Tech

HOUSTON - (April 27, 2020) - Delivering water to city dwellers can become far more efficient, according to Rice University researchers who say it should involve a healthy level of recycled wastewater.

Using Houston as a model, researchers at Rice's Brown School of Engineering have developed a plan that could reduce the need for surface water (from rivers, reservoirs or wells) by 28% by recycling wastewater to make it drinkable once again.

While the cost of energy needed for future advanced purification systems would be significant, they say the savings realized by supplementing fresh water shipped from a distance with the "direct potable reuse" of municipal wastewater would more than make up for the expense.

And the water would be better to boot.

A comprehensive model of the environmental and economic impact and benefits of such a system was developed by Rice researchers associated with the National Science Foundation-backed Nanosystems Engineering Research Center for Nanotechnology-Enabled Water Treatment (NEWT).

Rice environmental engineer Qilin Li is corresponding author and postdoctoral research Lu Liu lead author of the study that appears in Nature Sustainability.

It shows how Houston's planned reconfiguration of its current wastewater treatment system, by which it will eventually consolidate the number of treatment plants from 39 to 12, can be enhanced to "future-proof" water distribution in the city.

"All the technologies needed to treat wastewater to drinking water quality are available," Li said. "The issue is that today, they're still pretty expensive. So a very important part of the paper is to look at how cheap the technology needs to become in order for the whole thing to make sense financially and energy-wise."

Advanced water treatment happens to be a subject of intense study by scientists and engineers at the many institutions, including Rice, associated with NEWT.

"Another way to improve potable water would be to cut its travel time," she said. Water delivered by a system with many distribution points would pick up fewer chemical and biological contaminants en route. Houston, she noted, already has well-distributed wastewater treatment, and making that water drinkable would facilitate shorter travel times to homes.

The model shows there will always be a tradeoff between the acquisition of potable water, the energy required to treat it, the cost of transporting it without affecting its quality, and attempts to find a reasonable balance between those factors. The study evaluated these conflicting objectives and exhaustively examined all possibilities to find systems that strike a balance.

"Ultimately, we want to know what our next-generation water supply system should look like," Li said. "How does the scale of the system affect distribution? Should it be one gigantic, centralized water source or several smaller distributed sources?

"In that case, how many sources should there be, how big of an area should each supply and where should they be located? These are all questions we are studying," she said. "A lot of people have talked about this, but very little quantitative work has been done to show the numbers."

Li admitted Houston may not be the most representative of major municipal infrastructure systems because the city's wastewater system is already highly distributed, but its water supply system is not. The challenge of having a highly centralized water supply was demonstrated by a dramatic 96-inch water main break this February that cut off much of the city's supply.

"That was an extraordinary example, but there are many small leaks that go undetected underground that potentially allow contaminants into homes," she said.

The study only looked at direct potable reuse, which the model shows as a more economic option for established cities, but she said the best option for a new development -- that is, building a distribution system for the first time -- may be to have separate delivery of potable and nonpotable water.

"That would be prohibitive cost-wise in a place like Houston, but it would be cheaper for a new community, where wastewater effluent can be minimally treated, not quite drinkable but sufficient for irrigation or flushing toilets," Li said.

"Though maybe it would be to Houston's advantage to use detention ponds that already exist throughout the city to store stormwater and treat it for nonpotable use."

A UCLA-led research team today reports that it has developed a new method for delivering DNA into stem cells and immune cells safely, rapidly and economically. The method, described in the journal Proceedings of the National Academy of Sciences, could give scientists a new tool for manufacturing gene therapies for people with cancer, genetic disorders and blood diseases.

The study's co-senior author is Paul Weiss, a UCLA distinguished professor of chemistry and biochemistry, of bioengineering and of materials science and engineering. "We are figuring out how to get gene-editing tools into cells efficiently, safely and economically," he said. "We want to get them into enormous numbers of cells without using viruses, electroshock treatments or chemicals that will rip open the membrane and kill many of the cells, and our results so far are promising."

In current practice, cells used for genetic therapies are sent to specialized labs, which can take up to two months to produce an individualized treatment. And those treatments are expensive: A single regimen for one patient can cost hundreds of thousands of dollars.

"We hope our method could be used in the future to prepare treatments that can be performed at the patient's bedside," Weiss said.

The method could be used with CRISPR, the genetic engineering technique that enables DNA to be edited with remarkable precision. However, using CRISPR efficiently, safely and economically in medical therapies has proven to be a challenge -- one this new method may be able to solve.

The technique uses high-frequency acoustic waves coupled with millions of cells that flow through an "acoustofluidic device" in a cell culture liquid. The device was invented by the research team as part of the study; inside of it are tiny speakers that convert electrical signals to mechanical vibrations that are used to manipulate the cells.

That procedure opens up pores along the cells' membranes that allow DNA and other biological cargo to enter the cells, and it enables the researchers to insert the cargo without the risk of damaging the cells by contacting them directly.

Dr. Steven Jonas, the study's co-senior author and a UCLA clinical instructor in pediatrics, likened the soundwaves' ability to move cells to the experience when audience members actually feel the sound at a concert.

"At a concert hall, you can feel the bass -- and if you can feel the sound, the cell can feel the acoustic wave," said Jonas, a member of the California NanoSystems Institute at UCLA, the UCLA Jonsson Comprehensive Cancer Center and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "We can engineer the acoustic waves to direct the cells as needed."

The researchers delivered short strands of DNA called plasmids into human blood cells and blood-forming stem cells that were intended specifically for laboratory research, and pumped millions of such cells through the acoustofluidic device. Once inside a cell, a plasmid can be made into a protein that may be missing or damaged, or it can give the cell new capabilities.

"When combined with new gene-editing approaches, the method enables us to correct a DNA sequence that is miscoded in a disease," said Weiss, who also is a member of CNSI.

Plasmids used as templates for gene editing can make the correction because they have the right coded sequence for the desired protein, he explained.

Lead author Jason Belling, a UCLA graduate student in chemistry and biochemistry, was able to insert plasmids into the model cells used for testing about 60% of the time, without using any chemical and physical treatments.

"The viability is very high compared with other techniques," Weiss said, "but we still want higher efficiencies and are working toward that."

