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A team of researchers at Baylor College of Medicine is gaining ground in their search for solutions to the global problem of bacterial antibiotic resistance, which was responsible for nearly 1.3 million deaths in 2019.
The team reports in the journal Science Advances a drug that, in laboratory cultures and animal models, significantly reduces the ability of bacteria to develop antibiotic resistance, which might prolong antibiotic effectiveness. The drug, called dequalinium chloride (DEQ), is a proof-of-concept for evolution-slowing drugs.
“Most people with bacterial infections get better after completing antibiotic treatment, but there are also many cases in which people decline because the bacteria develop resistance to the antibiotic, which then can no longer kill the bacteria,” said corresponding author Dr. Susan M. Rosenberg, Ben F. Love Chair in Cancer Research and professor of molecular and human genetics, biochemistry and molecular biology and molecular virology and microbiology at Baylor. She also is a program leader in Baylor’s Dan L Duncan Comprehensive Cancer Center (DLDCCC).
In this study, Rosenberg and her colleagues looked for drugs that could prevent or slow down E. coli bacteria from developing resistance to two antibiotics when exposed to a third antibiotic, ciprofloxacin (cipro), the second most prescribed antibiotic in the U.S. and one associated with high bacterial resistance rates.
The resistance is caused by new gene mutations that occur in the bacteria during infection. The drug DEQ reduces the speed at which new mutations are formed in bacteria, the team finds.
Previous work from the Rosenberg lab had shown that bacterial cultures in the lab exposed to cipro turn up mutation rate. They found a mutational “program” that is switched on by bacterial stress responses. Stress responses are genetic programs that instruct cells to increase production of protective molecules during stress, including stress from low concentrations of cipro. Low concentrations occur at the beginning and end of antibiotic therapies and if doses are missed.
The same stress responses also increase the ability to make genetic mutations, the Rosenberg group, then many other labs, have shown. Some of the mutations can confer resistance to cipro, while other mutations can allow resistance to antibiotics not yet encountered. Mutation-generating processes that are turned on by stress responses are called stress-induced mutation mechanisms.
Bacteria with antibiotic resistance mutations can then sustain an infection in the presence of cipro. This study is the first to show that in animal infections treated with cipro, the bacteria activate a known stress-induced genetic mutational process. Cipro resistance occurs mostly by the bacteria developing new mutations, both clinically and in the laboratory, rather than by acquiring genes that confer antibiotic resistance from other bacteria.
Looking to prevent the development of antibiotic resistance, the researchers screened 1,120 drugs approved for human use for their ability to dial down the master bacterial stress response, which they showed counters the emergence of resistance mutations. In addition, and counterintuitively, they wanted “stealth” drugs that would not slow bacterial proliferation, which would confer a growth advantage to any bacterial mutants that resist the mutation-slowing drug itself. That is, drugs that are not antibiotics themselves.
“We found that DEQ fulfilled both requirements. Given together with cipro, DEQ reduced the development of mutations that confer antibiotic resistance, both in laboratory cultures and in animal models of infection, and bacteria did not develop resistance to DEQ,” said first author Yin Zhai, a postdoctoral associate in the Rosenberg lab. “In addition, we achieved this mutation-slowing effect at low DEQ concentrations, which is promising for patients. Future clinical trials are needed to evaluate the ability of DEQ to decelerate bacterial antibiotic resistance in patients.”
Other contributors to this work include John P. Pribis, Sean W. Dooling, Libertad Garcia-Villada, P.J. Minnick, Jun Xia, Jingjing Liu, Qian Mei, Devon M. Fitzgerald, Christophe Herman, P.J. Hastings and Mauro Costa-Mattioli. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, the Dan L Duncan Comprehensive Cancer Center and Rice University.
This work was supported by NIH Directors Pioneer Awards DP1-AI52073 and DP1-AG072751, and NIH grants R35-GM122598 and R01-CA250905, P30-AI036211, P30-CA125123 and S10-RR024574, the Dan L Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. Further support was provided by the State of Nebraska LB595 and LB692 and NIH/NIEHS R00ES033259 awards.

