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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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15 pages, 2629 KiB  
Article
Improving Phylogenetic Signals of Mitochondrial Genes Using a New Method of Codon Degeneration
by Xuhua Xia
Life 2020, 10(9), 171; https://doi.org/10.3390/life10090171 - 30 Aug 2020
Cited by 2 | Viewed by 2800
Abstract
Recovering deep phylogeny is challenging with animal mitochondrial genes because of their rapid evolution. Codon degeneration decreases the phylogenetic noise and bias by aiming to achieve two objectives: (1) alleviate the bias associated with nucleotide composition, which may lead to homoplasy and long-branch [...] Read more.
Recovering deep phylogeny is challenging with animal mitochondrial genes because of their rapid evolution. Codon degeneration decreases the phylogenetic noise and bias by aiming to achieve two objectives: (1) alleviate the bias associated with nucleotide composition, which may lead to homoplasy and long-branch attraction, and (2) reduce differences in the phylogenetic results between nucleotide-based and amino acid (AA)-based analyses. The discrepancy between nucleotide-based analysis and AA-based analysis is partially caused by some synonymous codons that differ more from each other at the nucleotide level than from some nonsynonymous codons, e.g., Leu codon TTR in the standard genetic code is more similar to Phe codon TTY than to synonymous CTN codons. Thus, nucleotide similarity conflicts with AA similarity. There are many such examples involving other codon families in various mitochondrial genetic codes. Proper codon degeneration will make synonymous codons more similar to each other at the nucleotide level than they are to nonsynonymous codons. Here, I illustrate a “principled” codon degeneration method that achieves these objectives. The method was applied to resolving the mammalian basal lineage and phylogenetic position of rheas among ratites. The codon degeneration method was implemented in the user-friendly and freely available DAMBE software for all known genetic codes (genetic codes 1 to 33). Full article
(This article belongs to the Special Issue Molecular Phylogenetics and Mitochondrial Evolution)
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42 pages, 2508 KiB  
Review
The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes
by James Chapman, Yi Shiau Ng and Thomas J. Nicholls
Life 2020, 10(9), 164; https://doi.org/10.3390/life10090164 - 26 Aug 2020
Cited by 55 | Viewed by 7451
Abstract
Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several [...] Read more.
Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several thousand copies of the mitochondrial genome, located within the mitochondrial matrix in close association with the cristae ultrastructure. The organisation of mtDNA around the mitochondrial network requires mitochondria to be dynamic and undergo both fission and fusion events in coordination with the modulation of cristae architecture. The dysregulation of these processes has profound effects upon mtDNA replication, manifesting as a loss of mtDNA integrity and copy number, and upon the subsequent distribution of mtDNA around the mitochondrial network. Mutations within genes involved in mitochondrial dynamics or cristae modulation cause a wide range of neurological disorders frequently associated with defects in mtDNA maintenance. This review aims to provide an understanding of the biological mechanisms that link mitochondrial dynamics and mtDNA integrity, as well as examine the interplay that occurs between mtDNA, mitochondrial dynamics and cristae structure. Full article
(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)
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32 pages, 2158 KiB  
Review
Functional Mammalian Amyloids and Amyloid-Like Proteins
by Maria S. Rubel, Sergey A. Fedotov, Anastasia V. Grizel, Julia V. Sopova, Oksana A. Malikova, Yury O. Chernoff and Aleksandr A. Rubel
Life 2020, 10(9), 156; https://doi.org/10.3390/life10090156 - 21 Aug 2020
Cited by 38 | Viewed by 6941
Abstract
Amyloids are highly ordered fibrous cross-β protein aggregates that are notorious primarily because of association with a variety of incurable human and animal diseases (termed amyloidoses), including Alzheimer’s disease (AD), Parkinson’s disease (PD), type 2 diabetes (T2D), and prion diseases. Some amyloid-associated diseases, [...] Read more.
