Publisher Health

While newly approved drugs for Alzheimer’s show some promise for slowing the memory-robbing disease, the current treatments fall far short of being effective at regaining memory. What is needed are more treatment options targeted to restore memory, said Buck Assistant Professor Tara Tracy, PhD, the senior author of a study that proposes an alternate strategy for reversing the memory problems that accompany Alzheimer’s disease and related dementias.
Since most current research on potential treatments for Alzheimer’s focuses on reducing the toxic proteins, such as tau and amyloid beta, that accumulate in the brain as the disease progresses, the team veered away from this route to explore an alternative. “Rather than trying to reduce toxic proteins in the brain, we are trying to reverse the damage caused by Alzheimer’s disease to restore memory,” said Tracy. The findings appear in the February 1 issue of The Journal of Clinical Investigation.
The work hinges on a protein called KIBRA, named because it is found in the kidney and the brain. In the brain, it is primarily localized at the synapses, which are the connections between neurons that allow memories to be formed and recalled. Research has shown that KIBRA is required for synapses to form memories, and Tracy’s team has found that brains with Alzheimer’s disease are deficient in KIBRA.
“We wondered how the lower levels of KIBRA affected signaling at the synapse, and whether understanding that mechanism better could yield some insight into how to repair the synapses damaged during the course of Alzheimer’s disease,” said Buck Staff Scientist ??Grant Kauwe, PhD, co-first author of the study. “What we identified is a mechanism that could be targeted to repair synaptic function, and we are now trying to develop a therapy based on this work.”
The team first measured the levels of KIBRA in the cerebrospinal fluid of humans. They found that higher levels of KIBRA in the cerebrospinal fluid, but lower levels in the brain, corresponded to the severity of dementia.
“We also found this amazing correlation between increased tau levels and increased KIBRA levels in the cerebrospinal fluid,” said Tracy. “It was very surprising how strong the relationship was, which really points to the role of KIBRA being affected by tau in the brain.” The team is exploring this phenomenon further, in hopes that KIBRA could be used as a biomarker of synaptic dysfunction and cognitive decline that could be useful for diagnosis, treatment planning, and tracking disease progression and response to therapy.
To figure out how KIBRA affects synapses, the team created a shortened functional version of the KIBRA protein. In laboratory mice that have a condition mimicking human Alzheimer’s disease, they found that this protein can reverse the memory impairment associated with this type of dementia. They found that KIBRA rescues mechanisms that promote the resilience of synapses.
“Interestingly, KIBRA restored synaptic function and memory in mice, despite not fixing the problem of toxic tau protein accumulation,” said Kristeen Pareja-Navarro, co-first author of the study. “Our work supports the possibility that KIBRA could be used as a therapy to improve memory after the onset of memory loss, even though the toxic protein that caused the damage remains.”
Along with other treatments that already exist or will come in the future, a KIBRA therapy to repair synapses could be a valuable addition. “Reducing toxic proteins is of course important, but repairing synapses and improving their function is another critical factor that could help,” said Tracy. “That’s how I see this making the biggest impact in the future.”

People with ischemic (clot-caused) stroke had better early recovery of cognitive function if treated with intravenous injections of a combination of biologically active components of ginkgo biloba during the first two weeks after the stroke, according to a preliminary study to be presented at the American Stroke Association’s International Stroke Conference 2024. The meeting will be held in Phoenix, Feb. 7-9, and is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.
Ginkgo biloba is an herb extracted from the dried leaves and seeds of the gingko tree, one of the oldest living tree species and native to East Asia. It is widely used in traditional Chinese medicine and available as a supplement in the U.S. Compounded therapies of the active ingredients of gingko biloba, delivered by IV, are widely used to treat stroke in China because of its potential antioxidant properties that may protect nerve cells from damage. Ginkgo biloba is not approved by the U.S. Food and Drug Administration for any medicinal use, and there is not enough evidence to support any non-FDA approved use, according to the National Center for Complementary and Integrative Health, a division of the National Institutes of Health.
In early 2023, researchers from this study published the results of a multicenter trial in China indicating that people with ischemic stroke had better recovery from their overall stroke symptoms if they were treated with daily injections of ginkgo diterpene lactone meglumine (GDLM), a combination of the biologically active components of ginkgo biloba. The current investigation analyzed the cognitive recovery of participants in that study.
“If our positive results are confirmed in other trials, GDLM injections may someday be used to improve cognitive function for patients after ischemic stroke,” said Anxin Wang, Ph.D., an associate professor of clinical epidemiology at the Beijing Tiantan Hospital of the Capital Medical University in Beijing.
The researchers analyzed the cognitive recovery of 3,163 stroke survivors (average age of 63 years; 36% women) treated for mild to moderate ischemic stroke at 100 centers in China. Starting within 48 hours of the stroke, about half of the stroke survivors were randomly selected to receive daily, intravenous injections of 25 mg of GDLM for 14 days, while the other half received daily, intravenous placebo injections. Cognitive performance was assessed before treatment, at 14 days and at 90 days using the Montreal Cognitive Assessment scale (MoCA), a 30-point face-to-face screening test of cognitive performance often used with stroke survivors. At baseline — within 48 hours of the stroke and before beginning treatment, most patients’ cognitive status was moderately impaired, with an average score of 17 out of 30.
Compared to their initial cognitive screening results: By day 14, stroke survivors who received the ginkgo biloba compound injections had improved cognitive scores in comparison to those who received the placebo (an average of 3.93 points vs. 3.62 points higher, respectively); and By day 90, those who received the ginkgo biloba compound injections had even more improved cognitive scores compared to those who received the placebo (an average of 5.51 points vs. 5.04 points).”The proportion of patients who reached a clinically significant level of improvement was 20% higher in the GDLM group, indicating that GDLM injections may improve cognitive function in patients with acute ischemic stroke,” Wang said. “Since the follow-up time in this study was only 90 days, the longer-term effect of GDLM injections requires longer-term research.”
“GDLM has shown a neuroprotective effect through multiple mechanisms, such as expanding brain blood vessels and improving brain cells tolerance to hypoxia (inadequate oxygen) and increasing cerebral blood flow. GDLM also has neuroprotective antioxidation, anti-inflammation and anti-apoptosis (cell death) properties,” Wang said. “Additionally, laboratory studies have previously indicated that GDLM may promote secretion of chemicals associated with avoiding neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease.”