B cells are thought to play a critical role in innate and adaptive immunity, but their exact role in anti-tumor immunity remains unknown. Researchers at Brigham and Women’s Hospital with expertise in immunology collaborated with experts in dermatology from Massachusetts General Hospital to further understand the role of B cells and identify a subset of cells that may play a critical role. In collaboration with the Broad Institute they used a technique called single-cell profiling, which allows them to look at all the genes in the cell to study these B cells in mouse and human cancers.
They found a cell surface receptor called TIM-1 expressed on these B cells during melanoma growth. They also characterized multiple accompanying cell surface proteins that were involved in the B cell’s immune function. Interestingly, they found that deleting a molecule TIM-1, but not any of the other accompanying proteins, dramatically decreased tumor growth. The researchers concluded that TIM-1 controls B cell activation and immune response that combats cancer, including activating another type of the killer tumor-specific T cells for inhibiting tumor growth.
“The collaboration across institutions was extremely fruitful as we combined our immunology expertise at the Brigham with work at David Fisher’s MGH laboratory where seminal discoveries in skin malignancies have been made,” said lead author Lloyd Bod, PhD, of the Department of Neurology at the Brigham, who conducted this work while completing his postdoctoral fellowship at the Brigham. Bod is now an Assistant Professor and an independent investigator at the Mass General Cancer Center. “The collaboration allowed us to test and demonstrate the therapeutic potential of targeting TIM-1 in melanoma models.”

The cause of a common kidney disease likely lies outside the kidney, according to a new study led by Columbia University researchers. The study, which uncovered 16 new locations in the genome linked to immunoglobulin A (IgA) nephropathy, confirms an earlier hypothesis that the immune system has an important role in driving the disease and points toward new strategies for detecting and treating it.
No targeted treatments have been approved to treat IgA nephropathy, largely because the underlying cause of the disease has not been well understood.
Identifying genes linked to a disease can provide clues to its source and guide the development of new drugs, but thousands of patients are needed for such studies. For IgA nephropathy, those numbers are difficult to achieve.
Though common compared to other forms of kidney disease related to the immune system, IgA nephropathy is hard to diagnose, and confirmed patients are difficult to find. “The diagnosis requires a kidney biopsy, which is an invasive procedure that carries a lot of risks, so the diagnosis is frequently missed,” says Krzysztof Kiryluk, MD, associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and lead author of the study.
Kiryluk and his colleagues tackled the numbers problem by building a vast network of collaborators, eventually including nephrologists, geneticists, and other scientists scattered across four continents. Each collaborator recruited biopsied patients locally and sent blood samples to Kiryluk’s Columbia team for DNA extraction and analysis.
With samples from almost 40,000 subjects, the researchers compared DNA from IgA nephropathy cases to DNA from people who do not have the disease. The study, which took 10 years to complete and involved nearly 200 scientists and clinicians at more than 100 institutions, is the largest ever of the genetics of IgA nephropathy.
Many of the new genes identified in the study are involved in the production of IgA antibodies, reinforcing the idea that regulation of IgA levels is the key factor behind the disease.
“That’s a very important finding because IgA nephropathy is considered to be a kidney disease, but it seems like its source is outside the kidney,” says Kiryluk.
“We also developed a genetic risk profile that may help identify patients at highest risk of progression to kidney failure,” says Ali Gharavi, MD, the Jay Meltzer, MD, Professor of Nephrology and Hypertension and co-leader of the study.
The researchers also identified proteins produced by the newly identified genes that look like the best targets for drug development. And they identified two drugs already studied for other conditions that may have potential as IgA nephropathy treatments.
“A recent analysis found that drug targets backed by genetic studies are more likely to succeed,” Kiryluk says, “and we hope that pharmaceutical companies will start developing new therapies based on our findings.”