Amyloids are highly ordered fibrous cross-β protein aggregates that are notorious primarily because of association with a variety of incurable human and animal diseases (termed amyloidoses), including Alzheimer’s disease (AD), Parkinson’s disease (PD), type 2 diabetes (T2D), and prion diseases. Some amyloid-associated diseases, in particular T2D and AD, are widespread and affect hundreds of millions of people all over the world. However, recently it has become evident that many amyloids, termed “functional amyloids,” are involved in various activities that are beneficial to organisms. Functional amyloids were discovered in diverse taxa, ranging from bacteria to mammals. These amyloids are involved in vital biological functions such as long-term memory, storage of peptide hormones and scaffolding melanin polymerization in animals, substrate attachment, and biofilm formation in bacteria and fungi, etc. Thus, amyloids undoubtedly are playing important roles in biological and pathological processes. This review is focused on functional amyloids in mammals and summarizes approaches used for identifying new potentially amyloidogenic proteins and domains. Full article
(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)
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20 pages, 1859 KiB  
Review
Amyloidogenic Intrinsically Disordered Proteins: New Insights into Their Self-Assembly and Their Interaction with Membranes
by Federica Scollo and Carmelo La Rosa
Life 2020, 10(8), 144; https://doi.org/10.3390/life10080144 - 8 Aug 2020
Cited by 31 | Viewed by 5103
Abstract
Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins’ family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer’s, Type II Diabetes Mellitus, Parkinson’s, and Creutzfeldt–Jakob’s diseases. The [...] Read more.
Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins’ family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer’s, Type II Diabetes Mellitus, Parkinson’s, and Creutzfeldt–Jakob’s diseases. The molecular mechanism of toxicity is under intense debate, as many hypotheses concerning the involvement of the amyloid and the toxic oligomers have been proposed. However, the main role is represented by the interplay of protein and the cell membrane. Thus, the understanding of the interaction mechanism at the molecular level is crucial to shed light on the dynamics driving this phenomenon. There are plenty of factors influencing the interaction as mentioned above, however, the overall view is made trickier by the apparent irreproducibility and inconsistency of the data reported in the literature. Here, we contextualized this topic in a historical, and even more importantly, in a future perspective. We introduce two novel insights: the chemical equilibrium, always established in the aqueous phase between the free and the membrane phospholipids, as mediators of protein-transport into the core of the bilayer, and the symmetry-breaking of oligomeric aggregates forming an alternating array of partially ordered and disordered monomers. Full article
(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)
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19 pages, 1378 KiB  
Article
Evaluation of GammaH2AX in Buccal Cells as a Molecular Biomarker of DNA Damage in Alzheimer’s Disease in the AIBL Study of Ageing
by Mohammad Sabbir Siddiqui, Maxime Francois, Stephanie Rainey-Smith, Ralph Martins, Colin L. Masters, David Ames, Christopher C. Rowe, Lance S. Macaulay, Michael F. Fenech and Wayne R. Leifert
Life 2020, 10(8), 141; https://doi.org/10.3390/life10080141 - 6 Aug 2020
Cited by 3 | Viewed by 3229
Abstract
In response to double-stranded breaks (DSBs) in chromosomal DNA, H2AX (a member of histone H2A family) becomes phosphorylated to form γH2AX. Although increased levels of γH2AX have been reported in the neuronal nuclei of Alzheimer’s disease (AD) patients, the understanding of γH2AX responses [...] Read more.
In response to double-stranded breaks (DSBs) in chromosomal DNA, H2AX (a member of histone H2A family) becomes phosphorylated to form γH2AX. Although increased levels of γH2AX have been reported in the neuronal nuclei of Alzheimer’s disease (AD) patients, the understanding of γH2AX responses in buccal nuclei of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In the current study, endogenous γH2AX was measured in buccal cell nuclei from MCI (n = 18) or AD (n = 16) patients and in healthy controls (n = 17) using laser scanning cytometry (LSC). The γH2AX level was significantly elevated in nuclei of the AD group compared to the MCI and control group, and there was a concomitant increase in P-trend for γH2AX from the control group through MCI to the AD group. Receiver-operating characteristic curves were carried out for different γH2AX parameters; γH2AX in nuclei resulted in the greatest area under the curve value of 0.7794 (p = 0.0062) with 75% sensitivity and 70% specificity for the identification of AD patients from control. In addition, nuclear circularity (a measure of irregular nuclear shape) was significantly higher in the buccal cell nuclei from the AD group compared with the MCI and control groups. Additionally, there was a positive correlation between the nuclear circularity and γH2AX signals. The results indicated that increased DNA damage is associated with AD. Full article
(This article belongs to the Special Issue Cellular Senescence in Health, Disease and Aging: Blessing or Curse?)
