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Adaptation is driven by the selection for beneficial mutations that provide a fitness advantage in the specific environment in which a population is evolving. However, environments are rarely constant or predictable. When an organism well adapted to one environment finds itself in another, pleiotropic effects of mutations that made it well adapted to its former environment will affect its success. To better understand such pleiotropic effects, we evolved both haploid and diploid barcoded budding yeast populations in multiple environments, isolated adaptive clones, and then determined the fitness effects of adaptive mutations in 'non-home' environments in which they were not selected. We find that pleiotropy is common, with most adaptive evolved lineages showing fitness effects in non-home environments. Consistent with other studies, we find that these pleiotropic effects are unpredictable: they are beneficial in some environments and deleterious in others. However, we do find that lineages with adaptive mutations in the same genes tend to show similar pleiotropic effects. We also find that ploidy influences the observed adaptive mutational spectra in a condition-specific fashion. In some conditions, haploids and diploids are selected with adaptive mutations in identical genes, while in others they accumulate mutations in almost completely disjoint sets of genes., Competing Interests: VC, MJ, LH, PH, DY, YL, AA, SH, DP, MD, GS No competing interests declared, (© 2023, Chen, Johnson, Hérissant et al.)

Introduction: Quitting smoking, the critical path to reach the global targets of reducing tobacco use, can bring major and immediate health benefits to smokers. Exploring factors that help individuals to quit smoking is of great importance. The present study explored influencing factors on smoking cessation, in order to provide comprehensive reference for tobacco control policies., Methods: Ex-smokers and current smokers were recruited online in this cross-sectional survey, from 1 October to 31 November 2022, in China. The observational data were collected using a questionnaire to collect information with respect to sociodemographic characteristics of smokers, attitudes towards smoking cessation, details of smoking cessation, and different potential factors related to smoking cessation through open-ended questions., Results: A total of 638 smokers from 30 provinces were recruited as eligible respondents, with a mean age of 37.3 ± 11.7 years and a mean smoking history of 15.9 ± 13.7 years. The percentage of males was 92.3%. Of the 638 respondents, only 3.9% had no intention to stop smoking. Among 155 subjects who had quitted smoking successfully, willpower (55.5%) was considered as the most important contributing factor. Among 365 subjects who tried to quit but failed, lack of willpower (28.2%), tobacco dependence (16.2%), influence of surrounding smokers or smoking environments (15.9%), bad moods (9.9%), stress from work or life (7.9%), habits (7.1%), socialization (4.1%), and easy availability of tobacco (2.7%) were considered as the adverse factors leading to failure in quitting smoking., Conclusions: Willpower and support from family members were the vital factors that lead to successful smoking cessation. Future tobacco control policies should also focus on addressing withdrawal symptoms and creating smoke-free environments as well as other factors., Competing Interests: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported., (© 2023 Wang J.H. et al.)

The study aimed to examine the cohesive tie effect on reading comprehension through the grammatical knowledge cognition process. The present meta-analysis examined the correlation between grammatical knowledge and reading comprehension based on empirical results published between 1998 and 2021. This study selected 86 studies with a total of 14,852 readers whose grades were grouped from primary school to university. The results showed that the overall correlation effect size between grammatical knowledge and reading comprehension was large, and the significant interaction effect of the grade group was confirmed through moderator analysis. The results suggested that the grammatical knowledge's function of the cohesive tie has a transfer effect across different text comprehension scripts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zheng, Miao, Dong and Yuan.)

Objectives: To explore the influencing factors of bone cement leakage in the paravertebral vein after vertebroplasty for the treatment of osteoporotic vertebral compression fractures (OVCFs) and to determine the correlation between the puncture-side bone cement/vertebral body volume ratio and bone cement leakage in the paravertebral vein., Methods: This was a retrospective analysis of 495 patients (585 vertebral bodies) with OVCFs treated from August 2018 to May 2021 in our hospital. The patients' postoperative CT data were imported into Mimics software, and the three-dimensional(3D) reconstruction function was used to calculate the bone cement volume (BCV), puncture-side bone cement volume (PSBCV), and vertebral body volume (VBV); the bone cement/vertebral body volume ratio (BCV/VCV%) and puncture-side bone cement/vertebral body volume ratio (PSBCV/VCV%) were additionally calculated. Sex, Age, Body mass index(BMI), Bone density, BCV, PSBCV, VBV, BCV/VCV%, and PSBCV/VCV were compared between the leakage group and the non-leakage group. Logistic regression analysis was used to assess the correlations between the factors that statistically significantly differed between the two groups and the presence of leakage in the paravertebral veins. A receiver operating characteristic (ROC) curve was used to determine the diagnostic value of the PSBCV/VCV% and to obtain the optional cut-off value., Results: A total of 102 males and 393 females with an average age of 72.89 (52 ~ 93) years were included in our study. There were 57 cases of cement leakage (59 vertebral bodies) in the paravertebral vein. There were 438 patients (526 vertebral bodies) without paravertebral cement leakage. Univariate analysis showed that the differences in sex, bone density, PSBCV, and PSBCV/VCV% between the two groups were statistically significant (P < 0.05). Logistic regression analysis showed that there were correlations between sex, bone density, and PSBCV/VCV% and the presence of paravertebral cement leakage (P < 0.05). The ROC curve showed that the area under the curve of the PSBCV/VCV% for the diagnosis of cement leakage in the paravertebral vein was greater than 0.65, and P < 0.05, indicating a diagnostic value. The best cut-off point for the diagnosis of paravertebral cement leakage with the PSBCV/VCV% was 13.68%, with a sensitivity of 84.7% and specificity of 37.8%., Conclusion: Sex, bone density, and PSBCV/VCV% are risk factors for cement leakage in the paravertebral veins after vertebroplasty for the treatment of OVCFs; the PSBCV/VCV% is strongly associated with paravertebral venous leakage, and the optimal PSBCV/VCV% is 13.68%. When the PSBCV/VCV% exceeds the optimal value, the risk of cement leakage in the paravertebral vein becomes significantly increased., (© 2022. The Author(s).)