In a 2022 American Heart Association Scientific Statement: Complementary and Alternative Medicines in the Management of Heart Failure, it was noted there may be some benefits and potentially serious risks to complementary and alternative medicines, so involving the health care team is critical.
“While this American Heart Association statement focused on the use of supplements in patients with heart failure, the same approach and caution should be used when treating all cardiovascular diseases including stroke,” said Chair of the scientific statement writing committee Sheryl L. Chow, Pharm.D., FAHA, an associate professor of pharmacy practice and administration at Western University of Health Sciences in Pomona, California, and an associate clinical professor of medicine at the University of California, Irvine. “Stroke patients should not take gingko biloba or other herbs or supplements without discussing it with their doctor and pharmacist. If this new research proves to be effective in future clinical trials it may be a valuable tool for after-stroke care; however, efficacy and safety would need to be demonstrated to meet the same standards as all prescription medications and secure FDA approval.” Dr. Chow was not involved in this study.
The study was an exploratory analysis conducted within a larger trial, so the results need to be confirmed in an independent trial. These results of adults in China may not be generalizable to people in other countries.

Unexplained rapid weight loss in older people could be a sign of underlying disease and can be linked with increased risk of falls and fractures, as well as a poorer long-term prognosis.
The understanding of factors that could contribute to rapid weight loss remains poor, with current treatments including correcting suboptimal dietary and physical activity behaviors.
New research by Edith Cowan University (ECU) Postdoctoral Research Fellow Dr Cassandra Smith noted that abdominal aortic calcification (AAC), a marker of advanced blood vessel disease, was linked to higher risk of rapid weight loss in the 929 older women who participated in the study
Rapid weight loss is defined as a more than five percent decrease in body weight within any 12-month interval over five years of observations.
“Rapid weight loss, when it occurs in older women can be a sign of bad things to come such as early institutionalisation, cognitive decline, Alzheimer’s disease, and pose a higher risk for falls and fractures,” Dr Smith said.
During a five-year observation, 39.4 percent of the patients had rapid weight loss, which was associated with a 49 percent increase in the risk of dying in the next 9.5 years. This risk of dying increased to 87 percent in women who experienced rapid weight loss of more than ten percent in a 12-month interval.
When looking at the one-in-two women that had moderate to extensive AAC, they were 36 percent and 58 percent more likely to have rapid weight loss over the five years. The results remained similar after adjusting for dietary factors, blood pressure and cholesterol. Importantly this link was still seen in women meeting protein and energy and physical activity recommendations.

Dr Smith said the explanations for the relationship between AAC and rapid weight loss remained unclear. One hypothesis is that AAC could limit blood flow to the gut, which could affect the absorption of nutrients.
“This has the potential to change how we treat those older individuals who present with rapid weight loss,” Dr Smith said.
“The traditional approach would be to increase protein and energy intake, but data is showing us that it could actually be vascular disease that is driving that weight loss, in which case using the traditional approaches may not help with body composition.”
“Given the poor outcomes commonly associated with rapid weight loss in older adults, AAC may be a tool to identify those older women with highest risk. It also opens the door to an opportunity for cardiovascular disease risk screening and to consider disease in other vascular beds or organs that may be influencing body composition.”
“The next steps of this research are to replicate these findings in other cohorts, to perform studies with blood flow measures and the capacity to track macronutrient absorption.”

