Culture

OAK BROOK, Ill. - Racket sports like tennis and racquetball appear to accelerate knee joint degeneration in overweight people with osteoarthritis, according to a study being presented at the annual meeting of the Radiological Society of North America (RSNA).

Knee joint osteoarthritis, a gradual wearing down of the protective cartilage that cushions the ends of the bones, is a major cause of pain and disability worldwide, affecting approximately 14 million people in the U.S. alone. Excess body weight is a major risk factor.

Physical activity offers a host of benefits for people who are overweight, but the wrong type of exercise could potentially damage knee joints and hasten the need for knee replacement surgery. The effects of different types of exercise on overweight people have seldom been studied with MRI, the most sensitive imaging method for assessing structural changes to the knee joint.

For the new study, researchers used high-powered MRI to assess the rate of degeneration of the knee joint in 415 overweight and/or obese patients, average age 59, drawn from the Osteoarthritis Initiative, a National Institutes of Health-supported study of individuals with mild to moderate osteoarthritis.

Study participants kept detailed records of their participation in six different types of physical activity, including ball sports, bicycling, jogging/running, elliptical trainer, racket sports and swimming. The researchers performed baseline MRIs and then measured changes in the patients' knees over four years using the modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). A higher score indicates more degeneration.

Patients regularly participating in racket sports saw their overall WORMS score increase significantly, compared to patients regularly using the elliptical trainer over the study period. Surprisingly, the overall WORMS score also increased significantly in the racket sports group compared to the jogging/running group. Racket sports participants saw significantly greater degeneration in the medial tibial cartilage compartment, the compartment on the inside of the knee where arthritis often first appears.

Participants using the elliptical trainer showed the smallest changes in structural degeneration over four years.

"In our study, progression of overall knee joint degeneration was consistently higher in overweight and/or obese patients engaging in racket sports," said the study's lead author Silvia Schirò, M.D., from the University of California San Francisco and the University of Parma in Parma, Italy. "We also found that workouts using an elliptical trainer were associated with reduced progression of overall knee joint and cartilage defects. Moreover, our findings showed that when comparing different low impact activities with each other, such as bicycling, elliptical trainer and swimming, the elliptical trainer was associated with the lowest increase in WORMS sub-scores over 48 months."

The more rapid degeneration of the knee joints in people who participated in racket sports is likely due to the high-speed lateral movements inherent to such sports, Dr. Schirò said. These movements can affect the femoral-tibia compartment, a structure in the knee made up of the femur condyle, the rounded end of the thighbone that helps it slide over the tibia, or shinbone, and the meniscus, the rubbery, C-shaped cartilage between the thighbone and the shinbone.

"A large lateral force imparted at the foot during side-to-side movements may be driving large knee adduction moments, a key feature in medial compartment disease, which imparts high compressive loads on the medial tibia and femoral condyle," she said. "In support of this premise, the racket sports group showed elevated cartilage degeneration in the medial tibia."

The researchers theorize that joint mechanics are impaired in overweight and obese individuals, with a harmful joint overload triggering increased contact stress on the meniscus. Damage to the meniscus compromises the protective cushion on the cartilage of the knee.

"High impact physical activity with elevated load and high shear forces may trigger and accelerate this process," Dr. Schirò said. "Moreover, participants who played racket sports showed significantly more meniscal degeneration when compared to the remainder of the study group."

The data suggests that overweight individuals who continue to play racket sports could slow degeneration in their knees by making modifications to their activities, such as switching to sports with less fast-paced and high shear loads like badminton or doubles tennis.

However, Dr. Schirò emphasized that the degenerative process is complex and individual joint mechanics are highly variable.

"It is possible that some individuals with sufficient strength and motor control may be able to safely play these sports," she said. "Our data suggests that as a group, though, overweight and obese individuals who play racket sports are at higher risk for disease progression."

BOSTON - Findings from a team led by investigators at Massachusetts General Hospital (MGH), reported in the online journal mBio, may help scientists develop a more effective vaccine for cholera, a bacterial disease that causes severe diarrhea and dehydration and is usually spread through contaminated water.

The bacterium that causes cholera, called Vibrio cholerae, settles within the intestines after ingestion. There, it secretes a toxin that causes intestinal cells to secrete massive amounts of fluid, eventually leading to death from dehydration and shock if untreated. The disease is a significant problem in many impoverished regions of the world.

Interestingly, immune responses to the toxin do not protect against cholera, but previous research led by investigator Edward Ryan, MD, director of Global Infectious Diseases at MGH, has shown antibodies that bind V. cholerae's sugar coating--called O-specific polysaccharide (OSP)--do offer protection.

