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Category: genetics – Page 81

Learn more about the Cognitive Science Student Association and the California Cognitive Science Conference at https://cssa.berkeley.edu.

Amy Arnsten — Yale University.

Abstract.
The recently evolved prefrontal cortex (PFC) subserves many of our highest-order cognitive functions, generating and sustaining the mental representations that underlie working memory, abstract reasoning, and top-down control of thought, action, and emotion. Due to the pioneering research of Patricia Goldman-Rakic, we have learned much about the neural basis underlying the ability of the dorsolateral prefrontal cortex (dlPFC) to generate mental representations, where microcircuits in deep layer III have extensive recurrent excitatory connections to maintain neuronal firing in the absence of sensory stimulation, while GABAergic interneurons provide lateral inhibition to refine the contents of working memory. However, these dlPFC circuits are also tremendously dependent on arousal state, with a narrow inverted U response to levels of acetylcholine, dopamine and norepinephrine. Even quite mild uncontrollable stress increases the release of dopamine and norepinephrine in the PFC, which rapidly impairs PFC functioning by 1) stimulating D1 and alpha-1-receptors, respectively, 2) these, in turn, activate feedforward calcium-cAMP signaling within spines, which then 3) open nearby potassium channels to disconnect PFC networks and take the PFC “off-line”. With chronic stress exposure, there is actual atrophy of PFC dendrites and spines. Understanding the neural events that weaken vs. strengthen PFC connectivity and function has led to the development of treatments for patients with stress-related PFC dysfunction, e.g. guanfacine and prazosin. This knowledge is also helping to illuminate the etiology of cognitive disorders, as genetic insults in schizophrenia often increase the activity of these stress signaling pathways, and the molecules that regulate the stress signaling pathways are lost with advancing age, leading to tau pathology as seen in Alzheimer’s disease.

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Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan.

Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture.

We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.

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Researchers have developed a genetic algorithm for designing phononic crystal nanostructures, significantly advancing quantum computing and communications.

The new method, validated through experiments, allows precise control of acoustic wave propagation, promising improvements in devices like smartphones and quantum computers.

Quantum Computing Revolution

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Treating cancer can sometimes feel like a game of Whac-A-Mole. The disease can become resistant to treatment, and clinicians never know when, where and what resistance might emerge, leaving them one step behind. But a team led by Penn State researchers has found a way to reprogram disease evolution and design tumors that are easier to treat.

They created a modular genetic circuit that turns cancer cells into a “Trojan horse,” causing them to self-destruct and kill nearby drug-resistant cancer cells. Tested in human cell lines and in mice as proof of concept, the circuit outsmarted a wide range of .

The findings were published today, July 4, in the journal Nature Biotechnology. The researchers also filed a provisional application to patent the technology described in the paper.

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The advent of quantum computers promises to revolutionize computing by solving complex problems exponentially more rapidly than classical computers. However, today’s quantum computers face challenges such as maintaining stability and transporting quantum information.

Phonons, which are quantized vibrations in periodic lattices, offer new ways to improve these systems by enhancing qubit interactions and providing more reliable information conversion. Phonons also facilitate better communication within quantum computers, allowing the interconnection of them in a network.

Nanophononic materials, which are artificial nanostructures with specific phononic properties, will be essential for next-generation quantum networking and . However, designing phononic crystals with desired characteristics at the nano-and micro-scales remains challenging.

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This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF.

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This study uncoversthe pivotal role of the enzyme METTL4 in promoting tumor metastasis through the mediation of nuclear N6-methyldeoxyadenosine (6mA) in mammalian cells. By utilizing cellular models, the study demonstrates how hypoxia induces METTL4 to mediate 6mA modifications. This process, in turn, activates genes essential for tumor metastasis, including the involvement of specific long noncoding RNA and a novel HIF-1α co-activator, ZMIZ1. These findings not only shed light on the epigenetic mechanisms driving tumor progression but also establish METTL4 as a prognostic marker for cancer and a potential target for therapeutic intervention. The promise of this discovery lies in its potential to inspire new strategies for combating hypoxia-induced tumor progression, opening avenues for further research and development in cancer treatment.

DNA N6-methyldeoxyadenosine (6mA) has been recognized in various organisms for its role in gene regulation. However, its function in mammalian cells, particularly in the context of cancer, has remained elusive. Previous studies have shown that 6mA modifications can influence gene expression and are present in several species, indicating a potential regulatory role in tumorigenesis. This research addresses a critical gap in understanding the nuclear role of 6mA and its enzymatic mediator METTL4, in mammalian tumor cells, particularly under hypoxia (a common condition in tumor microenvironments that promotes metastasis). The study posits that METTL4-mediated 6mA deposition is a key epigenetic modification that activates metastasis-inducing genes. This finding offers a new perspective on the mechanisms of tumor progression and identifying novel targets for therapeutic intervention.

According to recent World Health Organization statistics, cancer remains a leading cause of death globally, with metastatic cancers posing significant treatment challenges. This study’s revelations underscore the urgent need for novel therapeutic strategies to address the complex mechanisms of cancer metastasis. By linking the research findings to SDG 3, which aims to ensure healthy lives and promote well-being for all, the study highlights the potential for significant advancements in cancer treatment. Ultimately, the study paves the way for improved health outcomes and underscores the importance of continued investment in research and development to combat the global cancer burden.

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