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Genes Oct 2020Cytochrome P450 2D6 () is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including... (Review)
Review
Cytochrome P450 2D6 () is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside.
Topics: Alleles; Cytochrome P-450 CYP2D6; Genotype; Humans; Metabolism, Inborn Errors; Pharmacogenetics; Phenotype; Polymorphism, Genetic
PubMed: 33143137
DOI: 10.3390/genes11111295 -
Viruses Feb 2022Virus-like particles resemble infectious virus particles in size, shape, and molecular composition; however, they fail to productively infect host cells. Historically,... (Review)
Review
Virus-like particles resemble infectious virus particles in size, shape, and molecular composition; however, they fail to productively infect host cells. Historically, the presence of virus-like particles has been inferred from total particle counts by microscopy, and infectious particle counts or plaque-forming-units (PFUs) by plaque assay; the resulting ratio of particles-to-PFUs is often greater than one, easily 10 or 100, indicating that most particles are non-infectious. Despite their inability to hijack cells for their reproduction, virus-like particles and the defective genomes they carry can exhibit a broad range of behaviors: interference with normal virus growth during co-infections, cell killing, and activation or inhibition of innate immune signaling. In addition, some virus-like particles become productive as their multiplicities of infection increase, a sign of cooperation between particles. Here, we review established and emerging methods to count virus-like particles and characterize their biological functions. We take a critical look at evidence for defective interfering virus genomes in natural and clinical isolates, and we review their potential as antiviral therapeutics. In short, we highlight an urgent need to better understand how virus-like genomes and particles interact with intact functional viruses during co-infection of their hosts, and their impacts on the transmission, severity, and persistence of virus-associated diseases.
Topics: Animals; Colony-Forming Units Assay; Defective Viruses; Genome, Viral; Humans; Microscopy, Electron, Transmission; Viral Plaque Assay; Virion; Virus Diseases; Virus Replication
PubMed: 35215979
DOI: 10.3390/v14020383 -
Biology Jul 2022Metabolic rate and its covariation with body mass vary substantially within and among species in little understood ways. Here, I critically review explanations (and... (Review)
Review
Metabolic rate and its covariation with body mass vary substantially within and among species in little understood ways. Here, I critically review explanations (and supporting data) concerning how cell size and number and their establishment by cell expansion and multiplication may affect metabolic rate and its scaling with body mass. Cell size and growth may affect size-specific metabolic rate, as well as the vertical elevation (metabolic level) and slope (exponent) of metabolic scaling relationships. Mechanistic causes of negative correlations between cell size and metabolic rate may involve reduced resource supply and/or demand in larger cells, related to decreased surface area per volume, larger intracellular resource-transport distances, lower metabolic costs of ionic regulation, slower cell multiplication and somatic growth, and larger intracellular deposits of metabolically inert materials in some tissues. A cell-size perspective helps to explain some (but not all) variation in metabolic rate and its body-mass scaling and thus should be included in any multi-mechanistic theory attempting to explain the full diversity of metabolic scaling. A cell-size approach may also help conceptually integrate studies of the biological regulation of cellular growth and metabolism with those concerning major transitions in ontogenetic development and associated shifts in metabolic scaling.
PubMed: 35892962
DOI: 10.3390/biology11081106 -
Virus Evolution Jan 2019Many organisms disperse in groups, yet this process is understudied in viruses. Recent work, however, has uncovered different types of collective infectious units, all... (Review)
Review
Many organisms disperse in groups, yet this process is understudied in viruses. Recent work, however, has uncovered different types of collective infectious units, all of which lead to the joint delivery of multiple viral genome copies to target cells, favoring co-infections. Collective spread of viruses can occur through widely different mechanisms, including virion aggregation driven by specific extracellular components, cloaking inside lipid vesicles, encasement in protein matrices, or binding to cell surfaces. Cell-to-cell viral spread, which allows the transmission of individual virions in a confined environment, is yet another mode of clustered virus dissemination. Nevertheless, the selective advantages of dispersing in groups remain poorly understood in most cases. Collective dispersal might have emerged as a means of sharing efficacious viral transmission vehicles. Alternatively, increasing the cellular multiplicity of infection may confer certain short-term benefits to viruses, such as overwhelming antiviral responses, avoiding early stochastic loss of viral components required for initiating infection, or complementing genetic defects present in different viral genomes. However, increasing infection multiplicity may also entail long-term costs, such as mutation accumulation and the evolution of defective particles or other types of cheater viruses. These costs and benefits, in turn, should depend on the genetic relatedness among collective infectious unit members. Establishing the genetic basis of collective viral dispersal and performing controlled experiments to pinpoint fitness effects at different spatial and temporal scales should help us clarify the implications of these spread modes for viral fitness, pathogenicity, and evolution.
PubMed: 31249695
DOI: 10.1093/ve/vez014 -
Journal of Neurochemistry May 2020Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes... (Review)
Review
Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019: Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.
Topics: Animals; Biomarkers; Congresses as Topic; Humans; Inclusion Bodies; Mutation; Portugal; Synucleinopathies; alpha-Synuclein
PubMed: 31957016
DOI: 10.1111/jnc.14965 -
Heliyon Nov 2022Banana is an important food crop responsible for ensuring food security, nutrition, and employment for a significant portion of the world population. It has fairly broad... (Review)
Review
Banana is an important food crop responsible for ensuring food security, nutrition, and employment for a significant portion of the world population. It has fairly broad genetic diversity and is distributed widely across the globe. Due to its socio-economic importance, there has been growing demand for healthy and improved planting materials of banana. In recent years many companies and organizations are working hard to narrow down the gap between demand and supply of quality planting materials. The other challenges includes its susceptibility to adverse environmental conditions, attack of various pests/pathogens and improvement of nutritional quality of bananas. To address these issues, refinement of existing techniques and introduction of new experimental tools are required. However, the genetic improvement of bananas to a large extent is limited by using conventional methods due to polyploidy, heterozygosity, and sterility of this plant. For rapid multiplication and obtaining disease free and healthy plants, efficient propagation techniques and fine tuning of the existing protocols are being tried in many laboratories across the globe. Besides, for developing a successful protocol for propagation of different cultivars of bananas, a deeper understanding of the factors associated with various steps of its multiplication till transfer to the land is immensely critical. Similarly, developing biotic and abiotic stress tolerant banana and enhancing its commercial value through biotechnological interventions could be very useful. The key intent of this review is to highlight the research endeavor in this direction, associated challenges and future prospects.