Fighting disease-causing bacteria becomes more difficult when antibiotics stop working. People with pre-existing conditions in particular can carry resistant germs and suffer from repeated infections for years, according to a study by the University of Basel and University Hospital Basel.
Pneumonia, urinary tract infections, sepsis: diseases like these can become fatal without antibiotics. Some bacteria have developed the ability to break down beta-lactam antibiotics like penicillins and cephalosporins, making them ineffective. Once a patient’s body has been colonized by these resistant bacteria, they can persist for a long time, reports Professor Sarah Tschudin Sutter’s research group in the scientific journal Nature Communications.
The team at the Department of Clinical Research of the University of Basel and University Hospital Basel analyzed multiple samples taken from over 70 individuals over a period of ten years. The researchers looked at a much longer period of time than previous studies and focused on older people with pre-existing conditions. Their key question: whether and how resistant Klebsiella pneumoniae and Escherichia coli bacteria in the body change over this long period and how they differ in various parts of the body.
Recurring illness
DNA analysis indicates that the bacteria initially adapt quite quickly to the conditions in the colonized parts of the body, but undergo few genetic changes thereafter. The resistant bacteria could still be detected in the patients up to nine years later. “These patients not only repeatedly become ill themselves, they also act as a source of infection for other people — a reservoir for these pathogens,” says Dr. Lisandra Aguilar Bultet, the study’s lead author.
“This is crucial information for choosing a treatment,” explains Professor Tschudin Sutter. If someone has previously been infected with resistant bacteria and later requires another course of treatment because of a new infection, there is a risk that standard antibiotics will again fail to work.
Transmission of resistance
In addition, the researchers found that in some patients, bacterial strains of the same species, as well as of different species (specifically, Klebsiella pneumoniae and Escherichia coli), share identical genetic mechanisms of resistance through what are known as mobile genetic elements (such as plasmids). The most likely explanation is that they have transmitted these elements to each other.
Hospitals use special protective measures if a patient has been infected with resistant bacteria in the past. In everyday life, however, it is difficult to reduce the risk of pathogen transmission.
These findings about the bacterial genetic diversity expected to develop in individual patients over time are a valuable basis for future studies to analyze factors found in both bacteria and patients that correlate with duration of colonization and progression from colonization to infection.

Research team at the University of Freiburg develops 3D-printed pneumatic logic modules that control the movements of soft robots using only air pressure. These modules enable logical switching of the air flow and can thus imitate an electrical control system. The modules make it possible for the first time to produce flexible and electronics-free soft robots entirely in a 3D printer using conventional printing material.
In the future, soft robots will be able to perform tasks that cannot be done by conventional robots. These soft robots could be used in terrain that is difficult to access and in environments where they are exposed to chemicals or radiation that would harm electronically controlled robots made of metal. This requires such soft robots to be controllable without any electronics, which is still a challenge in development. A research team at the University of Freiburg has now developed 3D-printed pneumatic logic modules that control the movements of soft robots using air pressure alone. These modules enable logical switching of the air flow and can thus imitate electrical control. The modules make it possible for the first time to produce flexible and electronics-free soft robots entirely in a 3D printer using conventional filament printing material. The team led by Dr. Stefan Conrad, Dr. Falk Tauber, Joscha Teichmann and Prof. Dr. Thomas Speck from the Cluster of Excellence “Living, Adaptive and Energy-autonomous Materials Systems (livMatS)” has published its results in the journal Science Robotics.
“Our design makes it possible for anyone with 3D printing experience to produce such logic modules and use them to control a soft robot without the need for high-end printing equipment,” says Conrad. “This marks a significant step towards completely electronics-free pneumatic control circuits that can replace increasingly complex electrical components in soft robots in the future.”
Modules can perform Boolean operations and direct airflow into movement elements in a targeted manner
The modules consist of two pressurised chambers. A 3D-printed channel runs between these chambers. By compressing the channel, the expanding chambers can stop the air flow in it and regulate it like a valve. By opening and closing the valve in a targeted manner, the modules can perform the Boolean logic functions “AND,” “OR” and “NOT” in a similar way to electrical circuits and direct the air flow into the movement elements of the soft robot. Which function the individual module performs is determined by the chambers into which air pressure is applied. Depending on the material selected, the modules can be operated with a pressure of between 80 and more than 750 kilopascals. Compared to other pneumatic systems, they have a fast response time of around 100 milliseconds.
Wide range of applications
“The potential applications of these modules are enormous. We have developed a flexible 3D-printed robotic walker that is controlled by an integrated circuit using air pressure. The flexibility of the logic modules is demonstrated by the fact that this walker can even withstand the load of a car driving over it,” says Tauber. “As an example of more complex control systems, we have also developed an electronics-free drinks dispenser.”

