But now Northwestern Medicine scientists report results of the first in-human clinical trial in which they used a novel, skull-implantable ultrasound device to open the blood-brain barrier and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously.

The four-minute procedure to open the blood-brain barrier is performed with the patient awake, and patients go home after a few hours. The results show the treatment is safe and well tolerated, with some patients getting up to six cycles of treatment.

This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on the concentrations of chemotherapy in the human brain. Opening the blood-brain barrier led to an approximately four- to six-fold increase in drug concentrations in the human brain, the results showed.

Scientists observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. The drugs are not used to treat these patients because they do not cross blood-brain barrier in normal circumstances.

In addition, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication, the scientists discovered. The findings will allow optimization of the sequence of drug delivery and ultrasound activation to maximize the drug penetration into the human brain, the authors said.

“This is potentially a huge advance for glioblastoma patients,” said lead investigator Dr. Adam Sonabend, an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurosurgeon.

Temozolomide, the current chemotherapy used for glioblastoma, does cross the blood-brain barrier, but is a weak drug, Sonabend said.

The paper will be published May 2 in The Lancet Oncology.

The blood-brain barrier is a microscopic structure that shields the brain from the vast majority of circulating drugs. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Patients with brain cancer cannot be treated with most drugs that are otherwise effective for cancer elsewhere in the body, as these do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathology and cancer require their delivery to the brain.

In the past, studies that injected paclitaxel directly into the brain of patients with these tumors observed promising signs of efficacy, but the direct injection was associated with toxicity such as brain irritation and meningitis, Sonabend said.

Blood-brain barrier recloses after an hour

The scientists discovered that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, and most of the blood-brain barrier integrity is restored within one hour after this procedure in humans.

“There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream,” Sonabend said.

Previous human studies showed that the blood-brain barrier is completely restored 24 hours after brain sonication, and based on some animal studies, the field assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window might be shorter.

In another first, the study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the blood-brain barrier in a volume of brain that is nine times larger than the initial device (a small single-ultrasound emitter implant). This is important because to be effective, this approach requires coverage of a large region of the brain adjacent to the cavity that remains in the brain after removal of glioblastoma tumors.

Clinical trial for patients with recurrent glioblastoma

The findings of the study are the basis for an ongoing phase 2 clinical trial the scientists are conducting for patients with recurrent glioblastoma. The objective of the trial — in which participants receive a combination of paclitaxel and carboplatin delivered to their brain with the ultrasound technique — is to investigate whether this treatment prolongs survival of these patients. A combination of these two drugs is used in other cancers, which is the basis for combining them in the phase 2 trial.

In the phase 1 clinical trial reported in this paper, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They started treatment within a few weeks after the implantation.

Scientists escalated the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets of patients, studies were performed during surgery to investigate the effect of this ultrasound device on drug concentrations. The blood-brain barrier was visualized and mapped in the operating room using a fluorescent die called fluorescein and by MRI obtained after ultrasound therapy.

“While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases,” Sonabend said.

Other Northwestern authors include: A. Gould, C. Amidei, R. Ward, K. A. Schmidt, D.Y. Zhang, C. Gomez, J.F. Bebawy, B.P. Liu, I.B. Helenowski, R.V. Lukas, K. Dixit, P. Kumthekar, V. A. Arrieta. Lesniak, H. Zhang and R. Stupp.

This work is funded by the grants 1R01CA245969-01A1 and P50CA221747 from the National Cancer Institute of the National Institutes of Health and SPORE support from the Moceri Family Foundation and the Panattoni family.

Hoarding disorder affects around 2% of the population but remains a largely misunderstood mental health condition. It was only added to the International Classification of Diseases in 2019, having previously been classified under Obsessive Compulsive Disorder (OCD).

Published in the British Journal of General Practice, the new guidance was written by Dr Sharon Morein and Dr Sanjiv Ahluwalia of Anglia Ruskin University (ARU) in Cambridge, England, to help health professionals spot the signs of hoarding disorder and intervene.

ARU experts have also organised a free conference on Wednesday, 10 May to provide the public with more information about the condition.

Hoarding disorder involves clutter in the home environment taking over living spaces, as well as excessive acquisition and difficulty discarding possessions, and affects an individual’s quality of life.

However, it typically comes to the fore only when patients seek support for other mental health or physical conditions and can then act as a barrier to treatment due to concerns about hygiene, safety, or access to the home.

People with hoarding disorder most commonly suffer from depression, while other comorbidities include Obsessive Compulsive Disorder (OCD), and Attention Deficit Hyperactivity Disorder (ADHD).

Dr Morein, an Associate Professor in Psychology at Anglia Ruskin University (ARU) and leader of the ARU Possessions and Hoarding Collective said: “Labels can be very useful in the healthcare system and can be the first stage for people receiving the support they need.