Phenotypic variation within a species is often structured geographically in clines. In Drosophila americana, a longitudinal cline for body colour exists within North America that appears to be due to local adaptation. The tan and ebony genes have been hypothesized to contribute to this cline, with alleles of both genes that lighten body colour found in D. americana. These alleles are similar in sequence and function to the allele fixed in D. americana's more lightly pigmented sister species, Drosophila novamexicana. Here, we examine the frequency and geographic distribution of these D. novamexicana-like alleles in D. americana. Among alleles from over 100 strains of D. americana isolated from 21 geographic locations, we failed to identify additional alleles of tan or ebony with as much sequence similarity to D. novamexicana as the D. novamexicana-like alleles previously described. However, using genetic analysis of 51 D. americana strains derived from 20 geographic locations, we identified one new allele of ebony and one new allele of tan segregating in D. americana that are functionally equivalent to the D. novamexicana allele. An additional 5 alleles of tan also showed marginal evidence of functional similarity. Given the rarity of these alleles, however, we conclude that they are unlikely to be driving the pigmentation cline. Indeed, phenotypic distributions of the 51 backcross populations analysed indicate a more complex genetic architecture, with diversity in the number and effects of loci altering pigmentation observed both within and among populations of D. americana. This genetic heterogeneity poses a challenge to association studies and genomic scans for clinal variation, but might be common in natural populations., (© 2020 John Wiley & Sons Ltd.)

