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The diagnosis of Parkinson’s disease has shaken many lives. More than 10 million people worldwide are living with it. There is no cure, but if symptoms are noticed early, the disease can be controlled. As Parkinson’s disease progresses, along with other symptoms speech changes.
Lithuanian researcher from Kaunas University of Technology (KTU), Rytis Maskeliūnas, together with colleagues from the Lithuanian University of Health Sciences (LSMU), tried to identify early symptoms of Parkinson’s disease using voice data.
Parkinson’s disease is usually associated with loss of motor function — hand tremors, muscle stiffness, or balance problems. According to Maskeliūnas, a researcher at KTU’s Department of Multimedia Engineering, as motor activity decreases, so does the function of the vocal cords, diaphragm, and lungs: “Changes in speech often occur even earlier than motor function disorders, which is why the altered speech might be the first sign of the disease.”
Expanding the AI language database
According to Professor Virgilijus Ulozas, at the Department of Ear, Nose, and Throat at the LSMU Faculty of Medicine, patients with early-stage of Parkinson’s disease, might speak in a quieter manner, which can also be monotonous, less expressive, slower, and more fragmented, and this is very difficult to notice by ear. As the disease progresses, hoarseness, stuttering, slurred pronunciation of words, and loss of pauses between words can become more apparent.
Taking these symptoms into account, a joint team of Lithuanian researchers has developed a system to detect the disease earlier.

“We are not creating a substitute for a routine examination of the patient — our method is designed to facilitate early diagnosis of the disease and to track the effectiveness of treatment,” says KTU researcher Maskeliūnas.
According to him, the link between Parkinson’s disease and speech abnormalities is not new to the world of digital signal analysis — it has been known and researched since the 1960s. However, as technology advances, it is becoming possible to extract more information from speech.
In their study, the researchers used artificial intelligence (AI) to analyse and assess speech signals, where calculations are done and diagnoses made in seconds rather than hours. This study is also unique — the results are tailored to the specifics of the Lithuanian language, in this way expanding the AI language database.
The algorithm will become a mobile app in the future
Speaking about the progress of the study, Kipras Pribuišis, lecturer at the Department of Ear, Nose, and Throat at the LSMU Faculty of Medicine, emphasises that it was only carried out on patients already diagnosed with Parkinson’s: “So far, our approach is able to distinguish Parkinson’s from healthy people using a speech sample. This algorithm is also more accurate than previously proposed.”
In a soundproof booth, a microphone was used to record the speech of healthy and Parkinson’s patients, and an artificial intelligence algorithm “learned” to perform signal processing by evaluating these recordings. The researchers highlight that the algorithm does not require powerful hardware and could be transferred to a mobile app in the future.
“Our results, which have already been published, have a very high scientific potential. Sure, there is still a long and challenging way to go before it can be applied in everyday clinical practice,” says Maskeliūnas.
According to the researcher, the next steps include increasing the number of patients to gather more data and determining whether the proposed algorithm is superior to alternative methods used for early diagnosis of Parkinson’s. In addition, it will be necessary to check whether the algorithm works well not only in laboratory-like environments but also in the doctor’s office or in the patient’s home.

A camera-trap study of two ecosystems — one with pumas and one without — adds to scientists’ understanding of the many ways apex predators influence the abundance, diversity and habits of other animals, including smaller carnivores.
Reported in the journal Ecosphere, the study followed multiple members of the order Carnivora, looking at how the largest carnivore in each locale influenced the behavior and presence of other animals in the same vicinity.
“Nobody’s really looked at how the whole carnivore community changes when you lose that top predator,” said Alex Avrin, who led the research as an M.S. student at the University of Illinois Urbana-Champaign with Max Allen, a research scientist at the Illinois Natural History Survey and professor of natural resources and environmental sciences at the U. of I. Avrin is now a scientist with the California Fish and Wildlife Service.
Previous studies have shown that pumas tend to suppress populations of medium-sized carnivores like coyotes, which do their best to avoid pumas, Avrin said. Reduced coyote populations allow other medium-sized carnivores to flourish. This has a cascading effect on many other species.
Pumas also leave behind a lot of carrion, allowing a host of scavengers — from microbes to birds and other animals — to feast on the remains that the pumas don’t consume, Avrin said. Coyotes tend to target smaller species and eat most of what they kill, leaving less behind for other creatures.
The researchers wanted to compare the dynamics of ecosystems with and without pumas.

“We specifically wanted to look at whether, in the absence of pumas, coyotes step up and fill that role of the apex predator,” she said.
Over several weekslong or monthslong sessions between 2011 and 2019, the researchers deployed grids of motion-activated cameras in various locales in the southern Santa Cruz Mountains of California and across the vast military installation of Fort Hood, Texas. The Santa Cruz site has a healthy population of pumas as well as bobcats, gray foxes, raccoons, striped skunks and coyotes. Fort Hood has those same carnivorous mammals except pumas. It also hosts the eastern spotted skunk and the ringtail, a member of the raccoon family. All of these species were included in the new analysis.
“We used the photos to get an idea of which species were at each site, what areas they were using and how frequently we detected them,” Avrin said. “And we used a couple of different measures to look at how the smaller carnivores behaved around both the pumas and coyotes.”
The two locales were similar enough to make these comparisons, “but of course climate, human land use and other variables differed between the sites,” she said.
