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Amyloid fiber formation is a specific form of protein aggregation, often resulting from the misfolding of native proteins. Aimed at modeling the crowded environment of the cell, recent experiments showed a reduction in fibrillation halftimes for amyloid-forming peptides in the presence of cosolutes that are preferentially excluded from proteins and peptides. The effect of excluded cosolutes has previously been attributed to the large volume excluded by such inert cellular solutes, sometimes termed \"macromolecular crowding\". Here, we studied a model peptide that can fold to a stable monomeric β-hairpin conformation, but under certain solution conditions aggregates in the form of amyloid fibrils. Using Circular Dichroism spectroscopy (CD), we found that, in the presence of polyols and polyethylene glycols acting as excluded cosolutes, the monomeric β-hairpin conformation was stabilized with respect to the unfolded state. Stabilization free energy was linear with cosolute concentration, and grew with molecular volume, as would also be predicted by crowding models. After initiating the aggregation process with a pH jump, fibrillation in the presence and absence of cosolutes was followed by ThT fluorescence, transmission electron microscopy, and CD spectroscopy. Polyols (glycerol and sorbitol) increased the lag time for fibril formation and elevated the amount of aggregated peptide at equilibrium, in a cosolute size and concentration dependent manner. However, fibrillation rates remained almost unaffected by a wide range of molecular weights of soluble polyethylene glycols. Our results highlight the importance of other forces beyond the excluded volume interactions responsible for crowding that may contribute to the cosolute effects acting on amyloid formation.

Humans are exposed to thousands of man-made chemicals in the environment. Some chemicals mimic natural endocrine hormones and, thus, have the potential to be endocrine disruptors. Most of these chemicals have never been tested for their ability to interact with the estrogen receptor (ER). Risk assessors need tools to prioritize chemicals for evaluation in costly in vivo tests, for instance, within the U.S. EPA Endocrine Disruptor Screening Program. We describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) and demonstrate the efficacy of using predictive computational models trained on high-throughput screening data to evaluate thousands of chemicals for ER-related activity and prioritize them for further testing. CERAPP combined multiple models developed in collaboration with 17 groups in the United States and Europe to predict ER activity of a common set of 32,464 chemical structures. Quantitative structure-activity relationship models and docking approaches were employed, mostly using a common training set of 1,677 chemical structures provided by the U.S. EPA, to build a total of 40 categorical and 8 continuous models for binding, agonist, and antagonist ER activity. All predictions were evaluated on a set of 7,522 chemicals curated from the literature. To overcome the limitations of single models, a consensus was built by weighting models on scores based on their evaluated accuracies. Individual model scores ranged from 0.69 to 0.85, showing high prediction reliabilities. Out of the 32,464 chemicals, the consensus model predicted 4,001 chemicals (12.3%) as high priority actives and 6,742 potential actives (20.8%) to be considered for further testing. This project demonstrated the possibility to screen large libraries of chemicals using a consensus of different in silico approaches. This concept will be applied in future projects related to other end points. Mansouri K, Abdelaziz A, Rybacka A, Roncaglioni A, Tropsha A, Varnek A, Zakharov A, Worth A, Richard AM, Grulke CM, Trisciuzzi D, Fourches D, Horvath D, Benfenati E, Muratov E, Wedebye EB, Grisoni F, Mangiatordi GF, Incisivo GM, Hong H, Ng HW, Tetko IV, Balabin I, Kancherla J, Shen J, Burton J, Nicklaus M, Cassotti M, Nikolov NG, Nicolotti O, Andersson PL, Zang Q, Politi R, Beger RD, Todeschini R, Huang R, Farag S, Rosenberg SA, Slavov S, Hu X, Judson RS. 2016. Collaborative Estrogen Receptor Activity Prediction Project. Environ Health Perspect 124:1023-1033; http://dx.doi.org/10.1289/ehp.1510267.

Solving combinatorial optimization problems involves a two-stage process that follows the model-and-run approach. First, a user is responsible for formulating the problem at hand as an optimization model, and then, given the model, a solver is responsible for finding the solution. While optimization technology has enjoyed tremendous theoretical and practical advances, the process has remained unchanged for decades. To date, transforming problem descriptions into optimization models remains a barrier to entry. To alleviate users from the cognitive task of modeling, we study named entity recognition to capture components of optimization models such as the objective, variables, and constraints from free-form natural language text, and coin this problem as Ner4Opt. We show how to solve Ner4Opt using classical techniques based on morphological and grammatical properties and modern methods leveraging pre-trained large language models and fine-tuning transformers architecture with optimization-specific corpora. For best performance, we present their hybridization combined with feature engineering and data augmentation to exploit the language of optimization problems. We improve over the state-of-the-art for annotated linear programming word problems. Large-language models (LLMs) are not yet versatile enough to turn text into optimization models or extract optimization entities. Still, when augmented with Ner4Opt annotations, the compilation accuracy of LLM-generated models improves significantly. We open-source our Ner4Opt library, release our training and fine-tuning procedures, and share our trained artifacts. We identify several next steps and discuss important open problems toward automated modeling.