We may be on the cusp of an era of astonishing innovation — the limits of which aren’t even clear yet.Hype springs eternal in medicine, but lately the horizon of new possibility seems almost blindingly bright. “I’ve been running my research lab for almost 30 years,” says Jennifer Doudna, a biochemist at the University of California, Berkeley. “And I can say that throughout that period of time, I’ve just never experienced what we’re seeing over just the last five years.”A Nobel laureate, Doudna is known primarily for Crispr, the gene-editing Swiss Army knife that has been called “a word processor” for the human genome and that she herself describes as “a technology that literally enables the rewriting of the code of life.” The work for which Doudna shared the Nobel Prize was published more than a decade ago, in 2012, opening up what seemed like an almost limitless horizon for Crispr-powered therapies and cures. But surveying the recent landscape of scientific breakthroughs, she says the last half-decade has been more remarkable still: “I think we’re at an extraordinary time of accelerating discoveries.” The pandemic has exhausted many Americans of medicine, and it has become common to process the last few years as a saga of defeat and failure. And yet these brutal years — which brought more than a million American deaths and probably 20 million deaths worldwide, and seemed to return even the hypermodern citadels of the wealthy West to something like the experience of premodern plague — might also represent an unprecedented watershed of medical innovation. Beyond Crispr and Covid vaccines, there are countless potential applications of mRNA tools for other diseases; a new frontier for immunotherapy and next-generation cancer treatment; a whole new world of weight-loss drugs; new insights and drug-development pathways to chase with the help of machine learning; and vaccines heralded as game-changing for some of the world’s most intractable infectious diseases.“It’s stunning,” says the immunologist Barney Graham, the former deputy director of the Vaccine Research Center and a central figure in the development of mRNA vaccines, who has lately been writing about a “new era for vaccinology.” “You cannot imagine what you’re going to see over the next 30 years. The pace of advancement is in an exponential phase right now.” ‘World-changing’ innovationsIt is sometimes hard to see the silver lining for the cloud, particularly when it’s as dark as the last three years have been. But at the very center of the American Covid experience, amid all the death and suffering and despite the dysfunction that midwifed it into being, sits what would have stood out, in any previous era, as an astonishing biomedical miracle: the coronavirus vaccines. Drug-development timelines in previous history had swallowed whole decades; experts warned not to expect a resolution for years. But the mRNA sequence of the first shot was designed in a weekend, and the finished vaccines arrived within months, an accelerated timeline that saved perhaps several million American lives and tens of millions worldwide — numbers that are probably larger than the cumulative global death toll of the disease. The miracle of the vaccines wasn’t just about lives saved from Covid. As the first of their kind to be approved by the Food and Drug Administration, they brought with them a very long list of potential future mRNA applications: H.I.V., tuberculosis, Zika, respiratory syncytial virus (R.S.V.), cancers of various and brutal kinds. And the vaccine innovations stretch beyond mRNA: A “world-changing” vaccine for malaria, which kills 600,000 globally each year, is being rolled out in Ghana and Nigeria, and early trials for next-generation dengue vaccines suggest they may reduce symptomatic infection by 80 percent or more. Not every innovation arriving now or soon to market comes from U.S. research or shares the same saga of development. But many of their back stories do rhyme, often stretching back several decades through the time of the Human Genome Project, which was completed in 2003, and the near-concurrent near-doubling of the National Institutes of Health’s budget, which helped unleash what Donna Shalala, President Bill Clinton’s secretary for health and human services, last year called “a golden age of biomedical research.” Illustration by Ibrahim RayintakathA couple of decades later, it looks like a golden age for new treatments. New trials of breast-cancer drugs have led to survival rates hailed in The Times as “unheard-of,” and a new treatment for postoperative lung-cancer patients may cut mortality by more than half. Another new treatment, for rectal cancer, turned every single member of a small group of cases into cancer-free survivors. Ozempic and Wegovy have already changed the landscape for obesity in America — a breakthrough that has been described and debated so much in terms of cosmetic benefits and medical moral hazard that it can be easy to forget