique lifestyle of TM7, but experimentally test whether the hypotheses based on genomic studies or clinical observation actually stands,” Dr. He said. “Now, we have a manipulatable model system for TM7, which is truly a major advantage.”

Co-authors of the study include: Dr. Jing Tian, Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Key Laboratory of Digital Stomatology; Dr. Daniel R. Utter, Division of Geological and Planetary Sciences, California Institute of Technology; Dr. Lujia Cen, Department of Microbiology, The Forsyth Institute; Dr. Pu-Ting Dong, Department of Microbiology, The Forsyth Institute, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine; Dr. Wenyuan Shi, CEO and Chief Scientific Officer, The Forsyth Institute; Dr. Batbileg Bor, Department of Microbiology, The Forsyth Institute; Dr. Man Qin, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases; Jeffrey S. McLean, Department of Periodontics, University of Washington; and Dr. Xuesong He, Department of Microbiology, The Forsyth Institute, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine.

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Article: bioengineer.org

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Are Researchers One Step Closer to Developing the Theory of Impulse Circuits?

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Computers play an important role in many aspects of life today. Digital computers are the most widely used, while quantum computers are well known. However, the least known computers are the so-called Stochastic Pulse Computers. Their work is based on highly parallel logical operations between trains of electrical pulses, where the pulses occur at random times, as in neurons, the nerve cells in the brains of humans and mammals.

Computers play an important role in many aspects of life today. Digital computers are the most widely used, while quantum computers are well known. However, the least known computers are the so-called Stochastic Pulse Computers. Their work is based on highly parallel logical operations between trains of electrical pulses, where the pulses occur at random times, as in neurons, the nerve cells in the brains of humans and mammals.

The main motivation for the growing interest in research on RPC computers over the past decade is the hope that they could solve faster and with less energy consumption tasks that are normally easy for living beings, but difficult for digital computers, such as instantaneous responses to stimuli, pattern recognition, robustness to errors and damage in the system, learning, and autonomy.

In a recent study published in Scientific Reports, researchers from the Croatian Centre of Excellence for Advanced Materials and Sensors, Dr Mario Stipčević of the Ruđer Bošković Institute (RBI) and Mateja Batelić, a student at the Faculty of Science at the University of Zagreb (FS), Croatia, describe new or improved versions of RPC circuits that use quantum randomness for the first time, but also go a significant step further and lay the first foundation for RPC circuit theory.

Namely, while circuits for processing information in a digital computer can be assembled from logic circuits as building blocks based on the well-known Boolean theory, a similar theory for RPC circuits does not yet exist. Therefore, the synthesis of circuits for an RPC is limited to trial and error through experimentation or simulation.

‘’The central part of our paper is the formulation and proof of the so-called entropy budget theorem, which can be used to easily verify whether a given mathematical (or logical) operation can be performed or “calculated” by any physical circuit, and if so, how much excess entropy must be available to a circuit in order to perform the given operation.

In this paper, we demonstrate the theorem using several examples of mathematical operations. Perhaps the most interesting proof is the existence of a deterministic half-sum circuit (a + b) / 2. However, this circuit is not yet known, and finding it is a challenge for further research,” says Mario Stipčević, head of the Laboratory of Photonics and Quantum Optics at the Ruđer Bošković Institute.

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PSMA PET Validates EAU Classification System to Determine Risk of Prostate Cancer Recurrence

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Reston, VA (January 20, 2022)—New research has confirmed the accuracy of the novel European Association of Urology (EAU) risk classification system that groups prostate cancer patients based on their risk of recurrence. Prostate-specific membrane antigen (PSMA) PET imaging of men with prostate cancer validated the EAU groupings and provided insights that could further refine risk assessment for patients. This study was published in the January issue of The Journal of Nuclear Medicine.

Credit: Justin Ferdinandus, Wolfgang P. Fendler, Andrea Farolfi, et al.

Reston, VA (January 20, 2022)—New research has confirmed the accuracy of the novel European Association of Urology (EAU) risk classification system that groups prostate cancer patients based on their risk of recurrence. Prostate-specific membrane antigen (PSMA) PET imaging of men with prostate cancer validated the EAU groupings and provided insights that could further refine risk assessment for patients. This study was published in the January issue of The Journal of Nuclear Medicine.

The diagnostic workup of prostate cancer has changed rapidly over the past few years. Recently, the EAU introduced a clinical system separating patients with rising PSA values after first-line therapy (prostate surgery or radiation) into groups of those with high risk and those with low risk for development of metastases. Shortly after this, the U.S. Food and Drug Administration approved 68Ga-PSMA-11 as the first PET drug to target the PSMA for men with prostate cancer.

