Mutational biases favor complexity increases in protein interaction networks after gene duplication.

Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.

α-(Aminomethyl)acrylates as acceptors in radical-polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping.

We demonstrate that α-(aminomethyl)acrylates are suitable acceptors for 1,4-additions of dialkylzincs in aerobic conditions. The air-promoted radical-polar crossover process involves the 1,4-addition of an alkyl radical followed by homolytic substitution at the zinc atom of dialkylzinc. Coordination of the nitrogen atom to zinc enables this SH2 process which represents a rare example of alkylzinc-group transfer to a tertiary α-carbonyl radical. The zinc enolate thus formed readily undergoes ß-fragmentation unless it is trapped by electrophiles in situ. Enolates of substrates having free N-H bonds undergo protodemetalation to provide ultimately the 1,4-addition adduct. In the presence of carbonyl acceptors, aldol condensation occurs providing overall a tandem 1,4-addition-aldol process. When a tert-butanesulfinyl moiety is present on the nitrogen atom, these electrophilic substitution reactions occur with good levels of chiral induction, paving the way to enantioenriched ß2-amino acids and ß2,2-amino acids.

Epistasis between promoter activity and coding mutations shapes gene evolvability.

The evolution of protein-coding genes proceeds as mutations act on two main dimensions: regulation of transcription level and the coding sequence. The extent and impact of the connection between these two dimensions are largely unknown because they have generally been studied independently. By measuring the fitness effects of all possible mutations on a protein complex at various levels of promoter activity, we show that promoter activity at the optimal level for the wild-type protein masks the effects of both deleterious and beneficial coding mutations. Mutations that are deleterious at low activity but masked at optimal activity are slightly destabilizing for individual subunits and binding interfaces. Coding mutations that increase protein abundance are beneficial at low expression but could potentially incur a cost at high promoter activity. We thereby demonstrate that promoter activity in interaction with protein properties can dictate which coding mutations are beneficial, neutral, or deleterious.

Asymmetrical dose responses shape the evolutionary trade-off between antifungal resistance and nutrient use.

Antimicrobial resistance is an emerging threat for public health. The success of resistance mutations depends on the trade-off between the benefits and costs they incur. This trade-off is largely unknown and uncharacterized for antifungals. Here, we systematically measure the effect of all amino acid substitutions in the yeast cytosine deaminase Fcy1, the target of the antifungal 5-fluorocytosine (5-FC, flucytosine). We identify over 900 missense mutations granting resistance to 5-FC, a large fraction of which appear to act through destabilization of the protein. The relationship between 5-FC resistance and growth sustained by cytosine deamination is characterized by a sharp trade-off, such that small gains in resistance universally lead to large losses in canonical enzyme function. We show that this steep relationship can be explained by differences in the dose-response functions of 5-FC and cytosine. Finally, we observe the same trade-off shape for the orthologue of FCY1 in Cryptoccocus neoformans, a human pathogen. Our results provide a powerful resource and platform for interpreting drug target variants in fungal pathogens as well as unprecedented insights into resistance-function trade-offs.

Correlation between protein abundance and sequence conservation: what do recent experiments say?

Cells evolve in a space of parameter values set by physical and chemical forces. These constraints create associations among cellular properties. A particularly strong association is the negative correlation between the rate of evolution of proteins and their abundance in the cell. Highly expressed proteins evolve slower than lowly expressed ones. Multiple hypotheses have been put forward to explain this relationship, including, for instance, the requirement for higher mRNA stability, misfolding avoidance, and misinteraction avoidance for highly expressed proteins. Here, we review some of these hypotheses, their predictions, and how they are supported to finally discuss recent experiments that have been performed to test these predictions.

BUBR1 Pseudokinase Domain Promotes Kinetochore PP2A-B56 Recruitment, Spindle Checkpoint Silencing, and Chromosome Alignment.

The balance of phospho-signaling at the outer kinetochore is critical for forming accurate attachments between kinetochores and the mitotic spindle and timely exit from mitosis. A major player in determining this balance is the PP2A-B56 phosphatase, which is recruited to the kinase attachment regulatory domain (KARD) of budding uninhibited by benzimidazole 1-related 1 (BUBR1) in a phospho-dependent manner. This unleashes a rapid, switch-like phosphatase relay that reverses mitotic phosphorylation at the kinetochore, extinguishing the checkpoint and promoting anaphase. Here, we demonstrate that the C-terminal pseudokinase domain of human BUBR1 is required to promote KARD phosphorylation. Mutation or removal of the pseudokinase domain results in decreased PP2A-B56 recruitment to the outer kinetochore attenuated checkpoint silencing and errors in chromosome alignment as a result of imbalance in Aurora B activity. Our data, therefore, elucidate a function for the BUBR1 pseudokinase domain in ensuring accurate and timely exit from mitosis.

Similarities in biological processes can be used to bridge ecology and molecular biology.