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28 pages, 2112 KiB  
Review
Emerging Roles of Long Non-Coding RNAs in Renal Fibrosis
by Jinwen Lin, Zhengqian Jiang, Chenxi Liu, Dawei Zhou, Jiayu Song, Yuxuan Liao and Jianghua Chen
Life 2020, 10(8), 131; https://doi.org/10.3390/life10080131 - 1 Aug 2020
Cited by 18 | Viewed by 4886
Abstract
Renal fibrosis is an unavoidable consequence that occurs in nearly all of the nephropathies. It is characterized by a superabundant deposition and accumulation of extracellular matrix (ECM). All compartments in the kidney can be affected, including interstitium, glomeruli, vasculature, and other connective tissue, [...] Read more.
Renal fibrosis is an unavoidable consequence that occurs in nearly all of the nephropathies. It is characterized by a superabundant deposition and accumulation of extracellular matrix (ECM). All compartments in the kidney can be affected, including interstitium, glomeruli, vasculature, and other connective tissue, during the pathogenesis of renal fibrosis. The development of this process eventually causes destruction of renal parenchyma and end-stage renal failure, which is a devastating disease that requires renal replacement therapies. Recently, long non-coding RNAs (lncRNAs) have been emerging as key regulators governing gene expression and affecting various biological processes. These versatile roles include transcriptional regulation, organization of nuclear domains, and the regulation of RNA molecules or proteins. Current evidence proposes the involvement of lncRNAs in the pathologic process of kidney fibrosis. In this review, the biological relevance of lncRNAs in renal fibrosis will be clarified as important novel regulators and potential therapeutic targets. The biology, and subsequently the current understanding, of lncRNAs in renal fibrosis are demonstrated—highlighting the involvement of lncRNAs in kidney cell function, phenotype transition, and vascular damage and rarefaction. Finally, we discuss challenges and future prospects of lncRNAs in diagnostic markers and potential therapeutic targets, hoping to further inspire the management of renal fibrosis. Full article
(This article belongs to the Section Physiology and Pathology)
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13 pages, 1951 KiB  
Review
The Conformational Plasticity Vista of PDZ Domains
by Javier Murciano-Calles
Life 2020, 10(8), 123; https://doi.org/10.3390/life10080123 - 27 Jul 2020
Cited by 8 | Viewed by 3490
Abstract
The PDZ domain (PSD95-Discs large-ZO1) is a widespread modular domain present in the living organisms. A prevalent function in the PDZ family is to serve as scaffolding and adaptor proteins connecting multiple partners in signaling pathways. An explanation of the flexible functionality in [...] Read more.
The PDZ domain (PSD95-Discs large-ZO1) is a widespread modular domain present in the living organisms. A prevalent function in the PDZ family is to serve as scaffolding and adaptor proteins connecting multiple partners in signaling pathways. An explanation of the flexible functionality in this domain family, based just on a static perspective of the structure–activity relationship, might fall short. More dynamic and conformational aspects in the protein fold can be the reasons for such functionality. Folding studies indeed showed an ample and malleable folding landscape for PDZ domains where multiple intermediate states were experimentally detected. Allosteric phenomena that resemble energetic coupling between residues have also been found in PDZ domains. Additionally, several PDZ domains are modulated by post-translational modifications, which introduce conformational switches that affect binding. Altogether, the ability to connect diverse partners might arise from the intrinsic plasticity of the PDZ fold. Full article
(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)
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21 pages, 3825 KiB  
Article
Profiling and Identification of Omeprazole Metabolites in Mouse Brain and Plasma by Isotope Ratio-Monitoring Liquid Chromatography-Mass Spectrometric Method
by Seok-Ho Shin, Yuri Park, Min-Ho Park, Jin-Ju Byeon, Byeong ill Lee, Jangmi Choi and Young G. Shin
Life 2020, 10(7), 115; https://doi.org/10.3390/life10070115 - 19 Jul 2020
Cited by 8 | Viewed by 4638
Abstract
Neuro–inflammation is known to be one of the pathogenesis for the degenerative central nervous system (CNS) disease. Recently various approaches for the treatment of brain diseases by controlling neuro-inflammation in the brain have been introduced. In this respect, there is a continuous demand [...] Read more.
