Selection Of Mutants Research Articles

Evolution of Rabies Virus Isolates: Virulence Signatures and Effects of Modulation by Neutralizing Antibodies.

Lyssavirus rabies (RABV) is an RNA virus and, therefore, is subject to mutations due to low RNA polymerase replication fidelity, forming a population structure known as a viral quasispecies, which is the core of RNA viruses' adaptive strategy. Under new microenvironmental conditions, the fittest populations are selected, and the study of this process on the molecular level can help determine molecular signatures related to virulence. Our aim was to survey gene signatures on nucleoprotein and glycoprotein genes that might be involved in virulence modulation during the in vitro evolution of RABV lineages after serial passages in a neuronal cell system with or without the presence of neutralizing antibodies based on replicative fitness, in vivo neurotropism and protein structure and dynamics. The experiments revealed that amino acids at positions 186 and 188 of the glycoprotein are virulence factors of Lyssavirus rabies, and site 186 specifically might allow the attachment to heparan as a secondary cell receptor, while polymorphism at position 333 might allow the selection of escape mutants under suboptimal neutralizing antibodies titers.

Morphological Characteristics Selection of Acid-tolerant Leucaena leucocephala Mutant to Addition of IBA Hormone (Indole butyric acid) in Tissue Culture

Leucaena leucocephala is a legume forage plant that has a high protein content. Tissue culture is a technique that can be used to select mutants for forage plants in vitro. IBA (Indole butyric acid) is one type of auxin that can induce rooting and growth in plants. This study aimed to select the morphological characteristics of the acid-tolerant Leucaena leucocephala mutant to the addition of the hormone IBA in tissue culture. The design used in this study was a completely randomized design (CRD) with lamtoro plant explants as many as 11 acid-tolerant mutant lines pH 3.4 resulting from 400 gy irradiation which had been treated on 300 ppm Al3+ acid media, namely the K1-K11 strain (mutant+MS+1ppm IBA) and 2 parent trees Leucaena leucocephala without gamma irradiation, namely P0 as Leucaena leucocephala parent+MS+0ppm IBA, P1 as Leucaena leucocephala parent + MS + 1 ppm IBA with 15 replicates. The treatment which had a significant effect was continued with the test Tukey. Variables observed were an increase in root length, plant vertical height, number of shoots, and percentage of rooted plants. The increase in root length and increase in plant vertical height showed the best results on the K10 mutant strain, the number of shoots showed the best results on the K9 and K11 mutant strains, and the highest percentage of rooted plants on the K3 and K11 mutant strains. The addition of IBA can increase the morphological characteristics of the Leucaena leucocephala mutant.

Evolution of flowering time genes in rice: From the paleolithic to the anthropocene.

The evolutionary paths of humans and plants have crossed more than once throughout millennia. While agriculture contributed to the evolution of societies in prehistory, human selection of desirable traits contributed to the evolution of crops during centuries of cultivation. Among cereal crops, rice is currently grown around the globe and represents staple food for almost half of the world population. Over time, rice cultivation has expanded from subtropical to temperate regions thanks to artificial selection of mutants with impaired response to photoperiod. Additional regulatory mechanisms control flowering in response to diverse environmental cues, anticipatingor delaying the floral transition to produce seeds in more favourable conditions. Nevertheless, the changing climate is threatening grain production because modern cultivars are sensitive to external fluctuations that go beyond their physiological range. One possibility to guarantee food production could be the exploitation of novel varieties obtained by crossing highly productive Asian rice with stress tolerant African rice. This review explores the genetic basis of the key traits that marked the long journey of rice cultivation from the end of the paleolithic to the anthropocene, with a focus on heading date. By 2050, will rice plants of the future flower in the outer space?

In Vitro and In Vivo Properties of CUO246, a Novel Bacterial DNA Gyrase/Topoisomerase IV Inhibitor.

CUO246, a novel DNA gyrase/topoisomerase IV inhibitor, is active in vitro against a broad range of Gram-positive, fastidious Gram-negative, and atypical bacterial pathogens and retains activity against quinolone-resistant strains in circulation. The frequency of selection for single step mutants of wild-type S. aureus with reduced susceptibility to CUO246 was <4.64 × 10-9 at 4× and 8× MIC and remained low when using an isogenic QRDR mutant (<5.24 × 10-9 at 4× and 8× MIC). Biochemical assays indicated that CUO246 had potent inhibitory activity against both DNA gyrase (GyrAB) and topoisomerase IV (ParCE). Furthermore, CUO246 showed rapid bactericidal activity in time-kill assays and potent in vivo efficacy against S. aureus in a neutropenic murine thigh infection model. These results suggest that CUO246 may be useful in treating infections by various causative agents of acute skin and skin structure infections, respiratory tract infections, and sexually transmitted infections.

The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii.

The objective of this study was to evaluate whether combinations of sulbactam, meropenem, and polymyxin-B could reduce or close the gap of mutant selection window (MSW) of individual antibiotics against Acinetobacter baumannii harboring OXA-23. MICs of three antimicrobials used alone and in combination (meropenem/polymyxin-B or meropenem/polymyxin-B/sulbactam) were obtained in 11 clinical isolates and mutant prevention concentrations were determined in 4 of the 11 isolates. All isolates were resistant to meropenem or polymyxin-B. Combining meropenem and polymyxin-B with or without sulbactam resulted in synergistic bactericidal activities. Pharmacokinetic (PK) simulations of drug concentrations in the blood and epithelial lining fluid coupled with pharmacodynamic (PD) evaluations revealed that the fractions of time over the 24-h in terms of free drug concentration within the MSW (fTMSW) and above the MPC (fT>MPC) were optimized by combination therapy. The resultant clinical regimens of meropenem, polymyxin-B, and sulbactam evaluated in the PK-PD analysis were 2 g q8h, 2.5 mg/kg loading dose followed by 1.5 mg/kg q12h, and 3 g q8h, respectively, in patients with normal renal function. Subsequent corresponding equivalent exposure regimens would depend on the extent of renal failure. The overall results indicate that combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can confer potential efficacy against A. baumannii harboring OXA-23, and reduce the opportunity for bacteria to develop further resistance. This study provides a framework for pharmacodynamic evaluation of drug-resistant mutant suppression in an antimicrobial co-administration setting. The results thereby lay the groundwork for additional studies and future clinical confirmation is warranted.

Macrocyclization of Quinazoline-Based EGFR Inhibitors Leads to Exclusive Mutant Selectivity for EGFR L858R and Del19.

Activating mutations in the epidermal growth factor receptor (EGFR) are frequent oncogenic drivers of non-small-cell lung cancer (NSCLC). The most frequent alterations in EGFR are short in-frame deletions in exon 19 (Del19) and the missense mutation L858R, which both lead to increased activity and sensitization of NSCLC to EGFR inhibition. The first approved EGFR inhibitors used for first-line treatment of NSCLC, gefitinib and erlotinib, are quinazoline-based. However, both inhibitors have several known off-targets, and they also potently inhibit wild-type (WT) EGFR, resulting in side effects. Here, we applied a macrocyclic strategy on a quinazoline-based scaffold as a proof-of-concept study with the goal of increasing kinome-wide selectivity of this privileged inhibitor scaffold. Kinome-wide screens and SAR studies yielded 3f, a potent inhibitor for the most common EGFR mutation (EGFR Del19: 119 nM) with selectivity against the WT receptor (EGFR: >10 μM) and the kinome.

Optimizing Antibody-Antigen Binding Affinities with the ADAPT Platform.

The ADAPT (Assisted Design of Antibody and Protein Therapeutics) platform guides the selection of mutants that improve/modulate the affinity of antibodies and other biologics. Predicted affinities are based on a consensus z-score from three scoring functions. Computational predictions are interleaved with experimental validation, significantly enhancing the robustness of the design and selection of mutants. A key step is an initial exhaustive virtual single-mutant scan that identifies hot spots and the mutations predicted to improve affinity. A small number of proposed single mutants are then produced and assayed. Only the validated single mutants (i.e., having improved affinity) are used to design double and higher-order mutants in subsequent rounds of design, avoiding the combinatorial explosion that arises from random mutagenesis. Typically, with a total of about 30-50 designed single, double, and triple mutants, affinity improvements of 10- to 100-fold are obtained.

Structure-based modification of ortho-amidophenylaminopyrimidines as a novel mutant EGFR inhibitor against resistant non-small cell lung cancer

The challenge of acquired drug resistance in patients with epidermal growth factor receptor (EGFR)-mediated non-small cell lung cancer (NSCLC) has not been overcome, especially the tertiary C797S mutation of EGFR. Herein, it was reported the structure-based design of ortho-amidophenylaminopyrimidines as new mutant EGFR (EGFRL858R/T790M/C797S and EGFRL858R/T790M) inhibitors (type I‒II). Among them, target Ⅱd exhibited the strongest activity against EGFRL858R/ T790M/C797S (IC50=5.51 nM) and EGFRL858R/T790M (IC50=33.35 nM) kinases, and suppressed Ba/F3 cells harboring EGFRL858R/ T790M/C797S and EGFR19Del/T790M/C797S mutants with IC50 values of 0.433 μM and 1.485 μM, respectively. In particular, compared with Ⅰb (IC50=3.656 μM) which was the best inhibitor of type I, Ⅱd (IC50=0.442 μM) displayed enhanced antiproliferative effect against gefitinib-resistant H1975 cells harboring the EGFRL858R/T790M mutation. Ⅱd also demonstrated promising EGFRL858R/T790M/C797S mutant selectivity, and was 70-fold less potent against the wild type EGFR. In addition, Ⅱd behaved low toxicity against the normal human liver cells L02, which was 28-fold less potent. Moreover, both DAPI staining and apoptosis assays demonstrated that Ⅱd induced apoptosis in the resistant H1975 cells. Cycle assays showed that Ⅱd arrested the cell cycle at the G2/M phase. Western blot analysis revealed that Ⅱd suppressed phosphorylation of the EGFR and the downstream signaling ERK1/2 level in NSCLC cells. Hence, these results suggested that Ⅱd might be useful as a potent mutant EGFR inhibitor and was effective in both third- and fourth-generation EGFR-mutant NSCLC, the activity would not be limited by the C797S mutation for further development in the treatment of resistant NSCLC.

MT-Forward Algorithm for Prediction of Project Categories Based on Selection of Mutants

Mutation testing is an effective technique for errors. Although effective, mutation testing has the main limitation that it is awfully expensive because it requires a series of tests on each mutant. Therefore, many researchers have focused on presenting various techniques to reduce the cost of mutation testing. In this study, the MT-Forward algorithm was developed. The concept of MT-Forward is mutation testing that connects the selection and prediction methods. As a result of the selection, the mutant operator can make a more efficient selection of the number of mutants obtained. The shrinkage of the selected mutants was from 1,019 live mutants to 749 live mutants as a priority. There are 15 features used in this study. The required features are obtained from the Locmetrix Test, Coverage Test, and Mutation Testing. The accuracy value of each method is almost the same, which distinguishes this study is the selection of important operators who prioritize improvement programs without reducing the level of accuracy. Where the PMS Method uses 43 Mutant Operators, PMT Method 22 Mutant Operators, while MT-Forward uses 7 mutant operators as priority mutant operators. The method used to evaluate the performance of the algorithm is 5-fold cross-validation. The accuracy of each method is PMS 57.14%, PMT Method 57.14%, and MT-Forward is 95.00%. MT-Forward states that combining mutant selection techniques and project category prediction is important for fixing faults.

Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant Acinetobacter baumannii.

Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant Acinetobacter baumannii at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit in vitro synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of A. baumannii harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant A. baumannii and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize fTMSW and fT>MPC from drug exposures in the blood. Mean fT>MPC were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean fTMSW was reduced to <30% and <15%, respectively, in the triple antibiotic combination. Due to the low free drug concentration of amikacin and polymyxin-B simulated in the epithelial lining fluid, the two predicted pharmacodynamic parameters in the lung after intravenous administration were not optimal even in the combination therapy setting.

Biochemical studies highlight determinants for metal selectivity in the Escherichia coli periplasmic solute binding protein NikA.

Nickel is an essential micronutrient for the survival of many microbes. On account of the toxicity of nickel and its scarcity in the environment, microbes have evolved specific systems for uptaking and delivering nickel to enzymes. NikA, the solute binding protein for the ATP-binding cassette (ABC) importer NikABCDE, plays a vital role in the nickel homeostasis of Escherichia coli by selectively binding nickel over other metals in the metabolically complex periplasm. While the endogenous ligand for NikA is known to be the Ni(II)-(L-His)2 complex, the molecular basis by which NikA selectively binds Ni(II)-(L-His)2 is unclear, especially considering that NikA can bind multiple metal-based ligands with comparable affinity. Here we show that, regardless of its promiscuous binding activity, NikA preferentially interacts with Ni(II)-(L-His)2, even over other metal-amino acid ligands with an identical coordination geometry for the metal. Replacing both the Ni(II) and the L-His residues in Ni(II)-(L-His)2 compromises binding of the ligand to NikA, in part because these alterations affect the degree by which NikA closes around the ligand. Replacing H416, the only NikA residue that ligates the Ni(II), with other potential metal-coordinating amino acids decreases the binding affinity of NikA for Ni(II)-(L-His)2 and compromises uptake of Ni(II) into E. coli cells, likely due to altered metal selectivity of the NikA mutants. Together, the biochemical and in vivo studies presented here define key aspects of how NikA selects for Ni(II)-(L-His)2 over other metal complexes, and can be used as a reference for studies into the metal selectivity of other microbial solute binding proteins.

Directed Evolution of Soluble α-1,2-Fucosyltransferase Using Kanamycin Resistance Protein as a Phenotypic Reporter for Efficient Production of 2'-Fucosyllactose.

2'-Fucosyllactose (2'-FL), the most abundant fucosylated oligosaccharide in human milk, has multiple beneficial effects on human health. However, its biosynthesis by metabolically engineered Escherichia coli is often hampered owing to the insolubility and instability of α-1,2-fucosyltransferase (the rate-limiting enzyme). In this study, we aimed to enhance 2'-FL production by increasing the expression of soluble α-1,2-fucosyltransferase from Helicobacter pylori (FucT2). Because structural information regarding FucT2 has not been unveiled, we decided to improve the expression of soluble FucT2 in E. coli via directed evolution using a protein solubility biosensor that links protein solubility to antimicrobial resistance. For such a system to be viable, the activity of kanamycin resistance protein (KanR) should be dependent on FucT2 solubility. KanR was fused to the C-terminus of mutant libraries of FucT2, which were generated using a combination of error-prone PCR and DNA shuffling. Notably, one round of the directed evolution process, which consisted of mutant library generation and selection based on kanamycin resistance, resulted in a significant increase in the expression level of soluble FucT2. As a result, a batch fermentation with the ΔL M15 pBCGW strain, expressing the FucT2 mutant (F#1-5) isolated from the first round of the directed evolution process, resulted in the production of 0.31 g/l 2'-FL with a yield of 0.22 g 2'-FL/g lactose, showing 1.72- and 1.51-fold increase in the titer and yield, respectively, compared to those of the control strain. The simple and powerful method developed in this study could be applied to enhance the solubility of other unstable enzymes.

Characterization of Mungbean Mutants [Vigna radiata (L.) Wilczek] in M4 and M5 Generations

Background: An understanding the mungbean mutant lines with the check varieties can help in identifying mutants in better adoption. The present experiment was conducted to assess the genetic variation and morpho-metric characteristics of mungbean mutants in M4 and M5 generation. Methods: A set of 7 M3 progenies along with parent Pratap and 5 check was evaluated for M4 and M5 generation using randomized complete block design with three replications during kharif 2018 and summer 2019 in the experimental area of Instructional cum Research Farm, College of Agriculture, Assam Agricultural University, Jorhat, Assam. Result: Significant differences were observed for most of the traits in both M4 and M5 generation. High heritability estimate coupled with high genetic advance as per cent of mean was documented for numbers of branches per plant, pods per plant, percentage of disease incidence, 100 seeds weight and seed yield per plant in both the generation indicate the pre-ponderance of additive gene action. Seed yield per plant was found to be significantly and positively correlated with numbers of pods per cluster, seeds per pod, pod length and 100 seeds weight at genotypic and phenotypic level in both M4 and M5 generation. The traits 100 seeds weight and branches per plant had showed positive direct effect on seed yield in both the generations; hence these two traits might be most effective for selection of higher yield mutants in mung bean.

Evolution of Quorum Sensing in Pseudomonas aeruginosa Can Occur via Loss of Function and Regulon Modulation.

ABSTRACTPseudomonas aeruginosa populations evolving in cystic fibrosis lungs, animal hosts, natural environments and in vitro undergo extensive genetic adaption and diversification. A common mutational target is the quorum sensing (QS) system, a three-unit regulatory system that controls the expression of virulence factors and secreted public goods. Three evolutionary scenarios have been advocated to explain selection for QS mutants: (i) disuse of the regulon, (ii) cheating through the exploitation of public goods, or (ii) modulation of the QS regulon. Here, we examine these scenarios by studying a set of 61 QS mutants from an experimental evolution study. We observed nonsynonymous mutations in all three QS systems: Las, Rhl, and Pseudomonas Quinolone Signal (PQS). The majority of the Las mutants had large deletions of the Las regulon, resulting in loss of QS function and the inability to produce QS-regulated traits, thus supporting the first or second scenarios. Conversely, phenotypic and gene expression analyses of Rhl mutants support network modulation (third scenario), as these mutants overexpressed the Las and Rhl receptors and showed an altered QS-regulated trait production profile. PQS mutants also showed patterns of regulon modulation leading to strain diversification and phenotypic tradeoffs, where the upregulation of certain QS traits is associated with the downregulation of others. Overall, our results indicate that mutations in the different QS systems lead to diverging effects on the QS trait profile in P. aeruginosa populations. These mutations might not only affect the plasticity and diversity of evolved populations but could also impact bacterial fitness and virulence in infections.IMPORTANCE Pseudomonas aeruginosa uses quorum sensing (QS), a three-unit multilayered network, to coordinate expression of traits required for growth and virulence in the context of infections. Despite its importance for bacterial fitness, the QS regulon appears to be a common mutational target during long-term adaptation of P. aeruginosa in the host, natural environments, and experimental evolutions. This raises questions of why such an important regulatory system is under selection and how mutations change the profile of QS-regulated traits. Here, we examine a set of 61 experimentally evolved QS mutants to address these questions. We found that mutations involving the master regulator, LasR, resulted in an almost complete breakdown of QS, while mutations in RhlR and PqsR resulted in modulations of the regulon, where both the regulon structure and the QS-regulated trait profile changed. Our work reveals that natural selection drives diversification in QS activity patterns in evolving populations.

Domestication of newly evolved hexaploid wheat-A journey of wild grass to cultivated wheat.

Domestication of wheat started with the dawn of human civilization. Since then, improvement in various traits including resistance to diseases, insect pests, saline and drought stresses, grain yield, and quality were improved through selections by early farmers and then planned hybridization after the discovery of Mendel’s laws. In the 1950s, genetic variability was created using mutagens followed by the selection of superior mutants. Over the last 3 decades, research was focused on developing superior hybrids, initiating marker-assisted selection and targeted breeding, and developing genetically modified wheat to improve the grain yield, tolerance to drought, salinity, terminal heat and herbicide, and nutritive quality. Acceptability of genetically modified wheat by the end-user remained a major hurdle in releasing into the environment. Since the beginning of the 21st century, changing environmental conditions proved detrimental to achieving sustainability in wheat production particularly in developing countries. It is suggested that high-tech phenotyping assays and genomic procedures together with speed breeding procedures will be instrumental in achieving food security beyond 2050.

Practical Mutation Testing at Scale: A view from Google

Mutation analysis assesses a test suite’s adequacy by measuring its ability to detect small artificial faults, systematically seeded into the tested program. Mutation analysis is considered one of the strongest test-adequacy criteria. Mutation testing builds on top of mutation analysis and is a testing technique that uses mutants as test goals to create or improve a test suite. Mutation testing has long been considered intractable because the sheer number of mutants that can be created represents an insurmountable problem–both in terms of human and computational effort. This has hindered the adoption of mutation testing as an industry standard. For example, Google has a codebase of two billion lines of code and more than 150,000,000 tests are executed on a daily basis. The traditional approach to mutation testing does not scale to such an environment; even existing solutions to speed up mutation analysis are insufficient to make it computationally feasible at such a scale. To address these challenges, this paper presents a scalable approach to mutation testing based on the following main ideas: (1) mutation testing is done incrementally, mutating only <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">changed code</i> during code review, rather than the entire code base; (2) mutants are filtered, removing mutants that are likely to be irrelevant to developers, and limiting the number of mutants per line and per code review process; (3) mutants are selected based on the historical performance of mutation operators, further eliminating irrelevant mutants and improving mutant quality. This paper empirically validates the proposed approach by analyzing its effectiveness in a code-review-based setting, used by more than 24,000 developers on more than 1,000 projects. The results show that the proposed approach produces orders of magnitude fewer mutants and that context-based mutant filtering and selection improve mutant quality and actionability. Overall, the proposed approach represents a mutation testing framework that seamlessly integrates into the software development workflow and is applicable to industrial settings of any size.

Comparative analysis of gamma rays and electron beam in altering rice (Oryza sativa L.) grain size

Main objective of this study was to alter the grain size of drought tolerant Anna (R) 4 rice variety, because it fetches less market due to its long slender grain type. Hence to reduce the grain size, the seeds of Anna (R) 4rice were irradiated with physical mutagens namely gamma rays and electron beam. The small grain size mutants from 200, 250, 300 and 350 Gy were advanced to M2 and further generations. The maximum kernel length reduction obtained was 6.04 and 5.71 mm in M2 generation of gamma rays and electron beam respectively. On selection of small grain mutants over generations, the more number of mutants was realisedfrom electron beam in M4 generation especially at 300 Gy, in terms of reduced kernel length, kernel width and grain weight. This offers chance to selecting early maturing and high grain yield per plant over wild type. These findings indicated that mutation approach by electron beam offers high chance of getting small grain size mutants as well as grain yield improvement than gamma rays.

Drug Combinations to Prevent Antimicrobial Resistance: Various Correlations and Laws, and Their Verifications, Thus Proposing Some Principles and a Preliminary Scheme.

Antimicrobial resistance (AMR) has been a serious threat to human health, and combination therapy is proved to be an economic and effective strategy for fighting the resistance. However, the abuse of drug combinations conversely accelerates the spread of AMR. In our previous work, we concluded that the mutant selection indexes (SIs) of one agent against a specific bacterial strain are closely related to the proportions of two agents in a drug combination. To discover probable correlations, predictors and laws for further proposing feasible principles and schemes guiding the AMR-preventing practice, here, three aspects were further explored. First, the power function (y = axb, a > 0) correlation between the SI (y) of one agent and the ratio (x) of two agents in a drug combination was further established based on the mathematical and statistical analyses for those experimental data, and two rules a1 × MIC1 = a2 × MIC2 and b1 + b2 = −1 were discovered from both equations of y = a1xb1 and y = a2xb2 respectively for two agents in drug combinations. Simultaneously, it was found that one agent with larger MPC alone for drug combinations showed greater potency for narrowing itself MSW and preventing the resistance. Second, a new concept, mutation-preventing selection index (MPSI) was proposed and used for evaluating the mutation-preventing potency difference of two agents in drug combination; a positive correlation between the MPSI and the mutant prevention concentration (MPC) or minimal inhibitory concentration (MIC) was subsequently established. Inspired by this, the significantly positive correlation, contrary to previous reports, between the MIC and the corresponding MPC of antimicrobial agents against pathogenic bacteria was established using 181 data pairs reported. These results together for the above three aspects indicate that the MPCs in alone and combination are very important indexes for drug combinations to predict the mutation-preventing effects and the trajectories of collateral sensitivity, and while the MPC of an agent can be roughly calculated from its corresponding MIC. Subsequently, the former conclusion was further verified and improved via antibiotic exposure to 43 groups designed as different drug concentrations and various proportions. The results further proposed that the C/MPC for the agent with larger proportion in drug combinations can be considered as a predictor and is the key to judge whether the resistance and the collateral sensitivity occur to two agents. Based on these above correlations, laws, and their verification experiments, some principles were proposed, and a diagram of the mutation-preventing effects and the resistant trajectories for drug combinations with different concentrations and ratios of two agents was presented. Simultaneously, the reciprocal of MPC alone (1/MPC), proposed as the stress factors of two agents in drug combinations, together with their SI in combination, is the key to predict the mutation-preventing potency and control the trajectories of collateral sensitivity. Finally, a preliminary scheme for antimicrobial combinations preventing AMR was further proposed for subsequent improvement research and clinic popularization, based on the above analyses and discussion. Moreover, some similar conclusions were speculated for triple or multiple drug combinations.

Connecting environmental and evolutionary microbiology for the development of new agrobiotechnological tools.

Connecting environmental and evolutionary microbiology for the development of new agrobiotechnological tools.

A Literature Review on Recent Advancements in the Treatment of Human Immunodeficiency Virus

Abstract: The aim of this study is to conduct an extensive literature review on recent advancements in the treatment of human immunodeficiency virus (HIV). This is because in extant studies, the care of the HIV infected patient has changed dramatically in the last few years. Potent new antiretroviral drugs combined with updated treatment strategies have now achieved efficient inhibition of HIV replication in most patients. Classes of drugs include both nucleoside and non-nucleoside inhibitors of the viral enzyme reverse transcriptase (RT) and inhibitors of the viral protease and integrase enzymes. The methodology used in this study was reviewed from secondary sources of information including journals, articles, newspaper, and textbooks. In this study, authors found that a major drawback of the highly active antiretroviral therapy (HAART) is the selection of resistant mutants under suboptimal dosage, in advanced stages of disease or after pre-treatment with mono- or double-combination regimens. In addition, monitoring of antiretroviral therapy is achieved by measurement of viral load using nucleic acid amplification techniques. Strict adherence to HIV drug regimens was reported to be essential for reaching and maintaining therapeutic levels of anti-retro-virals and avoiding development of drug-resistant HIV strains. This strict dosage-taking adherence makes HIV therapies among the most challenging treatments with which to adhere. Future researchers are encouraged to adopt a scientific approach in investigating the various constructs that have emerged in this study in other to provide more generalized findings for the research community and public policy makers. Keywords: Antiretroviral Drugs: Combination Therapy: Medication: Transmission: Inhibitors: Immune System.