As expected, the analysis revealed that wherever pumas were present, coyotes were rarely seen. While other carnivores also appeared to avoid pumas, they were much more likely to be detected by the same camera traps as pumas — just at different times. Even bobcats and gray foxes used areas frequented by pumas more often than the researchers expected.

In Fort Hood, where pumas were absent, coyotes had a different effect on the other carnivores.
“If coyotes were filling that same apex role that pumas do, we would expect them to suppress bobcats — their next largest competitor — releasing the smaller carnivores,” Avrin said. “And what we found is that they really just suppressed everything — bobcats and the other carnivores.”
The coyotes appeared to exert less of a suppressive effect on the other carnivores than the pumas had on coyotes, she said.
“This is a correlational study, so we can’t say definitively that the absence of pumas caused these other effects,” she said. But the study strongly suggests that coyotes do not replace the apex predator in an ecosystem that lacks pumas.
“So yes, when you lose an apex predator, pretty much your whole ecosystem is going to change,” Avrin said.
“In the absence of pumas, you’ll likely have more intensive grazing by deer, especially in areas near water, which can affect stream flows and other species,” she said. “Coyotes, because they can’t control those bigger prey populations the same way, don’t have the same effect. They likely end up suppressing smaller prey populations, which then changes things in a different way.”
“This study gives us a fuller picture of the changes that occur when an apex predator goes missing,” Allen said. “While many people think that smaller carnivores can move into the apex role, we see that mesocarnivores like coyotes don’t provide the same effects as a true apex predator. This highlights how important it is to keep each species in place for an intact ecological community.”
The National Science Foundation, the Gordon and Betty Moore Foundation, the U.S. Army Engineer Research and Development Center and the Illinois Natural History Survey supported this research. The INHS is a division of the Prairie Research Institute at the U. of I.

A protein that prepares DNA for replication also prevents the replication process from running out of control, according to a new study by Weill Cornell Medicine researchers. The work, published Jan. 5 in Molecular Cell, solves a mystery that has long puzzled biologists.
The cells of humans and all other higher organisms use a complex system of checkpoints and “licensing” proteins to ensure that they replicate their genomes precisely once before dividing. In preparation for cell division, the licensing proteins attach to specific regions in the DNA, designating them as replication origins. When the DNA synthesis phase of the cell cycle begins, replication begins only at those licensed sites, and only initiates, or “fires” once, according to the current model.
That model was missing a crucial point, though. “The same factor that is allowing for this licensing to happen is only degraded after these replication origins have fired,” said senior author Dr. Tobias Meyer, the Joseph Hinsey Professor in Cell and Developmental Biology at Weill Cornell Medicine. “In principle, the cell could load these licensing machines onto DNA that’s already replicated, so, instead of two copies, you’re getting three or four copies of that segment of the DNA, and these cells would be expected to lose genome integrity and die or become cancerous.”
Figuring out how cells avoid that fate has been tricky. “We needed to be studying events in the first minutes of the DNA synthesis phase of the cell cycle, so it’s a very transient period,” said first author Nalin Ratnayeke, a graduate student who worked on this project both at Stanford University and at Weill Cornell Medicine in Dr. Meyer’s lab. The lab moved to Weill Cornell Medicine in 2020. To solve this difficult experimental problem, Ratnayeke used computer-aided microscopy to monitor thousands of growing cells simultaneously, catching the replicating cells in the act and analyzing the activities of their licensing and replication factors.
The work revealed that a well-known licensing factor, CDT1, not only licenses a segment of DNA to become a replication origin, but also acts as a brake for DNA replication, preventing an essential replication enzyme called CMG helicase from functioning. To start synthesizing DNA, the cell’s enzymes must first break down CDT1. “Previously proposed mechanisms for coordinating this transition from the licensing phase of the cell cycle to the firing phase of the cell cycle have depended on inhibiting licensing factors,” said Ratnayeke, adding that “the mechanism that we identified here is actually the opposite … the licensing factor CDT1 itself is preventing the progression of DNA synthesis.”
To confirm their results, the scientists collaborated with colleagues at the Medical Research Council in Cambridge, UK, who found that the inhibitory mechanism can be recapitulated in a simplified system that reproduces the entire DNA synthesis process with purified components in a test tube. “That allowed us to reconstitute all the components for DNA synthesis, and to prove that CMG helicase is directly inhibited by CDT1,” said Dr. Meyer, who is also a professor of biochemistry and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
Because failures in replication licensing can kill cells or make them cancerous, the results provide a new understanding of cell health and disease. “Future work to identify mechanistically what’s going on with Cdt1 inhibition will give greater insight into the biophysics of how CMG helicase functions, and will pinpoint specific regions of this complex that can be targeted using drugs,” said Ratnayeke.

It’s clear that chronic stress can impact our behavior, leading to problems like depression, reduced interest in things that previously brought us pleasure, even PTSD.
Now scientists have evidence that a group of neurons in a bow-shaped portion of the brain become hyperactive after chronic exposure to stress. When these POMC neurons become super active, these sort of behavioral problems result and when scientists reduce their activity, it reduces the behaviors, they report in the journal Molecular Psychiatry.