Objective: To evaluate the accuracy and safety of a combined 3D printed guide template (combined template) to assist iliosacral (IS) screw placement for sacral fracture and dislocation., Methods: A total of 37 patients, 24 men and 13 women, age from 22 to 68 years old, diagnosed with a sacral fracture and dislocation were involved in this study for retrospective analysis from January 2016 to February 2018. There were 19 patients in the template group (42 screws) and 18 patients in the conventional group (31 screws). In the combined template group, IS screw placement was assisted by a combined 3D printed template; in the conventional group, the IS screws were placed freehand under fluoroscopy. The accuracy of the IS screw placement was evaluated by comparing the screw angle and the location of the screw entry point between the actual and the simulated screw in the combined template group. The safety of the IS screw placement was evaluated by comparing the quality of the reduction, the grading of the screws, the operation time, and radiation exposure times between groups., Results: A total of 73 pedicle screws were placed in 37 patients: 42 screws (30 S1, 12 S2) in the combined template group and 31 screws (23 S1, 8 S2) in the conventional group. In the conventional group, 1 patient developed symptoms of L5 nerve stimulation. In the combined template group, the average operative time of each screw was 25.01 ± 2.90 min, with average radiation exposure times of 12.05 ± 4.00. In the conventional group, the average operative time of each screw was 46.24 ± 9.59 min, with an average radiation exposure time of 56.10 ± 6.75. There were significant differences in operation and radiation exposure times between groups. The rate of screw perforation was lower in the combined template group (2 of 42 screws, 0 at grade III and 2 at grade II) than in the conventional group (5 of 38 screws, 2 at grade III and 3 at grade III). In the combined template group, the mean distance between the entry points of the actual and simulated screws was 1.4 ± 0.9 mm, with a mean angle of deviation of 2.1° ± 1.6°. All patients were followed up once every 3 months and were followed for 3 to 12 months., Conclusion: Using the combined template to assist with the insertion of IS screws delivered good accuracy, less fluoroscopy and shorter operation time, and avoided neurovascular injury as a result of screw malposition., (© 2020 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Using mathematical model and computer simulation to predict biological processes and optimize the target production is an important strategy for optimizing fermentation process. However, the inherent uncertainty of the kinetic model severely limits the predictive capability. In this study, optimize target production, such as productivity and yield of 1, 3-propanediol produced by Klebsiella pneumoniae using glycerol as substrate, the ensemble modeling approach was used to reduce the model's uncertainty for fermentation process as much as possible, and effectively improve its prediction performance. Firstly, through sensitivity analysis, the parameters having significant influence on the model were determined as the adjustable parameters for the ensemble modeling. After comparison, the appropriate threshold coefficient of the model error was determined, and the sampling method was used to generate as many equivalent parameter sets as possible. Each set of parameters was separately applied for the simulation, and all the predicted values were integrated for the weighted average. Therefore, the expected value of the prediction was obtained. Compared with the traditional simulation using single parameter set, the ensemble modeling method achieved the lower relative error between the prediction and the experimental value and the greatly improved model prediction performance. Moreover, the optimal productivity and yield of 1, 3-propanediol and the corresponding operating conditions were obtained, respectively. The ensemble modeling approach effectively compensates for the uncertainties of the model, making its prediction performance more practical, which is important for computer simulations to predict and guide the actual production process., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To construct a novel non-viral vector loaded with growth and differentiation factor-5 (GDF-5) plasmid using chitosan, hyaluronic acid, and chondroitin sulfate for osteoarthritis (OA) gene therapy., Methods: Nano-microspheres (NMPs) were prepared by mixing chitosan, hyaluronic acid, and chondroitin sulfate. GDF-5 plasmid was encapsulated in the NMPs through electrostatic adsorption. The basic characteristics of the NMPs were observed, and then they were co-cultured with chondrocytes to observe their effects on extracellular matrix (ECM) protein expression. Finally, NMPs loaded with GDF-5 were injected into the articular cavities of rabbits to observe their therapeutic effects on OA in vivo., Results: NMPs exhibited good physicochemical properties and low cytotoxicity. Their average diameter was (0.61±0.20) μm, and encapsulation efficiency was (38.19±0.36)%. According to Cell Counting Kit-8 (CCK-8) assay, relative cell viability was 75%-99% when the total weight of NMPs was less than 560 μg. Transfection efficiency was (62.0±2.1)% in a liposome group, and (60.0±1.8)% in the NMP group. There was no significant difference between the two groups (P>0.05). Immunohistochemical staining results suggested that NMPs can successfully transfect chondrocytes and stimulate ECM protein expression in vitro. Compared with the control groups, the NMP group significantly promoted the expression of chondrocyte ECM in vivo (P<0.05), as shown by analysis of the biochemical composition of chondrocyte ECM. When NMPs were injected into OA model rabbits, the expression of ECM proteins in chondrocytes was significantly promoted and the progression of OA was slowed down., Conclusions: Based on these data, we think that these NMPs with excellent physicochemical and biological properties could be promising non-viral vectors for OA gene therapy.

To investigate the relationship between the yield of 1,3-propanediol (1,3-PD) and the flux variation in metabolic pathways of Klebsiella pneumoniae, an optimized calculation method was constructed on basis of dynamic flux balance analysis by combining genome-scale flux balance analysis with a kinetic model of extracellular metabolites. Through optimizing calculations, a more completely expanded metabolic pathway was obtained, which includes the previously reported metabolic pathway and additional three pathways or site: a pentose phosphate pathway (PPP) elicited at the dihydroxyacetone (DHA) node to provide more reducing equivalents; a branch of synthetic amino acids at the 3-phosphoglycerate (3PG) node; and the α-ketoglutarate site in the tricarboxylic acid (TCA) cycle leading to anabolic pathways for glutamate and other amino acids. On this basis, the relationships between the dynamic flux distribution of the important nodes in the metabolic pathway and the yield of 1,3-propanediol were analyzed. First, dynamic flux change from DHA to the PPP is positively correlated with the yield. Second, variation in flux in the TCA cycle is also positively correlated with the yield of 1,3-propanediol. In addition, the influence of the feedback loop formed by the cofactor tetrahydrofolate on the flux change of TCA in the amino acid anabolic pathway was examined. These results are of important reference value and have guiding significance for the extension of the glycerol metabolism pathway in K. pneumoniae, the rational transformation of genetic engineering in bacteria, and the optimization of metabolic pathways for industrial production.