Researchers from the UAB and the ICN2 have developed an innovative material to fight against the spread of pathogens, infections and antimicrobial resistance. Inspired by the substances secreted by mussels to adhere to rocks, it can be used as a coating to protect healthcare fabrics and provides an effective alternative to commonly used materials such as paper, cotton, surgical masks and commercial plasters. The research was published in the Chemical Engineering Journal.
The overuse of antibiotics has led to the development of antimicrobial resistance (AMR), a growing threat to public health worldwide. AMR occurs when bacteria change over time and no longer respond to drugs, antibiotics and other related antimicrobial medicines, making infections harder to treat and increasing the risk of pathogen spread, severe illness and death. In fact, the World Health Organization (WHO) and United Nations (UN) have reported that AMR poses a major threat to human health around the world, probably overtaking cancer as the world’s leading cause of death by 2050. In this scenario, the development of novel and more efficient antibacterial materials has become essential to reduce pathogen spread, thus preventing infections. Of relevance is the control of bacterial populations in health environments such as hospitals and other healthcare units to avoid the so-called nosocomial infections, mainly due to bacterial colonization on biomedical surfaces.
Today, this type of infection is the sixth leading cause of death in industrialized countries, and much higher in the developing world, specially affecting immunocompromised and intensive care patients (e.g., burns) and those with chronic pathologies such as diabetes. Among the different materials that may spread bacterial populations, fabrics represent an integral part of patient care: from the clothes of doctors, surgeons and nurses to medical curtains, bed sheets, pillow coverings, masks, gloves, and bandages, which are directly in contact with sutures and wounds. For all these reasons, antibacterial coatings for medical fabrics have become a very active field of research.
Researchers from the UAB Department of Biochemistry and Molecular Biology, the UAB Institute for Neuroscience (INc-UAB), and the Catalan Institute for Nanoscience and Nanotechnology (ICN2) have developed a family of biocompatible and bioinspired coatings produced by the co-polymerization between catechol derivatives and amino-terminal ligands. Based on this, they have demonstrated that the use of these mussel-inspired coatings as efficient antimicrobial materials, based on their ability to evolve chemically over time in the presence of air and humid atmospheres, favoring the continuous formation of Reactive Oxygen Species (ROS). In fact, in addition to the formation of ROS, the synthetic methodology results in an excess of superficial free amino groups that induced the disruption of pathogen membranes.
“One of the main components found in the coatings (catechol and polyphenol derivatives) is found in the strands secreted by mussels, which are responsible for their adhesion to rocks under extreme conditions, under saline water,” explain UAB professor Victor Yuste ICN2 researcher Salvio Suárez. “The fact that the coatings we have developed are inspired by this organism allows them to adhere to practically any type of surface and, in addition, are highly resistant to different environmental conditions such as humidity or the presence of fluids. In addition, natural compounds help to obtain more biodegradable, biocompatible materials with lower antimicrobial resistance compared to other bactericidal systems that end up generating resistance and, therefore, rapidly lose effectiveness.”
All of the commonly used sanitary equipment such as paper, cotton, surgical masks, and commercial plasters exhibited intrinsic multi-pathway antibacterial activity with rapid responses against a broad spectrum of microbial species. This included microorganisms that have developed resistance to extreme environmental conditions (such as B. subtilis), as well as pathogens considered as the primary source responsible for many current infections, particularly those acquired in healthcare facilities. These pathogens encompass multi-resistant microorganisms from both Gram-negative (E. coli and P. aeruginosa) and Gram-positive (S. aureus, methicillin-resistant S. aureus — MRSA and E. faecalis). These materials have also exhibited efficacy against fungi such as C. albicans and C. auris.
Moreover, its efficient application was demonstrated in wet atmospheres, as those found in healthcare environments, where respiratory droplets and/or other biofluids are present, thus reducing the risks of indirect contact transmission. Such antimicrobial activity was attributed to a direct contact killing process, where the pathogen is initially attached to the coating by catechol molecules and other polyphenol derivatives. Then, a multi-pathway antibacterial effect is activated, mainly focused on a sustained generation of biosafety levels of ROS and electrostatic interactions with protic amino groups exposed to the surface. These antibacterial mechanisms induced a fast (180 minutes for bacteria and 24 hours for fungi) and efficient (over 99 %) response against pathogens, causing irreversible damage to the microorganisms.