Scientists at the Medical College of Georgia at Augusta University looked in the hypothalamus, key to functions like releasing hormones and regulating hunger, thirst, mood, sex drive and sleep, at a population of neurons called the proopiomelanocortin, or POMC, neurons, in response to 10 days of chronic, unpredictable stress. Chronic unpredictable stress is widely used to study the impact of stress exposure in animal models, and in this case that included things like restraint, prolonged wet bedding in a tilted cage and social isolation.
They found the stressors increased spontaneous firing of these POMC neurons in male and female mice, says corresponding author Xin-Yun Lu, MD, PhD, chair of the MCG Department of Neuroscience and Regenerative Medicine and Georgia Research Alliance Eminent Scholar in Translational Neuroscience.
When they directly activated the neurons, rather than letting stress increase their firing, it also resulted in the apparent inability to feel pleasure, called anhedonia, and behavioral despair, which is essentially depression. In humans, indicators of anhedonia might include no longer interacting with good friends and a loss of libido. In mice, their usual love for sugar water wains, and male mice, who normally like to sniff the urine of females when they are in heat, lose some of their interest as well.
Conversely when the MCG scientists inhibited the neurons’ firing, it reduced these types of stress-induced behavioral changes in both sexes.

The results indicate POMC neurons are “both necessary and sufficient” to increase susceptibility to stress, and their increased firing is a driver of resulting behavioral changes like depression. In fact, stress overtly decreased inhibitory inputs onto POMC neurons, Lu says.
The POMC neurons are in the arcuate nucleus, or ARC, of the hypothalamus, a bow-shaped brain region already thought to be important to how chronic stress affects behavior.
Occupying the same region is another population of neurons, called AgRP neurons, which are important for resilience to chronic stress and depression, Lu and her team reported in Molecular Psychiatry in early 2021.
In the face of chronic stress, Lu’s lab reported that AgRP activation goes down as behavioral changes like anhedonia occur, and that when they stimulated those neurons the behaviors diminished. Her team also wanted to know what chronic stress does to the POMC neurons.
AgRP neurons, better known for their role in us seeking food when we are hungry, are known to have a yin-yang relationship with POMC neurons: When AgRP activation goes up, for example, POMC activation goes down.

“If you stimulate AgRP neurons it can trigger immediate, robust feeding,” Lu says. Food deprivation also increases the firing of these neurons. It’s also known that when excited by hunger signals, AgRP neurons send direct messages to the POMC neurons to release the brake on feeding.
Their studies found that chronic stress disrupts the yin-yang balance between these two neuronal populations. Although AgRP’s projection to POMC neurons is clearly important for their firing activity, the intrinsic mechanism is probably the major mechanism underlying hyperactivity of POMC neurons by chronic stress, Lu says.
The intrinsic mechanism may include potassium channels in POMC neurons that are known to respond to a range of different signals, and when open, lead to potassium flowing out of the cell, which dampens neuronal excitation. While the potential role of these potassium channels in POMC neurons in response to stress needs study, the scientists suspect stress also affects the potassium channels and that opening those channels might be a possible targeted treatment to restrain the wildly firing POMC neurons.
Excessive activity of neurons is also known to produce seizures and there are anticonvulsants given to open potassium channels and decrease that excessive firing. There is even some early clinical evidence that these drugs might also be helpful in treating depression and anhedonia, and what the Lu lab is finding may help explain why.
Lu hasn’t looked yet, but she wants to further explore the role of these channels to better understand how stress affects them in POMC neurons and how best to target the channels if their findings continue to indicate they play a key role in exciting POMC neurons.
Chronic stress affects all body systems, according to the American Psychological Association. Even muscles tense to keep our guard up against injury and pain. Stress can cause shortness of breath, particularly in those with preexisting respiratory problems like asthma. Longer term, it can increase the risk for hypertension, heart attack and stroke, even alter the good bacteria in our gut that helps us digest food.
The research was funded by the National Institutes of Health.

In the course of optimising key procedures of genome editing, researchers from the department of Developmental Biology / Physiology at the Centre for Organismal Studies of Heidelberg University have succeeded in substantially improving the efficiency of molecular genetic methods such as CRISPR/Cas9 and related systems, and in broadening their areas of application. Together with colleagues from other disciplines, the life scientists fine-tuned these tools to enable, inter alia, effective genetic screening for modelling specific gene mutations. In addition, initially inaccessible DNA sequences can now be modified. According to Prof. Dr Joachim Wittbrodt, this opens up extensive new areas of work in basic research and, potentially, therapeutic application.
Genome editing means the deliberate altering of DNA with molecular genetic methods. It is used to breed plants and animals, but also in basic medical and biological research. The most common procedures include the “gene scissors” CRISPR/Cas9 and its variants known as base editors. In both cases, enzymes have to be transported into the nucleus of the target cell. Upon arrival, the CRISPR/Cas9 system cuts the DNA at specific sites, which causes a double strand break. New DNA segments can then be inserted at that site. Base editors use a similar molecular mechanism but they do not cut the DNA double strand. Instead, an enzyme coupled with the Cas9 protein performs a targeted exchange of nucleotides — the basic building blocks of the genome. In three successive studies, Prof. Wittbrodt’s team succeeded in considerably enhancing the efficiency and applicability of these methods.