Neuro–inflammation is known to be one of the pathogenesis for the degenerative central nervous system (CNS) disease. Recently various approaches for the treatment of brain diseases by controlling neuro-inflammation in the brain have been introduced. In this respect, there is a continuous demand for CNS drugs, which could be safer and more effective. Omeprazole, a well-known proton-pump inhibitor (PPI) is generally prescribed for the treatment of peptic ulcer. In addition to the anti-gastric acid secretion mechanism, recent studies showed that omeprazole or PPIs would likely have anti-inflammation effects in vitro and in vivo, but their effects on anti-inflammation in brain are still unknown. In this study, omeprazole and its metabolites in a mouse’s brain after various routes of administration have been explored by stable isotope ratio-patterning liquid chromatography–mass spectrometric method. First, a simple liquid chromatography–mass spectrometric (LC–MS) method was established for the quantification of omeprazole in mouse plasma and brain. After that, omeprazole and its stable isotope (D3–omeprazole) were concomitantly administered through various routes to mice in order to identify novel metabolites characteristically observed in the mouse brain and were analyzed using a different LC–MS method with information-dependent analysis (IDA) scan. With this unique approach, several new metabolites of omeprazole were identified by the mass difference between omeprazole and stable isotope in both brain and plasma samples. A total of seventeen metabolites were observed, and the observed metabolites were different from each administration route or each matrix (brain or plasma). The brain pharmacokinetic profiles and brain-to-plasma partition coefficient (Kp) were also evaluated in a satellite study. Overall, these results provide better insights to understand the CNS-related biological effects of omeprazole and its metabolites in vivo. Full article
(This article belongs to the Special Issue Drug Metabolism and Pharmacokinetics 2020)
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20 pages, 4161 KiB  
Article
Optimization of Molecular Dynamics Simulations of c-MYC1-88—An Intrinsically Disordered System
by Sandra S. Sullivan and Robert O.J. Weinzierl
Life 2020, 10(7), 109; https://doi.org/10.3390/life10070109 - 10 Jul 2020
Cited by 10 | Viewed by 4940
Abstract
Many of the proteins involved in key cellular regulatory events contain extensive intrinsically disordered regions that are not readily amenable to conventional structure/function dissection. The oncoprotein c-MYC plays a key role in controlling cell proliferation and apoptosis and more than 70% of the [...] Read more.
Many of the proteins involved in key cellular regulatory events contain extensive intrinsically disordered regions that are not readily amenable to conventional structure/function dissection. The oncoprotein c-MYC plays a key role in controlling cell proliferation and apoptosis and more than 70% of the primary sequence is disordered. Computational approaches that shed light on the range of secondary and tertiary structural conformations therefore provide the only realistic chance to study such proteins. Here, we describe the results of several tests of force fields and water models employed in molecular dynamics simulations for the N-terminal 88 amino acids of c-MYC. Comparisons of the simulation data with experimental secondary structure assignments obtained by NMR establish a particular implicit solvation approach as highly congruent. The results provide insights into the structural dynamics of c-MYC1-88, which will be useful for guiding future experimental approaches. The protocols for trajectory analysis described here will be applicable for the analysis of a variety of computational simulations of intrinsically disordered proteins. Full article
(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)
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14 pages, 1079 KiB  
Review
Interaction of Oxidative Stress and Misfolded Proteins in the Mechanism of Neurodegeneration
by Andrey Y. Abramov, Elena V. Potapova, Viktor V. Dremin and Andrey V. Dunaev
Life 2020, 10(7), 101; https://doi.org/10.3390/life10070101 - 30 Jun 2020
Cited by 79 | Viewed by 6696
Abstract
Aggregation of the misfolded proteins β-amyloid, tau, huntingtin, and α-synuclein is one of the most important steps in the pathology underlying a wide spectrum of neurodegenerative disorders, including the two most common ones—Alzheimer’s and Parkinson’s disease. Activity and toxicity of these proteins depends [...] Read more.
Aggregation of the misfolded proteins β-amyloid, tau, huntingtin, and α-synuclein is one of the most important steps in the pathology underlying a wide spectrum of neurodegenerative disorders, including the two most common ones—Alzheimer’s and Parkinson’s disease. Activity and toxicity of these proteins depends on the stage and form of aggregates. Excessive production of free radicals, including reactive oxygen species which lead to oxidative stress, is proven to be involved in the mechanism of pathology in most of neurodegenerative disorders. Both reactive oxygen species and misfolded proteins play a physiological role in the brain, and only deregulation in redox state and aggregation of the proteins leads to pathology. Here, we review the role of misfolded proteins in the activation of ROS production from various sources in neurons and glia. We discuss if free radicals can influence structural changes of the key toxic intermediates and describe the putative mechanisms by which oxidative stress and oligomers may cause neuronal death. Full article
(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)
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35 pages, 2166 KiB  
Review
Neuroprotection or Neurotoxicity of Illicit Drugs on Parkinson’s Disease
by Carla Ferreira, Catarina Almeida, Sandra Tenreiro and Alexandre Quintas
Life 2020, 10(6), 86; https://doi.org/10.3390/life10060086 - 11 Jun 2020
Cited by 10 | Viewed by 10189
Abstract
Parkinson’s Disease (PD) is currently the most rapid growing neurodegenerative disease and over the past generation, its global burden has more than doubled. The onset of PD can arise due to environmental, sporadic or genetic factors. Nevertheless, most PD cases have an unknown [...] Read more.