Phenotypic plasticity is an evolvable property of biological systems that can arise from environment-specific regulation of gene expression. To better understand the evolutionary and molecular mechanisms that give rise to plasticity in gene expression, we quantified the effects of 235 single-nucleotide mutations in the Saccharomyces cerevisiae TDH3 promoter ( P TDH3 ) on the activity of this promoter in media containing glucose, galactose, or glycerol as a carbon source. We found that the distributions of mutational effects differed among environments because many mutations altered the plastic response exhibited by the wild-type allele. Comparing the effects of these mutations with the effects of 30 P TDH3 polymorphisms on expression plasticity in the same environments provided evidence of natural selection acting to prevent the plastic response in P TDH3 activity between glucose and galactose from becoming larger. The largest changes in expression plasticity were observed between fermentable (glucose or galactose) and nonfermentable (glycerol) carbon sources and were caused by mutations located in the RAP1 and GCR1 transcription factor binding sites. Mutations altered expression plasticity most frequently between the two fermentable environments, with mutations causing significant changes in plasticity between glucose and galactose distributed throughout the promoter, suggesting they might affect chromatin structure. Taken together, these results provide insight into the molecular mechanisms underlying gene-by-environment interactions affecting gene expression as well as the evolutionary dynamics affecting natural variation in plasticity of gene expression., Competing Interests: The authors declare no conflict of interest.

Heritable differences in gene expression are caused by mutations in DNA sequences encoding cis-regulatory elements and trans-regulatory factors. These two classes of regulatory change differ in their relative contributions to expression differences in natural populations because of the combined effects of mutation and natural selection. Here, we investigate how new mutations create the regulatory variation upon which natural selection acts by quantifying the frequencies and effects of hundreds of new cis- and trans-acting mutations altering activity of the TDH3 promoter in the yeast Saccharomyces cerevisiae in the absence of natural selection. We find that cis-regulatory mutations have larger effects on expression than trans-regulatory mutations and that while trans-regulatory mutations are more common overall, cis- and trans-regulatory changes in expression are equally abundant when only the largest changes in expression are considered. In addition, we find that cis-regulatory mutations are skewed toward decreased expression while trans-regulatory mutations are skewed toward increased expression. We also measure the effects of cis- and trans-regulatory mutations on the variability in gene expression among genetically identical cells, a property of gene expression known as expression noise, finding that trans-regulatory mutations are much more likely to decrease expression noise than cis-regulatory mutations. Because new mutations are the raw material upon which natural selection acts, these differences in the frequencies and effects of cis- and trans-regulatory mutations should be considered in models of regulatory evolution., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In Bilateria, Pax6, Six, Eya and Dach families of transcription factors underlie the development and evolution of morphologically and phyletically distinct eyes, including the compound eyes in Drosophila and the camera-type eyes in vertebrates, indicating that bilaterian eyes evolved under the strong influence of ancestral developmental gene regulation. However the conservation in eye developmental genetics deeper in the Eumetazoa, and the origin of the conserved gene regulatory apparatus controlling eye development remain unclear due to limited comparative developmental data from Cnidaria. Here we show in the eye-bearing scyphozoan cnidarian Aurelia that the ectodermal photosensory domain of the developing medusa sensory structure known as the rhopalium expresses sine oculis (so)/six1/2 and eyes absent/eya, but not optix/six3/6 or pax (A&B). In addition, the so and eya co-expression domain encompasses the region of active cell proliferation, neurogenesis, and mechanoreceptor development in rhopalia. Consistent with the role of so and eya in rhopalial development, developmental transcriptome data across Aurelia life cycle stages show upregulation of so and eya, but not optix or pax (A&B), during medusa formation. Moreover, pax6 and dach are absent in the Aurelia genome, and thus are not required for eye development in Aurelia. Our data are consistent with so and eya, but not optix, pax or dach, having conserved functions in sensory structure specification across Eumetazoa. The lability of developmental components including Pax genes relative to so-eya is consistent with a model of sense organ development and evolution that involved the lineage specific modification of a combinatorial code that specifies animal sense organs.

Genetic variation segregating within a species reflects the combined activities of mutation, selection, and genetic drift. In the absence of selection, polymorphisms are expected to be a random subset of new mutations; thus, comparing the effects of polymorphisms and new mutations provides a test for selection. When evidence of selection exists, such comparisons can identify properties of mutations that are most likely to persist in natural populations. Here we investigate how mutation and selection have shaped variation in a cis-regulatory sequence controlling gene expression by empirically determining the effects of polymorphisms segregating in the TDH3 promoter among 85 strains of Saccharomyces cerevisiae and comparing their effects to a distribution of mutational effects defined by 236 point mutations in the same promoter. Surprisingly, we find that selection on expression noise (that is, variability in expression among genetically identical cells) appears to have had a greater impact on sequence variation in the TDH3 promoter than selection on mean expression level. This is not necessarily because variation in expression noise impacts fitness more than variation in mean expression level, but rather because of differences in the distributions of mutational effects for these two phenotypes. This study shows how systematically examining the effects of new mutations can enrich our understanding of evolutionary mechanisms. It also provides rare empirical evidence of selection acting on expression noise.