“It is really important that doctors and other frontline healthcare professionals are aware that hoarding disorder is a diagnosable medical condition and that it is usually linked to other issues so that proper support can be offered.

“Typically, hoarding disorder is something that sneaks up on people — it doesn’t happen overnight — and people don’t necessarily recognise they have a problem. One of the major difficulties with hoarding disorder is that sufferers often don’t seek help themselves, and it only presents itself to medical professionals alongside other issues. The sooner the problem is spotted, the sooner support can be provided.”

To help people understand more about hoarding disorder, the ARU Possessions and Hoarding Collective is hosting a free conference at ARU’s Cambridge campus on Wednesday, 10 May.

The event, which will feature expert speakers including Professor Nick Neave of Northumbria University, will explain more about the disorder and the latest support strategies, and is aimed at service providers who help people with hoarding as part of their role, those affected by the hoarding behaviour of others, as well as individuals who themselves are struggling with hoarding.

Dr Morein added: “The ARU Possessions and Hoarding Collective is a group of academics and professionals aiming to improve our understanding of how people interact with their possessions.

“As part of our work, we research how hoarding can affect individuals and their families, as well as how service provision is currently delivered, and how it can be improved. We are inviting all these groups to attend the event in Cambridge on 10 May as we aim to increase awareness and ultimately provide better support for all.”

In a study of mice, the researchers found that mutations in Foxp2 disrupt the formation of dendrites and neuronal synapses in the brain’s striatum, which plays important roles in the control of movement. Mice with these mutations also showed impairments in their ability to produce the high-frequency sounds that they use to communicate with other mice.

Those malfunctions arise because Foxp2 mutations prevent the proper assembly of motor proteins, which move molecules within cells, the researchers found.

“These mice have abnormal vocalizations, and in the striatum there are many cellular abnormalities,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and an author of the paper. “This was an exciting finding. Who would have thought that a speech problem might come from little motors inside cells?”

Fu-Chin Liu PhD ’91, a professor at National Yang Ming Chiao Tung University in Taiwan, is the senior author of the study, which appears today in the journal Brain. Liu and Graybiel also worked together on a 2016 study of the potential link between Foxp2 and autism spectrum disorder. The lead authors of the new Brain paper are Hsiao-Ying Kuo and Shih-Yun Chen of National Yang Ming Chiao Tung University.

Speech control

Children with Foxp2-associated apraxia tend to begin speaking later than other children, and their speech is often difficult to understand. The disorder is believed to arise from impairments in brain regions, such as the striatum, that control the movements of the lips, mouth, and tongue. Foxp2 is also expressed in the brains of songbirds such as zebra finches and is critical to those birds’ ability to learn songs.

Foxp2 encodes a transcription factor, meaning that it can control the expression of many other target genes. Many species express Foxp2, but humans have a special form of Foxp2. In a 2014 study, Graybiel and colleagues found evidence that the human form of Foxp2, when expressed in mice, allowed the mice to accelerate the switch from declarative to procedural types of learning.

In that study, the researchers showed that mice engineered to express the human version of Foxp2, which differs from the mouse version by only two DNA base pairs, were much better at learning mazes and performing other tasks that require turning repeated actions into behavioral routines. Mice with human-like Foxp2 also had longer dendrites — the slender extensions that help neurons form synapses — in the striatum, which is involved in habit formation as well as motor control.

In the new study, the researchers wanted to explore how the Foxp2 mutation that has been linked with apraxia affects speech production, using ultrasonic vocalizations in mice as a proxy for speech. Many rodents and other animals such as bats produce these vocalizations to communicate with each other.

While previous studies, including the work by Liu and Graybiel in 2016, had suggested that Foxp2 affects dendrite growth and synapse formation, the mechanism for how that occurs was not known. In the new study, led by Liu, the researchers investigated one proposed mechanism, which is that Foxp2 affects motor proteins.

One of these molecular motors is the dynein protein complex, a large cluster of proteins that is responsible for shuttling molecules along microtubule scaffolds within cells.

“All kinds of molecules get shunted around to different places in our cells, and that’s certainly true of neurons,” Graybiel says. “There’s an army of tiny molecules that move molecules around in the cytoplasm or put them into the membrane. In a neuron, they may send molecules from the cell body all the way down the axons.”

A delicate balance

The dynein complex is made up of several other proteins. The most important of these is a protein called dynactin1, which interacts with microtubules, enabling the dynein motor to move along microtubules. In the new study, the researchers found that dynactin1 is one of the major targets of the Foxp2 transcription factor.

