Sandusky, OH, January 12, 2021 – OTC PR WIRE — PAO Group, Inc. (OTC PINK: PAOG) today confirmed an update covering the company’s 2021 cannabis pharmaceutical and nutraceutical development outlook is scheduled this Thursday Jan 14th, 2021.
In 2020, PAOG acquired a hemp cultivation business from Puration, Inc. (OTC PINK: PURA) and RespRx from Kali-Extracts, Inc. (OTC PINK: KALY). RespRx is a cannabis treatment under development for Chronic Obstructive Pulmonary Disease (COPD) derived from a patented cannabis extraction method – U.S. Patent No. 9,199,960 entitled “METHOD AND APPARATUS FOR PROCESSING HERBACEOUS PLANT MATERIALS INCLUDING THE CANNABIS PLANT.”
The global asthma and COPD market is expected to reach $50 billion by 2022.
PAOG recently announced a key contract with a Contract Research Organization (CRO) to advance the company’s RespRx formula through the process to becoming an approved pharmaceutical treatment.
The company also recently confirmed that the company expects to realize and report in Q4 2020 the first revenue from assets acquired in the course of 2020.
Look for the update this Thursday to learn more.
Learn more about PAOG at www.paogroupinc.com.
Forward-Looking Statements: Certain statements in this news release may contain forward-looking information within the meaning of Rule 175 under the Securities Act of 1933 and Rule 3b-6 under the Securities Exchange Act of 1934, and are subject to the safe harbor created by those rules. All statements, other than statements of fact, included in this release, including, without limitation, statements regarding potential future plans and objectives of the company are forward-looking statements that involve risks and uncertainties. There can be no assurance that such statements will prove to be accurate and actual results and future events could differ materially from those anticipated in such statements. Technical complications, which may arise, could prevent the prompt implementation of any strategically significant plan(s) outlined above. The Company undertakes no duty to revise or update any forward-looking statements to reflect events or circumstances after the date of this release.
No Trees Harmed: MIT Aims to One Day Grow Your Kitchen Table in a Lab
You’ve likely heard the buzz around lab-grown (or cultured) meat. We can now take a few cells from a live animal and grow those cells into a piece of meat. The process is kinder to animals, consumes fewer resources, and has less environmental impact.
MIT researchers will soon publish a paper describing a proof-of-concept for lab-grown plant tissues, like wood and fiber, using a similar approach. The research is early, but it’s a big vision. The idea is to grow instead of build some products made of biomaterials.
Consider your average wooden table. Over the years, a tree (or trees) converted sunlight, minerals, and water into leaves, wood, bark, and seeds. When it reached a certain size, the tree was logged and transported to a sawmill to be made into lumber. The lumber was then transported to a factory or wood shop where it was cut, shaped, and fastened together.
Now, imagine the whole process happening at the same time in the same location. That’s the futuristic idea at play here. Wood grown from only the cells you’re interested in (no seeds, leaves, bark, or roots) could be manipulated to produce desirable properties and grown directly into shapes (like a kitchen table). Fewer 18-wheelers and power tools.
No fuss, no muss.
And of course, once refined, the technique wouldn’t be confined to growing tables. Other products could be made from a variety of biomaterials. In theory, and at scale, the process would be more efficient, less wasteful, and save a few forests too.
That’s the vision. But first, researchers need to figure out if it’s even viable.
Coaxing Wood From Cells
Lead author and MIT PhD student in mechanical engineering, Ashley Beckwith, said she was inspired by time spent on a farm. Viewed through the exacting lens of an engineer, Beckwith was struck by agriculture’s inefficiencies. The weather and seasons are beyond our control. We use land and resources to grow whole plants but only use bits and pieces of them for food or materials.
“That got me thinking: Can we be more strategic about what we’re getting out of our process? Can we get more yield for our inputs?” Beckwith said in an MIT release about the research. “I wanted to find a more efficient way to use land and resources so that we could let more arable areas remain wild, or to remain lower production but allow for greater biodiversity.”