A challenge when using CRISPR/Cas9 consists in the efficient delivery of the required Cas9 enzymes to the nucleus. “The cell has an elaborate ‘bouncer’ mechanism. It distinguishes between proteins that are allowed to translocate into the nucleus and those that are supposed to stay in the cytoplasm,” explains Dr Tinatini Tavhelidse-Suck from Prof. Wittbrodt’s team. Access is enabled here by a tag made up of a few amino acids that functions like an “admission ticket.” The scientists have now come up with a kind of generally valid “VIP admission ticket” which lets enzymes equipped with it into the nucleus very quickly. They have named it “high efficiency-tag,” “hei-tag” for short. “Other proteins that have to penetrate the cell nucleus are also more successful with ‘hei-tag’,” concludes Dr Thomas Thumberger, who is also a researcher at the Centre for Organismal Studies (COS). In cooperation with pharmacologists from Heidelberg University, the team could show that Cas9 in connection with the “hei-tag” ticket can enable highly efficient, targeted genome alterations not only in the model organism medaka, the Japanese ricefish (Oryzias latipes), but also in mammalian cell cultures and mouse embryos.
In a further study, the Heidelberg scientists showed that base editors operate highly efficiently in the living organism and are even suited to genetic screening. In an experiment with Japanese rice fish, they were able to show that these locally limited, targeted modifications in individual buildings blocks of the DNA achieve an outcome that is otherwise only obtained by the comparatively laborious breeding of organisms with altered genes. The research team at COS, in cooperation with Dr Dr Jakob Gierten, a paediatric cardiologist at Heidelberg University Hospital, focused on certain genetic mutations. These mutations were suspected of triggering congenital heart defects in humans. Through modifying individual building blocks of the DNA of the relevant genes in the model organism, the scientists were able to imitate and study fish embryos with the described heart defects. The targeted intervention led to visible changes in the heart already during early stages of fish embryonic development, say Bettina Welz and Dr Alex Cornean, two of the first authors of the study from Prof. Wittbrodt’s team. That enabled the researchers to confirm the original suspicion and establish a causal connection between genetic alteration and clinical symptoms.
The precise intervention in the genome of the fish embryos was made possible through especially developed software ACEofBASEs, which is available online. It allows for identifying genetic locations that very efficiently lead to desired changes in the target genes and the resultant proteins. The scientists say that the Japanese ricefish is an excellent genetic model organism for modelling mutations like those identified from the respective patients. “Our method enables an efficient screening analysis and could therefore offer a starting point for developing individualised medical treatment,” according to Jakob Gierten.
A third study, again from the Wittbrodt group, deals with the limitations of base editors. For such an editor to bind the DNA of a target cell, there has to be a certain sequence motif. It is called Protospacer Adjacent Motif, PAM for short. “If this motif is lacking near the DNA building block to be changed, it is impossible to exchange nucleotides,” explains Dr Thumberger. A team under his direction has now found a way to get around this limitation. Two base editors in a single cell are used in succession. In an initial step, a new DNA binding motif for a further base editor is generated, upon which this second editor, which is applied simultaneously, can edit a site that was inaccessible before. This staggered use turned out to be highly efficient, explains Kaisa Pakari, the first author of the study. With this trick, the Heidelberg scientists were able to increase the number of possible application sites of established base editors by 65 percent. Now DNA sequences that were initially inaccessible can also be modified.
“Optimising the existing tools for genome editing and their fine-tuned application results in enormously varied possibilities for basic research and, potentially, novel therapeutic approaches,” Joachim Wittbrodt underlines.
The research findings were published in the journals eLife and Development. The investigations were part of the research carried out in the “3D Matter Made to Order” Cluster of Excellence, which is run jointly by Heidelberg University and the Karlsruhe Institute of Technology. The research studies and scientists involved were funded by the European Research Council, the German Research Foundation, the German Centre for Cardiovascular Research, the German Heart Foundation, and the Joachim Herz Foundation.

Discovering new drugs has become increasingly rare for independent large pharmaceutical companies in recent times. Almost 60% of new drugs are discovered through mergers and acquisitions and drug licensing. Now, researchers from Ritsumeikan University, Japan, shed light on the recent trends of spinouts from academia and investments in the U.S.A and Europe, foreshadowing a promising shift in the industry’s interorganizational deal networks to improve research and development productivity in the future.
It is a challenging feat to launch a new drug in the market, given the low probability of success during the research and development (R&D) phase and the high costs involved. In recent times, industry trends in external innovation for drug discovery are rapidly changing. With an improved understanding of disease biology, decision-making can be more streamlined through the effective use of scientific information.
In this quest, researchers in Japan led by Associate Professor Kota Kodama of Ritsumeikan University are uncovering how the trends in interorganizational deals in the pharmaceutical industry are changing to improve R&D productivity and drug discovery. “The network structure of innovation creation in the pharmaceutical industry has changed with the increasing emergence of start-up companies spinning out from academia and research institutions as players in the source of innovation,” explains Dr. Kodama, while discussing their investigations into these changing trends, the results of which were made available online on 27 December 2022 and published in volume 28 issue 3 of the journal Drug Discovery Today on March 1, 2023.
Their research suggests that the knowledge necessary for breakthrough innovation in drug discovery is more often than not obtained through alliance networks. Over the past decade, large research-based pharmaceutical companies have used research collaborations, innovation incubators, academic centers of excellence, public-private partnerships, mergers and acquisitions (M&As), drug licensing, and corporate venture capital funds as typical methods for external innovation. The researchers now aim to define the changes in the network structure and nature of such alliances that have occurred over the past decade to provide future strategic insights for industry and academic players involved in drug discovery.