Parkinson’s Disease (PD) is currently the most rapid growing neurodegenerative disease and over the past generation, its global burden has more than doubled. The onset of PD can arise due to environmental, sporadic or genetic factors. Nevertheless, most PD cases have an unknown etiology. Chemicals, such as the anthropogenic pollutant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amphetamine-type stimulants, have been associated with the onset of PD. Conversely, cannabinoids have been associated with the treatment of the symptoms’. PD and medical cannabis is currently under the spotlight, and research to find its benefits on PD is on-going worldwide. However, the described clinical applications and safety of pharmacotherapy with cannabis products are yet to be fully supported by scientific evidence. Furthermore, the novel psychoactive substances are currently a popular alternative to classical drugs of abuse, representing an unknown health hazard for young adults who may develop PD later in their lifetime. This review addresses the neurotoxic and neuroprotective impact of illicit substance consumption in PD, presenting clinical evidence and molecular and cellular mechanisms of this association. This research area is utterly important for contemporary society since illicit drugs’ legalization is under discussion which may have consequences both for the onset of PD and for the treatment of its symptoms. Full article
(This article belongs to the Section Pharmaceutical Science)
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17 pages, 4264 KiB  
Review
Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases
by Pakhuri Mehta, Przemysław Miszta, Przemysław Rzodkiewicz, Olga Michalak, Piotr Krzeczyński and Sławomir Filipek
Life 2020, 10(4), 50; https://doi.org/10.3390/life10040050 - 24 Apr 2020
Cited by 28 | Viewed by 11907
Abstract
The histamine H4 receptor, belonging to the family of G-protein coupled receptors, is an increasingly attractive drug target. It plays an indispensable role in many cellular pathways, and numerous H4R ligands are being studied for the treatment of several inflammatory, [...] Read more.
The histamine H4 receptor, belonging to the family of G-protein coupled receptors, is an increasingly attractive drug target. It plays an indispensable role in many cellular pathways, and numerous H4R ligands are being studied for the treatment of several inflammatory, allergic, and autoimmune disorders, including pulmonary fibrosis. Activation of H4R is involved in cytokine production and mediates mast cell activation and eosinophil chemotaxis. The importance of this receptor has also been shown in inflammatory models: peritonitis, respiratory tract inflammation, colitis, osteoarthritis, and rheumatoid arthritis. Recent studies suggest that H4R acts as a modulator in cancer, neuropathic pain, vestibular disorders, and type-2 diabetes, however, its role is still not fully understood. Full article
(This article belongs to the Section Pharmaceutical Science)
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27 pages, 38043 KiB  
Article
Synthetic Biology for Terraformation Lessons from Mars, Earth, and the Microbiome
by Nuria Conde-Pueyo, Blai Vidiella, Josep Sardanyés, Miguel Berdugo, Fernando T. Maestre, Victor de Lorenzo and Ricard Solé
Life 2020, 10(2), 14; https://doi.org/10.3390/life10020014 - 9 Feb 2020
Cited by 33 | Viewed by 14713
Abstract
What is the potential for synthetic biology as a way of engineering, on a large scale, complex ecosystems? Can it be used to change endangered ecological communities and rescue them to prevent their collapse? What are the best strategies for such ecological engineering [...] Read more.