Jonas -- whose expertise is in treating childhood cancer and blood disorders -- said the research has the potential to benefit adults and children with cancer, immune system disorders and genetic diseases.

"If the delivery works, and it seems to, this research is an important step toward bringing new therapies more broadly to the patients who need them," Jonas said. "Traditionally, we have treated cancers with chemotherapy, surgery, radiation and bone marrow transplantations. Now, we're at an amazing era of medicine, where we can use different types of gene therapies that can train the immune system to fight cancer."

Jonas said some existing treatments can take a patient's T cells and adapt them with a gene that encodes for a receptor that allows it to target the cancer.

"We want to be the delivery service that gets these therapeutic packages to the cells," he said. "I want to treat my patients with cells that are engineered in this way."

For the technique to lead to viable treatments for disease, it would need to allow doctors to process at least a couple hundred million cells -- and in some cases, billions of cells -- safely, rapidly and cost-effectively for each patient.

The new approach is still the subject of research and is not available to treat human patients.

The study's other co-authors include Duke University professor Tony Huang, a pioneer of acoustofluidics and a UCLA alumnus; Dr. Stephen Young, distinguished professor of medicine and human genetics at the David Geffen School of Medicine at UCLA; and Dr. Satiro De Oliveira, a UCLA assistant professor of pediatrics.

Diagnosing emphysema and classifying its severity have long been more art than science.

"Everybody has a different trigger threshold for what they would call normal and what they would call disease," said U. Joseph Schoepf, M.D., director of cardiovascular imaging for MUSC Health and assistant dean for clinical research in the Medical University of South Carolina College of Medicine. And until recently, scans of damaged lungs have been a moot point, he said.

"In the past, if you lost lung tissue, that was it. The lung tissue was gone, and there was very little you could do in terms of therapy to help patients," he said.

But with advancements in treatment in recent years has come an increased interest in objectively classifying the disease, Schoepf said. That's where artificial intelligence and imaging could come into play.

Schoepf was principal investigator in a study looking at the results of Siemens Healthineers' AI-Rad Companion as compared with traditional lung function tests. The study, published online in the American Journal of Roentgenology in March, showed that the algorithm within AI-Rad Companion, which examines chest scans, provides results comparable with lung function tests, which measure how forcefully a person can exhale. Showing that the artificial intelligence software works is the first step toward possibly using chest scans to quantify the severity of the lung disease and track the progress of treatment.

In the study, researchers went back and looked at the chest scans and lung function tests of 141 people. Chest scans aren't currently part of the guidelines for diagnosing chronic obstructive pulmonary disease, an umbrella term that includes emphysema, chronic bronchitis and other lung diseases, Schoepf said, because there hasn't been an objective means to evaluate scans.

However, he anticipates a role for imaging scans if it can be shown that they offer a benefit in terms of objectivity and quantification.

Philipp Hoelzer, customer engagement manager with Siemens Healthineers, said having an objective measurement could help in assessing the value of new treatments or drugs. The Siemens Healthineers team sees the program as a way for artificial intelligence to work in tandem with the clinical expertise of radiologists, he said.

"Taking away manual, repetitive tasks, like those that require a lot of measurement, is of great benefit to a radiologist, especially when reading cases that may have 20 or more nodules," he said. "Interpreting the images, and the abstract thinking that goes along with it, will remain with the radiologist."

The program can also offer a concrete aid to doctors trying to impress upon patients the necessity of making changes. It can create a 3D model of the patient's lungs, showing the existing damage.

"If you could visualize it and provide the information in image terms, you could better communicate with the patient and hopefully nudge the patient into smoking cessation or lifestyle changes," Hoelzer said.

A potential additional benefit is that AI-Rad Companion automatically looks for problems across multiple organ systems, including measuring the aorta and bone density. As Schoepf moves into a prospective study phase, he'll be examining whether the artificial intelligence finds things that humans miss. And it can be easy for humans to miss problems that they aren't specifically looking for, he said.

"We're told the patient has these types of symptoms, and then we basically go look for stuff that could explain those symptoms. So, we're often blind to things that do not necessarily relate to the organ system we're interested in," he said.

It can also be difficult for humans to create an accurate measurement of a three-dimensional structure within the body from a two-dimensional scan - something that isn't a problem for the artificial intelligence program. It can automatically combine multiple 2D images to produce 3D measurements.

Schoepf wants to see whether the program improves patient management by prompting early treatment of problems, like a widened aorta or decreased bone density, before the problems become painfully obvious to both doctor and patient.

Further, addressing the dynamically changing health care environment, significant efforts are currently in the final stages to train the artificial intelligence software in the detection and characterization of COVID-19-related lung changes. Hopefully, this would provide physicians with a tool to better differentiate the rather non-specific lung findings of COVID-19 pneumonia from other infectious or inflammatory lung disorders and more objectively quantify the extent of disease.

In terms of the measures for which it was originally developed, Schoepf said MUSC Health will test the system for three months before determining whether to deploy it more extensively. With a regional network that now includes hospitals across the state, it could be a useful tool in standardizing care.

"It's a great chance for patients to get better care. We have world-class radiologists here, but these systems add a little extra," he said.

In what is believed to be a first-of-its-kind study to evaluate the safety of a type of immunotherapy before surgery in patients with an aggressive form of skin cancer, researchers report that the treatment eliminated pathologic evidence of cancer in nearly half of the study participants undergoing surgery. In patients whose tumors respond, this treatment approach offers the potential to reduce the extent of surgery and may also slow or eliminate tumor relapses that often occur after surgery.

A report on the Merkel cell cancer trial, directed by investigators at the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins Kimmel Cancer Center in collaboration with the University of Washington Seattle Cancer Care Alliance and 10 other medical centers across the U.S. and Europe, will be published April 23 in the Journal of Clinical Oncology. An additional review article by Bloomberg~Kimmel Institute experts, published Jan. 31 in the journal Science, also points to the potential strategic value of giving immune checkpoint inhibitor therapy earlier in the course of cancer treatment.