These innovative coatings follow a simple one-step and scalable synthesis under mild conditions, using affordable materials and green chemistry-based methodologies. Moreover, the polyphenolic nature of their compositions and the absence of additional external antimicrobial agents enhance the simplicity of the bio-inspired coatings and avoid the induction of AMR and its cytotoxic effects on host cells and the environment. Worth mentioning is that different parameters such as color, thickness and adhesion were fine-tuned, thus offering an adaptable solution for the different demands of the final material application. In general, the designed bio-inspired coatings have demonstrated a huge potential for further translation into clinics, as they represent a feasible alternative to existing antimicrobial materials.
This study is the result of a collaboration between researchers from the UAB (Professor Víctor J. Yuste from the Department of Biochemistry and Molecular Biology and the Institute of Neuroscience) and the ICN2 (Daniel Ruiz-Molina and Salvio Suárez-García). The first author of the study is PhD student of the UAB Department of Biochemistry and Molecular Biology José Bolaños-Cardet.
Funding:
This work was supported by grant PID2021-127983OB-C21 financed by MCIN/AEI/10.13039/501100011033/ and ERDR “A way to make Europe,” and SAF2017-83206-R funded by MCIN/Government of Spain and ERDR “A way to make Europe.” The ICN2 is funded by the CERCA/Government of Catalonia. The ICN2 receives the support of the Severo Ochoa Centres of Excellence programme, Grant CEX2021-001214-S, funded by MCIN/AEI/10.13039.501100011033. JB-C is recipient of a “Research Trainee” fellowship (2020/D/LE/CC/3) from the Universitat Autònoma de Barcelona.

A large multicenter clinical trial co-led by University of Maryland School of Medicine researchers large multicenter clinical trial co-led by University of Maryland School of Medicine researchers found that an antiseptic containing iodine resulted in about one-quarter fewer post-surgical infections in patients with limb fractures compared to another frequently used skin antiseptic. The results of the study of nearly 8,500 patients across the United States and Canada were published today in the New England Journal of Medicine.
The study — which compared the two most commonly used alcohol-based solutions, one with iodine povacrylex, and the other with chlorhexidine gluconate — may prompt changes in the type of antiseptic orthopaedic surgeons use to prepare the skin to repair fractures. Researchers saw the benefit in patients with closed, or simple fractures, where the skin remains intact, but not in compound fractures with open wounds, although they noted that using the iodine preparation was not harmful to these open-fracture patients.
“Our results suggest that the use of iodine povacrylex in alcohol as a preoperative skin antiseptic could prevent surgical-site infections in thousands of patients with closed fractures each year,” said co-principal investigator Gerard Slobogean, MD, MPH, an Associate Professor of Orthopaedics and Director of Clinical Research in the Department of Orthopaedics at the University of Maryland School of Medicine (UMSOM). He is also an orthopaedic trauma surgeon at the R Adams Cowley Shock Trauma Center at the University of Maryland Medical Center (UMMC).
Each year, more than a million Americans suffer a broken bone in the arm, leg, or pelvis that requires surgery, and about 3 percent of these patients develop a surgical-site infection. The source of bacteria could be the patient’s skin, the injury environment, or from the hospital. Although some guidelines have favored using chlorhexidine gluconate over other iodine products, there has not been a consensus on the most effective agent.
Dr. Slobogean and his colleagues believe that the trial, which included 8,485 patients treated at 25 trauma centers, is the largest randomized clinical trial ever conducted to compare the two antiseptics, which allowed them to detect important differences in infection. They said that the findings may also be relevant to other surgical specialties.
More than 6,700 patients who had surgery to treat a closed lower extremity or pelvic fracture and 1,700 patients who had surgery to treat an open fracture participated in the study.
The R Adams Cowley Shock Trauma Center and University of Maryland Capital Region Health’s (UM Capital) trauma center in Largo, Md., were among more than two dozen trauma centers to enroll patients. UMMC and UM Capital are part of the 11-hospital University of Maryland Medical System (UMMS).