What is the potential for synthetic biology as a way of engineering, on a large scale, complex ecosystems? Can it be used to change endangered ecological communities and rescue them to prevent their collapse? What are the best strategies for such ecological engineering paths to succeed? Is it possible to create stable, diverse synthetic ecosystems capable of persisting in closed environments? Can synthetic communities be created to thrive on planets different from ours? These and other questions pervade major future developments within synthetic biology. The goal of engineering ecosystems is plagued with all kinds of technological, scientific and ethic problems. In this paper, we consider the requirements for terraformation, i.e., for changing a given environment to make it hospitable to some given class of life forms. Although the standard use of this term involved strategies for planetary terraformation, it has been recently suggested that this approach could be applied to a very different context: ecological communities within our own planet. As discussed here, this includes multiple scales, from the gut microbiome to the entire biosphere. Full article
(This article belongs to the Section Synthetic Biology and Systems Biology)
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15 pages, 2706 KiB  
Article
A Strategy for Combinatorial Cavity Design in De Novo Proteins
by Christina Karas and Michael Hecht
Life 2020, 10(2), 9; https://doi.org/10.3390/life10020009 - 23 Jan 2020
Cited by 11 | Viewed by 4638
Abstract
Protein sequence space is vast; nature uses only an infinitesimal fraction of possible sequences to sustain life. Are there solutions to biological problems other than those provided by nature? Can we create artificial proteins that sustain life? To investigate these questions, we have [...] Read more.
Protein sequence space is vast; nature uses only an infinitesimal fraction of possible sequences to sustain life. Are there solutions to biological problems other than those provided by nature? Can we create artificial proteins that sustain life? To investigate these questions, we have created combinatorial collections, or libraries, of novel sequences with no homology to those found in living organisms. Previously designed libraries contained numerous functional proteins. However, they often formed dynamic, rather than well-ordered structures, which complicated structural and mechanistic characterization. To address this challenge, we describe the development of new libraries based on the de novo protein S-824, a 4-helix bundle with a very stable 3-dimensional structure. Distinct from previous libraries, we targeted variability to a specific region of the protein, seeking to create potential functional sites. By characterizing variant proteins from this library, we demonstrate that the S-824 scaffold tolerates diverse amino acid substitutions in a putative cavity, including buried polar residues suitable for catalysis. We designed and created a DNA library encoding 1.7 × 106 unique protein sequences. This new library of stable de novo α-helical proteins is well suited for screens and selections for a range of functional activities in vitro and in vivo. Full article
(This article belongs to the Special Issue Design and Validation of Tools for Microbial Synthetic Biology Applications)
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41 pages, 4490 KiB  
Concept Paper
Physicochemical Foundations of Life that Direct Evolution: Chance and Natural Selection are not Evolutionary Driving Forces
by Didier Auboeuf
Life 2020, 10(2), 7; https://doi.org/10.3390/life10020007 - 21 Jan 2020
Cited by 17 | Viewed by 7878
Abstract
The current framework of evolutionary theory postulates that evolution relies on random mutations generating a diversity of phenotypes on which natural selection acts. This framework was established using a top-down approach as it originated from Darwinism, which is based on observations made of [...] Read more.
The current framework of evolutionary theory postulates that evolution relies on random mutations generating a diversity of phenotypes on which natural selection acts. This framework was established using a top-down approach as it originated from Darwinism, which is based on observations made of complex multicellular organisms and, then, modified to fit a DNA-centric view. In this article, it is argued that based on a bottom-up approach starting from the physicochemical properties of nucleic and amino acid polymers, we should reject the facts that (i) natural selection plays a dominant role in evolution and (ii) the probability of mutations is independent of the generated phenotype. It is shown that the adaptation of a phenotype to an environment does not correspond to organism fitness, but rather corresponds to maintaining the genome stability and integrity. In a stable environment, the phenotype maintains the stability of its originating genome and both (genome and phenotype) are reproduced identically. In an unstable environment (i.e., corresponding to variations in physicochemical parameters above a physiological range), the phenotype no longer maintains the stability of its originating genome, but instead influences its variations. Indeed, environment- and cellular-dependent physicochemical parameters define the probability of mutations in terms of frequency, nature, and location in a genome. Evolution is non-deterministic because it relies on probabilistic physicochemical rules, and evolution is driven by a bidirectional interplay between genome and phenotype in which the phenotype ensures the stability of its originating genome in a cellular and environmental physicochemical parameter-depending manner. Full article
(This article belongs to the Section Evolutionary Biology)
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28 pages, 6302 KiB  
Review
Synthetic Approaches for Nucleic Acid Delivery: Choosing the Right Carriers
by Rong Ni, Ruilu Feng and Ying Chau
Life 2019, 9(3), 59; https://doi.org/10.3390/life9030059 - 9 Jul 2019
Cited by 57 | Viewed by 8808
Abstract
The discovery of the genetic roots of various human diseases has motivated the exploration of different exogenous nucleic acids as therapeutic agents to treat these genetic disorders (inherited or acquired). However, the physicochemical properties of nucleic acids render them liable to degradation and [...] Read more.