Using data from the Cortellis Competitive Intelligence database, the researchers identified nearly 50,000 deals of various kinds related to pharmaceutical R&D across pharmaceutical, digital health software, animal drug, and medical device companies to uncover trends in the creation of new drugs for human use. They also studied the trends of 13 of the largest pharmaceutical companies with annual revenues of more than US$10 billion, who saw an improvement in their CAGR (compound annual growth rate) since 2015. The researchers noticed that the rising CAGR correlated to a significant change in M&A-related deals after 2015, indicating that M&A-related deals drive revenue growth for large pharmaceutical companies.
Furthermore, the number of organizations involved in interorganizational deals has been increasing yearly from 2012 to 2021. Although the number of organizations involved and the number of deals may be increasing, the density of the deal networks is decreasing annually, suggesting that networks are becoming more non-cohesive. The concentration of business relationships between organizations of certain areas in the network changed to dispersion around 2015, and new networks connecting different groups started to form after 2017. These trends are an important illustration of how the industry landscape is gradually evolving away from the traditional network in which large pharmaceutical companies drove drug discovery output. Now, interorganizational deals among more diverse players have become active and are driving R&D productivity for startups in biotechnology and pharmaceuticals.
A clear increase in the number of academia-owned spinouts of advanced technology and expansion of investment in start-ups is a positive sign. The emergence of new chemical modalities, such as biologics, oligonucleotides, and peptides that differ from traditional small molecule drug discovery indicate remarkable changes that have taken place over the past two decades. The trend of increased financing for start-up companies in personalized drug development is beneficial for patent creation and will positively impact innovation creation in the coming years. “The presence of academia to support the technologies of these start-ups is becoming very important, and government and private support and investment in this area is boosting innovation. Our study shows that such medium- and long-term support may ultimately benefit the health and well-being of humankind,” concludes an optimistic Dr. Kodama.

It’s a good news, bad news story. Patients whose brain tumors have a mutated enzyme called IDH1 typically live longer than those without the mutation. But even as these tumors are initially less aggressive, they always come back. A key reason: The tumors are resistant to radiation treatment and are invasive.
In a new study, researchers at the University of Michigan Rogel Cancer Center uncovered a gene that is overexpressed in mutated IDH1. Studies in human cells and a novel mouse model both show that this gene, called ZMYND8, plays a critical role in the radiation resistance. When they knocked down the gene, the glioma cells became responsive to radiation treatment.
“These tumors almost always recur, and when they do, the tumors are much more aggressive. This finding gives us a new therapeutic avenue to treat these patients. It’s a very promising and novel therapeutic target,” said Maria G. Castro, Ph.D., R.C. Schneider Collegiate Professor of Neurosurgery at Michigan Medicine. Castro is senior author on the study, published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
The researchers used two cell cultures obtained from surgical biopsies of patients with mutated IDH1 glioma. Cells were treated with an inhibitor designed to block a metabolite produced by the mutated IDH1. From there, they screened the RNA and found a gene called ZMYND8.
“After treating with the mIDH1 inhibitor, we found this gene, ZMYND8, was significantly downregulated. It’s overexpressed in mutant IDH1 glioma cells, but when you treat the cells with an inhibitor, ZMYND8 protein expression goes down. And when this gene goes down, the cells become radiosensitive,” said study first author Stephen V. Carney, a Cancer Biology graduate student in the Castro/Lowenstein Lab.
ZMYND8 is known to be a regulator of DNA damage response. Radiation therapy works by damaging DNA. When ZMYND8 protein expression is high, researchers saw radiation resistance. When ZMYND8 was knocked out, the radiation led to DNA damage and increased glioma cell death.

The researchers also developed a new mouse model of mutated IDH1 glioma, which confirmed that knocking out ZMYND8 sensitized the tumors to radiation therapy, leading to increased survival.
“ZMYND8 contributes to the survival of mutant IDH1 glioma in response to radiation. Our study shows that we now have a new way of treating these tumors by using mRNA-based therapeutics in which we can downregulate the expression of ZMYND8 to render the cells radiosensitive,” said study author Pedro R. Lowenstein, M.D., Ph.D., Richard C. Schneider Collegiate Professor of Neurosurgery at Michigan Medicine.
The researchers also combined ZMYND8 knockdown with other cancer drugs, such as PARP and HDAC inhibitors. They found these other drugs synergized to make the cells more responsive to radiation, suggesting potential for combination therapy for patients with mutant IDH1 glioma.
More research is needed, but Castro envisions working with colleagues at the U-M Biointerfaces Institute to design RNA-based inhibitors to target ZMYND8, which could be delivered using nanoparticles specially designed to cross the challenging blood-brain barrier. It’s a technique they’ve already tested in previous research.