that obesity is among the largest risk factors for preventable death in the United States. Next-generation alternatives may prove even more effective, and there are signs of huge off-label implications: At least anecdotally, in some patients the drugs appear to curb compulsive behavior across a range of hard-to-treat addictions. And although the very first person to receive Crispr gene therapy in the United States received it just four years ago, for sickle-cell disease, it has since been rolled out for testing on congenital blindness, heart disease, diabetes, cancer and H.I.V. So far only two applications for such treatments have been submitted to the F.D.A., but all told, some 400 million people worldwide are afflicted by one or more diseases arising from single-gene mutations that would be theoretically simple for Crispr to fix. And when Doudna allows herself to imagine applications a decade or two down the line, the possibilities sound almost intoxicating: offering single-gene protection against high cholesterol and therefore coronary artery disease, for instance, or, in theory, inserting a kind of genetic prophylaxis against Alzheimer’s or dementia. ‘Can we actually do it?’In January, a much-talked-about paper in Nature suggested that the rate of what the authors called disruptive scientific breakthroughs was steadily declining over time — that, partly as a result of dysfunctional academic pressures, researchers are more narrowly specialized than in the past and often tinkering around the margins of well-understood science. But when it comes to the arrival of new vaccines and treatments, the opposite story seems more true: whole branches of research, cultivated across decades, finally bearing real fruit. Does this mean we are riding an exponential curve upward toward radical life extension and the total elimination of cancer? No. The advances are more piecemeal and scattered than that, and indeed there are those who believe that progress should be moving faster still. In the midst of the pandemic, a number of calls for greater acceleration have been issued, some emphasizing the need to reduce costs for drug development, which have doubled every decade since the 1970s, perhaps by redesigning clinical trials or employing what are called human-challenge trials, or by streamlining the drug-approval process. Graham, who is now a senior adviser for global health equity at the Morehouse School of Medicine, emphasizes questions of global distribution and access: Will the new technologies actually get where they are needed most? “The biology and the science that we need is already in place,” he says. “The question now to me is: Can we actually do it?”In 1987, the economist Robert Solow commented that you could see the computer revolution everywhere but the productivity statistics — that despite intuitions about how fully information technology had transformed all forms of work in America, the step-change hadn’t really made a mark on the country’s economy in any obvious statistical way. Until a few years ago, perhaps, you might have said the same about billions of dollars spent researching potential H.I.V. vaccines or the decoding of the human genome, which unleashed a venture-capital-like boom-and-bust biotech hype cycle that sputtered out before most Americans had seen any real gains from it. Sometimes these things just take a little time. David Wallace-Wells is a staff writer at the magazine and the author of “The Uninhabitable Earth: Life After Warming.”

It could be the shopping trip that saves your life: supermarket trolleys are helping to diagnose atrial fibrillation which can then be treated to prevent disabling or fatal strokes. The research is presented today at ACNAP 2023, a scientific congress of the European Society of Cardiology (ESC).1
“This study shows the potential of taking health checks to the masses without disrupting daily routines,” said study author Professor Ian Jones of Liverpool John Moores University, UK. “Over the course of two months, we identified 39 patients who were unaware that they had atrial fibrillation. That’s 39 people at greater risk of stroke who received a cardiologist appointment.”
More than 40 million people around the world have atrial fibrillation, the most common heart rhythm disorder.2 Atrial fibrillation increases the risk of stroke by five-fold. These strokes are often fatal or disabling. Anticoagulation substantially lowers risk, but many people only discover they have atrial fibrillation after they have a stroke.3 Screening programmes are therefore needed to identify people with the condition so they can receive preventive medication.
The SHOPS-AF study investigated whether embedding electrocardiogram (ECG) sensors into the handles of supermarket trolleys could effectively identify shoppers with atrial fibrillation (see photo).4,5 Ten trolleys had a sensor placed in the handle and were used across four supermarkets with pharmacies in Liverpool during the two month study.
