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Category: genetics – Page 152

Reversing schizophrenia with gene therapy year 2023.

Copy-number variations in the ARHGAP10 gene encoding Rho GTPase–activating protein 10 are associated with schizophrenia. Model mice (Arhgap10 S490P/NHEJ mice) that carry “double-hit” mutations in the Arhgap10 gene mimic the schizophrenia in a Japanese patient, exhibiting altered spine density, methamphetamine-induced cognitive dysfunction, and activation of RhoA/Rho-kinase signaling. However, it remains unclear whether the activation of RhoA/Rho-kinase signaling due to schizophrenia-associated Arhgap10 mutations causes the phenotypes of these model mice. Here, we investigated the effects of fasudil, a brain permeable Rho-kinase inhibitor, on altered spine density in the medial prefrontal cortex (mPFC) and on methamphetamine-induced cognitive impairment in a touchscreen‑based visual discrimination task in Arhgap10 S490P/NHEJ mice. Fasudil (20 mg/kg, intraperitoneal) suppressed the increased phosphorylation of myosin phosphatase–targeting subunit 1, a substrate of Rho-kinase, in the striatum and mPFC of Arhgap10 S490P/NHEJ mice. In addition, daily oral administration of fasudil (20 mg/kg/day) for 7 days ameliorated the reduced spine density of layer 2/3 pyramidal neurons in the mPFC. Moreover, fasudil (3–20 mg/kg, intraperitoneal) rescued the methamphetamine (0.3 mg/kg)-induced cognitive impairment of visual discrimination in Arhgap10 S490P/NHEJ mice. Our results suggest that Rho-kinase plays significant roles in the neuropathological changes in spine morphology and in the vulnerability of cognition to methamphetamine in mice with schizophrenia-associated Arhgap10 mutations.

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Michael Levin’s 2019 paper “The Computational Boundary of a Self” is discussed. The main topics of conversation include Scale-Free Cognition, Surprise & Stress, and the Morphogenetic Field. Michael Levin is a scientist at Tufts University; his lab studies anatomical and behavioral decision-making at multiple scales of biological, artificial, and hybrid systems. He works at the intersection of developmental biology, artificial life, bioengineering, synthetic morphology, and cognitive science.

🚩The Computational Boundary of a Self: Developmental Bioelectricity Drives Multicellularity and Scale-Free Cognition (can read in browser or download as pdf)
https://www.frontiersin.org/articles/10.3389/fpsyg.2019.02688/full.

❶ Scale-Free Cognition.
3:05 Ultimate question of the embodied mind.
5:50 The most difficult interview to prepare for.
6:55 One of my favorite papers of all time (screenshare)
7:40 The Computational Boundary of a Self.
9:25 Defining intelligence (cybernetics)
10:30 Cognitive light cones.
16:50 All intelligence is collective intelligence.
17:35 Nested selves vs. one integrated self (Not Integrated Information Theory)
21:10 The same dynamics in the brain occur in every tissue of the body.
22:50 Why scale “free” cognition?

❷ Stress & Surprise.

Continue reading “What are Cognitive Light Cones? (Michael Levin Interview)” | >

The gene-editing system CRISPR-Cas9 which has revolutionized genetic engineering over the past decade involves cutting DNA strands which is a process that can be quite hard to control and can result in unwanted genetic changes. Now, thanks to researchers at the Massachusetts Institute of Technology and the University of California, San Francisco (UCSF), a new gene-editing technology called CRISPRoff can change that, according to a press release.

“Fast forward four years [from the initial grant], and CRISPRoff finally works as envisioned in a science fiction way,” says co-senior author Luke Gilbert. “It’s exciting to see it work so well in practice.”

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Hoping to improve on those earlier efforts, Matthew Daugherty, a biochemist at the University of California San Diego, and colleagues used sophisticated computer software to trace the evolution of hundreds of human genes by searching for similar sequences in hundreds of other species. Genes that seemed to have appeared first in vertebrates and had no predecessors in earlier animals were good candidates for having jumped across from bacteria, particularly if they had counterparts in modern microbes. Among the dozens of potentially alien genes, one “blew me away,” Daugherty recalls.

The gene, called IRBP (for interphotoreceptor retinoid-binding protein), was already known to be important for seeing. The protein it encodes resides in the space between the retina and the retinal pigment epithelium, a thin layer of cells overlying the retina. In the vertebrate eye, when light hits a light-sensitive photoreceptor in the retina, vitamin A complexes become kinked, setting off an electrical pulse that activates the optic nerve. IRBP then shifts these molecules to the epithelium to be unkinked. Finally, it shuttles the restored molecules back to the photoreceptor. “IRBP,” Zhu explains, “is essential for the vision of all vertebrates.”

Vertebrate IRBP most closely resembles a class of bacterial genes called pepsidases, whose proteins recycle other proteins. Since IRBP is found in all vertebrates but generally not in their closest invertebrate relatives, Daugherty and his colleagues propose that more than 500 million years ago microbes transferred a pepsidase gene into an ancestor of all living vertebrates. Once the gene was in place, the protein’s recycling function was lost and the gene duplicated itself twice, explaining why IRBP has four copies of the original pepsidase DNA. Even in its microbial forebears, this protein may have had some ability to bind to light-sensing molecules, Daugherty suggests. Other mutations then completed its transformation into a molecule that could escape from cells and serve as a shuttle.

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Continue reading “Telomere Length Is Associated With Dementia Risk” | >

A group of molecular and chemical biologists at the University of California, San Diego, has found possible evidence of interdomain horizontal gene transfer leading to the development of the eye in vertebrates. In their study, reported in Proceedings of the National Academy of Sciences, Chinmay Kalluraya, Alexander Weitzel, Brian Tsu and Matthew Daugherty used the IQ-TREE software program to trace the evolutionary history of genes associated with vision.