“The results of this well-designed study provide some long overdue clarity to orthopaedic trauma surgeons with respect to which commonly used antiseptic skin preparation is more effective when preparing for fracture surgery,” said study co-author Todd Jaeblon, DO, an Associate Professor of Orthopaedics at UMSOM who treats patients at UM Capital.
Of the 3,205 closed-fracture patients who received 0.7% iodine povacrylex in 74% isopropyl alcohol, 77, or 2.4 percent, developed a surgical-site infection. That compares with 108, or 3.3 percent of the 3,272 patients who received 2% chlorhexidine gluconate in 70% isopropyl alcohol. In patients with open fractures, the number of patients who developed infections was similar between the two antiseptics — 54 patients, or 6.5 percent of 825 patients in the iodine group, and 60 patients, or 7.3% of the 826 patients in the chlorhexidine group.
“Extremity fractures and the challenging surgical-site infections that result from them pose a significant health care burden on our nation,” said Mark T. Gladwin, MD, who is the John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM, and Vice President for Medical Affairs, University of Maryland, Baltimore. “This pragmatic trial tested two widely used antiseptics, and its crossover design minimized selection bias. It also enrolled patients from 25 diverse hospitals in the U.S. and Canada, which improved the generalizability of the results; the strength of the study design could serve as a model for other researchers.”
The PREPARE (Pragmatic Randomized Trial Evaluating Preoperative Alcohol Skin Solutions in Fractured Extremities) trial was jointly led by UMSOM and McMaster University of Hamilton, Ontario. It was funded with $11.2 million from the Patient-Centered Outcomes Research Institute (PCORI), with additional support from the Canadian Institutes of Health Research.
“This trial represents a highly successful collaboration between McMaster University, the University of Maryland School of Medicine, and 25 trauma centers across Canada and the United States,” said co-principal investigator Sheila Sprague, PhD, an Associate Professor and Research Director at McMaster University. “This multidisciplinary approach allowed us to quickly and efficiently address an important clinical research question that will lead to the prevention of thousands of infections each year. Importantly, our collaborations will continue to grow to address other unanswered questions in orthopaedic trauma surgery.”
This is the second clinical study co-led by Dr. Slobogean and Dr. Sprague aimed at closing the gaps in the medical literature on the most effective infection-control techniques in orthopaedic surgery. In October 2022, they published the results of the Aqueous-PREP trial in The Lancet. They concluded that the choice of an aqueous antiseptic solution — either 10% povidone-iodine or 4% chlorhexidine gluconate — does not alter the risk of surgical-site infection for patients with an open fracture.
Both Aqueous-PREP and PREPARE follow a master protocol called PREP-IT (Program of Randomized Trials to Evaluate Preoperative Antiseptic Skin Solutions in Orthopaedic Trauma) to test infection prevention techniques in trials that will provide crucial evidence to help guide surgical practices.
This research was supported by the PREP-IT investigators, which includes a network of over 200 physicians, allied health care professionals, trauma patients, and clinical researchers.

University of Virginia scientists have developed a new approach to machine learning — a form of artificial intelligence — to identify drugs that help minimize harmful scarring after a heart attack or other injuries.
The new machine-learning tool has already found a promising candidate to help prevent harmful heart scarring in a way distinct from previous drugs. The UVA researchers say their cutting-edge computer model has the potential to predict and explain the effects of drugs for other diseases as well.
“Many common diseases such as heart disease, metabolic disease and cancer are complex and hard to treat,” said researcher Anders R. Nelson, PhD, a computational biologist and former student in the lab of UVA’s Jeffrey J. Saucerman, PhD. “Machine learning helps us reduce this complexity, identify the most important factors that contribute to disease and better understand how drugs can modify diseased cells.”
“On its own, machine learning helps us to identify cell signatures produced by drugs,” said Saucerman, of UVA’s Department of Biomedical Engineering, a joint program of the School of Medicine and School of Engineering. “Bridging machine learning with human learning helped us not only predict drugs against fibrosis [scarring] but also explain how they work. This knowledge is needed to design clinical trials and identify potential side effects.”
Combining Machine Learning, Human Learning
Saucerman and his team combined a computer model based on decades of human knowledge with machine learning to better understand how drugs affect cells called fibroblasts. These cells help repair the heart after injury by producing collagen and contract the wound. But they can also cause harmful scarring, called fibrosis, as part of the repair process. Saucerman and his team wanted to see if a selection of promising drugs would give doctors more ability to prevent scarring and, ultimately, improve patient outcomes.
Previous attempts to identify drugs targeting fibroblasts have focused only on selected aspects of fibroblast behavior, and how these drugs work often remains unclear. This knowledge gap has been a major challenge in developing targeted treatments for heart fibrosis. So Saucerman and his colleagues developed a new approach called “logic-based mechanistic machine learning” that not only predicts drugs but also predicts how they affect fibroblast behaviors.

They began by looking at the effect of 13 promising drugs on human fibroblasts, then used that data to train the machine learning model to predict the drugs’ effects on the cells and how they behave. The model was able to predict a new explanation of how the drug pirfenidone, already approved by the federal Food and Drug Administration for idiopathic pulmonary fibrosis, suppresses contractile fibers inside the fibroblast that stiffen the heart. The model also predicted how another type of contractile fiber could be targeted by the experimental Src inhibitor WH4023, which they experimentally validated with human cardiac fibroblasts.
Additional research is needed to verify the drugs work as intended in animal models and human patients, but the UVA researchers say their research suggests mechanistic machine learning represents a powerful tool for scientists seeking to discover biological cause-and-effect. The new findings, they say, speak to the great potential the technology holds to advance the development of new treatments — not just for heart injury but for many diseases.
“We’re looking forward to testing whether pirfenidone and WH4023 also suppress the fibroblast contraction of scars in preclinical animal models,” Saucerman said. “We hope this provides an example of how machine learning and human learning can work together to not only discover but also understand how new drugs work.”
The research was supported by the National Institutes of Health, grants HL137755, HL007284, HL160665, HL162925 and 1S10OD021723-01A1.