Shoppers were asked to use a modified trolley and hold the handlebar for at least 60 seconds. If the sensor did not detect an irregular heartbeat, it lit up green. These participants had a manual pulse check by a researcher to confirm there was no atrial fibrillation. If an irregular heartbeat was found, the sensor lit up red. The in-store pharmacist then did a manual pulse check and another sensor reading using a standalone bar not attached to a trolley with the participant standing still. The study cardiologist reviewed the ECG recordings of participants with a red light and/or irregular pulse. Participants were informed of the results, which were: 1) no atrial fibrillation; 2) unclear ECG and an invitation to repeat the measurement; or 3) atrial fibrillation confirmed and a cardiologist appointment within two weeks.
A total of 2,155 adults used a shopping trolley. ECG data were available for 220 participants who either had a red light on the sensor and/or an irregular pulse, suggesting atrial fibrillation. After ECG review by the study cardiologist, there was no evidence of atrial fibrillation in 115 participants, 46 recordings were unclear, and atrial fibrillation was diagnosed in 59 participants. The average age of the 59 participants with atrial fibrillation was 74 years and 43% were women. Of those, 20 already knew they had atrial fibrillation and 39 were previously undiagnosed.
To assess the accuracy of screening using this method, the researchers conducted three analyses: 1) excluding all 46 unclear ECGs; 2) assuming all unclear ECGs were atrial fibrillation; and 3) assuming all unclear ECGs were not atrial fibrillation. This showed that the sensor’s sensitivity ranged from 0.70 to 0.93 and specificity ranged from 0.15 to 0.97. This resulted in a positive predictive value of 0.24 to 0.56, meaning that only one-quarter to one-half of those found to have atrial fibrillation according to the sensor and/or manual pulse check actually had the condition (i.e. there were a high number of false positives). The negative predictive value was 0.55 to 1.00, meaning that around half of actual atrial fibrillation cases would be missed using this method (i.e. false negatives).
Professor Jones said: “Nearly two-thirds of the shoppers we approached were happy to use a trolley, and the vast majority of those who declined were in a rush rather than wary of being monitored. This shows that the concept is acceptable to most people and worth testing in a larger study. Before we conduct SHOPS-AF II, some adjustments are needed to make the system more accurate. For example, having a designated position on the bar to hold onto, as hand movement interfered with the readings. In addition, ESC Guidelines require just a 30 second ECG to diagnose atrial fibrillation,2 so we aim to find a sensor that will halve the time shoppers need to continuously hold the bar.”
He concluded: “Checking for atrial fibrillation while people do their regular shopping holds promise for preventing strokes and saving lives. A crucial aspect is providing immediate access to a health professional who can explain the findings and refer patients on for confirmatory tests and medication if needed.”

