scholarly journals Resonant fluctuations of selection pressure exponentially accelerate fitness valley crossing

2022 ◽  
Author(s):  
Mario E Di Salvo ◽  
Kimberly A Reynolds ◽  
Milo M Lin
Keyword(s):  
Protein Evolution ◽  
Selection Pressure ◽  
De Novo ◽  
Pressure Fluctuations ◽  
Time Dependent ◽  
Time Varying ◽  
Fluctuating Selection ◽  
Functional Protein ◽  
Protein Size

Two functional protein sequences can sometimes be separated by a fitness valley - a series of low or non-functional intermediate mutations that must be traversed to reach a more optimal or refined function. Time-varying selection pressure modulates evolutionary sampling of such valleys. Yet, how the amplitude and frequency of fluctuating selection influence the rate of protein evolution is poorly understood. Here, we derive a simple equation for the time-dependent probability of crossing a fitness valley as a function of evolutionary parameters: valley width, protein size, mutation rate, and selection pressure. The equation predicts that, under low selection pressure, the valley crossing rate is magnified by a factor that depends exponentially on valley width. However, after a characteristic time set by the evolutionary parameters, the rate rapidly decays. Thus, there is an optimal frequency of selection-pressure fluctuations that maximizes the rate of protein optimization. This result is reminiscent of the resonance frequency in mechanical systems. The equation unites empirical and theoretical results that were previously disconnected, and is consistent with time-dependent in vitro and clinical data. More generally, these results suggest that seasonal and climate oscillations could synchronously drive protein evolution at the resonant frequency across a range of organism hosts and timescales. This theory could also be applied to optimize de novo protein evolution in laboratory directed evolution using time-varying protocols.

scholarly journals A high-quality reference genome assembly of the saltwater crocodile, Crocodylus porosus, reveals patterns of selection in Crocodylidae

2019 ◽  
Author(s):  
Arnab Ghosh ◽  
Matthew G. Johnson ◽  
Austin B. Osmanski ◽  
Swarnali Louha ◽  
Natalia J. Bayona-Vásquez ◽  
...  
Keyword(s):  
Genome Assembly ◽  
De Novo ◽  
Genome Structure ◽  
Protein Domain ◽  
Structure Evolution ◽  
Functional Protein ◽  
High Quality ◽  
Saltwater Crocodile ◽  
Crocodylus Porosus

AbstractCrocodilians are an economically, culturally, and biologically important group. To improve researchers’ ability to study genome structure, evolution, and gene regulation in the clade, we generated a high-quality de novo genome assembly of the saltwater crocodile, Crocodylus porosus, from Illumina short read data from genomic libraries and in vitro proximity-ligation libraries. The assembled genome is 2,123.5 Mb, with N50 scaffold size of 17.7 Mb and N90 scaffold size of 3.8 Mb. We then annotated this new assembly, increasing the number of annotated genes by 74%. In total, 96% of 23,242 annotated genes were associated with a functional protein domain. Furthermore, multiple non-coding functional regions and mappable genetic markers were identified. Upon analysis and overlapping the results of branch length estimation and site selection tests for detecting potential selection, we found 16 putative genes under positive selection in crocodilians, ten in C. porosus and six in A. mississippiensis. The annotated C. porosus genome will serve as an important platform for osmoregulatory, physiological and sex determination studies, as well as an important reference in investigating the phylogenetic relationships of crocodilians, birds, and other tetrapods.

In Vitro Evolutionary Thermostabilization of Congerin II: A Limited Reproduction of Natural Protein Evolution by Artificial Selection Pressure

2005 ◽  
Vol 347 (2) ◽  
pp. 385-397 ◽  
Author(s):  
Clara Shionyu-Mitsuyama ◽  
Yoshimaro Ito ◽  
Ayumu Konno ◽  
Yukiko Miwa ◽  
Tomohisa Ogawa ◽  
...  
Keyword(s):  
Protein Evolution ◽  
Artificial Selection ◽  
Selection Pressure ◽  
Natural Protein

scholarly journals Computational redesign of a fluorogen activating protein with Rosetta