Ever since scientists proved that humans, along with other animals, developed due to , one problem has stood out—how could evolution possibly account for the development of something as complicated as the eyeball? Even Charles Darwin was said to be stumped by the question. In recent times, this seeming conundrum has been used by some groups as a means to discredit altogether. In this new effort, the team in California sought to answer the question once and for all.

Their work began with the idea that vision in vertebrates may have got its start by using light-sensitive genes transferred from microbes. To find out if that might be the case, the team submitted likely human gene candidates to the IQ-TREE program to look for similar genetic sequences in other creatures, most specifically, microbes.

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Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant tool against cancer. HER2+ and triple-negative breast cancers (TNBCs) are considered more immunogenic and suitable for this kind of treatment due to the higher rate of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. In TNBC, genetic aberrations further favor immunogenicity due to more neo-antigens in cancer cells. Methods: This review summarizes the principal ongoing conventional and investigational immunotherapies in breast cancer. Particularly, immune checkpoint inhibitors (ICIs) and their use alone or combined with DNA damage repair inhibitors (DDRis) are described.

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(Visit: http://www.uctv.tv/) Animal development is directed by a genetic toolkit shared by all animals — from fruit flies to frogs to human beings — rather than different animals having different genetic toolkits. UCLA Professor of Biological Chemistry Edward De Robertis explains that the field of evolutionary development (or Evo-Devo) seeks to understand how so many beautiful animal forms evolved through the use of the original genetic toolkit of the last common ancestor of all animals, urbilateria, which existed at least 560 million years ago. Recorded on 10.25.2016. Series: “UCLA Faculty Research Lectures” [12/2016] [Science] [Show ID: 31409].

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Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response to changes in activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones and their functional integration within dendritic regions, concurrent plasticity has historically been underassessed. Growing evidence for pathological disruptions in the excitation and inhibition (E/I) balance in neurological and neurodevelopmental disorders indicates the need for an improved, more “holistic” understanding of synaptic interplay. There continues to be a long-standing focus on the persistent strengthening of excitation (excitatory long-term potentiation; eLTP) and its role in learning and memory, although the importance of inhibitory long-term potentiation (iLTP) and depression (iLTD) has become increasingly apparent. Emerging evidence further points to a dynamic dialogue between excitatory and inhibitory synapses, but much remains to be understood regarding the mechanisms and extent of this exchange. In this mini-review, we explore the role calcium signaling and synaptic crosstalk play in regulating postsynaptic plasticity and neuronal excitability. We examine current knowledge on GABAergic and glutamatergic synapse responses to perturbances in activity, with a focus on postsynaptic plasticity induced by short-term pharmacological treatments which act to either enhance or reduce neuronal excitability via ionotropic receptor regulation in neuronal culture. To delve deeper into potential mechanisms of synaptic crosstalk, we discuss the influence of synaptic activity on key regulatory proteins, including kinases, phosphatases, and synaptic structural/scaffolding proteins. Finally, we briefly suggest avenues for future research to better understand the crosstalk between glutamatergic and GABAergic synapses.

Ligand-gated ion channel GABA type A receptors (GABAARs) mediate the majority of fast inhibition in the central nervous system, while glutamatergic AMPA receptors (AMPARs) and NMDA receptors (NMDARs) collectively mediate fast excitatory neurotransmission. NMDARs particularly play a unique role in synaptic plasticity due to high calcium permeability and voltage-dependent Mg2+ block typically relieved by AMPAR-mediated depolarization. Slow inhibition and excitation are generated by G protein-coupled, GABA type B (GABABRs) and metabotropic glutamate receptors (mGluRs), respectively. The concerted action of these receptors balances neuronal excitability. A close and coordinated spatial relationship between glutamatergic and GABAergic synapses on dendrites (Megías et al., 2001; Bleckert et al., 2013; Iascone et al., 2020), sometimes as near as on the same spine (Chen et al., 2012), facilitates synaptic input integration, dynamic calcium regulation, synaptic crosstalk, and coregulation.

Synaptic plasticity describes the ability of synapses to adapt their relative strength based on the overall level of activity or specific activity patterns, often by dynamic regulation of receptor-synaptic scaffold interactions or through trafficking. During development, it is heavily involved in dendritic growth, synaptogenesis, and the formation of neural circuits (reviewed in Akgül and McBain, 2016; Ismail et al., 2017; Jenks et al., 2021). In mature neurons, synaptic plasticity is responsible for synapse remodeling during experience. Genetic mutations or pathology leading to altered excitatory or inhibitory neurotransmission or impaired synaptogenesis typically result in deficits in synaptic plasticity, a common feature in neurodevelopmental and neurological disorders (Rudolph and Möhler, 2014; Mele et al., 2019), including autism (Hansel, 2019; Sohal and Rubenstein, 2019), down syndrome (Galdzicki et al., 2001; Schulz et al.

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What is antibiotic resistance? What is the global clinical antibacterial pipeline? What is the global preclinical antibacterial pipeline? Institutions associated with preclinical drug development Preclinical projects Trends in the preclinical antibacterial pipeline References Further reading.

The global preclinical antibacterial pipeline refers to innovative antibacterial candidate drugs that are under development with the aim of effectively eliminating newly emerged and pre-existing priority pathogens.

Antibacterial medicines or antibiotics treat bacterial infections in humans, animals, and plants. However, bacteria may eventually develop resistance against antibiotics-mediated killing by acquiring genetic mutations. Although antibiotic resistance occurs naturally, misuse or overuse of antibiotics can significantly escalate the process.

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