Merkel cell carcinoma is classified as an "orphan disease" by the National Cancer Institute, diagnosed in approximately 2,000 people annually in the U.S. It typically appears as a red, blue or flesh-colored lump on the skin in older people and those who have suppressed immune systems. About 80% of Merkel cell carcinomas are caused by a virus called the Merkel cell polyomavirus. The remaining cases are linked to sun or other ultraviolet light exposure and unknown factors. Merkel cell carcinoma can spread to the lymphatic system and other organs. Surgery, radiation therapy and chemotherapy have been the mainstays of treatment. However, for Merkel cell carcinomas advancing beyond the point of surgery, there were previously no treatment options that could prolong survival. Recently, drugs blocking the immune checkpoints PD-1 and PD-L1 were shown to be effective in advanced inoperable Merkel cell carcinomas, and were approved by the U.S. Food and Drug Administration in this treatment setting.

"Merkel cell carcinoma appears to respond very rapidly to anti-PD-1 immunotherapy in some patients with advanced disease," says lead study author Suzanne Topalian, M.D., associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. "This led us to test whether anti-PD-1 could be effective if given for a brief period before surgery, as so-called neoadjuvant therapy. Using this approach, we found that patients who had substantial tumor regressions on CT scans or in pathology studies of surgically removed tumor specimens had extended cancer recurrence-free survival that was statistically significant. Radiographic and pathologic tumor regressions following neoadjuvant anti-PD-1 therapy are therefore potential new, early markers that will help us predict what a patient's long-term outcome will be. This is critical information for oncologists planning treatment strategies for their patients."

Nivolumab, the immunotherapy drug used in this study, works against cancers including Merkel cell carcinoma by blocking PD-1, a molecule on the surface of immune cells that suppresses immune responses. Cancer cells often manipulate PD-1 by expressing its partner molecule PD-L1, sending a "stop" signal to the immune system. Blocking that signal with a checkpoint inhibitor such as nivolumab initiates a "go" signal, unleashing immune cells to attack cancer cells.

In the phase I/II trial of nivolumab in virus-associated cancers called CheckMate 358, patients with operable Merkel cell cancers received 240 mg of the anti-PD-1 drug intravenously on days one and 15 of the study, with surgery planned for day 29.

The trial was designed primarily to assess the safety and tolerability of nivolumab in this treatment setting. Investigators also assessed tumor regression using CT and MRI scans; studied the presence of cancer cells microscopically in surgically removed tumors; and studied pretreatment tumor biopsies to measure the presence of the polyomavirus causing Merkel cell carcinoma, the mutational burden (the quantity of gene mutations found in a tumor) and expression of the PD-L1 protein.

Overall, 39 patients with stage IIA-IV Merkel cell cancer (locally advanced or having spread to lymph nodes or internal organs) received at least one dose of nivolumab between January 2016 and March 2019. Among 36 patients who underwent surgery, 17 (47%) achieved a pathologic complete response, meaning that there were no live tumor cells anywhere in the surgical tissue. Among 33 patients undergoing surgery who also had imaging scans, 18 (54.5%) had radiographic tumor reductions of at least 30%. Each of these findings correlated significantly with prolonged recurrence-free survival. Patients were followed for a median of 20 months.

"These rates of pathologic and radiographic tumor regression after a brief four-week period of nivolumab therapy are very high compared to other cancer types in which anti-PD-1 treatment has been tried before surgery," Topalian says. "For instance, in lung cancer, the published rate of complete pathologic response after neoadjuvant anti-PD-1 monotherapy is 15%, and in melanoma it is 19-25%. Furthermore, substantial radiographic tumor regression is not common within such a brief treatment period in other cancer types."

Overall, among 36 patients who underwent surgery, recurrence-free survival rates were 77.5% at 12 months and 68.5% at 24 months after surgery. However, those with a complete pathologic response had a recurrence-free survival of 100% at 12 months and 88.9% at 24 months, compared with those without a complete pathologic response, who had recurrence-free survivals of 59.6% and 52.2% at 12 and 24 months, respectively. Similarly, patients with substantial radiographic tumor regressions before surgery experienced prolonged recurrence-free survival, compared with the other patients in the study. These effects of neoadjuvant nivolumab on recurrence-free survival in some patients appear to offer an advantage compared to historical reports of conventional care.

Three of 39 patients (7.7%) did not undergo surgery, one because of tumor progression, and two because of adverse effects from nivolumab. Treatment-related adverse events occurred in 18 of 39 patients (46.2%) and most commonly included skin rashes. Three patients (7.7%) had a severe adverse event, including immune-related colitis. The characteristics of adverse events were similar to those previously reported for anti-PD-1 drugs in patients with other cancer types.

Topalian cautions that the study was a relatively small one, and did not have a control group for comparison. All patients received the same treatment. However, she says, "We think these findings provide a rationale to conduct larger trials of neoadjuvant anti-PD-1 therapy in Merkel cell carcinoma, and have the potential to be practice-changing."

"To our knowledge, this is the first attempt to look at the role of anti-PD-1 therapy before surgery in patients with Merkel cell carcinoma who are candidates for complete surgical removal of their tumor," Topalian says. "We know that, historically, many of these patients would subsequently relapse after standard surgical and postoperative treatments. Even if we think we're removing all of the existing tumor at the time of surgery, in many patients the tumor has already spread to other parts of the body, at microscopic sites of metastasis that are too tiny to be detected with scans."

Investigators from the Bloomberg~Kimmel Institute co-led this study with researchers from the University of Washington Seattle Cancer Care Alliance, in collaboration with 10 other medical centers in the U.S. and Europe. The Bloomberg~Kimmel Institute team included Topalian; William Sharfman, M.D.; Julie Stein, M.D.; Elizabeth Engle, M.S.; and Janis Taube, M.D., M.Sc.

Separately, in a review paper published in Science by Topalian and Johns Hopkins colleagues Taube and Drew M. Pardoll, M.D., Ph.D., director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the researchers summarized scientific and medical knowledge about the use of immune checkpoint blockers before cancer surgery. This includes the first published report of neoadjuvant PD-1 pathway blocking antibodies, tested in non-small cell lung cancer at Johns Hopkins and described in the New England Journal of Medicine in 2018, and additional studies of immune checkpoint blockers in melanoma, bladder cancer and brain cancer from other research groups. There are many more neoadjuvant anti-PD-1 studies maturing now in other cancer types including breast and head and neck cancers, Topalian says.