The discovery of the genetic roots of various human diseases has motivated the exploration of different exogenous nucleic acids as therapeutic agents to treat these genetic disorders (inherited or acquired). However, the physicochemical properties of nucleic acids render them liable to degradation and also restrict their cellular entrance and gene translation/inhibition at the correct cellular location. Therefore, gene condensation/protection and guided intracellular trafficking are necessary for exogenous nucleic acids to function inside cells. Diversified cationic formulation materials, including natural and synthetic lipids, polymers, and proteins/peptides, have been developed to facilitate the intracellular transportation of exogenous nucleic acids. The chemical properties of different formulation materials determine their special features for nucleic acid delivery, so understanding the property–function correlation of the formulation materials will inspire the development of next-generation gene delivery carriers. Therefore, in this review, we focus on the chemical properties of different types of formulation materials and discuss how these formulation materials function as protectors and cellular pathfinders for nucleic acids, bringing them to their destination by overcoming different cellular barriers. Full article
(This article belongs to the Special Issue Modelling Life-Like Behavior in Systems Chemistry)
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14 pages, 324 KiB  
Article
Molecular Diversity Required for the Formation of Autocatalytic Sets
by Wim Hordijk, Mike Steel and Stuart A. Kauffman
Life 2019, 9(1), 23; https://doi.org/10.3390/life9010023 - 1 Mar 2019
Cited by 19 | Viewed by 5572
Abstract
Systems chemistry deals with the design and study of complex chemical systems. However, such systems are often difficult to investigate experimentally. We provide an example of how theoretical and simulation-based studies can provide useful insights into the properties and dynamics of complex chemical [...] Read more.
Systems chemistry deals with the design and study of complex chemical systems. However, such systems are often difficult to investigate experimentally. We provide an example of how theoretical and simulation-based studies can provide useful insights into the properties and dynamics of complex chemical systems, in particular of autocatalytic sets. We investigate the issue of the required molecular diversity for autocatalytic sets to exist in random polymer libraries. Given a fixed probability that an arbitrary polymer catalyzes the formation of other polymers, we calculate this required molecular diversity theoretically for two particular models of chemical reaction systems, and then verify these calculations by computer simulations. We also argue that these results could be relevant to an origin of life scenario proposed recently by Damer and Deamer. Full article
(This article belongs to the Special Issue Modelling Life-Like Behavior in Systems Chemistry)
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17 pages, 36310 KiB  
Review
Bottom-Up Approaches to Synthetic Cooperation in Microbial Communities
by Daniel Rodríguez Amor and Martina Dal Bello
Life 2019, 9(1), 22; https://doi.org/10.3390/life9010022 - 26 Feb 2019
Cited by 44 | Viewed by 12551
Abstract
Microbial cooperation pervades ecological scales, from single-species populations to host-associated microbiomes. Understanding the mechanisms promoting the stability of cooperation against potential threats by cheaters is a major question that only recently has been approached experimentally. Synthetic biology has helped to uncover some of [...] Read more.
Microbial cooperation pervades ecological scales, from single-species populations to host-associated microbiomes. Understanding the mechanisms promoting the stability of cooperation against potential threats by cheaters is a major question that only recently has been approached experimentally. Synthetic biology has helped to uncover some of these basic mechanisms, which were to some extent anticipated by theoretical predictions. Moreover, synthetic cooperation is a promising lead towards the engineering of novel functions and enhanced productivity of microbial communities. Here, we review recent progress on engineered cooperation in microbial ecosystems. We focus on bottom-up approaches that help to better understand cooperation at the population level, progressively addressing the challenges of tackling higher degrees of complexity: spatial structure, multispecies communities, and host-associated microbiomes. We envisage cooperation as a key ingredient in engineering complex microbial ecosystems. Full article
(This article belongs to the Special Issue Synthetic Biology: From Living Computers to Terraformation)
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24 pages, 963 KiB  
Review
Unity Makes Strength: A Review on Mutualistic Symbiosis in Representative Insect Clades
by Rosario Gil and Amparo Latorre
Life 2019, 9(1), 21; https://doi.org/10.3390/life9010021 - 25 Feb 2019
Cited by 26 | Viewed by 7215
Abstract
Settled on the foundations laid by zoologists and embryologists more than a century ago, the study of symbiosis between prokaryotes and eukaryotes is an expanding field. In this review, we present several models of insect–bacteria symbioses that allow for the detangling of most [...] Read more.
