New Tool Combines Ultrasound, Genetics to Activate Deep Brain Neurons Neurological disorders such as Parkinson’s disease and epilepsy have had some treatment success with deep brain stimulation, but those require surgical device implantation. A multidisciplinary team at Washington University in St.
Using a mouse model, Chen and the team delivered a viral construct containing TRPV1 ion channels to genetically-selected neurons. Then, they delivered small burst of heat via low-intensity focused ultrasound to the select neurons in the brain via a wearable device. The heat, only a few degrees warmer than body temperature, activated the TRPV1 ion channel, which acted as a switch to turn the neurons on or off.
Neurological disorders such as Parkinson’s disease and epilepsy have had some treatment success with deep brain stimulation, but those require surgical device implantation. A multidisciplinary team at Washington University in St. Louis has developed a new brain stimulation technique using focused ultrasound that is able to turn specific types of neurons in the brain on and off and precisely control motor activity without surgical device implantation.
The team, led by Hong Chen, assistant professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine, is the first to provide direct evidence showing noninvasive, cell-type-specific activation of neurons in the brain of mammal by combining ultrasound-induced heating effect and genetics, which they have named sonothermogenetics. It is also the first work to show that the ultrasound-genetics combination can robustly control behavior by stimulating a specific target deep in the brain.
Results of the three years of research, which was funded in part by the National Institutes of Health’s BRAIN Initiative, were published online in Brain Stimulation May 11, 2021.
Since the onset of the CRISPR genetic editing revolution, scientists have been working to leverage the technology in the development of gene drives that target pathogen-spreading mosquitoes such as Anopheles and Aedes species, which spread malaria, dengue and other life-threatening diseases.
Much less genetic engineering has been devoted to Culex genus mosquitoes, which spread devastating afflictions stemming from West Nile virus—the leading cause of mosquito-borne disease in the continental United States—as well as other viruses such as the Japanese encephalitis virus (JEV) and the pathogen causing avian malaria, a threat to Hawaiian birds.
University of California San Diego scientists have now developed several genetic editing tools that help pave the way to an eventual gene drive designed to stop Culex mosquitoes from spreading disease. Gene drives are designed to spread modified genes, in this case those that disable the ability to transmit pathogens, throughout the targeted wild population.
Great new episode with guest Ben K.D. Pearce on how and why our own genetic code was able to form in Earth’s warm little ponds as early as 4.5 billion years ago. Please have a listen.
Guest Ben K.D. Pearce, a Ph.D student in astrophysics and astrobiology at McMaster University in Toronto, and an expert on the origins of life’s building blocks here on Earth. We discuss the idea that all the genetic components from which life emerged were incredibly readily available biogenically very early in Earth’s evolution. As early as 4.5 billion years ago. Pearce is part of a group making great strides in learning how this all may have happened in Earth’s very ancient warm little ponds.
More on thymus regeneration. Unless I understood wrong one patient’s epigenetic clock went from his mid 50’s to early 40’s.
Foresight Biotech & Health Extension Meeting sponsored by 100 Plus Capital.
2021 program & apply to join: https://foresight.org/biotech-health-extension-program/
Greg Fahy, Intervene Immune.
Thymus Rejuvenation Progress Update.
- Designed and led the TRIIM trial; Published the first report of thymus regeneration in a normal human; Granted patents on methods for and applications of human thymus regeneration.
- Fellow of the American Aging Association.
(since 2005), Former Director of the American Aging Association (16 years)
- Editor-in-Chief, The Future of Aging: Pathways to Human Life Extension.
- Awarded the Society for Cryobiology’s Luyet Medal in 2016.
- In 2009, showed indefinite survival of rabbit kidney transplanted after cooling to-130°Celsius; Led 21CM team as co-winner of Small Mammal Brain Preservation Prize, 2018 winner of Large Mammal Brain Preservation Prize.
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Circa 2016
Accumulated evidence from genetic animal models suggests that the brain, particularly the hypothalamus, has a key role in the homeostatic regulation of energy and glucose metabolism. The brain integrates multiple metabolic inputs from the periphery through nutrients, gut-derived satiety signals and adiposity-related hormones. The brain modulates various aspects of metabolism, such as food intake, energy expenditure, insulin secretion, hepatic glucose production and glucose/fatty acid metabolism in adipose tissue and skeletal muscle. Highly coordinated interactions between the brain and peripheral metabolic organs are critical for the maintenance of energy and glucose homeostasis. Defective crosstalk between the brain and peripheral organs contributes to the development of obesity and type 2 diabetes. Here we comprehensively review the above topics, discussing the main findings related to the role of the brain in the homeostatic regulation of energy and glucose metabolism.
In normal individuals, food intake and energy expenditure are tightly regulated by homeostatic mechanisms to maintain energy balance. Substantial evidence indicates that the brain, particularly the hypothalamus, is primarily responsible for the regulation of energy homeostasis.1 The brain monitors changes in the body energy state by sensing alterations in the plasma levels of key metabolic hormones and nutrients. Specialized neuronal networks in the brain coordinate adaptive changes in food intake and energy expenditure in response to altered metabolic conditions ( Figure 1 ).2, 3.
For the first time, researchers have successfully sequenced the entire genome from the skull of Peştera Muierii 1, a woman who lived in today’s Romania 35000 years ago. Her high genetic diversity shows that the out of Africa migration was not the great bottleneck in human development but rather this occurred during and after the most recent Ice Age. This is the finding of a new study led by Mattias Jakobsson at Uppsala University and being published in Current Biology.
“She is a bit more like modern-day Europeans than the individuals in Europe 5000 years earlier, but the difference is much less than we had thought. We can see that she is not a direct ancestor of modern Europeans, but she is a predecessor of the hunter-gathers that lived in Europe until the end of the last Ice Age,” says Mattias Jakobsson, professor at the Department of Organismal Biology at Uppsala University and the head of the study.
