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Dairy consumption and cardiometabolic diseases: systematic review and updated meta-analyses of prospective cohort studies
Purpose of Review Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we
provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by
reviewing the literature and updating meta-analyses of observational studies.
Recent Findings We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and
stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with
a 3β4% lower risk of diabetes. Yogurt was non-linearly inversely associatedwith diabetes (RR = 0.86, 95%CI: 0.83β0.90 at 80 g/
d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with
an 8% lower risk of stroke.
Summary The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic
diseases
Evolution favors protein mutational robustness in sufficiently large populations
BACKGROUND: An important question is whether evolution favors properties such
as mutational robustness or evolvability that do not directly benefit any
individual, but can influence the course of future evolution. Functionally
similar proteins can differ substantially in their robustness to mutations and
capacity to evolve new functions, but it has remained unclear whether any of
these differences might be due to evolutionary selection for these properties.
RESULTS: Here we use laboratory experiments to demonstrate that evolution
favors protein mutational robustness if the evolving population is sufficiently
large. We neutrally evolve cytochrome P450 proteins under identical selection
pressures and mutation rates in populations of different sizes, and show that
proteins from the larger and thus more polymorphic population tend towards
higher mutational robustness. Proteins from the larger population also evolve
greater stability, a biophysical property that is known to enhance both
mutational robustness and evolvability. The excess mutational robustness and
stability is well described by existing mathematical theories, and can be
quantitatively related to the way that the proteins occupy their neutral
network.
CONCLUSIONS: Our work is the first experimental demonstration of the general
tendency of evolution to favor mutational robustness and protein stability in
highly polymorphic populations. We suggest that this phenomenon may contribute
to the mutational robustness and evolvability of viruses and bacteria that
exist in large populations
Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
The Shadows of the Past
We examined associations between two orientations based on historical group trauma, a form of enduring group victimhood (Perpetual Ingroup Victimhood Orientation [PIVO]) and the belief that oneβs group might itself become a victimizer (Fear of Victimizing [FOV]), and attitudes, cognitions, and emotions related to intergroup conflicts. PIVO was positively and FOV was negatively related to aggressive attitudes and emotions toward the outgroup (Studies 1a-1c, IsraeliβPalestinian conflict), and to the attribution of responsibility for a series of hostilities to the outgroup (Study 3, IsraeliβPalestinian conflict). PIVO was negatively and FOV positively related to support for forgiveness and reconciliation (Study 2, Northern Ireland conflict). In Experimental Study 4, FOV predicted greater accuracy in remembering harm, regardless of victimsβ group identity, whereas PIVO was associated with reduced accuracy only when victims were Palestinians (outgroup members). Taken together, these findings indicate that both orientations have a significant impact on intergroup conflicts and their resolution
Extreme genetic fragility of the HIV-1 capsid
Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies
Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles
Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIV's evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally-induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapy's unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long-term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents
Rapid Evolution of Pandemic Noroviruses of the GII.4 Lineage
Over the last fifteen years there have been five pandemics of norovirus (NoV) associated gastroenteritis, and the period of stasis between each pandemic has been progressively shortening. NoV is classified into five genogroups, which can be further classified into 25 or more different human NoV genotypes; however, only one, genogroup II genotype 4 (GII.4), is associated with pandemics. Hence, GII.4 viruses have both a higher frequency in the host population and greater epidemiological fitness. The aim of this study was to investigate if the accuracy and rate of replication are contributing to the increased epidemiological fitness of the GII.4 strains. The replication and mutation rates were determined using in vitro RNA dependent RNA polymerase (RdRp) assays, and rates of evolution were determined by bioinformatics. GII.4 strains were compared to the second most reported genotype, recombinant GII.b/GII.3, the rarely detected GII.3 and GII.7 and as a control, hepatitis C virus (HCV). The predominant GII.4 strains had a higher mutation rate and rate of evolution compared to the less frequently detected GII.b, GII.3 and GII.7 strains. Furthermore, the GII.4 lineage had on average a 1.7-fold higher rate of evolution within the capsid sequence and a greater number of non-synonymous changes compared to other NoVs, supporting the theory that it is undergoing antigenic drift at a faster rate. Interestingly, the non-synonymous mutations for all three NoV genotypes were localised to common structural residues in the capsid, indicating that these sites are likely to be under immune selection. This study supports the hypothesis that the ability of the virus to generate genetic diversity is vital for viral fitness
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