Settled on the foundations laid by zoologists and embryologists more than a century ago, the study of symbiosis between prokaryotes and eukaryotes is an expanding field. In this review, we present several models of insect–bacteria symbioses that allow for the detangling of most known features of this distinctive way of living, using a combination of very diverse screening approaches, including molecular, microscopic, and genomic techniques. With the increasing the amount of endosymbiotic bacteria genomes available, it has been possible to develop evolutionary models explaining the changes undergone by these bacteria in their adaptation to the intracellular host environment. The establishment of a given symbiotic system can be a root cause of substantial changes in the partners’ way of life. Furthermore, symbiont replacement and/or the establishment of bacterial consortia are two ways in which the host can exploit its interaction with environmental bacteria for endosymbiotic reinvigoration. The detailed study of diverse and complex symbiotic systems has revealed a great variety of possible final genomic products, frequently below the limit considered compatible with cellular life, and sometimes with unanticipated genomic and population characteristics, raising new questions that need to be addressed in the near future through a wider exploration of new models and empirical observations. Full article
(This article belongs to the Special Issue Evolution of Mutualistic Symbiosis)
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12 pages, 2318 KiB  
Article
Dynamical Task Switching in Cellular Computers
by Angel Goñi-Moreno, Fernando de la Cruz, Alfonso Rodríguez-Patón and Martyn Amos
Life 2019, 9(1), 14; https://doi.org/10.3390/life9010014 - 26 Jan 2019
Cited by 4 | Viewed by 5359
Abstract
We present a scheme for implementing a version of task switching in engineered bacteria, based on the manipulation of plasmid copy numbers. Our method allows for the embedding of multiple computations in a cellular population, whilst minimising resource usage inefficiency. We describe the [...] Read more.
We present a scheme for implementing a version of task switching in engineered bacteria, based on the manipulation of plasmid copy numbers. Our method allows for the embedding of multiple computations in a cellular population, whilst minimising resource usage inefficiency. We describe the results of computational simulations of our model, and discuss the potential for future work in this area. Full article
(This article belongs to the Special Issue Synthetic Biology: From Living Computers to Terraformation)
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18 pages, 3143 KiB  
Article
Metatranscriptomic Analysis of the Bacterial Symbiont Dactylopiibacterium carminicum from the Carmine Cochineal Dactylopius coccus (Hemiptera: Coccoidea: Dactylopiidae)
by Rafael Bustamante-Brito, Arturo Vera-Ponce de León, Mónica Rosenblueth, Julio César Martínez-Romero and Esperanza Martínez-Romero
Life 2019, 9(1), 4; https://doi.org/10.3390/life9010004 - 3 Jan 2019
Cited by 18 | Viewed by 7602
Abstract
The scale insect Dactylopius coccus produces high amounts of carminic acid, which has historically been used as a pigment by pre-Hispanic American cultures. Nowadays carmine is found in food, cosmetics, and textiles. Metagenomic approaches revealed that Dactylopius spp. cochineals contain two Wolbachia strains, [...] Read more.
The scale insect Dactylopius coccus produces high amounts of carminic acid, which has historically been used as a pigment by pre-Hispanic American cultures. Nowadays carmine is found in food, cosmetics, and textiles. Metagenomic approaches revealed that Dactylopius spp. cochineals contain two Wolbachia strains, a betaproteobacterium named Candidatus Dactylopiibacterium carminicum and Spiroplasma, in addition to different fungi. We describe here a transcriptomic analysis indicating that Dactylopiibacterium is metabolically active inside the insect host, and estimate that there are over twice as many Dactylopiibacterium cells in the hemolymph than in the gut, with even fewer in the ovary. Albeit scarce, the transcripts in the ovaries support the presence of Dactylopiibacterium in this tissue and a vertical mode of transmission. In the cochineal, Dactylopiibacterium may catabolize plant polysaccharides, and be active in carbon and nitrogen provisioning through its degradative activity and by fixing nitrogen. In most insects, nitrogen-fixing bacteria are found in the gut, but in this study they are shown to occur in the hemolymph, probably delivering essential amino acids and riboflavin to the host from nitrogen substrates derived from nitrogen fixation. Full article
(This article belongs to the Special Issue Evolution of Mutualistic Symbiosis)
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