2021 ◽  
Vol 17 (11) ◽  
pp. e1009555
Author(s):  
Nina G. Bozhanova ◽  
Joel M. Harp ◽  
Brian J. Bender ◽  
Alexey S. Gavrikov ◽  
Dmitry A. Gorbachev ◽  
...  
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Binding Pocket ◽  
Fluorescent Imaging ◽  
Fine Tuning ◽  
Ligand Docking ◽  
Pose Prediction ◽  
Functional Protein ◽  
Split System

The use of unnatural fluorogenic molecules widely expands the pallet of available genetically encoded fluorescent imaging tools through the design of fluorogen activating proteins (FAPs). While there is already a handful of such probes available, each of them went through laborious cycles of in vitro screening and selection. Computational modeling approaches are evolving incredibly fast right now and are demonstrating great results in many applications, including de novo protein design. It suggests that the easier task of fine-tuning the fluorogen-binding properties of an already functional protein in silico should be readily achievable. To test this hypothesis, we used Rosetta for computational ligand docking followed by protein binding pocket redesign to further improve the previously described FAP DiB1 that is capable of binding to a BODIPY-like dye M739. Despite an inaccurate initial docking of the chromophore, the incorporated mutations nevertheless improved multiple photophysical parameters as well as the overall performance of the tag. The designed protein, DiB-RM, shows higher brightness, localization precision, and apparent photostability in protein-PAINT super-resolution imaging compared to its parental variant DiB1. Moreover, DiB-RM can be cleaved to obtain an efficient split system with enhanced performance compared to a parental DiB-split system. The possible reasons for the inaccurate ligand binding pose prediction and its consequence on the outcome of the design experiment are further discussed.

scholarly journals Expanding functional protein sequence space using generative adversarial networks

2019 ◽  
Author(s):  
Donatas Repecka ◽  
Vykintas Jauniskis ◽  
Laurynas Karpus ◽  
Elzbieta Rembeza ◽  
Jan Zrimec ◽  
...  
Keyword(s):  
Protein Design ◽  
Sequence Space ◽  
Protein Sequence ◽  
Protein Function ◽  
De Novo ◽  
Protein Sequences ◽  
Generative Adversarial Networks ◽  
Functional Protein ◽  
Generative Adversarial Network

ABSTRACTDe novo protein design for catalysis of any desired chemical reaction is a long standing goal in protein engineering, due to the broad spectrum of technological, scientific and medical applications. Currently, mapping protein sequence to protein function is, however, neither computationionally nor experimentally tangible 1,2. Here we developed ProteinGAN, a specialised variant of the generative adversarial network 3 that is able to ‘learn’ natural protein sequence diversity and enables the generation of functional protein sequences. ProteinGAN learns the evolutionary relationships of protein sequences directly from the complex multidimensional amino acid sequence space and creates new, highly diverse sequence variants with natural-like physical properties. Using malate dehydrogenase as a template enzyme, we show that 24% of the ProteinGAN-generated and experimentally tested sequences are soluble and display wild-type level catalytic activity in the tested conditions in vitro, even in highly mutated (>100 mutations) sequences. ProteinGAN therefore demonstrates the potential of artificial intelligence to rapidly generate highly diverse novel functional proteins within the allowed biological constraints of the sequence space.

Einfluß der Glucose auf die [14C] Thymidin-Einbaurate von Ehrlich-Ascitescarcinomzellen in vitro

1969 ◽  
Vol 08 (02) ◽  
pp. 196-206 ◽  
Author(s):  
Dieter. Kummer
Keyword(s):  
De Novo

ZusammenfassungIn nahezu glucosefreier Suspension von Ehrlich-Ascitescarcinomzellen bewirkt die Zufuhr von Glucose 2,5 × 10–4 bis 10–2 M:1. Hemmung der [14C] Thymidin-Einbaurate in die Zellen.2. Aktivierung des Ribonucleotid-Reductase-Systems und damit Stimulierung der Desoxyribonucleotidsynthese (auch der Thymidintriphosphat-de-novo-Synthese).3. Blockierung der Thymidinkinase über Endprodukthemmung, wodurch die Minderung des [14C] Thymidin-Einbaus in die Zellen erklärbar ist.