"A big question is: How do these antibodies protect? The answer would help develop better vaccines," says Ryan, who is also a professor of Medicine at Harvard Medical School and a professor of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health. He notes current vaccines for cholera are not very protective in young children, who bear much of the global burden of cholera, and induce relatively short-term protection in recipients.

To investigate, Ryan and his colleagues analyzed antibodies recovered from humans who survived cholera. Experiments showed the antibodies block V. cholerae bacteria's motility. "V. cholerae are very mobile, and swimming is critical to their ability to cause disease," Ryan explains. "Interestingly, the tail-like flagellum in V. cholerae that propels swimming is coated with the OSP sugar." More detailed analyses demonstrated the human antibodies attached to this OSP coating to block the ability of V. cholerae to swim and cause disease.

"Our results support a unique mechanism of protection against a human pathogen. We are not aware of previous work demonstrating a comparable direct anti-motility effect of human antibodies," says Ryan.

BUFFALO, N.Y. -- In the TV series, "How It's Made," viewers often discover that common objects like pencils or rubber bands are quite complicated to make. The show walks people through complex production processes that lie behind familiar items.

A new paper in the journal Cell Reports does the same for saliva.

The study, which will be published on Nov. 17, breaks down, in detail, where the multitude of proteins floating in our saliva originate.

The research traces these vital proteins back to their source, showing which proteins are produced by each of the three major types of human salivary glands, and showing how individual cells within a single gland can secrete different proteins. The project also identifies proteins in the mouth that seem to be coming from outside of salivary glands, from places such as epithelial tissues or blood plasma.

"Saliva is important for tasting, for digesting, for swallowing, for defending us from the pathogens that we are constantly inhaling and consuming. The proteins in our mouth form an army, if you will, that's working constantly to protect us. Before this, scientists had an idea of the proteins that are found in the mouth, but we didn't have a complete picture of where they were coming from. We're addressing this gap," says Omer Gokcumen, PhD, associate professor of biological sciences in the University at Buffalo College of Arts and Sciences.

"From a biomedical perspective, our research opens the door for further studies into the functions of saliva and salivary glands, and the use of saliva as a diagnostic fluid. Our study takes a snapshot of how healthy salivary glands should function. Deviations from this healthy expectation can indicate disease," says Stefan Ruhl, PhD, DDS, professor of oral biology in the UB School of Dental Medicine.

The study's first author is Marie Saitou, PhD, a tenure-track researcher in biosciences at Norwegian University of Life Sciences, and a former postdoctoral researcher at the University of Chicago and UB. Saitou, Gokcumen and Ruhl led the study with Sarah Knox, PhD, associate professor of cell and tissue biology in the University of California, San Francisco (UCSF) School of Dentistry.

The biological factories that churn out our saliva

To explain how our bodies make saliva, the scientists first sought to understand which proteins are produced by each major type of salivary gland -- the parotid, submandibular and sublingual glands (humans have a pair of each).

To do this, the team used a method called transcriptomics to measure gene activity in each kind of gland. Gene activity provides insight into protein production, because each gene provides instructions for making a specific protein.

This endeavor enabled the scientists to understand the proteins that each gland generates, and how the glands differ from one another in terms of what they produce.

For instance, the study finds that the parotid and submandibular glands create a lot of salivary amylase, an enzyme that helps to digest starch, while the sublingual gland makes almost none. Meanwhile, the sublingual gland produces relatively large quantities of certain GalNAc transferases, a family of enzymes that's important in initiating a process called O-glycosylation that attaches a sugar to certain salivary mucin proteins. These are just a couple of examples.

"We show how the actions of different glands collectively help to produce a complex bodily fluid -- our saliva," Saitou says.

"Our work reveals that even a gland type itself is not homogenous: the saliva-producing acinar cells, which were once thought to produce the same proteins, and thus be the same cells, actually synthesize distinct saliva proteins, thus indicating a new level of cellular diversity," Knox says.

Gokcumen says the research is one step toward understanding the immense complexity of saliva. Beyond parsing out the origins of proteins made by salivary glands, the team also concluded that some proteins drifting in saliva likely don't originate from salivary glands, and that some important proteins that help to regulate gene expression are predominantly active in salivary glands, but not in a litany of other tissues.

"Salivary proteins are a gateway to our body," Gokcumen says. "When they do not function properly, we suffer. Our work brings us one step closer to understanding their complex origins and the intricate interplay between them."