When people talk about preventing cancer, they generally mean preventing cancer from forming, she says. "However, these neoadjuvant immunotherapy studies speak to the possibility of preventing early-stage cancers from becoming end-stage. We think this is a very valuable approach. By using immune checkpoint blockers before definitive surgery for cancer, it may be possible in some patients to prevent to the disease from progressing to an inoperable stage. We look forward to a lot more information to come in this area."

Preliminary results of the Merkel cell carcinoma study were presented at the American Society of Clinical Oncology meeting in 2018. Other centers participating in that trial were the Levine Cancer Institute, Atrium Health, of Charlotte, N.C.; Winship Cancer Institute of Emory University, Atlanta; Université de Paris, Saint Louis Hospital, Paris; Institut Claudius Regaud, Toulouse, France; Memorial Sloan Kettering Cancer Center, New York; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.; SLK-Clinics, MOLIT Institute, Heilbronn, Germany; University of Pittsburgh Medical Center Hillman Cancer Center; University Medical Center Utrecht, Cancer Center, the Netherlands; and the University of Michigan Comprehensive Cancer Center, Ann Arbor, Mich. Bristol Myers Squibb, which sponsored the trial, also had co-authors.

The work was supported by Bristol Myers Squibb and ONO Pharmaceutical Company Limited. Some of the scientific correlative work conducted at Johns Hopkins was supported by The Mark Foundation for Cancer Research and National Cancer Institute R01 grant CA142779. Authors received no financial support or compensation for publication of the study.

The Science review was supported by the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, the National Cancer Institute (R01 CA142779), the Cancer Research Institute/Stand Up To Cancer-Immunology Translational Cancer Research Grant, Bristol Myers Squibb, the Barney Family Foundation, Moving for Melanoma of Delaware, the Laverna Hahn Charitable Trust, the Melanoma Research Alliance, the Harry J. Lloyd Charitable Trust, the Emerson Collective Foundation, and the Mark Foundation for Cancer Research.

Topalian reported stock and other ownership interests for herself or an immediate family member from Aduro Biotech, DNAtrix, Dragonfly Therapeutics, Ervaxx, Five Prime Therapeutics, RAPT Therapeutics, Potenza Therapeutics, Tizona Therapeutics, Trieza Therapeutics and WindMIL; consulting or advisory roles with Amgen, Compugen, DNAtrix, Dragonfly Therapeutics, Dynavax, Ervaxx, Five Prime Therapeutics, RAPT Therapeutucs, Immunocore, Immunomic Therapeutics, Janssen Oncology, MedImmune, Merck, Tizona Therapeutics and WindMIL; research funding from Bristol Myers Squibb, Compugen and Potenza Therapeutics; travel, accommodations and expenses from Bristol Myers Squibb, Dragonfly Therapeutics, Five Prime Therapeutics and Merck; and patent royalties from Aduro Biotech, Arbor Pharmaceuticals, Bristol Myers Squibb, Immunomic Therapeutics, NexImmune, and WindMIL. These relationships are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Bethesda, MD - Researchers have used threads made of engineered human tissue to weave blood vessels that could one day help repair diseased or damaged blood vessels.

"Blood vessels are just one example of what can be done with our new textile approach to tissue engineering," said research team leader Nicolas L'Heureux, PhD, director of research at Inserm/University of Bordeaux in France. "It can be used to make practically any shape by weaving, braiding or knitting the threads and allows very good control of the mechanical properties of the final product."

Synthetic blood vessel grafts made of woven synthetic polymer yarn are sometimes used to replace diseased arteries. However, the body recognizes the polymer as foreign, which causes blood to clot on these grafts and creates a scar that can clog the tube. Because blood vessels created with the new textile-based approach don't require any synthetic materials, they are likely to be accepted and become part of the body.

L'Heureux was scheduled to present this research at the American Association for Anatomy annual meeting in San Diego this month. Though the meeting, to be held in conjunction with the 2020 Experimental Biology conference, was canceled in response to the COVID-19 outbreak, the research team's abstract was published in this month's issue of The FASEB Journal.

The threads used for the new textile approach are made of a biomaterial called cell-assembled matrix (CAM) developed by L'Heureux's research team. CAM is mostly collagen, which is the most abundant protein the body and the protein that makes tissues and organs mechanically strong. CAM is well-accepted by the body because it is entirely human and not chemically modified.

In the new study, the researchers show that they can make yarn by cutting CAM sheets into ribbons that can be used directly or twisted into threads. They used these threads to weave blood vessels that displayed excellent mechanical properties without the need for any synthetic scaffolding or chemical treatments.

"It is time consuming and costly to get CAM layers to stick together," said L'Heureux. "The new textile assembly approach is not only more versatile but also has the potential to be automated which would make it even faster, easier and cheaper to use."

Because a collagen scaffold is an integral part of most organs, CAM could be used to jumpstart the regeneration of many tissues and organs. So far it has been used to make lab-grown skin for burn patients and guides that help repair nerve injuries.

The researchers are now building additional blood vessel prototypes and learning more about the best ways to handle CAM threads and ribbons. They will soon start testing the vascular grafts in animals as a step toward eventual clinical trials in people.

Bethesda, MD - Although today's rheumatoid arthritis treatments can reduce symptoms, they often come with serious side effects. Results from a new mouse study suggest that a new light-activated drug delivery method helps confine treatments to the joints, which could reduce whole-body side effects.

In the U.S., 1.3 million people are currently diagnosed with rheumatoid arthritis, a chronic disease that causes painful joint swelling that can eventually lead to bone loss and joint deformities.

"Our delivery system decreased arthritis in our experimental model while carrying and delivering much lower quantities of drug than is required for currently approved treatment," said Emilia Zywot, a doctoral candidate from the University of North Carolina in Chapel Hill and member of the team that developed the new drug delivery approach.

Ms. Zywot was scheduled to present this research at the American Society for Pharmacology and Experimental Therapeutics annual meeting in San Diego this month. Though the meeting, to be held in conjunction with the 2020 Experimental Biology conference, was canceled in response to the COVID-19 outbreak, the research team's abstract was published in this month's issue of The FASEB Journal.

For the new delivery approach, a drug is attached to vitamin B12 molecules that are engineered to respond to low levels of laser light. Transfusion is then used to deliver red blood cells loaded with the vitamin B12 molecules into mice, where the cells circulate until activated.