“Given the growing availability of PSMA-directed PET imaging, our study sought to assess disease in patients based on the EAU classifications while using PSMA PET to identify subgroups of patients, such as those with undetectable, locoregional or distant metastatic disease,” said Justin Ferdinandus, MD, nuclear medicine physician at University Hospital in Essen, Germany.

The multicenter, international study analyzed PSMA PET scans of nearly 2,000 patients with prostate cancer and rising PSA levels. Patterns of disease spread on PSMA PET imaging were used to classify prostate cancer patients into both low- and high-risk groups. High-risk groups were found to have higher rates of metastatic disease on PSMA PET compared to low-risk groups. However, PSMA PET also found metastatic disease in low-risk and no disease in high-risk patients.

“Our study underscores the utility of the EAU risk groups to determine risk of metastasis in biochemically recurrent prostate cancer. But not every high-risk patient has metastases and not every low-risk patient has locoregional or no disease,” said Wolfgang Fendler, MD, nuclear medicine physician at University Hospital in Essen.

He continued, “The ultimate aim of imaging is to provide the right treatment for each patient. As evidenced in this research, the accuracy of PSMA PET is essential to improve stratification and potentially outcomes both in low-risk and high-risk settings.” 

The authors of “PSMA PET validates higher rates of metastatic disease for European Association of Urology Biochemical Recurrence Risk Groups: an international multicenter study” include Justin Ferdinandus, Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; Wolfgang P. Fendler and Ken Hermann, Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany, and Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Andrea Farolfi, Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany, and Division of Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Samuel Washington, Department of Urology, University of California San Francisco, San Francisco, California, and Department of Epidemiology and Statistics, University of California San Francisco, San Francisco, California; Osama Mohamad, Department of Radiation Oncology, University of California San Francisco, San Francisco, California; Miguel H. Pampaloni and Thomas A. Hope, Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California; Peter J.H. Scott, Melissa Rodnick, Benjamin L. Viglianti and Morand Piert, Department of Radiology, University of Michigan, Ann Arbor, Michigan; Matthias Eiber, Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; and Johannes Czernin, Wesley R. Armstrong and Jeremie Calais, Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.

Visit JNM’s new website for the latest research, and follow our new Twitter and Facebook pages @JournalofNucMed.

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Please visit the SNMMI Media Center for more information about molecular imaging and precision imaging. To schedule an interview with the researchers, please contact Rebecca Maxey at (703) 652-6772 or [email protected].
 

About JNM and the Society of Nuclear Medicine and Molecular Imaging
The Journal of Nuclear Medicine (JNM) is the world’s leading nuclear medicine, molecular imaging and theranostics journal, accessed more than 13 million times each year by practitioners around the globe, providing them with the information they need to advance this rapidly expanding field. Current and past issues of The Journal of Nuclear Medicine can be found online at http://jnm.snmjournals.org.

JNM is published by the Society of Nuclear Medicine and Molecular Imaging (SNMMI), an international scientific and medical organization dedicated to advancing nuclear medicine and molecular imaging—precision medicine that allows diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes. For more information, visit www.snmmi.org.

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UCLA Researchers Develop Novel Microscopic Picoshell Particles

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Production of high-energy fats by microalgae may provide a sustainable, renewable energy source that can help tackle climate change. However, microalgae engineered to produce lipids rapidly usually grow slowly themselves, making it difficult to increase overall yields. 

Production of high-energy fats by microalgae may provide a sustainable, renewable energy source that can help tackle climate change. However, microalgae engineered to produce lipids rapidly usually grow slowly themselves, making it difficult to increase overall yields. 

UCLA bioengineers have created a new type of petri dish in the form of microscopic, permeable particles that can dramatically speed up research and development (R&D) timelines of biological products, such as fatty acids for biofuels. Dubbed PicoShells, the picoliter (trillionth of a liter), porous, hydrogel particles can enable more than one million individual cells to be compartmentalized, cultured in production-relevant environments, and selected based on growth and biomass accumulation traits using standard cell-processing equipment. 

Proceedings of the National Academy of Sciences recently published a study detailing how PicoShells work and their potential applications.