Much of the research in biology aims to understand the origin of diversity. Naturally, ecological diversity was the first object of study, but we now have the necessary tools to probe diversity at molecular scales. The inherent differences in how we study diversity at different scales caused the disciplines of biology to be organized around these levels, from molecular biology to ecology. Here, we illustrate that there are key properties of each scale that emerge from the interactions of simpler components and that these properties are often shared across different levels of organization. This means that ideas from one level of organization can be an inspiration for novel hypotheses to study phenomena at another level. We illustrate this concept with examples of events at the molecular level that have analogs at the organismal or ecological level and vice versa. Through these examples, we illustrate that biological processes at different organization levels are governed by general rules. The study of the same phenomena at different scales could enrich our work through a multidisciplinary approach, which should be a staple in the training of future scientists.

The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs.

Gene duplication is a driver of the evolution of new functions. The duplication of genes encoding homomeric proteins leads to the formation of homomers and heteromers of paralogs, creating new complexes after a single duplication event. The loss of these heteromers may be required for the two paralogs to evolve independent functions. Using yeast as a model, we find that heteromerization is frequent among duplicated homomers and correlates with functional similarity between paralogs. Using in silico evolution, we show that for homomers and heteromers sharing binding interfaces, mutations in one paralog can have structural pleiotropic effects on both interactions, resulting in highly correlated responses of the complexes to selection. Therefore, heteromerization could be preserved indirectly due to selection for the maintenance of homomers, thus slowing down functional divergence between paralogs. We suggest that paralogs can overcome the obstacle of structural pleiotropy by regulatory evolution at the transcriptional and post-translational levels.

Chemical and Immunological Characteristics of Aluminum-Based, Oil-Water Emulsion, and Bacterial-Origin Adjuvants.

Adjuvants are a diverse family of substances whose main objective is to increase the strength, quality, and duration of the immune response caused by vaccines. The most commonly used adjuvants are aluminum-based, oil-water emulsion, and bacterial-origin adjuvants. In this paper, we will discuss how the election of adjuvants is important for the adjuvant-mediated induction of immunity for different types of vaccines. Aluminum-based adjuvants are the most commonly used, the safest, and have the best efficacy, due to the triggering of a strong humoral response, albeit generating a weak induction of cell-mediated immune response. Freund's adjuvant is the most widely used oil-water emulsion adjuvant in animal trials; it stimulates inflammation and causes aggregation and precipitation of soluble protein antigens that facilitate the uptake by antigen-presenting cells (APCs). Adjuvants of bacterial origin, such as flagellin, E. coli membranes, and monophosphoryl lipid A (MLA), are known to potentiate immune responses, but their safety and risks are the main concern of their clinical use. This minireview summarizes the mechanisms that classic and novel adjuvants produce to stimulate immune responses.

A randomized multicenter study comparing seawater washes and carmellose artificial tears eyedrops in the treatment of dry eye syndrome.

PURPOSE: To investigate the safety and efficacy of sterile isotonic seawater washes vs standard treatment with carmellose artificial tears in dry eye syndrome (DES). PATIENTS AND METHODS: This is a randomized multicenter prospective study with 12 weeks of follow-up. A group of patients with DES (N=60) were treated with seawater spray (Quinton®) five times daily, and another similar group (N=60) were treated with carmellose artificial tears eyedrops (Viscofresh® 0.5%) five times a day. The parameters studied and measured were as follows: Ocular Surface Disease Index questionnaire score, Schirmer I test (without anesthesia) score, tear osmolarity (TearLab®), tear breakup time, tear meniscus height (meniscography OCT), fluorescein corneal staining score (National Eye Institute scale), lissamine green conjunctival staining score, and levels of IL-1 beta and IL-6 in tears (Luminex® 200). RESULTS: In the group treated with seawater, symptoms decreased by 68%, and the decrease was 26% statistically superior to the group treated with carmellose artificial tears eyedrops (P<.001). Levels of IL-1 beta and IL-6 in tears significantly decreased in the seawater group compared to the carmellose artificial tears group (19%/17% vs 52%/51%) (P<0.001). There were no statistically significant differences in the other measured parameters. There were no cases of poor tolerance or side effects. CONCLUSION: Administration of seawater is more effective than treatment with carmellose artificial tears in reducing symptoms and pro-inflammatory molecules (IL-1 beta and IL-6) in tears of patients with DES.

Aconsejan dar mayor importancia a la educación nutricional durante el embarazo / Nutrition education for women of childbearing age