The drug is only activated in areas that receive a low level of long-wavelength laser light, which can be administered from outside the body. This controllable activation allows a high concentration of drug to be released at the site of inflammation, thus requiring overall lower whole-body, or systemic, amounts of the drug for effective treatment.

To test their new method, the researchers administered the arthritis drug dexamethasone to arthritic mice via traditional injections and the light-based delivery system. Laser light was used to activate the light-responsive drug in an arthritic paw. They found that the light-based delivery system decreased arthritis using a three-fold lower dose of dexamethasone.

"We hope that our drug delivery platform will better control drug delivery and decrease the amount of systemic exposure and off-target effects," said Ms. Zywot. "We envision that it will be useful for any drug that can be synthetically attached to our light-responsive system, making it amenable to applications beyond arthritis."

The researchers plan to further investigate the light responsive drug delivery system in mouse models of arthritis to better understand efficacy of the new system compared to current treatments.

Bethesda, MD - Whether it is loud machinery at work, a busy freeway or a nearby airport, many people are exposed to high levels of noise. Two new mouse studies provide new insight into how this type of noise exposure can lead to high blood pressure and cancer-related DNA damage.

"Large studies have linked noise exposure to health problems in people," said Matthias Oelze, PhD, a postdoctoral fellow at the University Medical Center of Mainz in Germany. "Our new data provides additional mechanistic insights into these adverse health effects, especially high blood pressure and potentially cancer development, both leading causes of global death."

Oelze was scheduled to present this research at the American Society for Biochemistry and Molecular Biology annual meeting in San Diego this month. Though the meeting, to be held in conjunction with the 2020 Experimental Biology conference, was canceled in response to the COVID-19 outbreak, the research team's abstract was published in this month's issue of The FASEB Journal.

"These new findings, together with our other work on noise-associated cardiovascular effects, could lead to a better understanding of how noise influences health," said Oelze. "This information could help inform policies and regulations that better protect people against diseases related to noise exposure."

Oelze and colleagues found that healthy mice exposed to four days of aircraft noise were more likely to develop high blood pressure. For mice with pre-established high blood pressure, this noise exposure aggravated heart damage because of a synergistic increase of oxidative stress and inflammation in the cardiovascular and neuronal systems.

In another study, the researchers observed that the same noise exposure induced oxidative DNA damage in mice. This damage led to a highly mutagenic DNA lesion that was previously associated with the development of cancer in other settings.

The researchers are currently conducting several studies on the health effects of noise, including interactions of pre-established cardiovascular diseases with noise as well as behavioral effects of noise exposure in mice.

Bethesda, MD - A new study has shown that salt-tolerant bacteria can be used to enhance salt tolerance in various types of plants. The new approach could increase crop yield in areas dealing with increasing soil salinity.

Each year, about 2 million to 3 million hectares of irrigated farmland go out of production worldwide due to salinity problems, according to the U.S. Agency for International Development. Increased soil salinity not only reduces water uptake for crops but can often create a nutrient imbalance that decreases plant growth and yield.

Although salt levels in soil can increase naturally over time, especially in arid areas, farming practices also contribute. Irrigation water, especially recycled wastewater, contains salts that concentrate in the soil. Fertilizers also add salts to the soil.

"Agricultural soil loss continues to rise, posing a very real threat to many important crops," said research team leader Brent Nielsen, PhD, professor at Brigham Young University. "Our method for enhancing the salt tolerance of plants could be scaled up to allow farmers to use more of their land and improve yield. This would create a more stable income for farmers and a more reliable food supply for consumers."

Ashley Miller, a graduate student working in Nielsen's lab, was scheduled to present this research at the American Society for Biochemistry and Molecular Biology annual meeting in San Diego this month. Though the meeting, to be held in conjunction with the 2020 Experimental Biology conference, was canceled in response to the COVID-19 outbreak, the research team's abstract was published in this month's issue of The FASEB Journal.

In previous work, the researchers isolated salt-tolerant bacteria from plants growing in salty soils. They then immersed young alfalfa seedlings in liquid containing the individual salt-tolerant bacterial strains, a process called inoculation. The alfalfa inoculated with some of these salt-tolerant strains exhibited improved growth in high-salt conditions compared to plants not inoculated with bacteria. In the new work, they explored whether this salt tolerance could be transferred to other plants.

"We've found that salt tolerance can be transferred to many plant types," said Miller. "Initial studies with Kentucky Bluegrass have been particularly successful."

The researchers found that Kentucky Bluegrass grown in salty soil after inoculation with a Bacillus strain increased yield 8.4 times in dry weight compared with control plants grown in the same soil without the bacterial inoculation. The researchers continue to test whether salt tolerance can be conferred to additional plant varieties, with promising initial results. They are also working to understand how the bacteria confer salt tolerance.

Bethesda, MD - People who suffer frequent indigestion may find relief with a small device that hooks onto the ear known as a transcutaneous auricular vagus nerve stimulator, or taVNS. People who used taVNS showed significant improvements in their stomach's ability to accommodate and process a meal, according to a new study.

The research was scheduled to be presented at the American Physiological Society annual meeting in San Diego this month. Though the meeting, to be held in conjunction with the 2020 Experimental Biology conference, was canceled in response to the COVID-19 outbreak, the research team's abstract was published in this month's issue of The FASEB Journal.

Up to 15% of U.S. adults suffer from indigestion, also known as functional dyspepsia. The disorder can cause a premature sensation of fullness and stomach pain after a meal. Though its causes are not well understood, it is thought that the stomach may not stretch and contract appropriately when food is ingested, causing pressure and discomfort.

taVNS devices deliver short pulses of painless electrical current to the vagus nerve, a peripheral nerve (one outside the brain and spinal cord) that runs from the head to the abdomen. While taVNS has been explored as a possible treatment for epilepsy, depression and a variety of other conditions, the new research study is one of the first to assess the potential benefits of auricular taVNS for gastrointestinal problems. The study involved a particular type of taVNS device, Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), that delivers electrical pulses in tune with the respiratory rhythm.

"Our findings suggest that RAVANS has the ability to modulate the stomach's response to food ingestion, which may be impaired in functional dyspepsia patients," said lead study author Roberta Sclocco, PhD, a postdoctoral fellow at Massachusetts General Hospital and Harvard Medical School, who is also affiliated with Logan University in Missouri. "RAVANS is a non-invasive, safe peripheral nerve stimulation intervention and while our results are encouraging, further research is needed to estimate the optimal dose and timings of this intervention."