To test the idea, the team took cells from the leaves of a zinnia plant and fed them in a liquid growth medium. After the cells grew and divided, the researchers placed them in a gel scaffold and bathed the cells in hormones. You may be wondering what cells from zinnias—which are a small flowering plant—have to do with wood. Turns out, their properties can be “tuned” like stem cells to express desired attributes. The hormones, auxin and cytokinin, induced the zinnia cells to produce lignin, a polymer that makes wood firm.
By adjusting their hormonal knobs, the team was able to dial in lignin production. Further, the gel scaffold, which is itself firm, coaxed the cells to grow into a particular shape.
“The idea is not only to tailor the properties of the material, but also to tailor the shape from conception,” said Luis Fernando Velásquez-García, a principal scientist in MIT’s Microsystems Technology Laboratories, coauthor on the paper, and Beckwith’s coadvisor.
Velásquez-García’s lab works with 3D printing technology, and he sees the new technique as a kind of additive manufacturing, where each cell is a printer and the gel scaffold directs their production. While it’s still early, the team believes their work proves plant cells can be manipulated to produce a biomaterial with properties suitable for a specified use. But of course, much more work is required to take the idea beyond proof-of-concept.
The researchers say they need to figure out if what they’ve learned can be adapted to other cell types. The hormonal knobs and dials may differ species to species. Also, scaling up requires solving problems like maintaining healthy gas-exchange between cells. Pending more research, whether the idea makes a strong case compared to traditional methods outside of the lab is, of course, also an open question. But this isn’t unusual.
Early research answers the basic question: Is this idea worth pursuing further? It often, necessarily, leaves key questions unanswered, such as cost and scalability. Early experiments in lab-grown meat, for example, were incredibly costly and lacked key properties. The first lab-grown burger famously cost a few hundred thousand dollars but lacked the fatty (tasty) bits of a traditional ground-beef burger.
It wasn’t ready for prime time in terms of cost or quality, but in the years since, investment and interest have grown and costs declined. Now it’s not so laughable to imagine lab-grown meat in your local grocery or restaurant. Just last year, Singapore became the first country to approve lab-grown meat for commercial consumption.
Whether or not this particular vision gathers steam, seeing cells as miniature factories isn’t new. Increasingly, the worlds of bioengineering and manufacturing are colliding. Engineered cells are already being put to work in industrial settings, and last fall, a Japanese clothing brand offered a limited edition (and extremely pricey) sweater made of 30% fiber produced by gene-hacked bacteria grown in a bioreactor.
Down the road, it’s possible we’ll not only build furniture—but grow it too.
Regulating the ribosomal RNA production line
Cryo-electron microscopy study allows researchers to visualize structural changes in an E. coli enzyme synthesizing ribosomal RNA that shift it between turbo- and slow-modes depending on the bacteria’s growth rate
The enzyme that makes RNA from a DNA template is altered to slow the production of ribosomal RNA (rRNA), the most abundant type of RNA within cells, when resources are scarce and the bacteria Escherichia coli needs to slow its growth. Researchers used cryo-electron microscopy (cryo-EM) to capture the structures of the RNA polymerase while in complex with DNA and showed how its activity is changed in response to poor-growth conditions. A paper describing the research led by Penn State scientists appears January 22, 2020 in the journal Nature Communications.
“RNA polymerase is an enzyme that produces a variety of RNAs using information encoded in DNA,” said Katsuhiko Murakami, professor of biochemistry and molecular biology at Penn State and the leader of the research team. “This is one of the key steps in the central dogma of molecular biology: transferring genetic information from DNA to RNA, which in turn often codes for protein. It’s required for life and the process is basically shared from bacteria to humans. We are interested in understanding how the structure of RNA polymerase is changed for modulating its activity and function, but it’s been difficult to capture using traditional methods like X-ray crystallography, which requires crystallizing a sample to determine its structure.”
RNA polymerase functions by binding to specific DNA sequences called “promoters” found near the beginning of genes that are going to be made into RNA. To understand the structure and function of the polymerase during this interaction, researchers need to capture the polymerase while it is bound to the promoter DNA, but the interaction can be very unstable at some promoters. Crystallography can only capture RNA polymerase bound to a promoter if the complex is very stable, but for ribosomal RNA promoters this interaction tends to be unstable so that the polymerase can quickly escape to begin making the RNA. To see these interactions the researchers turned to cryo-EM, a method that allows them to visualize the structure of macromolecules in solution.