"Long wished-for diagnostic applications of saliva for monitoring systemic well-being and disease will need to measure quantitative differences of biomarkers in saliva," Ruhl says. "One obstacle always hampering progress in this arena was that we did not know exactly which proteins were intrinsically produced by the salivary glands, and which proteins diffused into saliva from surrounding tissue leakage. Also, we were lacking a reliable baseline, a standard, if you will, that tells us what are normal and healthy values for the protein components in saliva. Our paper helps resolve these conflicts, providing information that I expect will propel salivary diagnostic applications forward."

WASHINGTON, November 17, 2020 -- Monitoring how patients with multiple sclerosis or other degenerative diseases use their smartphones could provide valuable information to help get them better treatment.

In an article published in Chaos, by AIP Publishing, researchers used a mobile app to record the keystroke dynamics of a control group and those of subjects in various stages of multiple sclerosis treatment over the course of a year.

Keystroke dynamics show how quickly or slowly someone is typing on a touch screen, the amount of time between letters typed, the number of mistakes made and corrected while typing, and other behaviors. As part of the study, researchers at Amsterdam University Medical Center used a mobile app that tracks how a user is typing on their phone's keyboard.

In doing so, they observed changes over time in the way people with MS typed that were not seen in subjects who did not have the disease.

"The clinically relevant changes in keystroke dynamics can be seen as early warning signals for changes in disease activity of the patient prior to the change occurring," the authors wrote.

James Twose, one of the authors, called the study's findings a "first promising step" toward using keystrokes to help diagnose changes in patients with chronic diseases like MS.

"The dream is prediction," said Twose. "If there is some semblance of predictability, the joy would be to forecast the disease in a similar way you do with weather."

Multiple sclerosis patients generally make clinical visits every 3-12 months, according to the authors, and MRIs are the best way to measure changes in damage to the brain from the disease.

If doctors were able to use something like keystrokes to monitor patients on a more ongoing basis, they could better predict when new treatments are needed.

"In chronic diseases like MS and Alzheimer's disease and Parkinson's disease, there is inherent worsening over time," Twose said. "When it comes to typing, you need all your faculties to do this well. We notice when you have problems with that."

Such a system would be helpful to chronic disease sufferers for a variety of reasons. Consistent monitoring would give doctors a fuller picture of their condition than occasional clinic visits, which can only provide a snapshot of how they are doing at that moment. It also would be a boon for patients whose conditions make traveling to and from doctor appointments difficult.

Effector regulatory T cells (eTreg cells) are a specialized subset of white blood cells that keep the immune system in check. St. Jude Children's Research Hospital scientists have revealed the metabolic signaling mechanisms that regulate function of eTreg cells. The work may aid efforts to better understand and treat inflammatory diseases. The findings were published online today in Cell Metabolism.

"This process is quite fascinating to us, and helps explain how metabolites can drive selective signaling pathways to enforce the differentiation, persistence and function of eTreg cells," said corresponding author Hongbo Chi, Ph.D., of St. Jude Immunology. "We were looking specifically at suppression of autoimmunity that can develop spontaneously in our models, but we also know Treg cells play a role in multiple diseases."

Although eTreg cells are involved in prevention of autoimmune diseases, including lupus and rheumatoid arthritis, they are detrimental in other diseases, such as cancer. Understanding how metabolic signaling regulates Treg cell heterogeneity or function may help scientists develop more specific drugs to target these pathways to help treat disease. How metabolic pathways regulate the differentiation and persistence of eTreg cells, especially at the level of intracellular signaling, has been unclear until now.

Metabolic pathways exert control

The researchers showed that two-way metabolic signaling that intersects with T cell receptor signaling is critical to regulating eTreg cell function.

Investigators identified a class of metabolites called isoprenoids that are essential for the suppressive activity of activated Treg cells such as eTreg cells. Isoprenoids are required for cellular processes called posttranslational lipid modifications, specifically protein farnesylation and geranylgeranylation. These processes are mediated by Fntb and Pggt1b, respectively. Disruption of these processes by Treg cell-specific deletion of Fntb or Pggt1b causes mice to develop autoimmunity.

Further research into the metabolic signaling mechanisms revealed the discrete details of Treg cell-mediated immune suppression downstream of T cell receptor signaling. Fntb acts through two parallel pathways to promote eTreg cell persistence: the protein kinase mTORC1, which regulates metabolic reprogramming of Treg cells, and the immune receptor ICOS. Pggt1b enforces signaling through the small G protein Rac to support eTreg cell differentiation.