Sclocco and colleagues tested RAVANS in 12 volunteers with functional dyspepsia. All volunteers participated in two research sessions in which they wore the RAVANS device or control, ate a meal and underwent magnetic resonance imaging (MRI) scans 15, 65 and 80 minutes after eating.

MRI scans revealed the ratio of stomach volume to the volume of ingested food was higher during RAVANS, indicating that taVNS helped participants' stomachs expand to accommodate the meal. In addition, the stomach emptied more quickly during the 80 minutes following the meal during RAVANS.

The findings suggest that modulating the activity of the vagus nerve with taVNS could help reduce symptoms of indigestion, though Sclocco cautioned that patients should ask a doctor before trying it. Stimulating the vagus nerve can potentially affect many organs, including the heart. In addition, different taVNS technologies work in different ways, and more research is needed to identify the best approach for functional dyspepsia.

"While taVNS is relatively safe and without major side effects, systems currently available on the market are all different and not optimized for gastric applications," said Sclocco. "Patients with certain medical conditions may not be good candidates for this therapy and discussing the taVNS option with a medical doctor in the context of a patient's overall clinical picture is always advisable."

Sclocco noted that some people find relief from indigestion with non-technological and non-medical approaches, such as taking slow, deep breaths after eating. The researchers plan to test RAVANS in more volunteers to determine which patients are likely to benefit the most. The team is also working with industry partners to further develop this non-invasive stimulation approach.

Rockville, Md. --New research finds that nicotine-filled e-cigarettes cause increases in heart rate and blood pressure in young people, health issues that remain even after a vaping session. The research, originally slated for presentation at the APS annual meeting at Experimental Biology (canceled due to the coronavirus), is published in the April issue of The FASEB Journal.

E-cigarettes are often marketed to teens and young adults as a healthier alternative to traditional tobacco products. Previous studies have shown that active smoking of tobacco cigarettes leads to higher blood pressure and heart rate and lower muscle sympathetic nerve activity (MSNA). MSNA is a direct measurement of nerve traffic to blood vessels that quickly responds to changes in blood pressure. However, changes in cardiovascular and neural responses during e-cigarette vaping have not been as widely studied as responses to tobacco cigarettes.

Researchers from Michigan Technological University studied a group of healthy, 20-year-old nonsmokers. Each volunteer participated in two separate vaping sessions, separated by a month, in which they used a JUUL® e-cigarette containing nicotine or a similar nicotine-free placebo for 10 minutes. The research team took the volunteers' blood pressure readings before each vaping session and after a 10-minute recovery period post-vaping. Heart rate, blood pressure and MSNA were measured throughout the vaping sessions.

When the volunteers used the nicotine product, both blood pressure and heart rate increased. Heart rate dropped back to normal ranges, but blood pressure remained high during the recovery period. MSNA activity dropped during vaping and stayed lower than normal during recovery. The volunteers did not experience the same cardiovascular changes when vaping the placebo. These results suggest that nicotine-fueled e-cigarettes repress the transmission of nerve impulses that regulate blood pressure and heart rate (baroreflex function).

"We conclude that nonsmokers who use the JUUL® e-cigarette may put themselves at greater risk for acute and/or chronic hypertension," the researchers wrote.

Joshua Gonzalez, MS, from Michigan Technological University was slated to present "Acute effects of the JUUL® e-cigarette on blood pressure and peripheral sympathetic activity in young nonsmokers" at the APS annual meeting at Experimental Biology. Although the meeting was canceled in response to the COVID-19 outbreak, the research team's abstract is published in this month's issue of The FASEB Journal.

PROVIDENCE, R.I. [Brown University] -- When someone opens a laptop, a router can quickly locate it and connect it to the local Wi-Fi network. That ability is a basic element of any wireless network known as link discovery, and now a team of researchers has developed a means of doing it with terahertz radiation, the high-frequency waves that could one day make for ultra-fast wireless data transmission.

Because of their high frequency, terahertz waves can carry hundreds of times more data than the microwaves used to carry our data today. But that high frequency also means that terahertz waves propagate differently than microwaves. Whereas microwaves emanate from a source in an omni-directional broadcast, terahertz waves propagate in narrow beams.

"When you're talking about a network that's sending out beams, it raises a whole myriad of questions about how you actually build that network," said Daniel Mittleman, a professor in Brown's School of Engineering. "One of those questions is how does an access point, which you can think of as a router, find out where client devices are in order to aim a beam at them. That's what we're thinking about here."

In a paper published in Nature Communications, researchers from Brown and Rice University showed that a device known as a leaky waveguide can be used for link discovery at terahertz frequencies. The approach enables link discovery to be done passively, and in one shot.

The concept of a leaky waveguide is simple. It's just two metal plates with a space between them where radiation can propagate. One of the plates has a narrow slit cut into it, which allows a little bit of the radiation to leak out. This new research shows the device can be used for link discovery and tracking by exploiting one of its underlying properties: that different frequencies leak out of the slit at different angles.

"We input a wide range of terahertz frequencies into this waveguide in a single pulse, and each one leaks out simultaneously at a different angle," said Yasaman Ghasempour, a graduate student at Rice and co-author on the study. "You can think of it like a rainbow leaking out, with each color represents a unique spectral signature corresponding to an angle."

Now imagine a leaky waveguide placed on an access point. Depending upon where a client device is relative to the access point, it's going to see a different color coming out of the waveguide. The client just sends a signal back to the access point that says, "I saw yellow," and now the access point knows exactly where the client is, and can continue tracking it.

"It is not just about discovering the link once," Yasaman said. "In fact, the direction of transmission needs to be continually adjusted as the client moves. Our technique allows for ultra-fast adaptation which is the key to achieving seamless connectivity."

The setup also uses a leaky waveguide on the client side. On that side, the range of frequencies received through the slit in the waveguide can be used to determine the position of the router relative to the local rotation of the device -- like when someone swivels their chair while using a laptop.

