16 May 2022

Sunday reading (15.05)

Review of scientific periodicals for May 2-15

Ekaterina Petrova, PCR.news

Genome Editing

1. Scientists have described the molecular relationship of genetic mutations with autism spectrum disorders (ASD) and edited the genome of mutant brain organoids. Some neurological and psychiatric diseases, including ASD and schizophrenia, are associated with mutations in the TCF4 gene, which encodes transcription factor 4. One of these ASD is Pitt—Hopkins syndrome. To identify neural abnormalities in this syndrome, scientists from Brazil and the USA have grown brain organoids from patients' epithelial cells. The donor cells were first turned into stem cells, and then three-dimensional structures were obtained from them.

Mutant organoids were significantly smaller than normal ones, neurons in them developed worse and were less excitable, the formation of neural networks was disrupted. Experiments have shown that the TCF4 mutation associated with loss of function leads to dysregulation of the SOX genes and the Wnt pathway — two important molecular signals that ensure the reproduction of stem cells, their maturation into neurons and migration to the right part of the brain. According to the authors, it is the breakdowns in this signaling that contribute to the impairment of cognitive and motor functions in patients with a mutation in the TCF4 gene.

The team tried to use genetic manipulation to correct the expression of TCF4 in brain organoids. The scientists tested two approaches: the recently described CRISPR-based transepigenetic strategy and virus-mediated overexpression of an additional copy of the TCF4 gene under the control of TCF4 binding motifs. Both methods increased TCF4 levels, while the phenotypes of Pitt—Hopkins syndrome recovered to normal at molecular, cellular and electrophysiological levels.


2. Seagrasses form lush green meadows in many coastal areas around the world. These meadows serve as one of the most efficient carbon dioxide sinks on Earth: one square kilometer of algae stores almost twice as much carbon as forests on land. Scientists from the Max Planck Institute of Marine Microbiology and other scientific centers have found out that algae accumulate carbon in the form of sugar in their rhizosphere. The sea grass Posidonia oceanica releases a lot of sucrose and other sugars into the rhizosphere. The authors of the study suggest that the rhizosphere of algae around the world contains from 0.6 to 1.3 million tons of sugar — about the same as in 32 billion cans of Coca-Cola. Algae also secrete phenolic compounds into the soil, which in conditions of lack of oxygen inhibit the consumption of sucrose by microorganisms. "If the sucrose in the seaweed rhizosphere were degraded by microbes, at least 1.54 million tons of carbon dioxide would be released into the atmosphere," says the head of the research group, Manuel Liebeke.

3. Bats imitate the buzzing of bees to scare off predators. The authors of the study, published in Current Biology, noticed that large moths (Myotis myotis) begin to buzz when they are picked up. The buzzing sounded like bees. Scientists decided to find out why this is necessary and whether other animals notice this similarity. They compared the buzzing sounds of the common hornet (Vespa crabro) and honeybee (Apis mellifera) with the alarm sound made by bats. At most frequencies, the sounds of insects differed from the sound of large moths. Then scientists compared only those frequencies that owls can hear — the main enemies of bats. They found the similarity of sounds and assumed that this is what the moths are counting on. To test the hypothesis, scientists played the noise of bats and the buzzing of hornets to owls living in captivity. The owls reacted to the sounds of mice with the interest characteristic of a predator looking for prey. But the sounds of hornets frightened them and forced them to move away from the speakers. And when the birds were included in the recording of the "buzzing" of bats, they behaved the same way as when they heard insects. It turned out that owls are also confused by the mouse buzzing. This is the first documented case of mammalian mimicry under an insect.

4. The pink pigeon, endemic to the island of Mauritius, was endangered, but thanks to the efforts of scientists and nature conservation funds, its population increased. According to the authors of the new study, the measures taken are not enough to save the pigeon from extinction in the future. In the 1970s and 1980s, the pink pigeon passed through a very narrow bottleneck, as a result of which the gene pool of the population lost many variations, and the frequency of harmful mutations increased. In the second half of the 1980s, only 12 individuals remained in the wild. The demographic rescue program, which was carried out in 1970-2010, allowed to restore the population to 400-480 individuals, but the genetic diversity of the population remained very low. Scientists analyzed the genomes of pink pigeons living in nature and in zoos in Europe and the United States, and conducted computer simulations using the SLiM program to understand which strategy should be followed. It turned out that the pink pigeon carries a high genetic load — 15 lethal equivalents. If no measures are taken to preserve the species, then it can disappear in the wild within 100 years. The authors propose a "genetic rescue" plan — to release birds raised in zoos into the wild in order to reduce the level of inbreeding.


5. A team led by scientists from Massachusetts General Hospital (MGH) She discovered that cerebrospinal fluid (CSF) can exit the brain into the bone marrow of the skull through tiny channels. The scientists injected fluorescent indicators into the large cistern of the mice's brain and traced their migration through the perivascular spaces of the dural blood vessels, and then through hundreds of submillimeter channels of the skull into the bone marrow of the cranial vault. When scientists infected mice with bacteria that cause meningitis, the infection began to circulate in the cerebrospinal fluid. An hour after the injection of bacteria into the brain, almost all the stem cells of the bone marrow of the skull were labeled with the corresponding antibody. At the same time, there were no antibody-labeled cells in the peripheral bone marrow.