"We were able to dissect how metabolic regulation controls eTreg cell differentiation and maintenance," said first author and graduate student Wei Su of St. Jude Immunology. "This bidirectional interplay between intracellular signaling and metabolism allows eTreg cells to maintain the self-tolerance in our body."

"These pathways have been of long-standing interest outside of the immune system for a way to inhibit inflammatory responses," said study author Nicole Chapman, Ph.D., of St. Jude Immunology. "Our study provides a deeper understanding of the molecular interplay between signaling and metabolism and could allow for more potent and selective targeting of downstream metabolic functions in Treg cells."

Oak Brook, IL - The December edition of SLAS Discovery, "Drug Discovery Targeting COVID-19" is a special collection assembled by Associate Editor Timothy Spicer (Scripps, FL, USA), focusing on drug discovery efforts toward the current global pandemic of COVID-19caused by the novel coronavirus, SARS-CoV-2.

In this Special Issue, you will find seven papers published as open access articles.
The issue includes four reviews that cover the commonly utilized approach of repurposing drugs to rapidly treat COVID-19, as well as targeting the virus using new vaccines and clinical drugs.

The articles of original research focus on novel proteins necessary for virus replication. The article, "High-Throughput Screening for Drugs that Inhibit Papain-Like Protease in SARS-CoV-2," explores how an ultra-high throughput screening platform targeting PLPro was used to investigate over 13,000 clinically applicable drugs. The article, "Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3" tests drug-like ligands for their efficacy against the MAC domain of SARS2 Nsp3, a novel approach. In addition to these two articles, the December special issue contains an additional two articles of original research.

Articles of Original Research include:

Method Development and Application of an Accelerated Solution Stability Screen for Drug Discovery

Comparative Analysis of Multiple Immunoassays for Cytokine Profiling in Drug Discovery

Other articles include:

Potential Repurposed Therapeutics and New Vaccines against COVID-19 and Their Clinical Status

A Review of the Preclinical and Clinical Efficacy of Remdesivir, Hydroxychloroquine, and Lopinavir-Ritonavir Treatments Against COVID-19

Based on Principles and Insights of COVID-19 Epidemiology, Genome Sequencing, and Pathogenesis: Retrospective Analysis of Sinigrin and Prolixin RX (Fluphenazine) Provides Off-Label Drug Candidates

RNA-Dependent RNA Polymerase as a Target for COVID-19 Drug Discovery

Repurposing Nimesulide, a Potent Inhibitor of the B0AT1 Subunit of the SARS-CoV2 Receptor, as a Therapeutic Adjuvant of COVID-19

Recommended Guidelines for Developing, Qualifying, and Implementing Complex In Vitro Models (CIVMs) for Drug Discovery

Drug Discovery Targeting COVID-19

PULLMAN, Wash. -- Studies conducted in yeast show that exposure to ultraviolet light (UV) induces new types of DNA damage that may cause the deadliest form of skin cancer, malignant melanoma.

That's according to research conducted by a team featuring undergraduate students from Washington State University's School of Molecular Biosciences. The work, led by WSU researchers John Wyrick and Steven Roberts of the College of Veterinary Medicine, was published today, Nov. 17, in Cell Reports.

While melanoma has been associated with UV light, this study directly links UV exposure to the atypical mutations known to spread the disease. The results also indicate that UV light can induce a more diverse spectrum of mutations than previously suspected.

"There's been this debate: how much does UV light cause the mutations that actually cause the cancer?" Wyrick said. "Our research supports that UV light plays a major role in producing mutations specific to the growth and spread of melanoma."

As in humans, UV light damages DNA and produces mutations in baker's yeast, making it an excellent model to study how dangerous the resulting mutations can be.

Researchers irradiated yeast cells from 150 yeast colonies with UV lamps 15 times for 8-second intervals over the course of a month. They used UV-C radiation, the strongest form or ultraviolet light. The team then used whole-genome sequencing to identify an estimated 50,000 mutations that occurred in cells due to the UV irradiation.

The team found about half of all the mutations found in the irradiated cells were rare mutations linked to melanoma.

Until now, UV damage in DNA was thought to be confined to two of the DNA bases: C (cytosine) or T (thymine). However, this new research indicates that UV damage also occurs at low frequency at A (adenine) DNA bases, a surprising finding.

WSU students and researchers also showed that a single intense exposure of ultraviolet-B radiation, which is present in sunlight, could also induce the atypical mutations.

Haley Morris, an undergraduate biochemistry major, began working on the research as a first-year student.