“When you talk about RNA, most people think about messenger RNA (mRNA), which is the template for making proteins,” said Murakami. “But the most abundant type of RNA in cells doesn’t actually code for protein. Ribosomal RNA is the major structural component of the ribosome, which is the cellular machinery that builds proteins using messenger RNAs as templates. Ribosomal RNA synthesis accounts for up to 70 percent of total RNA synthesis in E. coli cells.”
When a cell divides, which E. coli can do every twenty minutes in nutrient-rich growth conditions, it needs to provide the two resulting daughter cells with enough ribosomes to function, so it is continually making ribosomal RNAs.
“If you do some back-of-the-envelope calculations, an E. coli cell needs to make around 70,000 ribosomes every 20 minutes,” said Murakami. “This means RNA polymerase starts ribosomal RNA synthesis every 1.7 seconds from each ribosomal RNA promoter. So, the polymerase has to bind the ribosomal RNA promoter transiently in order to quickly move onto the ribosomal RNA synthesis step. This is not an ideal for a crystallographic approach, but in a cryo-EM study, we could capture this interaction and, in fact, see different several stages of the interaction in a single sample.”
The researchers were able to determine the three-dimensional structures of the RNA polymerase-promoter complex at two different stages. One when the DNA was still “closed,” before the two strands of the DNA molecule are separated allowing access to the template strand (they refer to this as a closed complex), and one when the DNA was “open” (called an open complex) and primed for RNA synthesis to begin.
“We found a large conformational change in part of the polymerase called the ? (sigma) factor when it binds to promoter DNA, which has never been observed before” said Murakami. “This change opens a gate that allows the DNA to enter a cleft in the polymerase and form the open complex quickly.”
When E. coli needs to slow its growth due to limited resources, two molecules–a global transcription regulator called DksA and a bacterial signaling molecule called ppGpp, bind directly with the polymerase to reduce production of ribosomal RNA. The research team investigated how the binding of these two factors alters the conformation of the polymerase and affects its activity in a promoter-specific manner.
“DksA and ppGpp binding to the polymerase alters its conformation, which prevents the opening of a gate and therefor the polymerase has to follow an alternative pathway to form the open complex,” said Murakami. “This is not an ideal pathway for the ribosomal RNA promoter and thus slow its activity. It’s exciting to see these conformational changes to the polymerase that have direct functional consequences. We couldn’t do this without the cryo-EM, so I’m very thankful to have access to this technology here at Penn State for optimizing experimental conditions for preparing cryo-EM specimens before sending them to the National Cryo-EM Facility at NCI/NIH for high-resolution data collections. We are going to be able to continue to analyze cellular components and complexes that were previously inaccessible.”
In addition to Murakami, the research team includes Yeonoh Shin and M. Zuhaib Qayyum at Penn State and Danil Pupov, Daria Esyunina, and Andrey Kulbachinskiy at the Russian Academy of Sciences. The research was funded by the U.S. National Institutes of Health, the Russian Science Foundation, and the Russian Foundation for Basic Research. Additional support was provided by the National Cancer Institute’s National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research.
No more needles for diagnostic tests?
Nearly pain-free microneedle patch can test for antibodies and more in the fluid between cells
Blood draws are no fun.
They hurt. Veins can burst, or even roll — like they’re trying to avoid the needle, too.
Oftentimes, doctors use blood samples to check for biomarkers of disease: antibodies that signal a viral or bacterial infection, such as SARS-CoV-2, the virus responsible for COVID-19; or cytokines indicative of inflammation seen in conditions such as rheumatoid arthritis and sepsis.
These biomarkers aren’t just in blood, though. They can also be found in the dense liquid medium that surrounds our cells, but in a low abundance that makes it difficult to be detected.
Engineers at the McKelvey School of Engineering at Washington University in St. Louis have developed a microneedle patch that can be applied to the skin, capture a biomarker of interest and, thanks to its unprecedented sensitivity, allow clinicians to detect its presence.
The technology is low cost, easy for a clinician or patients themselves to use, and could eliminate the need for a trip to the hospital just for a blood draw.