Small channels in the skull were described by the same group of scientists in 2018. Then the team found out that through them immune cells from the bone marrow can penetrate into the cerebrospinal fluid. A new study has shown that the movement of cerebrospinal fluid through these channels is also possible. So the nervous system can interact with the immune system, bypassing the blood-brain barrier. There are similar channels in the human skull, too.

6. The cerebrospinal fluid of young mice can improve the memory of older mice. The authors of a study published this week in Nature created a memory for aging mice: 20-month-old mice were electrocuted three times. There were several flashes of light and sound signals at the same time, so that the connection between the stimuli was felt. The researchers then injected the cerebrospinal fluid of 10-week—old mice into the brains of eight individuals, and an artificial cerebrospinal fluid into a control group of ten individuals. Three weeks later, the mice were reminded of the electric shock with the same sounds and light. Mice injected with a "young" liquor recalled the shock and froze in 40% of cases. In the control group, only 18% of the mice remembered the fear they had experienced. Next, the researchers studied the hippocampus of old mice — the part of the brain responsible for memory. It turned out that the cerebrospinal fluid promotes the synthesis of oligodendrocytes and their precursors — cells that provide myelination of axons, which improves nerve conduction. Scientists have found out that a specific cerebrospinal fluid protein, fibroblast growth factor Fgf17, is responsible for restoring oligodendrogenesis and memory. When the mice were injected with an antibody blocking Fgf17, their memory deteriorated.

Chronic pain

7. Patients with chronic pain often have concomitant psychological disorders or diseases: trauma, post-traumatic stress, depression. The authors of the study, published in Frontiers in Pain Research, studied the brains of 57 veterans with chronic back pain and psychological trauma. The intensity of pain and severity of injury in the group varied greatly. Using brain MRI, the researchers determined the strength of the connections between the areas of the brain associated with pain and injury. They then used a statistical method to group veterans based on the signatures of their brain connections, regardless of the level of pain and injury. Based on brain activity, the computer program automatically divided veterans into three groups: with low, medium or high levels of symptoms. The researchers suggested that the brain connectivity scheme found in the low-symptom group allows veterans to avoid some of the emotional consequences of pain and trauma, and also includes natural pain reduction opportunities. Conversely, the group with high symptoms demonstrated patterns of brain connections that may have increased their chances of anxiety and catastrophization when experiencing pain. Interestingly, the division proposed by the computer partially coincided with the subjective assessment of the veterans themselves. However, subjective feelings in this study would not allow us to distinguish between groups with low and medium levels of pain. According to the authors, the neurobiological assessment gives an idea of how these people will respond to brain stimulation and psychopharmacological effects.

8. An acute inflammatory reaction protects against the development of chronic pain, and prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) can harm. Many people are used to treating pain with anti-inflammatory drugs, but the authors of the work published in Science Translational Medicine doubt that this is correct. As part of the new study, they conducted a transcriptomic analysis of peripheral immune cells from 98 patients with acute lower back pain, who were followed for three months. Scientists have found thousands of dynamic transcriptomic changes in patients whose pain has passed in three months. At the same time, there were no such changes in the cells of participants with chronic pain. It turned out that neutrophil-mediated inflammation protects against the transition of pain from acute to chronic.

In rodent experiments, treatment with anti-inflammatory drugs led to the development of chronic pain. This effect could be reversed by the introduction of neutrophils. Three analgesics without anti-inflammatory properties (gabapentin, morphine and lidocaine) had a short-term analgesic effect, but did not affect the overall duration of the pain episode. Analysis of clinical data of people from the UK Biobank cohort showed that the use of NSAIDs, but not other analgesics, is associated with an increased risk of persistent pain. Thus, the treatment of acute pain with anti-inflammatory drugs can be counterproductive and even harmful, despite the analgesic effect at first.


9. A proline-rich diet is associated with the development of depression. Researchers from Spain asked a cohort of 116 people to fill out a questionnaire to assess the level of depression, and also measured the type and amount of amino acids in their diet. Proline correlated with symptoms of depression, but not in everyone. Then scientists measured the concentration of proline in plasma, and it turned out that in people without depression its concentration is low. It's all about gut bacteria: the microbiota of patients with high proline intake but low plasma proline levels was similar to the microbiota of people with low levels of depression. It was enriched with bacterial genes involved in the transport and metabolism of proline. That is, the better the bacteria utilize proline, the less likely depression is. The participants' microbiota was then transplanted into mice. Rodents who received the microbiota of depressed people with high plasma proline levels developed symptoms of depression. The transplantation also caused changes in the amino acid transport genes in the brain. Then the authors conducted an experiment with fruit flies Drosophila melanogaster, which can cause a depressive mood. The researchers isolated two types of bacteria associated with proline consumption and added them to sterilized fly food. Flies that consumed food with Lactobacillus were less depressed. But the Enterobacter in the feed made the flies more depressed. In flies with a genome modified in such a way that proline could not reach the brain, depression did not develop. The study may help in the search for new diet-based treatments for depression.


