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Category: genetics – Page 193

Evidence found of possible interdomain horizontal gene transfer leading to development of the eye in vertebrates

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.

Immune Checkpoint Inhibitors and Other Immune Therapies in Breast Cancer: A New Paradigm for Prolonged Adjuvant Immunotherapy

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.

Evolution and Development from Simple Animals to Humans via Ancestral Gene Networks

(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].

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance

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.

Exploring the Global Clinical and Preclinical Antibacterial Pipelines

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.

Dietary supplement helps combat resistance in breast cancer, finds study

Many cancer therapies do not produce the hoped-for results. A common reason for this is that the tumors develop resistance to the medications. This is the case, for example, with alpelisib, a drug that has been approved for use in Switzerland for the past few years as a treatment for advanced breast cancer.

A research group at the Department of Biomedicine of the University of Basel has now discovered that the loss of the neurofibromin 1 (NF1) gene leads to a reduced response to alpelisib. The researchers also found that the dietary supplement N-acetylcysteine restores the sensitivity of cancer cells to this treatment. The findings have been published in the journal Cell Reports Medicine on April 11.

At the moment, patients with advanced and metastatic breast cancer lack effective treatment options. The PI3K signaling pathway is often overactive in breast cancer due to mutations promoting tumor development. The approval of the PI3K inhibitor Alpelisib was therefore keenly anticipated.

Beyond DNA and RNA: The Expanding Toolbox of Synthetic Genetics

The remarkable physicochemical properties of the natural nucleic acids, DNA and RNA, define modern biology at the molecular level and are widely believed to have been central to life’s origins. However, their ability to form repositories of information as well as functional structures such as ligands (aptamers) and catalysts (ribozymes/DNAzymes) is not unique. A range of nonnatural alternatives, collectively termed xeno nucleic acids (XNAs), are also capable of supporting genetic information storage and propagation as well as evolution. This gives rise to a new field of “synthetic genetics,” which seeks to expand the nucleic acid chemical toolbox for applications in both biotechnology and molecular medicine. In this review, we outline XNA polymerase and reverse transcriptase engineering as a key enabling technology and summarize the application of “synthetic genetics” to the development of aptamers, enzymes, and nanostructures.

Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved.

The origin of life: RNA and protein co-evolution on the ancient Earth

How life emerged from simple non-life chemicals on the ancient Earth is one of the greatest mysteries in biology. The gene expression system of extant life is based on the interdependence between multiple molecular species (DNA, RNA, and proteins). While DNA is mainly used as genetic material and proteins as functional molecules in modern biology, RNA serves as both genetic material and enzymes (ribozymes). Thus, the evolution of life may have begun with the birth of a ribozyme that replicated itself (the RNA world hypothesis), and proteins and DNA joined later. However, the complete self-replication of ribozymes from monomeric substrates has not yet been demonstrated experimentally, due to their limited activity and stability. In contrast, peptides are more chemically stable and are considered to have existed on the ancient Earth, leading to the hypothesis of RNA-peptide co-evolution from the very beginning. Our group and collaborators recently demonstrated that peptides with both hydrophobic and cationic moieties (e.g., KKVVVVVV) form β-amyloid aggregates that adsorb RNA and enhance RNA synthesis by an artificial RNA polymerase ribozyme and a simple peptide with only seven amino acid types (especially rich in valine and lysine) can fold into the ancient β-barrel conserved in various enzymes, including the core of cellular RNA polymerases. These findings, together with recent reports from other groups, suggest that simple prebiotic peptides could have supported the ancient RNA-based replication system, gradually folded into RNA-binding proteins, and eventually evolved into complex proteins like RNA polymerase.

Keywords: RNA world; ancient proteins; central dogma; origin of life; peptide.

© 2023 Japanese Society of Developmental Biologists.

Ribozyme-mediated RNA synthesis and replication in a model Hadean microenvironment

Enzyme-catalyzed replication of nucleic acid sequences is a prerequisite for the survival and evolution of biological entities. Before the advent of protein synthesis, genetic information was most likely stored in and replicated by RNA. However, experimental systems for sustained RNA-dependent RNA-replication are difficult to realise, in part due to the high thermodynamic stability of duplex products and the low chemical stability of catalytic RNAs. Using a derivative of a group I intron as a model for an RNA replicase, we show that heated air-water interfaces that are exposed to a plausible CO2-rich atmosphere enable sense and antisense RNA replication as well as template-dependent synthesis and catalysis of a functional ribozyme in a one-pot reaction. Both reactions are driven by autonomous oscillations in salt concentrations and pH, resulting from precipitation of acidified dew droplets, which transiently destabilise RNA duplexes. Our results suggest that an abundant Hadean microenvironment may have promoted both replication and synthesis of functional RNAs.

© 2023. The Author(s).

Conflict of interest statement.

RNA-Catalyzed Polymerization of Deoxyribose, Threose, and Arabinose Nucleic Acids

An RNA-dependent RNA polymerase ribozyme that was highly optimized through in vitro evolution for the ability to copy a broad range of template sequences exhibits promiscuity toward other nucleic acids and nucleic acid analogues, including DNA, threose nucleic acid (TNA), and arabinose nucleic acid (ANA). By operating on various RNA templates, the ribozyme catalyzes multiple successive additions of DNA, TNA, or ANA monomers, although with reduced efficiency compared to RNA monomers. The ribozyme can also copy DNA or TNA templates to complementary RNAs, and to a lesser extent it can operate when both the template and product strands are composed of DNA, TNA, or ANA. These results suggest that polymerase ribozymes, which are thought to have replicated RNA genomes during the early history of life, could have transferred RNA-based genetic information to and from DNA, enabling the emergence of DNA genomes prior to the emergence of proteins. In addition, genetic systems based on nucleic acid-like molecules, which have been proposed as precursors or contemporaries of RNA-based life, could have been operated upon by a promiscuous polymerase ribozyme, thus enabling the evolutionary transition between early genetic systems.

Keywords: RNA world; XNA; origins of life; polymerase; reverse transcriptase; ribozyme.