Mittleman says that finding a novel way to make link discovery work in the terahertz realm is important because existing protocols for link discovery in microwaves simply won't work for terahertz signals. Even the protocols that have been developed for burgeoning 5G networks, which are much more directional than standard microwaves, aren't feasible for terahertz. That's because as narrow as 5G beams are, they're still around 10 times wider than the beams in a terahertz network.

"I think some people have assumed that since 5G is somewhat directional, this problem had been solved, but the 5G solution simply isn't scalable," Mittleman said. "A whole new idea is needed. This is one of those fundamental protocol pieces that you need to start building terahertz networks."

Tsukuba, Japan - Cells and tissues are far from being mere static structures. They have the ability to sense and dynamically react to external cues to ensure that they adapt to the ever-changing outside environment. Now, researchers from the University of Tsukuba have identified a novel protein that plays a central role in the transduction of external mechanical cues to cells in blood vessel walls. In a new study, they show how the protein thrombospondin-1 (Thbs1) ensures that blood vessel walls are strengthened during times of mechanical stress and conversely, how the absence of Thbs1 can result in weakened blood vessel walls.

All tissues, including blood vessels, are composed of different types of cells and proteins surrounding them, the latter also being called extracellular matrix (ECM). The ECM not only ensures that cells are stably anchored to an outside structure, but also serves as a means to transmit mechanical impulses. In blood vessels, the most important mechanical cues stem from the pulsatile blood flow as well as the constantly changing blood pressure. While a large number of proteins have been described to play a role in the interplay between cells and the ECM, a clear understanding of how this mechanical microenvironment is coordinated to maintain the structural and functional integrity of blood vessels has been lacking.

"Blood vessels are constantly exposed to strong mechanical forces from the outside, so they have to adapt to them by translating these cues into proper cellular responses," says corresponding author Professor Hiromi Yanagisawa. "The goal of our study was to further our understanding of the interaction between blood vessels and mechanical stress during normal biology and during times of high stress, such as in hypertension."

To achieve their goal, the researchers exposed rat vascular smooth muscle cells (SMCs) to cyclic stretch to mimic pulsatile blood flow and found that mechanical stress resulted in SMCs producing more Thbs1 and secreting it. They then discovered that Thbs1 interacted with certain integrins, a protein family that links cells to the ECM, to strengthen so called focal adhesions, which are anchor points that help maintain cellular tension as well as correctly orient cells in response to mechanical stretch.

"These findings show how Thbs1 plays a significant role in the cellular response to relatively mild mechanical stress," says lead author Professor Yoshito Yamashiro. "We next wanted to know how Thbs1 is involved in more extreme cases of mechanical stress, such as during severe hypertension."

To simulate hypertension, the researchers performed transverse aortic constriction (TAC) in mice. TAC forces the heart to pump blood against a severely narrowed aorta, resulting in high blood pressure and high mechanical stress on the aortic wall. Although all normal mice survived this procedure, one third of mice lacking Thbs1 died of aortic rupture as a result of weakened aortic wall due to disrupted interaction between blood vessel wall cells and the ECM.

"These are striking results that show how Thbs1 is a central extracellular mediator of mechanotransduction," says Professor Yanagisawa. "Our findings provide new insights into the biomechanics of the vessel wall, which is relevant to hypertension, one of the most prevalent diseases today. We hope that our findings will facilitate the development of novel therapeutic options for cardiovascular diseases."

The bacterium that causes syphilis, Treponema pallidum, likely uses a single gene to escape the immune system, research from UW Medicine in Seattle suggests.

The finding may help explain how syphilis can hide in the body for decades, thereby frustrating the immune system's attempts to eradicate it. It might also account for the bacterium's ability to re-infect people who had been previously been infected and should have acquired some immunity to it.

Although syphilis remains easily treated with penicillin, infection rates in the United States have increased steadily over the past two decades. The count rose to more than 115,000 new U.S. cases of the infection in 2018.

Worldwide there are an estimated 6 million new cases of syphilis among adults. The infection is responsible for an estimated 300,000 fetal and neonatal deaths annually.

However, despite its importance as a cause of disease, relatively little is known about the biology of Treponema pallidum.

One reason for this is that until recently it was impossible to grow it in a laboratory dish. As a consequence, many of the laboratory tools used to study other bacteria had not been developed for syphilis specifically.

In a new study, researchers compared the genomes of syphilis bacteria collected from a man who had been infected four times. He was enrolled in a UW Medicine study of spinal fluid abnormalities in individuals with syphilis conducted by Dr. Christina Marra, professor of neurolgy.

The samples were derived from his blood during two infections that occurred six years apart. Between those infections he had been infected and treated two additional times.

The researchers wanted to see if there were differences between the genomes of bacteria from the first and last infection. This differences might reveal how the genes of the bacteria had changed and how those changes might have enabled the bacteria to infect a person whose immune system had already seen and mounted an immune response to several different strains of syphilis.

Surprisingly, the researchers found that there were very few changes between the genomes from the two different samples -- except for one gene.

"Across the about 1.1 million bases that make up the bacteria's genome there were about 20 changes total. That's very low," said Dr. Alex Greninger, assistant professor of laboratory medicine at the UW School of Medicine, who led the research project. "But on this one gene, we saw hundreds of changes."

That gene, called Treponema pallidum repeat gene K (tprK), provides the instructions for the synthesis of a protein found on the surface of the bacterium. Proteins on the surface of a bacterium are typically more easily seen by immune cells and so are often prime targets for immune attack.

The study builds on decades of work from Drs. Sheila Lukehart and Arturo Centurion-Lara in the Department of Medicine at the University of Washington School of Medicine.

They first showed that TprK generated considerable diversity across seven discrete regions in which DNA sequences from elsewhere in the bacterium's genome could be swapped in and out. This process is called gene conversion.

Work in their lab demonstrated that bacterial cells with new tprK variants can evade the immune response to cause a persistent infection that can lead to the later stages of syphilis.

Amin Addetia, a research scientist in Greninger's lab and lead author on the study, said it was as though the bacterium has a deck of cards in its genome from which it can draw and deal to these variable regions, essentially changing the protein's "hand." These substitutions change the protein's appearance on the surface to allow it to elude the immune system.

"I've looked at a lot of bacterial genomes," Addetia said, "and they're a lot more interesting than the Treponema's, except for this one gene.It can generate an astounding number of diverse sequences within these variable regions without impairing the protein's ability to function."