PubMed: 36419664
DOI: 10.1016/j.heliyon.2022.e11636 -
Brain Sciences Mar 2022Math fluency is the ability to solve arithmetic facts quickly and accurately (i.e., addition and subtraction problems up to 20, and multiplication and division problems...
Math fluency is the ability to solve arithmetic facts quickly and accurately (i.e., addition and subtraction problems up to 20, and multiplication and division problems from the multiplication table). Curricula in primary school devote a significant period of time for learning and retrieval of arithmetic facts. Recently, a new computerized tool to assess math fluency-the BGU-MF (Ben-Gurion University Math Fluency) test-was developed and found to be a reliable and valid tool for adults. In the current study, we examine the performance of first to sixth-grade children in math fluency using the BGU-MF. The results present the performance of MF during childhood and emphasize that it continues to develop during primary school. Importantly, proficiency of MF differed by operations, and the automaticity of math facts was acquired in different grades. Moreover, we found that the BGU-MF is a reliable and valid tool not only for adults but also for children during primary school. Our study has educational implications for the teaching, practice, and retrieval of arithmetic facts.
PubMed: 35326327
DOI: 10.3390/brainsci12030371 -
Journal of International Relations and... 2022Resilience has become an oft-invoked concept in development and security policy circles and the subject of much debate in the literature. Yet, one aspect that needs to...
Resilience has become an oft-invoked concept in development and security policy circles and the subject of much debate in the literature. Yet, one aspect that needs to be further theorised is the complex relationship between resilience, conflict and gender. This introduction identifies the gradual congruence between the programmatic agendas of the United Nations Security Council Resolution 1325 (UNSCR 1325) and resilience-building approaches in peacebuilding and argues that this convergence needs to be further scrutinised. Our main argument is that it is time for the scholarship to go beyond the simple categorisation of resilience as being either the new paradigmatic solution to international interventions, conflicts and crises or a meaningless and useless governmental buzzword. Instead, the contributions found in this Special Issue see resilience in terms of multiplicity. Resilience, understood in terms of multiplicity and in a multidimensional way, appears a valuable analytical concept to study both the systemic nature of gendered power relations and their prevalence and adaptation over time, as well as the responses of individuals, communities and institutions to the gendered effects of conflict. To add empirical richness to the Special Issue, these conceptual connections are analysed in multiple geographical case studies, including Bosnia and Herzegovina, Sierra Leone, Cote d'Ivoire, Iraq, Liberia, Palestine and Rwanda.
PubMed: 36275638
DOI: 10.1057/s41268-022-00279-7 -
G3 (Bethesda, Md.) Jun 2020The R-package MoBPS provides a computationally efficient and flexible framework to simulate complex breeding programs and compare their economic and genetic impact....
The R-package MoBPS provides a computationally efficient and flexible framework to simulate complex breeding programs and compare their economic and genetic impact. Simulations are performed on the base of individuals. MoBPS utilizes a highly efficient implementation with bit-wise data storage and matrix multiplications from the associated R-package miraculix allowing to handle large scale populations. Individual haplotypes are not stored but instead automatically derived based on points of recombination and mutations. The modular structure of MoBPS allows to combine rather coarse simulations, as needed to generate founder populations, with a very detailed modeling of todays' complex breeding programs, making use of all available biotechnologies. MoBPS provides pre-implemented functions for common breeding practices such as optimum genetic contributions and single-step GBLUP but also allows the user to replace certain steps with personalized and/or self-written solutions.
Topics: Breeding; Humans; Models, Genetic; Myelin Proteins
PubMed: 32229505
DOI: 10.1534/g3.120.401193 -
Medicine Dec 2023To investigate the causal relationship between dried fruit intake and meniscal injuries using Mendelian randomization (MR). Data were pooled from large-scale genome wide...
To investigate the causal relationship between dried fruit intake and meniscal injuries using Mendelian randomization (MR). Data were pooled from large-scale genome wide association studies (GWAS), and genetic loci independently associated with dry fruit intake and meniscal injuries in populations of European origin were selected as instrumental variables. Three MR analyses, inverse variance weighting (IVW), weighted median (WME) and MR-Egger, were used to investigate the causal relationship between dried fruit intake and meniscal injuries. The results were tested for robustness by heterogeneity and multiplicity tests, and sensitivity analyses were performed using the "leave-one-out" method. The IVW results showed an OR (95 % CI) of 0.47 (0.28-0.78), P = .003, indicating a causal relationship between dried fruit intake and meniscus injury. And no heterogeneity and multiplicity were found by the test and sensitivity analysis also showed robust results. The present study used a 2-sample MR analysis, and by analyzing and exploring the genetic data, the study showed that too little intake of dry fruits is a risk factor for meniscal injuries.
Topics: Humans; Fruit; Genome-Wide Association Study; Mendelian Randomization Analysis; Causality; Meniscus
PubMed: 38050257
DOI: 10.1097/MD.0000000000036415