10. Stem cells can protect against the side effects of anti-cancer drugs. Immune checkpoint inhibitors are effective in various types of cancer, but patients may develop type 1 diabetes during treatment. Researchers from Osaka University have found in experiments on mice that stem cell therapy can protect against such a side effect. They gave mice a monoclonal antibody against PD-L1 and divided them into two groups — one was injected into the tail vein with mesenchymal stem cells from human adipose tissue, the second was left without therapy as a control. In the control group, 16 out of 25 rodents developed diabetes. In the stem cell group, the incidence was reduced — diabetes developed in four out of 21 animals. Stem cells significantly reduced the accumulation of CXCL9-expressing macrophage T cells in pancreatic islets. The level of insulin increased almost twice, and the area of beta cells in the islets increased 2.7 times. Such cell therapy may be tested in clinical trials in the future. 

11. Sodium selenate can slow down the development of a behavioral variant of frontotemporal dementia - the second most common dementia in people under 60 years of age. Currently, there is no treatment for this disease. The average survival rate is 5-7 years from the moment of diagnosis. In almost half of cases of frontotemporal dementia, damage to neurons in the brain is caused by the accumulation of tau protein. Sodium selenate activates an enzyme in the brain that breaks down tau protein. Scientists from Australia conducted a study involving 12 patients with frontotemporal dementia aged 48 to 71 years. Participants took sodium selenate for 52 weeks: first 10 mg three times a day, and from the fourth week — 15 mg. First of all, the scientists evaluated safety, additionally conducted behavioral and cognitive tests, MRI and analysis of cerebrospinal fluid and blood for tau protein. The drug proved to be safe and was normally tolerated by patients for 12 months or more. Side effects — nail changes and alopecia — were mild and were observed in half of the participants. They had to reduce the single dose to 10 mg. Other side effects included headaches and muscle aches, fatigue, and diarrhea. During the course of treatment, patients experienced a slight deterioration in MRI, cognitive and behavioral indicators. Tau protein levels have not changed. The effectiveness was tested for 11 patients: four of them had neurodegeneration and cognitive and behavioral indicators worsened, seven people had no noticeable changes. The authors emphasize that it is impossible to talk about the effectiveness of treatment without a control group, and believe that it is worth conducting randomized controlled clinical trials of the drug.


12. A genetic analysis conducted by scientists from Australia and the International Consortium for the Genetics of Pain has found blood proteins that cause migraines and are associated with Alzheimer's disease. The study is published in Nature Communications. The authors used summary statistics of genome-wide association search to study the relationship between blood proteins and migraine. 325 blood proteins were included in the analysis. It turned out that people with migraine have elevated levels of DKK1 and PDGFB proteins in their blood and decreased levels of FARS2, GSTA4 and CHIC2. DKK1 and PDGFB proteins inhibit Wnt signaling pathways. This can lead to calcification of the brain and inflammation; as a result, pain occurs. Low levels of antioxidant blood proteins FARS2, GSTA4 and CHIC2 also contribute to migraine-related inflammation. Wnt signaling is also reduced in Alzheimer's disease. Professor Dale Nyholt, one of the authors of the work, believes that Wnt activators, which restore the Wnt/beta-catenin signaling pathway in the brain and are commonly used in Alzheimer's disease, may become new tools for migraine therapy.

Synthetic biology

13. Scientists have created semi—synthetic proteoglycans - this opens up more opportunities to study the functions of these molecules. Proteoglycan is a complex molecule based on a simple cow protein. This protein contains special sites to which any of the many molecular chains of glycosaminoglycans (GAG) bind. In the cell, the addition of GAG is catalyzed by enzymes. The authors of the new work have constructed proteoglycan core proteins that are almost identical to ordinary proteins, but contain special chemical switches that allow you to change the number, location and types of GAG chains that bind to them. With the help of synthetic proteoglycans, scientists were able to assess how both GAG chains and bark proteins affect the function of molecules. In particular, they used synthetic proteoglycans to study the role of proteoglycans in the differentiation of stem cells and the spread of breast cancer cells through the extracellular matrix.


14. Albert Einstein College of Medicine (USA) received a grant from the National Institutes of Health in the amount of $11 million for five years to combat post-traumatic epilepsy (PTE). Such epilepsy develops in about one in 50 people who have suffered a traumatic brain injury. It is characterized by recurrent seizures that begin a week or more after a traumatic brain injury. There is still no way to identify patients at risk of developing PTE or prevent its onset. As part of the grant, it is planned to search for new biomarkers that predict the risk of developing PTE, and to test new drugs.

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