Very few complete genomes older than 30000 years have been sequenced. Now that the research team can read the entire genome from Peştera Muierii 1 (see the fact box below), they can see similarities with modern humans in Europe while also seeing that she is not a direct ancestor. In previous studies, other researchers observed that the shape of her cranium has similarities with both modern humans and Neanderthals. For this reason, they assumed that she had a greater fraction of Neanderthal ancestry than other contemporaries, making her stand out from the norm. But the genetic analysis in the current study shows that she has the same low level of Neanderthal DNA as most other individuals living in her time. Compared with the remains from some individuals who lived 5000 years earlier, such as Peştera Oase 1, she had only half as much Neanderthal ancestry.
Aberrant activation of Wnt/β-catenin pathway is a key driver of colorectal cancer (CRC) growth and of great therapeutic importance. In this study, we performed comprehensive CRISPR screens to interrogate the regulatory network of Wnt/β-catenin signaling in CRC cells. We found marked discrepancies between the artificial TOP reporter activity and β-catenin–mediated endogenous transcription and redundant roles of T cell factor/lymphoid enhancer factor transcription factors in transducing β-catenin signaling. Compiled functional genomic screens and network analysis revealed unique epigenetic regulators of β-catenin transcriptional output, including the histone lysine methyltransferase 2A oncoprotein (KMT2A/Mll1). Using an integrative epigenomic and transcriptional profiling approach, we show that KMT2A loss diminishes the binding of β-catenin to consensus DNA motifs and the transcription of β-catenin targets in CRC. These results suggest that KMT2A may be a promising target for CRCs and highlight the broader potential for exploiting epigenetic modulation as a therapeutic strategy for β-catenin–driven malignancies.
Colorectal cancer (CRC) represents one of the major malignancies and a leading cause of cancer-related death worldwide. Aberrant Wnt/β-catenin pathway plays a pivotal role in colon carcinogenesis (1). Cytoplasmic β-catenin is phosphorylated by a protein complex containing adenomatous polyposis coli (APC), AXIN1 or AXIN2, casein kinase 1α (CK1α), and glycogen synthase kinase-3β (GSK3β), leading to β-catenin destruction through ubiquitin-proteasome system. Wnt binding to the LDL receptor related protein 5/6 (LRP5/6)–frizzled receptors results in the disassembly of the β-catenin–destruction complex and consequent accumulation of β-catenin. β-Catenin then enters into the nucleus and binds to T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to initiate the transcription of β-catenin downstream targets (2).
Nearly all colorectal tumors (CRC) harbor genetic mutations that lead to the hyperactivation of β-catenin signaling. For example, germline or spontaneous mutations in tumor suppressor APC may cause constitutive activation of β-catenin in colon stem cells and the development of colonic polyps, which may eventually evolve into colorectal carcinomas. Hyperactivated β-catenin initiates the expression of various downstream targets through binding to the promoter regions via TCF/LEF transcription factors. Studies using transcriptomic approaches have characterized various β-catenin–responsive targets, such as cMYC, AXIN2, ASCL2, LGR5, and CD44. Collectively, these targets promote proliferation (e.g., cMYC) and maintain a stem cell state (e.g., LGR5 and ASCL2), highlighting the potential value of developing treatments that target β-catenin signaling in cancer. However, β-catenin itself is an intractable drug target (6, 7).
Posted in biotech/medical, genetics, neuroscience | Leave a Comment on RAB39B-mediated trafficking of the GluA2-AMPAR subunit controls dendritic spine maturation and intellectual disability-related behaviour
Mutations in the RAB39B gene cause X-linked intellectual disability (XLID), comorbid with autism spectrum disorders or early Parkinson’s disease. One of the functions of the neuronal small GTPase RAB39B is to drive GluA2/GluA3 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) maturation and trafficking, determining AMPAR subunit composition at glutamatergic postsynaptic neuronal terminals. Taking advantage of the Rab39b knockout murine model, we show that a lack of RAB39B affects neuronal dendritic spine refinement, prompting a more Ca2+-permeable and excitable synaptic network, which correlates with an immature spine arrangement and behavioural and cognitive alterations in adult mice. The persistence of immature circuits is triggered by increased hypermobility of the spine, which is restored by the Ca2+-permeable AMPAR antagonist NASPM.
A team of researchers from Verve Therapeutics and the Perelman School of Medicine at the University of Pennsylvania has developed a CRISPR gene-editing technique that lowered the levels of cholesterol in the blood of test monkeys. In their paper published in the journal Nature, the researchers describe their technique.
Prior research has shown that in some people, the PCSK9 gene codes excess PCSK9 protein production (which occurs mostly in the liver)—leading to an increase in lipoprotein cholesterol levels in the bloodstream. This is because it interferes with blood cells with LDL receptors that “grab” LDL and remove it. For this reason, pharmaceutical companies have developed therapies that reduce the production of PCSK9 protein. However, most do not work well enough, which is why there is still so much atherosclerotic cardiovascular disease. In this new effort, the researchers have tried another approach—altering the PCSK9 gene to make it stop coding for PCSK9 protein production.
The approach involved using a base editing technology made up of messenger RNA encoding for an adenine base editor along with guided RNA that was packaged in a lipid nanoparticle. Notably, the base editing technique was able to substitute a single nucleotide with another in the DNA without cutting the double helix. Prior research has shown the technique to be more precise, which means fewer errors than other CRISPR techniques. In their work, the researchers replaced an adenine with a guanine and a thymine with a cytosine, completely incapacitating the gene. Implementation of the therapy involved a one-time injection into the liver of cynomolgus monkeys.