The researchers focused on the striatum, one of the regions where Foxp2 is most often found, and showed that the mutated version of Foxp2 is unable to suppress dynactin1 production. Without that brake in place, cells generate too much dynactin1. This upsets the delicate balance of dynein-dynactin1, which prevents the dynein motor from moving along microtubules.

Those motors are needed to shuttle molecules that are necessary for dendrite growth and synapse formation on dendrites. With those molecules stranded in the cell body, neurons are unable to form synapses to generate the proper electrophysiological signals they need to make speech production possible.

Mice with the mutated version of Foxp2 had abnormal ultrasonic vocalizations, which typically have a frequency of around 22 to 50 kilohertz. The researchers showed that they could reverse these vocalization impairments and the deficits in the molecular motor activity, dendritic growth, and electrophysiological activity by turning down the gene that encodes dynactin1.

Mutations of Foxp2 can also contribute to autism spectrum disorders and Huntington’s disease, through mechanisms that Liu and Graybiel previously studied in their 2016 paper and that many other research groups are now exploring. Liu’s lab is also investigating the potential role of abnormal Foxp2 expression in the subthalamic nucleus of the brain as a possible factor in Parkinson’s disease.

The research was funded by the Ministry of Science and Technology of Taiwan, the Ministry of Education of Taiwan, the U.S. National Institute of Mental Health, the Saks Kavanaugh Foundation, the Kristin R. Pressman and Jessica J. Pourian ’13 Fund, and Stephen and Anne Kott.

Figure: GCK gene

Rasmus Hartmann-Petersen, Professor at the Department of Biology, explains:
– “The GCK gene, which codes for the enzyme glucokinase, regulates the secretion of insulin in the pancreas. GCK gene variants can therefore cause a form of hereditary diabetes. Although the connection between GCKand diabetes has been known for several years, we have, until now, only known the effect of a few percent of the possible variants of this gene”.

Together with colleagues at the PRISM centre, UCPH, who are currently studying the effects of genetic variations, the researchers measured the effect of all of the possible variants of GCK.

PhD student Sarah Gersing, who is the first author of the article, explains:
– “We used yeast cells to measure the activity of over 9000 different GCK variants. In this way, we were able to generate a list of the effects — both of already known variants, but also of variants that patients might carry, but that have not yet been discovered. This provides us with a reference for future GCK diagnostics”. 

Prof. Kresten Lindorff-Larsen, who heads the PRISM centre, continues:
– “Our results are quite unique; not only have we measured the effect of several thousand variants, but for many of the variants, we can now explain what they do to the glucokinase protein. In our centre, we have gathered researchers working across a range of research fields, bridging from data analysis and biophysics to cell biology and medicine, and it is now clear how this broad approach pays off in explaining how diseases arise”.

Gene variants of GCK can, among other things, cause a form of hereditary diabetes called “GCK maturity onset diabetes of the young” (GCK-MODY).

Professor of genetics, dr. med. Torben Hansen, who is also a member of the PRISM centre, says: – “Although GCK-MODY patients exhibit elevated blood glucose levels, this is often not associated with complications. Hence, unlike other forms of diabetes, most GCK-MODY patients might therefore not need to be treated with medication. However, due to missing or inaccurate genetic data, more than half of the GCK-MODY patients are classified with having either type 1 or type 2 diabetes – and are therefore unnecessarily medicated. We estimate that approx. 1% of those who have recently been diagnosed with type 2 diabetes in Denmark have a variant in the GCK gene, meaning that they don’t need treatment, or need to be treated differently. Our new map of GCK variants can hopefully help give these patients a more correct diagnosis.”

The next step for PRISM is to transfer these methods to other genes and diseases.
– “We are already well underway with genes involved in e.g., neurodegenerative diseases, and we are trying to develop precise methods that can provide us with insights on disease mechanisms”, says Rasmus Hartmann-Petersen.

 Kresten Lindorff-Larsen continues:
– “Our data gives us the opportunity to test and develop computational models for variant effects, which will then be transferable to other genes and diseases.”

– “Now, we have measured the effects of almost all variants of GCK, giving us knowledge on which variants that function, and which that do not. The next step is to understand why, and how the same underlying molecular mechanisms can give rise to a wide range of different diseases”, concludes Sarah Gersing.

A UCLA-led team of biologists wondered if those city-dwelling birds share common characteristics around the world that help them survive. In a paper published in Current Biology, they reveal the answer: Urban bird species tend to be smaller and less territorial and have greater ability to fly long distances. They also tend to have broader dietary and habitat niches, to lay more eggs at a time, to have longer lifespans and to live at a wider range of elevations than other species.

Several factors moderate the importance of those traits in how birds adapt to urban living, and the importance of those traits varies predictably across the planet.