Plasminogen Depletion during Streptokinase Treatment or Two-Chain Urokinase Incubation Correlates with Decreased Clot Lysability Ex Vivo and In Vitro

1993 ◽  
Vol 70 (06) ◽  
pp. 0998-1004 ◽  
Author(s):  
Páll T Önundarson ◽  
H Magnús Haraldsson ◽  
Lena Bergmann ◽  
Charles W Francis ◽  
Victor J Marder
Keyword(s):  
Myocardial Infarction ◽  
Ex Vivo ◽  
Time Dependent ◽  
State Variables ◽  
Thrombolytic Treatment ◽  
Direct Proportion ◽  
Plasmin Activity ◽  
Plasma Exposure ◽  
The Relationship

SummaryThe relationship between lytic state variables and ex vivo clot lysability was investigated in blood drawn from patients during streptokinase administration for acute myocardial infarction. A lytic state was already evident after 5 min of treatment and after 20 min the plasminogen concentration had decreased to 24%, antiplasmin to 7% and fibrinogen 0.2 g/1. Lysis of radiolabeled retracted clots in the patient plasmas decreased from 37 ± 8% after 5 min to 21 ± 8% at 10 min and was significantly lower (8 ± 9%, p <0.005) in samples drawn at 20, 40 and 80 min. Clot lysability correlated positively with the plasminogen concentration (r = 0.78, p = 0.003), but not with plasmin activity. Suspension of radiolabeled clots in normal plasma pre-exposed to 250 U/ml two-chain urokinase for varying time to induce an in vitro lytic state was also associated with decreasing clot lysability in direct proportion with the duration of prior plasma exposure to urokinase. The decreased lysability correlated with the time-dependent reduction in plasminogen concentration (r = 0.88, p <0.0005). Thus, clot lysability decreases in conjunction with the development of the lytic state and the associated plasminogen depletion. The lytic state may therefore limit reperfusion during thrombolytic treatment.

Plasma Contact Activation and Decrease of Factor V Activity on Negatively-Charged Polyelectrolytes

1984 ◽  
Vol 51 (01) ◽  
pp. 061-064 ◽  
Author(s):  
M C Boffa ◽  
B Dreyer ◽  
C Pusineri
Keyword(s):  
Time Dependent ◽  
Initial Contact ◽  
Factor Xii ◽  
Factor V ◽  
Contact Activation ◽  
Polyelectrolyte Complexes ◽  
Plasma Factor ◽  
Fresh Plasma ◽  
Direct Adsorption

SummaryThe effect of negatively-charged polymers, used in some artificial devices, on plasma clotting and kinin systems was studied in vitro using polyelectrolyte complexes.Contact activation was observed as an immediate, transient and surface-dependent phenomenon. After incubation of the plasma with the polymer a small decrease of factor XII activity was noticed, which corresponded to a greater reduction of prekallikrein activity and to a marked kinin release. No significant decrease of factor XII, prekallikrein, HMW kininogen could be detected immunologically. Only the initial contact of the plasma with the polyelectrolyte lead to activation, subsequently the surface became inert.Beside contact activation, factor V activity also decreased in the plasma. The decrease was surface and time-dependent. It was independent of contact factor activation, and appeared to be related to the sulfonated groups of the polymer. If purified factor V was used instead of plasma factor V, inactivation was immediate and not time-dependent suggesting a direct adsorption on the surface. A second incubation of the plasma-contacted polymer with fresh plasma resulted in a further loss of Factor V activity.