Although bacteria, viruses and parasites may have many proteins on their surfaces that the immune system could detect and attack, in many cases only one protein seems to attract most of the attention. Such proteins are called immunodominant.

They may protect the bacterium by catching the immune system's attention, Greninger said. "The protein acts like a distraction that draws the immune system away from proteins that might be the bacterium's Achilles heel. More work will be required to determine if this is the case in TprK."

Greninger said he hoped the findings might help researchers develop vaccines that allow the immune system either to attack TprK more effectively or to ignore TprK and target other, less variable syphilis proteins.

The Sanfilippo syndrome type C is a severe neurodegenerative disease which appearws during the first years of life and for which there is no treatment yet. A recent study, published in Journal of Clinical Medicine, has created brain cell models of neurons and astrocytes that allow researchers to better know the mechanisms of this syndrome and assess potential therapies.

The study was coordinated by a team of the Faculty of Biology of the University of Barcelona and the Institute of Biomedicine of the University of Barcelona (IBUB), the Rare Diseases Networking Biomedical Research Centre (CIBERER), the Research Institute Sant Joan de Déu (IRSJD), in collaboration with a group from Lund University (Sweden). Researchers from the Hospital Clínic de Barcelona took part in the study too.

The Sanfilippo syndrome type C is a lysosomal storage disorder caused by mutations in the HGSNAT gene, which takes part in the degradation of the heparan sulphate (HS), a polysaccharide which accumulates over the course of this pathology. In the study, researchers used the technology of induced pluripotent stem cells (iPSC) -an efficient methodology to study human diseases in cell models- to differentiate in neurons and astrocytes that reproduced the main features of this syndrome.

"The obtained results show the existing differences between the cell types and the importance of having relevant cell models to assess therapeutic approaches for specific diseases", notes Daniel Grinberg, co-author of the study and researcher at the UB, IBUB, CIBERER and IRSJD.

These iPSC cells -differentiated in cell lines of neurons and astrocytes- have shed light on experimental studies with each of both cell types and even their joint use in culture experiments to better reproduce the human brain.

In particular, the expressed neurons and astrocytes in specific cell markers show there is a differentiation in the cell lineage. The experts have assessed the presence of Sanfilippo C- typical phenotypes in induced neurons that showed a tendency to increase the heparan sulphate and lysosomal storage (cell organelles related to molecule degradation).

In previous studies, the research team had tested a therapeutic approach on the reduction of substrate in non-neural cell models (fibroblasts) using RNA interference. However, the use of this cell type shows obvious limitations, since it does not allow a reproduction of neurological problems of the Sanfilippo C disease. Moreover, treatments that were successfully tested in these fibroblast models could be ineffective in neurons and astrocytes, which proves the importance of research with different cell types.

More recently, the experts created and validated two different iPSC lines with the mutated HGSNAT gene with the original iPSC using the CRISPS/CAS9 technology (Benetó et al., 2019). Using the CRISP/CAS9 technology, researchers generated other isogenic iPSC lines with mutations in the NAGLU gene, the responsible for the Sanfilippo syndrome type B (Benetó et al., 2020).

In the midst of unprecedented climate change and population growth, the establishment of a method to rapidly create elite crop varieties via selective breeding is a matter of urgency to maintain the food supply. In order to select such cultivars, it is necessary to define and evaluate a metric for what is a 'superior variety' in an efficient manner. For example, the shape of seeds is understood to be a trait closely linked to the quality and yield of crops, and is thus an important factor when conducting selective breeding.

A team of scientists led by Yosuke Toda, Designated Assistant Professor at the Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, and Fumio Okura, Assistant Professor at the Institute of Scientific and Industrial Research, Osaka University, have developed a system which utilizes image analysis and artificial intelligence (AI) to analyze the shape of large numbers of seeds from a single image. The shape of the seed is an important agronomic trait for the yield and quality of crops, and a method for automatically determining and evaluating such from an image is an indispensable tool for plant breeding.

Dr. Toda's research team generated a training dataset to be used for machine learning (deep learning) by synthesizing randomized barley seed images on a virtual canvas. The trained model, using only the synthesized data, was able to detect and segment the individual seeds from images of various barley cultivars as accurately as when done manually, as well as being able to analyze seeds of other crops.

Training data is required to make use of deep learning. Usually, training data is prepared by hand, for example by labeling every object in the images with different colors. However, for objects such as seeds, whose number is vast, creating the training data is very time consuming (for example, having to individually color hundreds of seeds for tens or hundreds of images for each seed variety). Thus, it has been considered difficult to generate a machine learning model that can quickly and simply analyze the seed shapes of different varieties or species. Dr. Toda's research group succeeded in creating a large volume of training data from only a small number of seeds to effectively train the machine learning (deep learning) model. This approach is called domain randomization, and spares the effort involved in creating the training data, accelerating the development of machine learning models. In the proposed method, sample images of a small number of barley seeds whose shape information was already know were randomly arranged in virtual space, creating a large number and variety of synthesized images. The model trained with this dataset was able to detect the seeds and extract their shape data with the same degree of accuracy as when done by hand. No hand-annotated training dataset was required.

The experiment actually highlighted that the system can clearly identify the characteristic differences in shape of each crop. It is expected that in the future it will be possible to measure fine differences in the growth environment and variety, becoming a powerful tool for plant breeding.

Furthermore, the study showed that the same method can readily be employed to measure the seeds of a variety of different crops, such as rice, wheat, oats, and lettuce. These results strongly suggest that, regardless of crop, it is possible to make the automatic measurement of large numbers of seeds a reality.Beyond just a variety evaluation, this study is expected to contribute to the plant science domain by revealing characteristics of seeds not formerly observed by the human eye.

The majority of research into instance segmentation-based image analysis is conducted using existing datasets including things such as people and cars. On the other hand, plant image analysis has a variety of its own characteristics. Since there is great variation in plants' species, location and individual appearance, different training data is needed for respective applications. While this is also the case for others with multiple applications, the creation of new training data for plants is particularly difficult. The method of generating synthetic training data employed in this study can be used in a variety of applications. Based on the initiative of this research, it is expected that it will be possible to go beyond the analysis of seeds, and accelerate the development of a machine learning model for the measurement of various plant phenotypes.