The research, from the lab of Srikanth Singamaneni, the Lilyan & E. Lisle Hughes Professor in the Department of Mechanical Engineering & Material Sciences, was published online Jan. 22 in the journal Nature Biomedical Engineering.
In addition to the low cost and ease of use, these microneedle patches have another advantage over blood draws, perhaps the most important feature for some: “They are entirely pain-free,” Singamaneni said.
Finding a biomarker using these microneedle patches is similar to blood testing. But instead of using a solution to find and quantify the biomarker in blood, the microneedles directly capture it from the liquid that surrounds our cells in skin, which is called dermal interstitial fluid (ISF). Once the biomarkers have been captured, they’re detected in the same way — using fluorescence to indicate their presence and quantity.
ISF is a rich source of biomolecules, densely packed with everything from neurotransmitters to cellular waste. However, to analyze biomarkers in ISF, conventional method generally requires extraction of ISF from skin. This method is difficult and usually the amount of ISF that can be obtained is not sufficient for analysis. That has been a major hurdle for developing microneedle-based biosensing technology.
Another method involves direct capture of the biomarker in ISF without having to extract ISF. Like showing up to a packed concert and trying to make your way up front, the biomarker has to maneuver through a crowded, dynamic soup of ISF before reaching the microneedle in the skin tissue. Under such conditions, being able to capture enough of the biomarker to see using the traditional assay isn’t easy.
But the team has a secret weapon of sorts: “plasmonic-fluors,” an ultrabright fluorescence nanolabel. Compared with traditional fluorescent labels, when an assay was done on microneedle patch using plasmonic-fluor, the signal of target protein biomarkers shined about 1,400 times as bright and become detectable even when they are present at low concentrations.
“Previously, concentrations of a biomarker had to be on the order of a few micrograms per milliliter of fluid,” Zheyu (Ryan) Wang, a graduate student in the Singamaneni lab and one of the lead authors of the paper, said. That’s far beyond the real-world physiological range. But using plasmonic-fluor, the research team was able to detect biomarkers on the order of picograms per milliliter.
“That’s orders of magnitude more sensitive,” Ryan said.
These patches have a host of qualities that can make a real impact on medicine, patient care and research.
They would allow providers to monitor biomarkers over time, particularly important when it comes to understanding how immunity plays out in new diseases.
For example, researchers working on COVID-19 vaccines need to know if people are producing the right antibodies and for how long. “Let’s put a patch on,” Singamaneni said, “and let’s see whether the person has antibodies against COVID-19 and at what level.”
Or, in an emergency, “When someone complains of chest pain and they are being taken to the hospital in an ambulance, we’re hoping right then and there, the patch can be applied,” Jingyi Luan, a student who recently graduated from the Singamaneni lab and one of the lead authors of the paper, said. Instead of having to get to the hospital and have blood drawn, EMTs could use a microneedle patch to test for troponin, the biomarker that indicates myocardial infarction.
For people with chronic conditions that require regular monitoring, microneedle patches could eliminate unnecessary trips to the hospital, saving money, time and discomfort — a lot of discomfort.
The patches are almost pain-free. “They go about 400 microns deep into the dermal tissue,” Singamaneni said. “They don’t even touch sensory nerves.”
In the lab, using this technology could limit the number of animals needed for research. Sometimes research necessitates a lot of measurements in succession to capture the ebb and flow of biomarkers — for example, to monitor the progression of sepsis. Sometimes, that means lot of small animals.
“We could significantly lower the number of animals required for such studies,” Singamaneni said.
The implications are vast — and Singamaneni’s lab wants to make sure they are all explored.
There is a lot of work to do, he said: “We’ll have to determine clinical cutoffs,” that is, the range of biomarker in ISF that corresponds to a normal vs. abnormal level. “We’ll have to determine what levels of biomarker are normal, what levels are pathological.” And his research group is working on delivery methods for long distances and harsh conditions, providing options for improving rural healthcare.
“But we don’t have to do all of this ourselves,” Singamaneni said. Instead, the technology will be available to experts in different areas of medicine.
“We have created a platform technology that anyone can use,” he said. “And they can use it to find their own biomarker of interest.”