Platelets Stimulate Thromboplastin Synthesis in Human Endothelial Cells

1983 ◽  
Vol 49 (02) ◽  
pp. 069-072 ◽  
Author(s):  
U L H Johnsen ◽  
T Lyberg ◽  
K S Galdal ◽  
H Prydz
Keyword(s):  
Endothelial Cells ◽  
De Novo ◽  
Umbilical Vein ◽  
Time Dependent ◽  
De Novo Synthesis ◽  
Human Endothelial Cells ◽  
Tumor Promotor ◽  
Coagulation Assay ◽  
Platelet Aggregates ◽  
Umbilical Vein Endothelial Cells

SummaryHuman umbilical vein endothelial cells in culture synthesize thromboplastin upon stimulation with phytohaemagglutinin (PHA) or the tumor promotor 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The thromboplastin activity is further strongly enhanced in a time dependent reaction by the presence of gel-filtered platelets or platelet aggregates. This effect was demonstrable at platelet concentrations lower than those normally found in plasma, it may thus be of pathophysiological relevance. The thromboplastin activity increased with increasing number of platelets added. Cycloheximide inhibited the increase, suggesting that de novo synthesis of the protein component of thromboplastin, apoprotein III, is necessary.When care was taken to remove monocytes no thromboplastin activity and no apoprotein HI antigen could be demonstrated in suspensions of gel-filtered platelets, platelets aggregated with thrombin or homogenized platelets when studied with a coagulation assay and an antibody neutralization technique.

Особенности морфогенеза редкого вида Allium neriniflorum (Herb.) Backer в условиях in vitro

2019 ◽  
pp. 37-41 ◽  
Author(s):  
Альбина Шамсуновна Ахметова ◽  
Альфия Ануровна Зарипова
Keyword(s):  
De Novo

Показана возможность эффективного применения метода культуры тканей для размножения Allium neriniflorum (Herb.) Backer. Исследуемый вид является декоративным растением, размножение которого затруднено из-за низкой всхожести семян и ослабленной способности к формированию дочерних луковиц. Разработана технология клонального микроразмножения из стерильных луковиц. В качестве исходного материала использовали семена A. neriniflorum. Подобраны условия стерилизации, позволяющие достичь максимального числа (75 %) жизнеспособных эксплантов. Поверхностную стерилизацию проводили в ламинар-боксе с использованием в качестве стерилизующего агента 0,1 % раствор диацида. Семена сначала обрабатывали 70 % этанолом, затем стерилизующим раствором. Экспозиция стерилизующих растворов составляла от 5 до 9 мин. Показано, что способность к индуцированному морфогенезу существенно зависит от состава питательной среды. Максимальное число луковиц образовывалось на среде QL — 9 шт./эксплант. Исследуемые виды обладали высокой способностью к мультипликации и формированию полноценных растений при подобранных условиях культивирования in vitro. Выявленная морфогенетическая активность зачаточного побега, сегментов чешуй и донца стерильной луковицы A. neriniflorum, проявляющаяся в способности регенерировать побеги de novo, что возможно только в культуре in vitro, обеспечивает формирование полноценных луковиц. Луковицы, полученные in vitro, включали в последующие циклы микроразмножения. Культура тканей и органов in vitro позволяет размножать A. neriniflorum с более высоким коэффициентом размножения. От одной стерильной луковицы можно получить до 7000 луковиц в год. При традиционном вегетативном способе размножения материнская луковица формирует 1, редко 2 дочерние луковицы.

Study of Phosphocalcic Glasses from SiO2-CaO-P2O5 System with and Without Silver II. The bioactivity analysis by FTIR, SEM methods and microbiological study of silver-doped glasses

2017 ◽  
Vol 68 (6) ◽  
pp. 1188-1192
Author(s):  
Daniela Avram ◽  
Nicolae Angelescu ◽  
Dan Nicolae Ungureanu ◽  
Ionica Ionita ◽  
Iulian Bancuta ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Body Fluid ◽  
Pathogenic Bacteria ◽  
De Novo ◽  
Microbiological Examination ◽  
Doped Glasses ◽  
P2o5 System ◽  
Scanning Electron

The study in vitro of the glass powders bioactivity was performed by soaking them in simulated body fluid for 3 to 21 days at a temperature of 37�C and pH = 7.20. The synthesis de novo of hydroxyapatite, post soaking was confirmed by Fourier Transform Infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The study of the antimicrobial activity was performed by microbiological examination on two strains of pathogenic bacteria involved in postoperative nosocomial infections.

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