PicoShells consist of a hollow inner cavity where cells are encapsulated and a porous outer shell that allows for continuous solution exchange with the external environment so that nutrients, cell-communication molecules and cytotoxic cellular byproducts can transport freely in and out of the inner cavity. The shell also keeps the small groups of growing cells penned in, allowing researchers to study and compare their behaviors — what they do, how fast they grow, what they produce — to those of other groups inside various PicoShells. 

This new class of lab tool allows researchers to grow living, single-cell microorganisms — including algae, fungi and bacteria — under the same industrial-production conditions, such as in a bioreactor filled with wastewater or an outdoor cultivation pond. 

“PicoShells are like very tiny mesh balloons. The growing cells inside them are effectively fenced in but not sealed off,” said study leader Dino Di Carlo, UCLA’s Armond and Elena Hairapetian Professor in Engineering and Medicine at the UCLA Samueli School of Engineering. “With this new tool, we can now study the individual behaviors of millions of living cells in the relevant environment. This could shorten R&D-to-commercial production timelines for bioproducts from a few years to a few months. PicoShells could also be a valuable tool for fundamental biology studies.” 

PicoShells’ permeability can bring the lab to the industrial environment, allowing testing at a sectioned-off area of a working facility. Growth can occur more quickly and cell strains that perform well can be identified and selected for further screening. 

According to the researchers, another advantage of this new tool is that the analysis of millions of PicoShells is automated since they are also compatible with standard lab equipment used for high-volume cell processing.

Massive groups of cells, up to 10 million in one day, can be sorted and organized by certain characteristics. Continuous analysis could result in ideal sets of cells — ones that are already performing well in the environment with suitable temperature, nutrient composition and other properties that could be used in mass production — in just a few days rather than the several months it would take using current technologies.

The shells can be engineered to burst when the cells inside have divided and grown beyond their peak volume. Those free cells are still viable and can be recaptured for continued research or further selection. The researchers can also create shells with chemical groups that break down when exposed to biocompatible reagent, enabling a multifaceted approach to release selected cells.

“If we want to zero in on algae that are the best at producing biofuels, we can use PicoShells to organize, grow and process millions of single algal cells,” said lead author Mark van Zee, a bioengineering graduate student at UCLA Samueli. “And we can do that in machines that sort them using fluorescent tags that light up to signify fuel levels.”

Currently, cultivating and comparing such microorganisms are done mostly using traditional lab tools, such as microwell plates — cartons that hold several dozen small test tube-like volumes. However, these methods are slow and it is difficult to quantify their effectiveness because it can take weeks or months to grow large colonies for study. Other approaches, such as water-in-oil droplet emulsions, can be used to analyze cells in smaller volumes, but surrounding oils prevent the free exchange of medium into the water drops. Even cells or microorganisms that perform well in lab conditions may not do as well once they are placed in industrial environments, such as bioreactors or outdoor cultivation farms. As a result, cell strains that are developed in the lab often do not exhibit the same beneficial characteristic behavior when transferred to industrial production. 

Microwell plates also are limited in the number of experiments that can be performed, resulting in a great deal of trial and error in finding cell strains that work sufficiently well for mass production.

The researchers demonstrated the new tool by growing colonies of algae and yeast, comparing their growth and viability against other colonies grown in water-in-oil emulsions. For the algae, the team found that PicoShell colonies accumulated biomass rapidly while algae did not grow at all in water-in-oil emulsions. Similar results were found in their yeast experiments. By selecting the top growing algae in PicoShells, the researchers could increase the production of chlorophyll biomass by 8% after only a single cycle. 

The authors said PicoShells could offer a faster alternative to develop new algae and yeast strains, leading to improved biofuels, plastics, carbon-capture materials and even food products and alcoholic beverages. Further refinements to the technology, such as coating the shells with antibodies, could also lead to developing new types of protein-based medicines.

Di Carlo, van Zee and study co-author Joseph de Rutte Ph.D. ’20, a former member of Di Carlo’s research group, are named inventors on a patent application filed by the UCLA Technology Development Group.

The other UCLA authors on the paper are Rose Rumyan, Cayden Williamson, Trevor Burnes, Andrew Sonico Eugenio, Sara Badih, Dong-Hyun Lee and Maani Archang. Randor Radakovits from Synthetic Genomics of San Diego is also an author.

The study was supported by the Presidential Early Career Award for Scientists and Engineers and a planning award from the California NanoSystems Institute (CNSI) at UCLA.

Di Carlo holds faculty appointments in bioengineering, and mechanical and aerospace engineering at UCLA Samueli. He is a member of CNSI and the Jonsson Comprehensive Cancer Center at UCLA.

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