"This has a lot of real-world applications and could help identify causes of severe skin cancers," Morris said. "It's cool that something I enjoy and am a part of has the potential to help a lot of people."

DALLAS, Nov. 16, 2020 -- Patients with plaque build-up in their arteries, who suffered a transient ischemic attack (TIA) or a minor ischemic stroke, also called a warning stroke, and were treated with the newer blood thinner ticagrelor plus aspirin were 27% less likely to have another stroke within 30 days, according to late-breaking research presented today at the American Heart Association's Scientific Sessions 2020. The virtual meeting is Friday, November 13-Tuesday, November 17, 2020, and is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science for health care worldwide. The manuscript of this study is simultaneously published today in Stroke, a journal of the American Heart Association.

In this sub-analysis of the THALES trial, The Acute Stroke or Transient IscHemic Attack Treated with Ticagrelor and Aspirin for PrEvention of Stroke and Death trial, ticagrelor benefitted patients with plaque build-up in their arteries (atherosclerosis) more than patients whose stroke had another cause. These findings, coupled with previous research, show a combination of both ticagrelor and aspirin is more effective than either medication alone.

"In our opinion, health care professionals should now consider both ticagrelor and aspirin to prevent another stroke in patients who experience a warning stroke. Our research shows treating patients within 24 hours of their first symptoms using this newer regimen is effective, especially when the cause of the stroke is due to plaque build-up in the arteries," said the study's lead author Pierre Amarenco, M.D., professor of neurology at Paris University and chair of the department of Neurology and Stroke Center and the SOS-TIA clinic at Bichat hospital in Paris, France.

Of the more than 11,000 participants originally enrolled in the multinational THALES trial (conducted in 2018 and 2019), about one in five (2,351) had plaque build-up in their arteries. Researchers randomized those patients into two groups - aspirin plus ticagrelor or aspirin alone - to identify whether the combination of medications was a more effective treatment than either medication on its own.

After an initial dose of 180 mg, researchers added 90 mg twice a day of ticagrelor to 75-100 mg of daily aspirin for one month, and the risk of another stroke or death was reduced by 27% among these patients.

The THALES trial is a randomized, placebo-controlled, double-blind, international, multi-site study. It is currently in Phase III and began in January of 2018.

Researchers at Karolinska Institutet in Sweden report promising results from an in vitro combination therapy against COVID-19. In a study published in EMBO Molecular Medicine, the researchers show that a combination of remdesivir, an approved drug against COVID-19, and hrsACE2, a medicine currently in phase II trials for COVID-19 treatment, reduced the viral load of SARS-CoV-2 and inhibited viral replication in cell cultures and organoids.

Remdesivir, the only approved drug against COVID-19 disease, works by inhibiting an enzyme that prevents the virus from multiplying. In high doses, however, it can cause damage to the liver and the lungs.

Human recombinant soluble ACE2 (hrsACE2) is a genetically modified variant of the cell membrane protein angiotensin converting enzyme 2 (ACE2) that the coronavirus uses to enter our cells. Previous laboratory studies have shown that hrsACE2 lures the coronavirus to attach itself to the enzyme copy, hrsACE2, instead of to the actual cells, thereby reducing the viral load in cells.

In this study, the researchers tested combining remdesivir and hrsACE2 in cell cultures from monkeys, liver spheroids and 3D kidney replicas, so-called organoids grown from human stem cells.

By combining these two substances, the researchers were able to achieve a dual effect: reduced viral load and reduced viral proliferation to nearby cells. In addition, they achieved this effect with comparably low doses of each substance, which lowered their toxicity and made them safer to use.

"By targeting different aspects of the viral cycle simultaneously, we may be able to increase the effectiveness of the treatment while reducing the risk for potential side-effects," says Ali Mirazimi, corresponding author and adjunct professor in the Department of Laboratory Medicine, Karolinska Institutet. "Combination therapy is a model that has been used successfully in HIV therapeutics. So far, we have only tested our combination therapy in cell cultures and engineered tissues, but we hope that it can pave the way for clinical trials."

HrsACE2 is currently being evaluated in a double-blinded, placebo-controlled phase II trial involving 200 people with severe COVID-19.

Weak students in high-performing math classes, especially boys, feel more shame compared to students in low-performing math classes. Stronger students, in turn, feel more bored and enjoy mathematics less in high-performing math classes, according to a new study.