The only trait that didn’t appear to be consistent globally among urban-dwelling birds, the resesarchers found, was the shape of their bills.

By 2030, the paper notes, the amount of urban land cover worldwide will have grown by 1.2 million square kilometers (or more than 463,000 square miles) since 2000 — roughly tripling over a 30-year period. That increase in urban space would be larger than the land area of California and Texas combined.

The authors write that a dramatic loss of biodiversity will accompany that urbanization unless there are practical plans to preserve it.

“Identifying traits that help wildlife adapt or even thrive in cities can help urban planners bolster biodiversity by, for example, increasing green spaces, planting more and taller trees, building more varied potential habitats, or reducing housing density,” said the paper’s lead author, Monte Neate-Clegg, a UCLA postdoctoral researcher. “It can also help conservation biologists to identify which types of species are most threatened by urbanization.”

Neate-Clegg and Morgan Tingley, a UCLA associate professor of ecology and evolutionary biology, combined data including records of more than 125 million individual bird sightings from the public science project eBird to calculate an “urban association index” that describes how closely each species is associated with living in urban settings.

They applied the measure to 3,768 bird species — around 35% of all bird species — in 137 cities across six continents.

The index takes into account factors like physical characteristics of the birds themselves and the geographic, population and landscape characteristics of the cities.

“Many of the most common urban birds globally are very familiar to us here in the U.S., including the house sparrow, barn swallow, osprey, and peregrine falcon,” Tingley said. “Although, interestingly, the species with the strongest associations with urban areas are actually three species of parakeet and a tanager from South America. Plus, of course, the feral pigeon.”

Interestingly, some of the species with the highest scores on the index — meaning that they were most closely associated with urban living — were not native to their regions, but such species made up less than 4% of the dataset, suggesting that invasive species might not have as big of an advantage as logic would suggest. Bird families with high average scores on the index — indicating that many species within that family were common in cities — included starlings, swifts, swallows, parrots, orioles and blackbirds.

Traits like smaller body size, lower territoriality, greater ability to fly longer distances — which scientists refer to as “dispersal ability” — broader dietary and habitat niches, larger clutch sizes, all tend to make it easier for city birds to find food and suitable nesting places, and to raise young that survive.

Bird species that generally build nests on the ground were not likely to live in cities, for fairly obvious reasons.

“In a city like Los Angeles, for example, the American crow is a cosmopolitan species whose broad diet, arboreal nesting habits and long lifespan favor life in the concrete jungle,” Neate-Clegg said. “In contrast, canyon wrens are highly territorial insectivores with low dispersal ability that shun cities and keep to steep, rocky terrain.”

But cities’ geographic properties — most notably their latitude — moderated the importance of those traits. For example, a broad diet was more important in temperate cities such as New York, while habitat generalists were more prevalent in tropical cities such as Bogotá, Colombia. The cities’ population sizes and surrounding terrain also played important roles: Anchorage, Alaska, with its small population and plentiful natural surroundings, is home to large birds like bald eagles that mostly feed on fish from rivers and lakes. Meanwhile, smaller birds that don’t require as much raw land and that can adapt to eating a variety of foods to survive would be more likely to inhabit sprawling, densely populated metropolises like Bangkok.

A joint research team led by Associate Professor Yan Xu of the Osaka Metropolitan University Graduate School of Engineering has succeeded in regulating the flow of single molecules in solution by opening and closing a nanovalve in a nanofluidic device by applying external pressure.

The research team fabricated a nanofluidic device with a thin, flexible glass sheet on the top, and a hard glass plate with small structures that forms nanochannels and nanovalve seats on the bottom. By applying external pressure to the flexible glass sheet to open and close the valve, they succeeded in directly manipulating and controlling the flow of individual molecules in solution. They also found that when they trapped single fluorescent molecules in the nanospace inside the valve, the fluorescence of the single molecules became brighter. This happened because the small space made it harder for the single molecules to move around randomly. Professor Xu said that “this effect of fluorescence signal amplification could help with detecting very small amounts of pathogens for early diagnosis of diseases such as cancers and Parkinson’s disease, without requiring expensive equipment.”

The findings of this study could be a significant step towards freely assembling materials using single molecules as building blocks in solution. This technology has the potential to be useful in various fields, such as developing personalized medicines for rare diseases and creating better displays and batteries. Its applications are limitless.

“We have been addressing various challenges by proposing and promoting the concept of ‘Single-Molecule Regulated Chemistry (SMRC),’ where molecules are treated as building blocks and all processes involved in chemical and biochemical reactions in solution are performed on a single-molecule basis. The single-molecule valve marks the first step towards the goal, which could one day revolutionize chemistry, biology, and materials science, as well as transform various industries,” said Professor Xu.