Objetivo: El objetivo de este trabajo es analizar las fuentes de información y el nivel de conocimiento que poseen, sobre alimentación en el embarazo, las mujeres en edad fértil, diferenciando entre mujeres con hijos o sin hijos y valorando la influencia que la edad y la profesión pueden producir. Método: estudio poblacional, descriptivo y transversal con 117 mujeres en edad fértil, entre los 18 y 50 años, residentes en el municipio de Leganés. Resultados: Sólo un 4.3 % de las encuestadas conocía qué alimento era mejor fuente de hierro durante el embarazo y un 25.6 % sabía que las espinacas constituyen una buena fuente de ácido fólico. Las mujeres con edades comprendidas entre 41-50 años poseen un mejor conocimiento de la composición de los alimentos (52.16 % ± 29,7), al igual que aquellas mujeres que desempeñan un trabajo que requiere de titulación universitaria (51,34 % ± 35,79). En cuanto a las pautas dietéticas a seguir durante esta etapa, el porcentaje de aciertos se encuentra alrededor del 50 %. Una vez más, las mujeres de entre 41 y 50 años y aquéllas que desempeñan un trabajo que requiere de titulación universitaria presentan mayores porcentajes de aciertos (50.90 % ± 20.79 y 57.1 % ±16.9 respectivamente). Las enfermedades riesgosas durante el embarazo, como la preeclampsia y la toxoplasmosis son poco conocidas, con un nivel de aciertos que no supera la mitad de la muestra (42.7 % y 45.3 %, respectivamente); por edades, el grupo de 41 a 50 años vuelve a ser el que posee el mayor porcentaje de aciertos, con 66.7 % ± 13.10 %...(AU)

Aconsejan dar mayor importancia a la educación nutricional durante el embarazo / Nutrition education for women of childbearing age

Objetivo: El objetivo de este trabajo es analizar las fuentes de información y el nivel de conocimiento que poseen, sobre alimentación en el embarazo, las mujeres en edad fértil, diferenciando entre mujeres con hijos o sin hijos y valorando la influencia que la edad y la profesión pueden producir. Método: estudio poblacional, descriptivo y transversal con 117 mujeres en edad fértil, entre los 18 y 50 años, residentes en el municipio de Leganés. Resultados: Sólo un 4.3 % de las encuestadas conocía qué alimento era mejor fuente de hierro durante el embarazo y un 25.6 % sabía que las espinacas constituyen una buena fuente de ácido fólico. Las mujeres con edades comprendidas entre 41-50 años poseen un mejor conocimiento de la composición de los alimentos (52.16 % ± 29,7), al igual que aquellas mujeres que desempeñan un trabajo que requiere de titulación universitaria (51,34 % ± 35,79). En cuanto a las pautas dietéticas a seguir durante esta etapa, el porcentaje de aciertos se encuentra alrededor del 50 %. Una vez más, las mujeres de entre 41 y 50 años y aquéllas que desempeñan un trabajo que requiere de titulación universitaria presentan mayores porcentajes de aciertos (50.90 % ± 20.79 y 57.1 % ±16.9 respectivamente). Las enfermedades riesgosas durante el embarazo, como la preeclampsia y la toxoplasmosis son poco conocidas, con un nivel de aciertos que no supera la mitad de la muestra (42.7 % y 45.3 %, respectivamente); por edades, el grupo de 41 a 50 años vuelve a ser el que posee el mayor porcentaje de aciertos, con 66.7 % ± 13.10 %...

Phakic intraocular lenses to correct high myopia: Adatomed, Staar, and Artisan.

PURPOSE: To evaluate the feasibility and safety of using phakic intraocular lenses (IOLs) to correct high myopia by comparing 3 IOL models: Adatomed, Staar, and Artisan. SETTING: La Fe University Hospital, Department of Ophthalmology, and the Fundación Oftalmológica del Mediterráneo, Valencia, Spain. METHODS: In this prospective comparative study, a phakic IOL was implanted in 217 highly myopic eyes (118 patients). Fifty-nine eyes received an Adatomed IOL, 21 eyes a Staar IOL, and 137 eyes an Artisan IOL. The mean preoperative spherical equivalent was -15.39 diopters (D) +/- 2.83 (SD), -16.00 +/- 5.05 D, and -16.17 +/- 2.75 D in the Adatomed, Staar, and Artisan groups, respectively. The mean follow-up was 32.4 months (range 19 to 46 months) in the Adatomed group, 18.3 months (range 11 to 21 months) in the Staar group, and 121.4 months (range 38.4 to 154.3 months) in the Artisan group. At the follow-up examinations, intraocular pressure (IOP), IOL pigment deposits, cataract formation, and visual acuity were evaluated. RESULTS: The best corrected and uncorrected visual acuities improved in all eyes. No significant differences in visual acuity improvement were observed with the 3 materials, although the improvement was somewhat greater in eyes with the Artisan and Staar IOLs. The difference in mean IOP between preoperatively and the last follow-up examination was 1.5 mm Hg in the Staar group, 1.3 mm Hg in the Adatomed group, and 1.7 mm Hg in the Artisan group (P =.36, P =.26, and P =.32, respectively). The incidence of pigment deposits was similar in the Adatomed and Staar groups, with deposits in 32 eyes (54.23%) and 8 eyes (38.1%), respectively. Anterior cataract formation was higher in the Adatomed group (44.06%) than in the Staar group (9.52%); nuclear cataract developed in 2 Adatomed eyes (1.46%) only. CONCLUSIONS: There was a higher incidence of anterior subcapsular cataract formation in the Adatomed group than in the Staar group. Delayed cataract development and the cataract type in patients with Artisan IOLs indicate that age and axial length may be prognostic factors. Factors such as IOL design, material, and placement probably affect cataract formation in eyes with posterior chamber IOLs for high myopia, particularly the Adatomed IOL.