The interplay between ribonucleic acid (RNA) and proteins is not only important for maintaining cellular homeostasis but is also at the center of the tug-of-war between virus and host. Until now, there has been no method to globally map direct interactions of individual RNA regions in an unbiased fashion without the need for genetic modification of the target RNA or cell. Researchers from the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg and the Broad Institute of MIT and Harvard in the US have now developed a breakthrough tool that overcomes this limitation. Their findings were recently published in the journal Nucleic Acids Research.
When RNA viruses, including the coronavirus SARS-CoV-2, infect our cells, they utilize regulatory RNA elements to recruit proteins of virus and host in order to execute their own gene expression program and enable the production of viral progeny. Understanding the interactions of viral RNAs and the regulatory elements therein is therefore the first step towards identifying vulnerabilities in the viral replication process and facilitating the rational design of novel antivirals.
The method
Researchers from the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg, in collaboration with the Broad Institute of MIT and Harvard in the US, have recently developed a new method that, for the first time, enables the discovery of interactions for specific regions within a target RNA molecule. Using mass spectrometry, the technique, named SHIFTR, allows the unbiased and comprehensive mapping of proteins that interact with a specific RNA sequence — in living cells and without genetic modification.
“Until now, it has not been possible to study the interplay between proteins and individual RNA regions in live cells without genetic manipulation, for instance, by adding tag sequences to the target RNA. Our method, called SHIFTR, finally delivers this and is easy to execute, too. Beyond region-resolution, SHIFTR also requires orders of magnitudes fewer input material compared to the state-of-the-art, is highly scalable and cost-effective,” explains Mathias Munschauer, who leads a research group at the Helmholtz Institute Würzburg, a site of the Braunschweig Helmholtz Centre for Infection Research (HZI) in cooperation with the Julius-Maximilians-Universität (JMU) Würzburg.
“With this new tool we can determine the interactions for practically every cellular RNA and every regulatory element within these RNAs,” says Jens Aydin, a PhD student in Mathias Munschauer’s research group and the first author of the study in Nucleic Acids Research. “This can fundamentally change the way we look at RNA in the cell — a crucial milestone,” adds Munschauer.
SARS-CoV-2 in focus
Using the new method, the research team was able to shed further light on the replication process of SARS-CoV-2. The scientists separately examined different sequence regions within authentic SARS-CoV-2 RNAs produced during infection and were able to interrogate the 5′ and 3′ terminal regions of the viral RNA for the first time. These regions are known to contain untranslated regulatory elements that control protein synthesis and RNA stability, as well as the replication of the viral genome. In addition to known interactors, they uncovered previously unknown interactions with proteins linked to the biogenesis of viral RNAs. Some of these newly discovered interactions could serve as targets for innovative antiviral therapies.

In the future, SHIFTR can be harnessed to better understand how cellular transcriptomes, the entirety of RNA molecules in a cell, are regulated in health and disease, which may uncover novel regulatory interdependencies and drug targets. Moreover, researchers can also use the SHIFTR platform to characterize how RNA-based therapeutics interface with the regulatory machinery of the target cell, which could inspire efforts to design optimized RNA-based drugs, such as mRNA vaccines.
Funding
The study was supported by funding from the Helmholtz Young Investigator Group Program, the European Research Council (ERC), and the FOR-COVID Research Network. Nora Schmidt was additionally funded through the EMBO Long-Term Fellowship Program. The Helmholtz Association has provided the funding for the open access charge.

All dogs go to heaven. But a bulldog might find itself headed there years before a Border terrier, according to a new study of nearly 600,000 British dogs from more than 150 breeds.Large breeds and breeds with flattened faces had shorter average life spans than smaller dogs and those with elongated snouts, the researchers found. Female dogs also lived slightly longer than male ones. The results were published in the journal Scientific Reports on Thursday.

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Breed
Average Lifespan (years)