Additional authors:Kaushik Banerjee, Anzar Mujeeb, Brandon Zhu, Santiago Haase, Maria L. Varela, Padma Kadiyala, Claire E. Tronrud, Ziwen Zhu, Devarshi Mukherji, Preethi Gorla, Yilun Sun, Rebecca Tagett, Felipe J. Nunez, Maowu Luo, Weibo Luo, Mats Ljungman, Yayuan Liu, Ziyun Xia, Anna Schwendeman, Tingting Qin, Maureen A. Sartor, Joseph F. Costello, Daniel P. Cahill
Funding for this work is from National Institutes of Health grants R37-NS094804, R01-NS105556, R01-NS122536, R01-NS122165, R01-NS124167, R21-NS123879, R01-NS076991, R01-NS082311, R01-NS096756, R01-NS122234, R01-CA243916, T32-CA009676, PA18-906, the Pediatric Brain Tumor Foundation, Leah’s Happy Hearts Foundation, Ian’s Friends Foundation, Chad Tough Foundation, Smiles for Sophie Forever Foundation.
This work was supported by these Rogel Cancer Center Shared Resources: Cancer Data Science, Experimental Irradiation, Flow Cytometry, Preclinical Molecular Imaging, Single Cell Spatial Analysis, Tissue and Molecular Pathology.

In the age-old battle against mosquitoes, DEET has proven effective at keeping this nemesis at bay, but the repellent is smelly and its protection is short-lived. Now, researchers report in ACS’ Journal of Agricultural and Food Chemistry that they have designed safe alternatives that have some advantages over DEET, including a nice smell and much longer protection from bites.
DEET disrupts a mosquito’s ability to locate humans. Until recently, it was considered the gold standard among topical repellents, but some find its strong odor offensive. It has to be reapplied frequently, and at high concentrations, it can damage synthetic fabrics and plastics. Another popular repellent known as picaridin is now regarded as a better alternative, since its protective effect lasts longer, and it doesn’t have an odor or damage items. However, like DEET, it has to be reapplied after swimming or sweating.
So, Francesca Dani and colleagues wanted to look for alternatives to these established products. In prior work, the team used as starting materials two plant-based natural repellents that offered only short-term protection from mosquitoes. The researchers converted these terpenoids into cyclic acetals and hydroxyacetals, thereby extending their protective timespan beyond that of DEET. But the researchers wanted to improve on these initial products.
In the current work, the team synthesized additional cyclic hydroxyacetals from inexpensive, commercially available carbonyls. The new cyclic compounds had pleasant, much fainter odors and were easier to dissolve in water, meaning they can be formulated without high concentrations of alcohol. Some were as effective as DEET and picaridin at repelling Asian tiger mosquitoes, which have spread widely in the U.S. and carry diseases, including encephalitis, dengue and dog heartworm. And like picaridin, they provided human volunteers more than 95% protection from bites for at least eight hours, while DEET’s protection rapidly declined below that level after just two hours. Toxicity of some of the most active new compounds was comparable to or lower than the traditional repellents. Two hydroxyacetals were also less likely to cause immune reactions or to penetrate cell layers than picaridin. The researchers conclude that their compounds represent a new class of promising mosquito repellents that can compete favorably with DEET and picaridin in terms of efficacy and safety.

Suhellen Oliveira Da Silva was six months pregnant when she learned that the child she was carrying had the same disease that had left her firstborn son paralyzed and nearly mute. But this time, there was a treatment available that could make a profound difference. This baby could live a normal life.The problem was the price: The treatment cost the equivalent of $1.7 million, and the public health system in Brazil, where the family lives, was refusing to pay for it.So Ms. Da Silva went to court — and won. A judge ruled that the government had to buy the therapy for her younger son, Levi. Today, Levi, 2, chats and claps and crawls, all things his older brother Lorenzo, 10, has never been able to do.The treatment, called Zolgensma, a one-time infusion, is among the first in a new class of cutting-edge gene therapies that offer enormous promise for people with fatal or debilitating conditions — at hugely expensive prices. Its maker, the pharmaceutical company Novartis, has negotiated deals with national health systems and insurers to get the drug covered in many of the richest countries.Now, with its sales slowing, the company is pushing to get broad coverage in middle-income countries such as Brazil, where public health systems are often fragile and underfunded.Zolgensma, which treats a rare genetic disorder known as spinal muscular atrophy, or S.M.A., was for a time the world’s most expensive treatment. It has become a closely watched test of whether such therapies can win broad coverage around the globe, and what the trade-offs might be.Brazil’s experience with Zolgensma shows the challenges that the breathtaking prices of these therapies will pose for governments and insurers with limited budgets. Those challenges are poised to multiply in the next few years as more such treatments become available for larger groups of patients.After more than 100 successful lawsuits from families forcing the Brazilian public health system to pay for the treatment for their children, the government announced in December that it would begin covering Zolgensma by default for infants with the most severe cases of S.M.A. later this year.The government has agreed to pay the equivalent of about $1 million for each treatment — much less than what some other governments are paying, but still a staggering sum for Brazil’s strained health system.After his mother won access to Zolgensma in the courts, Levi received the therapy and can now chat, clap and crawl, all things Lorenzo has never been able to do.Levi, right, put a toy in his brother’s hand. While Levi has not met all of the normal developmental milestones of a child his age, he is mobile and talkative. At a government hearing on the coverage issue, a congresswoman, Adriana Ventura, expressed sympathy for the families seeking the treatment, but said, “We also cannot be irresponsible and approve something that is not sustainable in the long term.” She added the concern is that “in order to give to one, you have to take the basics from millions of others.”The expenditures for Zolgensma have already gobbled up a hugely disproportionate share of resources. An analysis led by a researcher at Brazil’s drug regulator found that the court-ordered expenditures in Zolgensma’s first 14 months of availability in Brazil could have paid for more than four million doses of the Covid-19 vaccine.Over the past decade, wealthy countries have devoted a growing share of their pharmaceutical budgets to paying for expensive drugs that treat a tiny fraction of their citizens. Their spending on so-called specialty drugs, which treat rare and often serious diseases and can come with enormous price tags, now represents about half of their drug expenditures. And it is expected to keep growing.