Published17 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Michelle RobertsDigital health editorSupermarket trolleys with a special sensor fitted to the handles can help spot a hidden heart-rhythm condition that increases the risk of stroke, a trial has found. Researchers in Liverpool asked local stores to stock the modified trolleys, which scan customers’ grip pulses for any irregularities while they shop. More than 2,000 shoppers used them. During the two months of the study, 39 people were newly identified as having atrial fibrillation (AF).They were referred on to see a heart doctor for advice. ‘My watch warned me I had an undiagnosed heart condition’Shop loyalty card data may help spot ovarian cancerStudent’s heart failure linked to energy drinksLead researcher Prof Ian Jones, from Liverpool John Moores University, said: “This study shows the potential of taking health checks to the masses without disrupting daily routines. “Nearly two-thirds of the shoppers we approached were happy to use a trolley and the vast majority of those who declined were in a rush rather than wary of being monitored. “This shows that the concept is acceptable to most people and worth testing in a larger study.”What is AF and is it dangerous?AF is when the heart beats irregularly or chaotically so the heart muscle cannot relax properly between contractionsPeople with AF might notice an irregular and fast pulse or heart palpitations Some have no symptoms though and it is only picked up during a check-up AF can increase the risk of blood clots in the heart that may lead to strokeAF is thought to affect more than a million people in the UK and 40 million globally. Anti-clotting medication for the blood may be recommended to lower the risk of possible complications, such as stroke.The trial findings are being presented at a European Society of Cardiology conference, in Edinburgh. The study received funding from Bristol Myers Squibb, which makes treatments for AF.Ten trolleys with a sensor in the handle – similar to those on gym exercise machines – were placed across four supermarkets with pharmacies.Image source, Liverpool John Moores University Shoppers were asked to hold the handle for a minute.If an irregular heartbeat was detected, the in-store pharmacist manually checked their pulse and they had an electrocardiogram (ECG) heart trace taken that was then reviewed by a cardiologist. Of these 220:115 showed no evidence of AF59 were found to have AF, 39 undiagnosed46 had readings that were unclearIf no irregular heartbeat was detected, a researcher manually checked their pulse – and of these, 10 were found to have AF.More on this story’My watch warned me I had a heart condition’Published10 MarchStudent’s heart failure linked to energy drinksPublished16 April 2021Related Internet LinksACNAP CongressThe BBC is not responsible for the content of external sites.

Dozens of clinics have closed or halted abortions since the Supreme Court’s decision to overturn Roe v. Wade. A grid […]

The law was to take effect on July 1. It is the only state law that specifically outlaws the most common abortion method in the country.A Wyoming judge on Thursday temporarily blocked the first state law specifically banning the use of pills for abortion, the most common method in the country.Just over a week before the ban was scheduled to take effect, Judge Melissa Owens of Teton County District Court granted a temporary restraining order, putting the law on hold pending further court proceedings.Ruling from the bench after a hearing that lasted about two hours, Judge Owens said that the plaintiffs, who include four health care providers, “have clearly shown probable success on the merits and that at least some of the plaintiffs will suffer possible irreparable injury” if the ban were to take effect.Medication abortion is already outlawed in states that have near-total bans, since those bans prohibit all forms of abortion. But Wyoming became the first state to outlaw the use of pills for abortion separate from an overall ban. The law was scheduled to take effect July 1.The ban, passed by the Legislature and signed by Gov. Mark Gordon in March, makes it illegal to “prescribe, dispense, distribute, sell or use any drug for the purpose of procuring or performing an abortion.”Doctors or anyone else found guilty of violating this law would be charged with a misdemeanor, punishable by up to six months in prison and a $9,000 fine. The law explicitly says that pregnant women would be exempt from charges and penalties.In the year since the Supreme Court overturned the national right to abortion, Wyoming’s Republican-controlled Legislature has been trying to ban abortions in the state.Last year, Judge Owens temporarily enjoined a near-total abortion ban, which she said appeared to contradict an amendment to Wyoming’s Constitution that guarantees adults the right to make their own health care decisions. An overwhelming majority of Wyoming citizens voted for that amendment in 2012.In March, the Legislature passed and the governor signed another near-total ban on abortions that tried to circumvent that constitutional amendment by declaring that abortion is not health care. Judge Owens temporarily blocked that law soon after it was signed, saying she questioned the state’s contention that abortion is not health care.The issue of whether abortion is health care was also a significant aspect of Thursday’s hearing on the medication abortion ban. Jay Jerde, a special assistant attorney general for Wyoming, argued that even though doctors and other health providers must be involved in abortions, there are many instances when “getting the abortion doesn’t implicate health care because it’s not restoring the woman’s body from pain, physical disease or sickness.”Judge Owens questioned Mr. Jerde’s argument. “Essentially the government under this law is making the decision for a woman,” she said, “rather than the woman making her own health care choice, which is what the overwhelming majority in Wyoming decided that we should get to do.”The plaintiffs in the case, who are challenging all of the bans in various lawsuits, include the only two abortion providers in Wyoming; an obstetrician-gynecologist who often treats high-risk pregnancies; an emergency room nurse; a fund that gives financing to abortion patients; and a woman who said her Jewish faith requires access to abortion if a pregnant woman’s physical or mental health or life is in danger.A ban on medication abortion would have a substantial impact because pills have been the method used in almost all recent abortions in the state, a lawyer for the plaintiffs, Marci Bramlet, told the court. Nationally, pills are now used in over half of abortions. Only one of Wyoming’s providers offers the other method, surgical abortions.“The ban seeks to only ban medication abortions, not all abortions, completely undermining the state’s stated goal of preserving prenatal life, and allows surgical abortions which are more invasive physically, financially and logistically,” Ms. Bramlet told the court. “The statute tells women, ‘You can have an abortion in Wyoming but not using the safe, effective, F.D.A.-approved medication available.’”