Lancashire Heeler
15.4

Tibetan Spaniel
15.2

Bolognese
14.9

Shiba Inu
14.6

Papillon
14.5

Havanese
14.5

Lakeland Terrier
14.2

Coton de Tulear
14.2

Border Terrier
14.2

Schipperke
14.2

Large Munsterlander
14.1

Lhasa Apso
14

Swedish Vallhund
14

German Spitz Mittel
14

Norwich Terrier
14

Australian Cattle Dog
14

Poodle
14

Cairn Terrier
14

Italian Greyhound
14

Miniature Dachshund
14

Welsh Springer Spaniel
14

Lowchen
13.9

Bearded Collie
13.9

Belgian Tervuren
13.8

Parson Russell Terrier
13.8

Finnish Lapphund
13.8

Bracco Italiano
13.8

Welsh Terrier
13.8

Tibetan Terrier
13.8

Australian Shepherd
13.7

Miniature Pinscher
13.7

Soft Coated Wheaten Terrier
13.7

Bedlington Terrier
13.7

Spanish Water Dog
13.7

Petit Basset Griffon Vendeen
13.7

Wire Fox Terrier
13.5

English Springer Spaniel
13.5

Irish Terrier
13.5

Norfolk Terrier
13.5

Sussex Spaniel
13.5

Vizsla
13.5

Chinese Crested
13.4

Whippet
13.4

Shetland Sheepdog
13.4

West Highland White Terrier
13.4

German Shorthaired Pointer
13.4

Brussels Griffon
13.3

Miniature Schnauzer
13.3

American Cocker Spaniel
13.3

Collie
13.3

Jack Russell Terrier
13.3

Silky Terrier
13.3

Puli
13.3

Yorkshire Terrier
13.3

English Cocker Spaniel
13.3

Tibetan Mastiff
13.3

Saluki
13.3

Pekingese
13.3

Dalmatian
13.2

Dachshund
13.2

Nova Scotia Duck Tolling Retriever
13.2

Polish Lowland Sheepdog
13.2

Pembroke Welsh Corgi
13.2

Golden Retriever
13.2

Cardigan Welsh Corgi
13.1

English Setter
13.1

Border Collie
13.1

Field Spaniel
13.1

Sealyham Terrier
13.1

Labrador Retriever
13.1

Samoyed
13.1

Maltese
13.1

Toy Manchester Terrier
13

Foxhound
13

German Wirehaired Pointer
13

Standard Schnauzer
13

Japanese Spitz
13

Portuguese Water Dog
13

Norwegian Elkhound
13

Toy Fox Terrier
12.9

Irish Setter
12.9

Weimaraner
12.8

Dandie Dinmont Terrier
12.8

Shih Tzu
12.8

Scottish Terrier
12.7

Briard
12.6

Beagle
12.5

Basset Hound
12.5

American Staffordshire Terrier
12.5

Bichon Frise
12.5

Japanese Chin
12.5

Kerry Blue Terrier
12.4

Gordon Setter
12.4

Skye Terrier
12.4

Keeshond
12.3

Clumber Spaniel
12.3

Miniature Bull Terrier
12.2

Pomeranian
12.2

Curly-Coated Retriever
12.2

Old English Sheepdog
12.1

Chow Chow
12.1

Basenji
12.1

Giant Schnauzer
12.1

Glen Of Imaal Terrier
12.1

Crossbreed
12

Airedale Terrier
12

Bull Terrier
12

Canaan Dog
12

Staffordshire Bull Terrier
12

Belgian Malinois
12

Borzoi
12

Kelpie
12

Rhodesian Ridgeback
12

Spinone Italiano
11.9

Siberian Husky
11.9

Chihuahua
11.8

Cavalier King Charles Spaniel
11.8

Boston Terrier
11.8

– Flat-Coated Retriever
11.7

Pug
11.6

Chesapeake Bay Retriever
11.6

Greyhound
11.5

Akita
11.4

German Shepherd Dog
11.3

Boxer
11.3

American Eskimo Dog
11.3

Alaskan Malamute
11.3

Bouvier des Flandres
11.3

Doberman Pinscher
11.2

Afghan Hound
11.1

Brittany
11.1

Dogue de Bordeaux
11.1

Newfoundland
11

Great Pyrenees
10.9

Black Russian Terrier
10.9

Irish Water Spaniel
10.8

Chinese Shar-Pei
10.6

Rottweiler
10.6

Great Dane
10.6

Scottish Deerhound
10.5

Bullmastiff
10.2

Anatolian Shepherd
10.1

Bernese Mountain Dog
10.1

Leonberger
10

Pharaoh Hound
10

Irish Wolfhound
9.9

Bulldog
9.8

French Bulldog
9.8

Affenpinscher
9.3

Bloodhound
9.3

Neapolitan Mastiff
9.3

Saint Bernard
9.3

Mastiff
9

Cane Corso
8.1

Presa Canario
7.7

Caucasian Shepherd Dog
5.4

There are exceptions to those broad trends, and the findings might not apply to dogs outside Britain, where breeding practices — and gene pools — may be different, the researchers noted.More research will be needed to determine why some breeds have shorter life spans than others. Some breeds are genetically predisposed to serious health problems, but breed-related differences in behavior, lifestyle, diet, environment or other factors could also play a role in shortening some dogs’ lives, experts said.“Now that we have identified these populations that are at risk of early death, we can start looking into why that is,” said Kirsten McMillan, an author of the new study and the data manager at Dogs Trust, a dog welfare charity in Britain that led the research. “This provides an opportunity for us to improve the lives of our dogs.”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber?