scholarly journals Exploiting the “survival of the likeliest” to enable evolution-guided drug design

2019 ◽  
Author(s):  
Chuan Liu ◽  
Scott M. Leighow ◽  
Haider Inam ◽  
Boyang Zhao ◽  
Justin R. Pritchard
Keyword(s):  
Drug Resistance ◽  
Drug Design ◽  
Large Scale ◽  
Evolutionary Dynamics ◽  
Stochastic Dynamics ◽  
Genetic Resistance ◽  
Experimental Studies ◽  
New Paradigm ◽  
Resistant Species ◽  
Codon Substitution

SummaryTheoretical treatments of evolutionary dynamics tend to model the probability that a single “resistant” species will arise in a population. However, experimental studies have identified a diversity of mutations that can lead to genetic resistance. By quantitatively predicting mutations that occur across an entire drug target during treatment, we identify and bridge a fundamental gap in drug resistance theory: that nucleotide/codon substitution biases can dictate which resistant variants arise in the clinic. We find that the likeliest mutation can beat the most resistant mutation. This creates a new paradigm in drug resistance that we term“survival of the likeliest”. We use epidemiological evidence in leukemia, isogenic experiments, stochastic dynamics, and large-scale simulations to support this theory. In addition, this work has strong implications for drug design because not all resistance liabilities are created equal. In pathogenic populations that exhibit survival of the likeliest, exploiting the least likely evolutionary path can minimize resistance across a population during widespread drug use, even when a vulnerability-free molecule or combination cannot be made.Data and Code Availabilityhttps://github.com/pritchardlabatpsu/SurvivalOfTheLikeliest/

Within-Host Viral Diversity: A Window into Viral Evolution

2020 ◽  
Vol 7 (1) ◽  
pp. 63-81 ◽  
Author(s):  
Adam S. Lauring
Keyword(s):  
Large Scale ◽  
Evolutionary Dynamics ◽  
Viral Evolution ◽  
Experimental Studies ◽  
Disease Spread ◽  
Viral Diversity ◽  
Host Diversity ◽  
Models Of Disease ◽  
Host Evolution ◽  
Viral Sequencing

The evolutionary dynamics of a virus can differ within hosts and across populations. Studies of within-host evolution provide an important link between experimental studies of virus evolution and large-scale phylodynamic analyses. They can determine the extent to which global processes are recapitulated on local scales and how accurately experimental infections model natural ones. They may also inform epidemiologic models of disease spread and reveal how host-level dynamics contribute to a virus's evolution at a larger scale. Over the last decade, advances in viral sequencing have enabled detailed studies of viral genetic diversity within hosts. I review how within-host diversity is sampled, measured, and expressed, and how comparative studies of viral diversity can be leveraged to elucidate a virus's evolutionary dynamics. These concepts are illustrated with detailed reviews of recent research on the within-host evolution of influenza virus, dengue virus, and cytomegalovirus.

Cloud Computing for BioLabs

2015 ◽  
pp. 1272-1293
Author(s):  
Abraham Pouliakis ◽  
Aris Spathis ◽  
Christine Kottaridi ◽  
Antonia Mourtzikou ◽  
Marilena Stamouli ◽  
...  
Keyword(s):  
Cloud Computing ◽  
Data Analysis ◽  
Drug Design ◽  
Large Scale ◽  
Future Research ◽  
New Paradigm ◽  
Computing Power ◽  
The Everyday ◽  
Potential Applications ◽  
Computational Resources

Cloud computing has quickly emerged as an exciting new paradigm providing models of computing and services. Via cloud computing technology, bioinformatics tools can be made available as services to anyone, anywhere, and via any device. Large bio-datasets, highly complex algorithms, computing power demanding analysis methods, and the sudden need for hardware and computational resources provide an ideal environment for large-scale bio-data analysis for cloud computing. Cloud computing is already applied in the fields of biology and biochemistry, via numerous paradigms providing novel ideas stimulating future research. The concept of BioCloud has rapidly emerged with applications related to genomics, drug design, biology tools on the cloud, bio-databases, cloud bio-computing, and numerous applications related to biology and biochemistry. In this chapter, the authors present research results related to biology-related laboratories (BioLabs) as well as potential applications for the everyday clinical routine.

Cloud Computing for BioLabs

2014 ◽  
pp. 228-249 ◽  
Author(s):  
Abraham Pouliakis ◽  
Aris Spathis ◽  
Christine Kottaridi ◽  
Antonia Mourtzikou ◽  
Marilena Stamouli ◽  
...  
Keyword(s):  
Cloud Computing ◽  
Data Analysis ◽  
Drug Design ◽  
Large Scale ◽  
Future Research ◽  
New Paradigm ◽  
Computing Power ◽  
The Everyday ◽  
Potential Applications ◽  
Computational Resources

Cloud computing has quickly emerged as an exciting new paradigm providing models of computing and services. Via cloud computing technology, bioinformatics tools can be made available as services to anyone, anywhere, and via any device. Large bio-datasets, highly complex algorithms, computing power demanding analysis methods, and the sudden need for hardware and computational resources provide an ideal environment for large-scale bio-data analysis for cloud computing. Cloud computing is already applied in the fields of biology and biochemistry, via numerous paradigms providing novel ideas stimulating future research. The concept of BioCloud has rapidly emerged with applications related to genomics, drug design, biology tools on the cloud, bio-databases, cloud bio-computing, and numerous applications related to biology and biochemistry. In this chapter, the authors present research results related to biology-related laboratories (BioLabs) as well as potential applications for the everyday clinical routine.

The sugar and alcohol industry in the biofuels and cogeneration era: a paradigm change (part II)

2014 ◽  
pp. 97-104 ◽  
Author(s):  
Electo Eduardo Silv Lora ◽  
Mateus Henrique Rocha ◽  
José Carlos Escobar Palacio ◽  
Osvaldo José Venturini ◽  
Maria Luiza Grillo Renó ◽  
...  
Keyword(s):  
Large Scale ◽  
New Technologies ◽  
Process Integration ◽  
Animal Feed ◽  
Raw Materials ◽  
Biofuel Production ◽  
New Paradigm ◽  
Alcohol Industry ◽  
Feed Production ◽  
Steam Parameters

The aim of this paper is to discuss the major technological changes related to the implementation of large-scale cogeneration and biofuel production in the sugar and alcohol industry. The reduction of the process steam consumption, implementation of new alternatives in driving mills, the widespread practice of high steam parameters use in cogeneration facilities, the insertion of new technologies for biofuels production (hydrolysis and gasification), the energy conversion of sugarcane trash and vinasse, animal feed production, process integration and implementation of the biorefinery concept are considered. Another new paradigm consists in the wide spreading of sustainability studies of products and processes using the Life Cycle Assessment (LCA) and the implementation of sustainability indexes. Every approach to this issue has as an objective to increase the economic efficiency and the possibilities of the sugarcane as a main source of two basic raw materials: fibres and sugar. The paper briefly presents the concepts, indicators, state-of-the-art and perspectives of each of the referred issues.

Recent Advances in the Rational Drug Design Based on Multi-target Ligands

2020 ◽  
Vol 27 (28) ◽  
pp. 4720-4740 ◽  
Author(s):  
Ting Yang ◽  
Xin Sui ◽  
Bing Yu ◽  
Youqing Shen ◽  
Hailin Cong
Keyword(s):  
Drug Resistance ◽  
Clinical Practice ◽  
Side Effects ◽  
Drug Design ◽  
Rational Drug Design ◽  
Health Conditions ◽  
Pharmacokinetic Parameters ◽  
Single Target ◽  
Rational Drug ◽  
Huge Challenge

Multi-target drugs have gained considerable attention in the last decade owing to their advantages in the treatment of complex diseases and health conditions linked to drug resistance. Single-target drugs, although highly selective, may not necessarily have better efficacy or fewer side effects. Therefore, more attention is being paid to developing drugs that work on multiple targets at the same time, but developing such drugs is a huge challenge for medicinal chemists. Each target must have sufficient activity and have sufficiently characterized pharmacokinetic parameters. Multi-target drugs, which have long been known and effectively used in clinical practice, are briefly discussed in the present article. In addition, in this review, we will discuss the possible applications of multi-target ligands to guide the repositioning of prospective drugs.

scholarly journals Leisure Time Sports Activities and Life Satisfaction: Deeper Insights Based on a Representative Survey from Germany

2020 ◽  
Author(s):  
Michael Mutz ◽  
Anne K. Reimers ◽  
Yolanda Demetriou
Keyword(s):  
Life Satisfaction ◽  
Large Scale ◽  
Leisure Time ◽  
Organizational Context ◽  
Experimental Studies ◽  
Well Being ◽  
Activity Level ◽  
Leisure Satisfaction ◽  
General Life Satisfaction ◽  
Sports Activities

Abstract Observational and experimental studies show that leisure time sporting activity (LTSA) is associated with higher well-being. However, scholars often seem to assume that 1) LTSA fosters “general” life satisfaction, thereby ignoring effects on domain satisfaction; 2) the effect of LTSA on well-being is linear and independent of a person’s general activity level; 3) the amount of LTSA is more important than the repertoire of LTSA, i.e. the number of different activities; 4) all kinds of LTSA are equal in their effects, irrespective of spatial and organisational context conditions. Using data from the German SALLSA-Study (“Sport, Active Lifestyle and Life Satisfaction”), a large-scale CAWI-Survey (N = 1008) representing the population ≥ 14 years, the paper takes a closer look on these assumptions. Findings demonstrate that LTSA is associated with general life satisfaction and domain-specific satisfaction (concerning relationships, appearance, leisure, work and health), but that the relationship is most pronounced for leisure satisfaction. Associations of sport with life satisfaction, leisure satisfaction and subjective health are non-linear, approaching an injection point from which on additional LTSA is no longer beneficial. Moreover, findings lend support to the notion that diversity in LTSA matters, as individuals with higher variation in sports activities are more satisfied. Finally, results with regard to spatial and organizational context suggest that outdoor sports and club-organized sports have additional benefits.

scholarly journals Why does the spread of COVID-19 vary greatly in different countries? Revealing the efficacy of face masks in epidemic prevention

2021 ◽  
Vol 149 ◽  
Author(s):  
Jincheng Wei ◽  
Shurui Guo ◽  
Enshen Long ◽  
Li Zhang ◽  
Bizhen Shu ◽  
...  
Keyword(s):  
Social Isolation ◽  
Large Scale ◽  
Experimental Studies ◽  
Weighted Average ◽  
Filtration Efficiency ◽  
Volume Distribution ◽  
Particle Sizes ◽  
Economic Activities ◽  
Protection Measure ◽  
Source Of Infection

Abstract The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is highly contagious, and the coronavirus disease 2019 (COVID-19) pandemic caused by it has forced many countries to adopt ‘lockdown’ measures to prevent the spread of the epidemic through social isolation of citizens. Some countries proposed universal mask wearing as a protection measure of public health to strengthen national prevention efforts and to limit the wider spread of the epidemic. In order to reveal the epidemic prevention efficacy of masks, this paper systematically evaluates the experimental studies of various masks and filter materials, summarises the general characteristics of the filtration efficiency of isolation masks with particle size, and reveals the actual efficacy of masks by combining the volume distribution characteristics of human exhaled droplets with different particle sizes and the SARS-CoV-2 virus load of nasopharynx and throat swabs from patients. The existing measured data show that the filtration efficiency of all kinds of masks for large particles and extra-large droplets is close to 100%. From the perspective of filtering the total number of pathogens discharged in the environment and protecting vulnerable individuals from breathing live viruses, the mask has a higher protective effect. If considering the weighted average filtration efficiency with different particle sizes, the filtration efficiencies of the N95 mask and the ordinary mask are 99.4% and 98.5%, respectively. The mask can avoid releasing active viruses to the environment from the source of infection, thus maximising the protection of vulnerable individuals by reducing the probability of inhaling a virus. Therefore, if the whole society strictly implements the policy of publicly wearing masks, the risk of large-scale spread of the epidemic can be greatly reduced. Compared with the overall cost of social isolation, limited personal freedoms and forced suspension of economic activities, the inconvenience for citizens caused by wearing masks is perfectly acceptable.

scholarly journals Evolutionary Genetics of Mycobacterium tuberculosis and HIV-1: “The Tortoise and the Hare”

2021 ◽  
Vol 9 (1) ◽  
pp. 147
Author(s):  
Ana Santos-Pereira ◽  
Carlos Magalhães ◽  
Pedro M. M. Araújo ◽  
Nuno S. Osório
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Evolutionary Dynamics ◽  
Evolutionary Genetics ◽  
Host Cells ◽  
Whole Genome Sequencing Data ◽  
Host Immune System ◽  
Viral Mutant ◽  
Hiv 1

The already enormous burden caused by Mycobacterium tuberculosis and Human Immunodeficiency Virus type 1 (HIV-1) alone is aggravated by co-infection. Despite obvious differences in the rate of evolution comparing these two human pathogens, genetic diversity plays an important role in the success of both. The extreme evolutionary dynamics of HIV-1 is in the basis of a robust capacity to evade immune responses, to generate drug-resistance and to diversify the population-level reservoir of M group viral subtypes. Compared to HIV-1 and other retroviruses, M. tuberculosis generates minute levels of genetic diversity within the host. However, emerging whole-genome sequencing data show that the M. tuberculosis complex contains at least nine human-adapted phylogenetic lineages. This level of genetic diversity results in differences in M. tuberculosis interactions with the host immune system, virulence and drug resistance propensity. In co-infected individuals, HIV-1 and M. tuberculosis are likely to co-colonize host cells. However, the evolutionary impact of the interaction between the host, the slowly evolving M. tuberculosis bacteria and the HIV-1 viral “mutant cloud” is poorly understood. These evolutionary dynamics, at the cellular niche of monocytes/macrophages, are also discussed and proposed as a relevant future research topic in the context of single-cell sequencing.

scholarly journals Frontline Maintenance Treatment for Ovarian Cancer

2021 ◽  
Vol 23 (8) ◽  
Author(s):  
Osnat Elyashiv ◽  
Yien Ning Sophia Wong ◽  
Jonathan A. Ledermann
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Dna Repair ◽  
Maintenance Treatment ◽  
Advanced Disease ◽  
Disease Recurrence ◽  
Primary Treatment ◽  
New Paradigm ◽  
Maintenance Strategies ◽  
Advanced Epithelial Ovarian Cancer

Abstract Purpose of Review Advanced epithelial ovarian cancer remains the most lethal gynaecological cancer. Most patients with advanced disease will relapse within 3 years after primary treatment with surgery and chemotherapy. Recurrences become increasing difficult to treat due to the emergence of drug resistance and 5-year survival has changed little over the last decade. Maintenance treatment, here defined as treatment given beyond primary chemotherapy, can both consolidate the response and prolong the control of disease which is an approach to improve survival. Recent Findings Here we review maintenance strategies such as targeting angiogenesis, interference of DNA repair through inhibition of PARP, combinations of targeting agents, and immunotherapy and hormonal therapy. Summary Much has been learnt from the success and challenges of these treatments that have in the last few years which led to significant reduction in disease recurrence, changed the guidelines for treatment, and established a new paradigm for the treatment of ovarian cancer.

scholarly journals Interventions to optimize medication use in nursing homes: a narrative review

2021 ◽  
Author(s):  
Anne Spinewine ◽  
Perrine Evrard ◽  
Carmel Hughes
Keyword(s):  
Nursing Homes ◽  
Large Scale ◽  
Adverse Drug Events ◽  
Experimental Studies ◽  
Medication Use ◽  
Nursing Home Residents ◽  
Qualitative Studies ◽  
Patient Centered ◽  
Barriers And Enablers ◽  
Specific Medication

Abstract Purpose Polypharmacy, medication errors and adverse drug events are frequent among nursing home residents. Errors can occur at any step of the medication use process. We aimed to review interventions aiming at optimization of any step of medication use in nursing homes. Methods We narratively reviewed quantitative as well as qualitative studies, observational and experimental studies that described interventions, their effects as well as barriers and enablers to implementation. We prioritized recent studies with relevant findings for the European setting. Results Many interventions led to improvements in medication use. However, because of outcome heterogeneity, comparison between interventions was difficult. Prescribing was the most studied aspect of medication use. At the micro-level, medication review, multidisciplinary work, and more recently, patient-centered care components dominated. At the macro-level, guidelines and legislation, mainly for specific medication classes (e.g., antipsychotics) were employed. Utilization of technology also helped improve medication administration. Several barriers and enablers were reported, at individual, organizational, and system levels. Conclusion Overall, existing interventions are effective in optimizing medication use. However there is a need for further European well-designed and large-scale evaluations of under-researched intervention components (e.g., health information technology, patient-centered approaches), specific medication classes (e.g., antithrombotic agents), and interventions targeting medication use aspects other than prescribing (e.g., monitoring). Further development and uptake of core outcome sets is required. Finally, qualitative studies on barriers and enablers for intervention implementation would enable theory-driven intervention design.

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