Ruxolitinib, a drug that is already approved by the U.S. Food and Drug Administration (FDA) for treating certain cancers and skin conditions, is effective at inhibiting CaMKII, a protein kinase linked to cardiac arrhythmias.
In a new study published June 21, 2023, in Science Translational Medicine, researchers from Johns Hopkins University and the University of Chicago invented a new reporting technique to monitor activity of CaMKII while screening the effects of nearly 5,000 FDA approved drugs on human cells that expressed the enzyme. The screen identified five previously unknown CaMKII inhibitors; ruxolitinib, which is used to treat cancers of the blood and bone marrow, along with skin conditions like atopic dermatitis and vitiligo, was the most effective.
CaMKII, or Calcium and calmodulin-dependent protein kinase II, is critical to cardiomyocytes, the muscle cells of the heart, where it maintains the balance of calcium. Activation of CaMKII helps facilitate rapid changes in heart activity, such as initiating a fight-or-flight response in the body. Overactivation can lead to impaired heart function and cell death, which can in turn lead to poor heart health outcomes like arrhythmia.
CaMKII is perhaps best known, however, for its role in the brain, where it is believed to play key roles in learning and memory. This has slowed the development of CaMKII inhibitors to treat arrythmia, for fear they could impact cognitive function.
“Finding an FDA approved drug means that millions of people have been taking CaMKII inhibitors, and in the case of ruxolitinib, there are no reported major problems with the brain,” said Mark Anderson, MD, PhD, a senior author of the paper and Dean of the Biological Sciences Division and Pritzker School of Medicine, Executive Vice President for Medical Affairs, and Paul and Allene Russell Professor at the University of Chicago. “That should give pharma and biotech companies confidence that they could carry out development of a CaMKII inhibitor program, because the biggest obstacle seems to be surmountable.”
The research began in Anderson’s lab at Johns Hopkins University, where he previously served as the William Osler Professor and Director of the Department of Medicine. Oscar Reyes Gaido, the study’s first author and an MD-PhD student in the lab, developed a new tool to measure activity of CaMKII in living cells. He started with a protein called green fluorescent protein (GFP), originally derived from jellyfish, that emits green light. He then engineered the GFP tag to detect CaMKII activation, making a new reporter called CaMKAR (CaMKII Activity Reporter). When this reporter was inserted into human heart cells, it helpfully glowed bright green whenever CaMKII became active, allowing researchers to monitor enzyme activity.
“This biosensor will be very useful for studying how CaMKII activity changes in both healthy and pathological contexts. Existing methods can measure CaMKII activity, but they lack the versatility and resolution to track in real time and with high sensitivity,” Reyes Gaido said. “This has been a real obstacle for studying enzyme biology in general, so this gives the field an important new tool.”
Using this tool, the researchers conducted a drug repurposing screen to test the effects of 4,475 approved compounds on cultured human cardiomyocytes. This identified five previously unknown CaMKII inhibitors: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. Of the five, ruxolitinib was the most effective at inhibiting CaMKII activity in cell and mouse models of CaMKII-driven arrhythmias. A 10-minute application of the drug was enough to prevent catecholaminergic polymorphic ventricular tachycardia (CPVT), a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. Crucially, the mice treated with ruxolitinib did not show any adverse cognitive effects when they were tested with memory and learning tasks.