“The situation simply isn’t sustainable,” said Ruth Lopert, a health economist at George Washington University. “Countries simply aren’t going to be able to afford these products, at the prices that are being asked.”Among the most unaffordable are gene therapies such as Zolgensma that promise to transform inherited disorders with a one-time treatment. Zolgensma’s list price of $2.1 million in the United States in 2019, believed to be the highest ever when it was set, has since been surpassed four times, and many more treatments expected to be as expensive are on the horizon.“This is the long hoped-for wave of innovation that will help address some life-threatening and fatal conditions,” said Dr. Steven Pearson, president of the Institute for Clinical and Economic Review, which assesses the value of medicines. “But if it comes all at once and the payments can’t be stretched out, it will have a crushing effect.”Wealthy countries have already been grappling with paying for the new therapies.In Europe, a product approved for a deadly neurological disorder known as metachromatic leukodystrophy was given list prices of up to $3.9 million. Germany’s health system last year agreed to pay for it at a discounted $2.6 million.Recife, Brazil. After families filed more than 100 lawsuits over the payment of the drug, the government announced it would begin covering Zolgensma for eligible infants this year.A delivery of oxygen for Lorenzo to Ms. Da Silva’s home.In the United States, the biotechnology company Bluebird Bio last year set price tags of $2.8 million when it won approvals to treat an inherited blood disorder called beta thalassemia and $3 million to treat a fatal neurological condition known as cerebral adrenoleukodystrophy. When European health systems previously refused to pay what Bluebird was asking for the products, the company withdrew them from the continent.While there are more than six million people worldwide with sickle cell, most of whom living in sub-Saharan Africa, the initial launches are expected to focus on tens of thousands of patients in the United States and Europe.Record-setting price tags for gene therapies have largely escaped the criticism that has followed other industry pricing decisions. The sentiment reflects just how powerful many of the gene therapies are — doctors sometimes go as far as to call them cures — and their unique position as one-time treatments. Such a therapy has just one chance to earn money, and in some cases can replace chronic treatments that would otherwise be given for the rest of a patient’s life at a much higher cumulative cost.Still, for middle-income countries, “if benefits of these therapies are immediate in terms of health but the potential savings happen in the future, that math may not work for them,” said Rena Conti, a health economist at the Questrom School of Business at Boston University.Tay Salimullah, a Novartis executive, said the company works closely with governments and health plans considering whether to cover Zolgensma, in some cases allowing them to spread out their payments over time, like a mortgage, or offering a price cut if the treatment doesn’t work.In Brazil, the agreement with Novartis calls for the government to split payments for each treatment into five equal parts over four years. If a patient dies, must be permanently ventilated or is unable to maintain certain motor functions two years after receiving Zolgensma, the government will not be required to make the subsequent payments.‘This Kid Has a Future’Until six years ago, there were no approved treatments for S.M.A., which affects about one in 10,000 newborns. Infants with the most severe form of the disorder were sent home and their families were told to prepare for them to die.Zolgensma and two other drugs approved since 2016 have opened up once unimaginable possibilities for S.M.A. patients. “I’m telling parents to keep putting money in their college fund because this kid has a future,” said Dr. Thomas Crawford, who treats S.M.A. patients at Johns Hopkins Medicine.Zolgensma works by replacing the missing or nonfunctioning gene causing S.M.A. with a working copy of the gene. It has been given to more than 2,500 children and approved for use in 46 countries. Novartis says more than 35 of those countries have “access pathways” in place.Studies show Zolgensma can stop infants and toddlers from continuing to lose nerve cells that control muscle movement, preventing further decline, but it cannot restore motor or muscle function that older children have already lost.A nurse helped Levi with his physical therapy at home. Studies show Zolgensma can prevent further decline, but cannot restore motor or muscle function that has already been lost.Levi’s weekly therapies were sketched out on a board at home.If Zolgensma is given soon after birth, children may develop no significant disabilities. Children who receive the drug when they are a little older may avoid a feeding or breathing tube, and may be capable of some movement, rather than a life spent immobile like Lorenzo.Patients have in most cases been able to access Zolgensma without issue in the United States, Britain and Canada, according to doctors and patient groups there. But several American parents and their attorneys described monthslong delays when health plans temporarily balked, during which children started showing signs of S.M.A. as they waited for treatment.In Brazil, where more than half the population relies on the public health system, families seeking Zolgensma for their children tried to raise funds through crowdfunding websites or obtain it without charge through a clinical trial.But most often, they turned to the courts. As of November, judges had forced the Brazilian health system to pay for 102 Zolgensma treatments at an average cost equivalent to $1.6 million, according to the Ministry of Health.A Right to HealthMs. Da