We don’t have to do all of this ourselves
Singamaneni and Erica L. Scheller, assistant professor of Medicine in the Division of Bone and Mineral Disease at the School of Medicine, worked together to investigate the concentration of biomarkers in local tissues.
Current approaches for such evaluation require the isolation of local tissues and do not allow successive and continuous inspection. Singamaneni and Scheller are developing a better platform to achieve long term monitoring of local biomarker concentration.
Srikanth Singamaneni, the Lilyan E. Lisle Hughes Professor in the Department of Mechanical Engineering & Materials Science, and Jai S. Rudra, assistant professor in the Department of Biomedical Engineering, worked together to look at cocaine vaccines, which work by blocking cocaine’s ability to enter the brain.
Current candidates for such a vaccine don’t confer long-lasting results; they require frequent boosting. Singamaneni and Rudra wanted a better way to determine when the effects of the vaccine had waned. “We’ve shown that we can use the patches to understand whether a person is still producing the necessary antibodies,” Singamaneni said. “No blood draw necessary.”
This Artificial Heart Will Soon Be on the Market in Europe
Heart disease is one of the leading causes of death in the world, particularly in the US and Western Europe. Medical science has come up with some ingenious solutions to common heart problems, like pacemakers (which correct abnormal heart rhythms), stents (to hold clogged arteries open so blood can flow through), and bypass surgery (which implants a healthy blood vessel from another part of the body to redirect blood around a blocked artery in the heart). These procedures have saved and extended the lives of millions of people.
Now there’s another solution for cardiac patients, and this one goes beyond fixing just an arrhythmia or single artery: a total artificial heart.
If you’re brimming with questions, like—How does it work? Wouldn’t the body reject such a large foreign object (and in such a crucial place?)? What keeps it running?—you’re not the only one.
The artificial heart is made by a French company called Carmat, and is designed for people with end-stage biventricular heart failure. That’s when both of the heart’s ventricles—chambers near the bottom of the heart that pull in and push out blood between the lungs and the rest of the body—are too weak to carry out their function.
Like a real heart, the artificial heart has two ventricles. One is for hydraulic fluid and the other for blood, and a membrane separates the two. The blood-facing side of the membrane is made of tissue from a cow’s heart. A motorized pump moves hydraulic fluid in and out of the ventricles, and that fluid moves the membrane to let blood flow through. There are four “biological” valves, thus called because they’re also made from cow heart tissue.
Embedded electronics, microprocessors, and sensors automatically regulate responses to the patient’s activity; if, for example, they’re exercising, blood flow will increase, just as it would with a real heart. This is what differentiates Carmat’s product from the artificial heart made by American company SynCardia; theirs is a fixed rate device, meaning once a beat rate is set for the heart, the beats per minute will stay the same regardless of patient activity.
Carmat’s device weighs 900 grams, or just under 2 pounds. This is about three times the weight of the average human heart. Externally, patients carry a small bag of actuator fluid, a controller, and a lithium-ion battery.
“The idea behind this heart, which was born nearly 30 years ago, was to create a device which would replace heart transplants, a device that works physiologically like a human heart, one that’s pulsating, self-regulated and compatible with blood,” Carmat CEO Stéphane Piat reportedly told Reuters.
At present, however, Carmat’s product isn’t a permanent solution; it’s been approved as a temporary replacement while patients wait for donor hearts, and is estimated to last about five years. In November 2020, Carmat reported that one patient had been living with the implanted heart for a record two years.
Scientists have long been working on re-creating working versions of human organs using synthetic materials. One of the organs most sorely needed is the kidney, and it’s also one of the hardest to re-create. In comparison, perhaps surprisingly, the heart is one of the less complicated organs; it doesn’t have the hundreds of thousands of intricately-structured nephrons of kidneys, nor the complex insulin-monitoring function of the pancreas; it’s really just a little pump to push blood through our bodies.
After receiving the CE marking (a sort of stamp for products sold in Europe to indicate conformity with health and safety standards) in late 2020, Carmat’s artificial heart will launch commercially in Germany and France in the second quarter of this year. The company also got approval from the US Food & Drug Administration to start an Early Feasibility Study in the US this year.
Image Credit: Carmat
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