Anderson said that new drugs based on ruxolitinib could be used in several ways to treat heart conditions. One would be what he called the “pill in a pocket” scenario. In the early stages of atrial fibrillation, people could take the medication occasionally as symptoms arise. Patients with CPVT are often resistant to standard treatments, and a ruxolitinib-based treatment could provide another option. Finally, there is evidence that inhibiting CaMKII during a heart attack can prevent heart muscle from dying, so emergency responders could potentially administer such a drug as part of standard practice.
“There’s been a long search for fundamental pathways that could be targets for therapeutics in arrhythmias,” Anderson said. “This could be a finding that will translate relatively rapidly into people now since it’s already been proven to be safe in humans.”

Just as space holds infinite mysteries, when we zoom in at the level of biomolecules (one trillion times smaller than a meter), there is still so much to learn.
Rensselaer Polytechnic Institute’s Catherine Royer, Constellation Chair Professor of Bioinformatics and Biocomputation at the Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS) and professor of biological sciences, is dedicated to understanding the conformational landscapes of biomolecules and how they modulate cell function. When biomolecules receive certain inputs, it can cause the atoms to rearrange and the biomolecule to change shape. This change in shape affects their function in cells, so understanding conformational dynamics is critical for drug development.
In research recently published in the Proceedings of the National Academy of Sciences, Royer and her team examined the conformational dynamics of a human transfer ribonucleic acid (tRNA) under high hydrostatic pressure. The high pressure led to an increased population of the tRNA-excited states that normally exist at very low levels, allowing new insights into tRNA function.
“We’re interested in observing the excited states because they lead to conformations outside of those that can be determined by X-ray crystallography, nuclear magnetic resonance (NMR), or electron microscopy,” said Royer. “We’re beginning to understand that there are far more biomolecular structures than previously thought and, for the development of therapeutics, we need to understand what these states look like.”
For this research, Royer used human tRNA rather than proteins, which are what she typically studies. “There hasn’t been much work done on excited states of large RNA molecules, so that’s what makes this research unique,” Royer said.
Royer and team learned that the excited states not only play a role in the normal function of tRNAs for protein translation from the messenger RNA, but likely also play a role in HIV infection. HIV newly infects about 1.5 million people worldwide each year.
“The NMR revealed that the hydrogen bonds holding the tRNA together are weakened in these excited states,” said Royer. “The small-angle X-ray scattering at high pressure, which we did at CHESS, revealed that the shape of the tRNA changed in these excited states. The areas that were altered by pressure also happen to be the areas that get hijacked by HIV during infection.” CHESS, or the Cornell High Energy Synchrotron Source, is a state-of-the-art synchrotron radiation facility and the only one in the U.S. that enables high-pressure small-angle X-ray scattering (SAXS) measurements on biomolecules.
Royer and her team surmise that the excited state configurations of the tRNA they observed under pressure could be exploited by the invading viral RNA to initiate HIV reverse transcription. This process is linked to the virus’ infectiousness.
“Dr. Royer’s research, together with her team, may advance our understanding of how HIV spreads,” said Deepak Vashishth, director of CBIS. “Further, over 80% of the microbial biomass on Earth exists at high pressure. Understanding how biomolecular sequences are adapted to function in high-pressure environments will yield new approaches for developing sturdier and more active biomolecules for biotechnology.”
“It’s an exciting time to be in high-pressure structural biology,” said Richard Gillilan of CHESS. “People have known for some time that biomolecules do interesting things under extreme pressure, but, until very recently, technologies like high-pressure NMR and SAXS just weren’t available to the general research community. Now, we can start to see what pressure does in molecular detail, and there is a lot of interest from multiple scientific fields, including biomedicine.”