Researchers at Åbo Akademi University, the University of Helsinki and the University of Turku have investigated whether the so-called big-fish-little-pond effect (BFLPE) can explain the relationship between feelings and mathematics and students' gender. BFLPE is based on students comparing themselves against the average ability of a group. Thus, if students have better-than-average ability, their academic self-image improves, and likewise, it deteriorates if students perceive themselves to be at a level of knowledge below the group average.

This is the first study to show that BFLPE affects feelings of pride and shame to a greater extent among students with weaker knowledge of mathematics than among students with strong math skills. The study is also the first to show that BFLPE affects feelings of pleasure and boredom more among students with a strong knowledge of mathematics. The study involved 1,322 Finnish students who were 14-15 years old, a total of 77 groups.

- We found that in groups where many students are strong in mathematics, the effect on pride related to one's own knowledge is often negative. This effect was particularly prominent among students with weak knowledge of mathematics. An interesting result was that boys experienced more shame in high-performance mathematics classes while girls did not, says Johan Korhonen, assistant professor of educational psychology at Åbo Akademi University.

This may have to do with mathematics being traditionally perceived as a male subject. According to the researchers, the social comparison between students does not necessarily explain why especially high-performing students experience boredom in the classroom--rather, this may have to do with pedagogical methods and expectations on students.

- As a way to reduce BFLPE, strategies could be developed for how to handle performance-related feelings in the classroom. For example, teachers could actively work with individualized and meaningful feedback, and refrain from stereotyping mathematics as a male subject. More encouragement for low-performing students in groups where there are high-performing students, combined with setting individual goals for everyone, could also help reduce the impact, says Korhonen.

Clean drinking water is considered to be one of the earth's most precious and threatened resources. Recent studies show that increasing concentrations of pharmaceuticals can be found in surface waters, which can end up in drinking water. TalTech environmental scientists are looking for ways to treat drinking water from hazardous pharmaceutical residues.

TalTech research group of the Laboratory of Environmental Technology led by Senior Researcher Niina Dulova published an article in the journal Environmental Research titled "Individual and simultaneous degradation of sulfamethoxazole and trimethoprim by ozone, ozone/hydrogen peroxide and ozone/persulfate processes: A comparative study".

Niina Dulova says, "Removal of hazardous micropollutants of different origins from water is still one of the unresolved problems in today's environmental technology. Our study investigated application of new efficient water treatment methods for elimination of two micropollutants: sulfamethoxazole and trimethoprim. These antibiotics are widely used to treat lung and kidney diseases both in veterinary and human medicine."

The application of advanced oxidation processes that take advantage of the high oxidizing capacity of radicals is considered to be the most effective tool for removal of micropollutants from water. These technologies are applied to remove poorly biodegradable substances from water almost completely through mineralization. Advanced oxidation processes can be classified in different ways, but they are mostly divided into categories according to the source of free radicals. Conventionally the oxidants used to form free radicals include hydrogen peroxide (H2O2) and ozone (O3), but in recent years other alternative oxidants, such as persulfate (PS), have been used increasingly.

"In our study we focused on the O3, combined O3/H2O2 and O3/PS processes. The latter, O3/PS technology, is an evolving promising solution in the field of radical-based oxidation processes. The efficiency of the O3/PS process in the decomposition of antibiotic residues (sulfamethoxazole, trimethoprim and a combination of sulfamethoxazole and trimethoprim) in water has not been studied previously and our findings are promising," Niina Dulova says.

The current EU Water Framework Directive does not address the issues of these antibiotic residues in water. Therefore, our wastewater treatment plants do not consider it necessary to tackle the problem. However, the situation will change over the next five years as the European Union is on the way towards establishing stricter water framework directives. This would also change the requirements for our water treatment plants. The best solution in this case would be the introduction of a new water treatment technology, i.e. a free radical based process," Dulova says.

Currently ozone is mainly used in water treatment plants for water disinfection, which, however, is not sufficient to remove hazardous pharmaceutical residues. Only using ozone also for oxidation would remove antibiotic residues from water.

Niina Dulova says, "If you ask why water containing antibiotic residues is hazardous to people, the answer is be very concrete: when exposed to water contaminated with such antibiotic residues, bacteria develop resistance to these antibiotics. This, in turn, makes it increasingly difficult to treat people exposed to these bacteria with antibiotics in the future."