Silva had never heard of S.M.A. when Lorenzo was diagnosed at 6 months old, in 2013. He had been developing normally, and then his progress suddenly stopped. Doctors said there was nothing to be done.When Ms. Da Silva learned in 2019 she was unexpectedly pregnant with Levi, doctors said he might never have disabilities from S.M.A. if she could get Zolgensma for him soon after he was born.The family had been struggling to make ends meet. Ms. Da Silva had quit her job as a travel agent in order to fight for full-time home care and therapies for Lorenzo; her husband, Azen Balbino, had spells of unemployment in Brazil’s recession. They knew they would need to rely on a process Brazilians call judicilizacão, in which they effectively sue the federal government by invoking the constitutionally protected right to health to force the public system to pay for a medication or therapy that it would not otherwise provide.While Ms. Da Silva was still pregnant, she enlisted the help of Viviane Guimarães, a lawyer in her northern Brazilian city of Recife who agreed to take her case. (Lawyers in such court battles typically do not charge the S.M.A. families they represent. When the government loses a case, it can be ordered to pay a fee to the successful family’s lawyer, but that payment is withheld when the government appeals a decision, as has happened with Levi’s case.)Levi, right, receives daily occupational and physical therapy and continues to progress in physical development. It’s unclear how much damage the disease has already done in spite of the treatments he has received.A home-care nurse picked out vitamins for Lorenzo from a drawer of medications and supplies.When Ms. Guimarães stood before the judge to make the case for a therapy with a huge cost, she argued that it would save the government money compared with other drugs Levi would need to take for life and with the cost of all the care he would need without it.Lorenzo receives three kinds of therapy every day. He watches cartoons while a physiotherapist makes a twice-daily visit to pummel on his chest and suction the secretions that would otherwise suffocate him. He communicates with Ms. Da Silva through a breathy whisper and by blinking and squinching the cheek he can still move. While this happens, Levi clambers over Lorenzo’s inert legs, singing along with the television and imperiously giving orders for things such as Popsicles and cookies to the health aide, one of three who take shifts to stand by Lorenzo’s bed 24 hours a day.While Levi has not met all of the normal developmental milestones of a child his age, he is mobile and talkative. He has daily occupational and physical therapy and continues to progress in physical development.When Ms. Guimarães won a favorable judgment in Levi’s court battle, the federal government had to set aside the money to purchase Zolgensma. Ms. Da Silva dashed to the bank to get the money sent by wire transfer to a Novartis account in Ireland, triggering the shipment of the medication. She and her husband rushed to São Paulo with Levi to be on standby at a hospital willing to do the infusion. He received the tiny vial of 47.8 milliliters of Zolgensma at 16 months old. Every time she sees her two boys together, Ms. Da Silva is reminded of the stunning power of Zolgensma. Her happiest moments, she said, come when she’s with Levi and he reaches up, pushes on her cheeks to get her attention and demands, “Mamãe, Mamãe” like any other toddler.“Levi speaks like a child who doesn’t have S.M.A.,” she said. Few Resources to SpareNovartis has so far brought in $3.7 billion in revenue from Zolgensma, charging different prices in different places based on its agreements with health systems and insurers. The company said it determines its local prices based on factors including a country’s gross domestic product.Countries have negotiated lower prices than the $2.1 million price tag that captured headlines. South Korea, for example, won’t pay more than the equivalent of $1.5 million per patient.The treatment is one of Novartis’s top sellers, but it has not become a mega-blockbuster in part because so few patients are eligible for it. And sales have begun to slow.Middle-income countries like Brazil could open the door to many more patients.The rented home on the outskirts of Recife where Ms. Da Silva and her family lived last year.One of Lorenzo’s action figures sat on a shelf in his room.Novartis has already won coverage for Zolgensma in Russia, Egypt and, most recently, Argentina, where the government announced this month that it had agreed to pay $1.3 million per treatment.Novartis’s chief executive, Dr. Vas Narasimhan, last year named three middle-income countries — Brazil, Turkey and India — as key expansion markets for Zolgensma. The company remains in negotiations over access to the treatment in more than 10 countries, including Ecuador.In Brazil, the government has agreed to cover the treatment only for babies with the most severe form of S.M.A. who can breathe independently for at least most of the day. They must also be under 6 months old.Under the deal with Novartis, the Brazilian government has agreed to pay for Zolgensma for no more than 250 babies over the next two years. If demand is higher than that, Novartis will chip in with 40 free treatments. At most, assuming a steady pace of treatments, the government would spend the equivalent of about $50 million for this first group of children this year and a total of $200 million over the four years after that.In comparison, a Brazilian program known as the people’s drugstore had a budget last year equivalent to about $380 million to serve over 21 million people, providing free access to drugs used to treat conditions such as asthma, diabetes and high blood pressure. The government allocated another $430 million last year for its program for H.I.V. and other sexually transmitted infections.The public health system provides health care to more than half of the roughly 216 million people in Brazil. In rural areas of the country, health centers may have a single doctor. Clinics and hospitals in low-income areas lack basic supplies and technology more sophisticated than X-ray machines.“We’re talking about a super expensive medication. But when you go to the hospital, the nurse doesn’t even have a pair of latex gloves,” said Ms. Guimarães, the Da Silva family lawyer. “But people are going to have to get comfortable with the debate,” she added, “because there are going to be many more therapies like this.”Lis Moriconi