Alzheimer's disease develops over decades. It begins with a fatal chain reaction in which masses of misfolded beta-amyloid proteins are produced that in the end literally flood the brain. Researchers including Mathias Jucker from the Hertie Institute for Clinical Brain Research (HIH) in Tübingen and the German Center for Neurodegenerative Diseases (DZNE) show in the journal Nature Neuroscience that this chain reaction starts much earlier in mice than commonly assumed. This means that in addition to the well-known early phase of the disease with protein deposits but without symptoms of dementia, there is an even earlier phase in which the chain reaction is triggered by invisible tiny seeds of aggregation. If this is confirmed to occur also in humans, a treatment addressing the causes of disease would have to prevent this process. The scientists have already identified an antibody that might accomplish this.

To this end, they searched among the already known antibodies directed against misfolded beta-amyloid proteins for antibodies that can recognize and possibly also eliminate these early seeds of aggregation that currently escape biochemical detection. Of the six antibodies investigated, only aducanumab had an effect: Transgenic mice that were treated for only 5 days before the first protein deposits manifested, later on in life showed only half of the usual amount of deposits in their brains. "This acute antibody treatment obviously removes seeds of aggregation, and the generation of new seeds takes quite some time, so that much less deposits are formed in the weeks and months after the treatment." Mathias Jucker commented on the findings. "Indeed, the mice had only half the brain damage six months after this acute treatment."

Although research on Alzheimer's has been dealing with seeds of aggregation for quite some time, nobody really knows what they look like. They are currently only defined by their role as triggers for this fatal chain reaction. In this respect, they are similar to so-called prions that cause BSE in cattle, scrapie in sheep and Creutzfeldt-Jakob disease in humans. Pathogenic prions force their correctly folded peers into their abnormal shape. Jucker and coworkers therefore used the antibody aducanumab to learn more about the structure of the seeds of aggregation. They were able to show that aducanumab recognizes protein aggregates, but not individual beta-amyloid chains. The scientists now hope to use the antibody as a fishhook to isolate and better describe these seeds of aggregation.

"Our results suggest that we need to focus more on this very early phase of Alzheimer's and look for biomarkers for it. We also need more antibodies that recognize different types of the seeds of aggregation and help us to understand how they trigger the chain reaction and how they can be used for therapy," Jucker said.

There is currently consensus that treatment of Alzheimer's disease must begin earlier, not when memory decline has already begun. However, the results of the Tübingen scientists are now redefining the term "earliness" in mice. Until now, the phase with protein deposits but without symptoms of dementia has been considered to be "early". The new studies suggest that a treatment of Alzheimer's that addresses the causes should start much earlier.

In a paper published in TECHNOLOGY, a team of researchers from Massachusetts General Hospital (MGH) have demonstrated 24-hour rat liver viability in a normothermic machine perfusion (NMP) system. Rat liver perfusion is an efficient and cost-effective method to study how various pharmacologic agents impact liver parenchyma.

Normothermic machine perfusion (NMP) has the challenge of mirroring in-vivo settings as closely as possible for the liver allograft. This allows drugs, enzymatic reactions, repair processes, and metabolic pathways to affect liver function to their full capacity. However, under normothermic conditions (35-38°C), the perfusions become exponentially more complex when the perfusion duration is extended, severely limiting our ability to observe liver physiology and pharmacologic effects after 6 hours.

This work builds on existing NMP systems with critical modifications in technique and design to
extend the perfusion time of a rat liver allograft without complications or ischemic events. Addressing these issues in NMP greatly expands the armamentarium of experiments that can be conducted to assess how livers responds to physiologic insults and pharmacologic agents over time ex-vivo.

Another major achievement of this research is the identification of perfusion metrics that are predictive of long-term (24-hour) perfusion success. Liver oxygen consumption and rises in intra-hepatic resistance (see image) are shown to be early predictive markers of perfusion system contamination. These markers can be utilized in future experiments to assess the stability of long NMP experiments which can save valuable time and resources in pharmacologic studies.

The team from MGH is working now to utilize long-term rat liver normothermic perfusions to trial different pharmacologic delivery mechanisms, such as lipid nanoparticles, as a novel method of targeted drug delivery.

An acebuchin-oil-enriched diet helps to reduce arterial blood pressure, as shown by a study carried out by the Cardiovascular Physiopathology research group at the Physiology Department of the University of Seville. Furthermore, their work shows that acebuche oil has a greater impact in reducing hypertension than extra virgin olive oil.

This research group from the US Faculty of Pharmacy, led by Professor Carmen María Vázquez Cueto together with Professor Alfonso Mate Barrero, has been investigating the physiopathological mechanisms involved in the development of arterial hypertension (AHT) for over 20 years, with special interest in finding natural products that help to alleviate the organ damage caused by this disorder. The acebuche, also know as the wild olive tree, is a variety of tree widely found throughout Spain and covering almost nine million hectares in Andalusia. However, little data is available on the composition and therapeutic potential of acebuchin oil. The studies mainly focus on the composition and pharmacological effects of olive tree leaves and extra virgin olive oil.

Following their research, in which they gave mice a diet enriched with acebuchin oil or extra virgin olive oil, the researchers detected that the acebuchin-oil-enriched diet significantly reduced blood pressure in hypertensive animals. However, a lesser antihypertensive effect was found in animals fed a diet enriched with extra virgin olive oil.

At the same time, the study showed that the diet enriched in acebuchin oil reduces ocular oxidative stress produced by AHT to a greater degree than the diet enriched in extra virgin olive oil. Furthermore, the former also has a greater impact in regulating the systems related with this oxidative stress.

In particular, the researchers studied variations in the morphology of the hypertensive retina, which are prevented by the acebuched-oil-enriched diet. AHT causes a change in the retina's morphology (showing "thinned" layers in the retina). This outcome can be counteracted with an acebuchin-oil-enriched diet, obtaining better results than with a diet enriched in extra virgin olive oil.

AHT is a high-prevalence disease on a global scale (30-45% of the general population) where systolic blood pressure values rise above 139 mmHg and/or diastolic blood pressure is above 89 mmHg. AHT damage manifests itself in different organs and is a major risk factor in cardiovascular, kidney, brain and eye diseases. In particular, AHT constitutes an important risk factor for the development of retinal vascular diseases, such as hypertensive retinopathy and retinal arterial and venous obstructions, which are associated with high-prevalence ocular pathologies such as cataracts, glaucoma, age-related macular degeneration and choroidopathies.

The Cardiovascular Physiopathology research group has applied to the Spanish Patent and Trademark Office (OEPM), through the University of Seville, for a patent on the "Use of acebuchin oil in retinal damage associated with arterial hypertension and associated retinal pathologies".

According to a new study from Copenhagen Business School, on the role of privacy and decentralization in the cryptocurrency community, developers are creating cryptocurrencies in such a way that regulatory oversight will not be possible, neither will any wait and see attempt to override them in the future. The research is published in the Journal of Information Technology.

"If decentralized privacy-preserving cryptocurrencies become popular in the future, to the point they can be routinely exchanged without users having to convert to other currencies and systems, there is no obvious way for regulators to impose post-hoc regulation," says Associate Professor Rob Gleasure from the Department of Digitalization, Copenhagen Business School.

"What the regulators do not realize is those who control the code will control the rules and so far, they have not accepted this and are in denial," he adds.

Monero cryptocurrency

"People tend to focus on less controversial systems like Bitcoin, Ethereum, Hyperledger, etc. We shine a light on those developing the most potentially disruptive currencies," says co-author Dr. Robin Renwick, a research analyst from the Applied Research and Innovation team at Trilateral Research.

The case study concentrated on Monero, seen as the posterchild for this privacy-focused cryptocurrency community. They have been described as anti-establishment and cypherpunk and, according to the U.S. Department of Justice using them is indicative of possible criminal conduct.

The research focused on the privacy attitudes of users, developers, cryptographic researchers, business architects and regulators and adopted a boundary object perspective to make sense of disagreements between these collaborating social worlds.

"What makes this research different is we were able to get good access to users and developers in a community that is not normally researched," adds Dr. Robin Renwick.

Privacy is personal

"Monero strongly believe the privacy trade-off that allows for our digital transactions to leave an explicit data trail behind it has not been worth it. They argue we went into this digital finance system and have given away all of our data, but we did not actually consent to this."

"Basically this whole system of crime detection has been built on tracking our transactions but Monero argue it won't work anymore as it wasn't fair to start with, so regulators will need to find another way to track crime," says Associate Professor Rob Gleasure.

The research points out that even if regulators tried to ban these privacy-preserving cryptocurrencies, it would be extremely hard to enforce across all jurisdictions - given the decentralised nature of these projects.

They recommend regulators and criminal investigators need to begin planning for the future possibility of exchanges which could ultimately mean identity linkable transaction records may not exist.

The Monero protocol, for example allows users and businesses to remain compliant, but keeps the control of this with the entity that owns the information, ultimately being able to be shared when required by investigative agencies or supervisory bodies, instead of transaction surveillance and monitoring.

"If these cryptocurrency communities have their own financial system which exists separately, and they become impossible to regulate, then it's important to understand and understand this early. Once regulators accept it, they can then begin developing new methods to compensate," concludes Associate Professor Rob Gleasure.