The ability to determine which environmental chemicals pose the greatest potential threats to human health remains one of the major concerns in regulatory toxicology. Computation methods that can accurately predict the chemicals’ toxic potential in silico are increasingly sought-after to replace in vitro high-throughput screening (HTS) as well as controversial and costly in vivo animal studies. To this end, we have built Quantitative Structure-Activity Relationship (QSAR) models of twelve (12) stress response and nuclear receptor signaling pathways toxicity assays as part of the 2014 Tox21 Challenge. Our models were built using the Random Forest, Deep Neural Networks and various combinations of descriptors and balancing protocols. All of our models were statistically significant for each of the 12 assays with the balanced accuracy in the range between 0.58 and 0.82. Our results also show that models built with Deep Neural Networks had high accuracy than those developed with simple machine learning algorithms and that dataset balancing led to a significant accuracy decrease.

Extracytoplasmic function (ECF) sigma factors are members of cell-surface signaling systems, abundant in the opportunistic pathogen Pseudomonas aeruginosa. Twenty genes coding for ECF sigma factors are present in P. aeruginosa sequenced genomes, most of them being part of TonB systems related to iron uptake. In this work, poorly characterized sigma factors were overexpressed in strain PA14, in an attempt to understand their role in the bacterium's physiology. Cultures overexpressing SigX displayed a biphasic growth curve, reaching stationary phase earlier than the control strain, followed by subsequent growth resumption. During the first stationary phase, most cells swell and die, but the remaining cells return to the wild type morphology and proceed to a second exponential growth. This is not due to compensatory mutations, since cells recovered from late time points and diluted into fresh medium repeated this behavior. Swollen cells have a more fluid membrane and contain higher amounts of shorter chain fatty acids. A proteomic analysis was performed to identify differentially expressed proteins due to overexpression of sigX, revealing the induction of several fatty acid synthesis (FAS) enzymes. Using qRT-PCR, we showed that at least one isoform from each of the FAS pathway enzymes were upregulated at the mRNA level in the SigX overexpressing strain thus pointing to a role for this ECF sigma factor in the FAS regulation in P. aeruginosa.

Ticks pose significant challenges to public and veterinary health, acting as vectors of several diseases that affect animals and humans. Traditional chemical control methods, such as pyrethroids and organophosphates, have led to increasing resistance and environmental contamination, highlighting the need and urgency for alternative strategies. This review explores contemporary approaches to tick control, emphasizing plant-derived acaricides and their integration with nanotechnology. Plant extracts, known for their acaricidal properties, disrupt several biological processes in ticks, reducing reproduction and survival rates. The advent of nanotechnology offers promising advances in increasing the efficacy of these natural extracts. Nanoparticles add properties to the systems where they act by improving the stability, bioavailability, and targeted delivery of plant-derived compounds, potentially overcoming the limitations of traditional acaricides. This synthesis of current knowledge highlights the potential of combining plant extracts with nanotechnology to develop sustainable and effective tick control solutions, addressing issues of acaricide resistance as well as environmental concerns. The review also identifies research gaps and suggests directions for future studies to optimize the application of nanotechnology in tick management.

Objectives The objective of this study was to evaluate the effect of non-steroidal anti-inflammatory drugs (NSAIDs) in controlling pulpal and periapical inflammation in vivo as a potential coadjutant systemic therapy for pulpitis. Materials and methods A suspension containing E. coli lipopolysaccharide (LPS; 1.0 μg/μL) was inoculated into the pulp chamber of the first molars of C57BL/6 mice ( n = 72), and the animals were treated daily with indomethacin or celecoxib throughout the experimental periods. After 7, 14, 21, and 28 days, the tissues were removed for histopathological, histoenzymology, histometric, and immunohistochemical evaluation. Results Inoculation of LPS into the pulp chamber induced the synthesis of the enzyme cyclooxygenase-2 (COX-2) in dental pulp and periapical region. Indomethacin and celecoxib treatment changed the profile of inflammatory cells recruited to dental pulp and to the periapex, which was characterized by a higher mononuclear cell infiltrate, compared to LPS inoculation alone which recruited a higher amount of polymorphonuclear neutrophils. Administration of indomethacin for 28 days resulted in the development of apical periodontitis and increased osteoclast recruitment, unlike celecoxib. Conclusions NSAIDs indomethacin and celecoxib changed the recruitment of inflammatory cells to a mononuclear profile upon inoculation of LPS into the pup chamber, but indomethacin enhanced periapical bone loss whereas celecoxib did not. Clinical relevance Celecoxib, a selective COX-2 inhibitor, can change the profile of inflammatory cells recruited to the dental pulp challenged with LPS and might a be potential systemic coadjutant for treatment of pulpitis.

The cattle tick Rhipicephalus microplus is a great sanitary problem and causes huge losses to livestock, being a vector of important diseases. The aim of this work was to verify the action of plant-derived material obtained from Tagetes patula on the life cycle of R. microplus, as well as to analyze the action of these extracts on ovary cells of engorged females. In the Adult Immersion Test, the crude ethanolic extract (TpEtOH) showed an efficacy of 99.2% (LC50 = 18.60 mg mL−1). From the repellency test, it was found that both the TpEtOH and essential oil were 100% efficient on the larval stage. In addition, in the Larval Package Test, a mortality of 98.37% was obtained with TpEtOH (LC50 = 3.798 mg mL−1). From the microscopic analysis of ovary cells, morphological changes in the chorion and cytoplasm of oocytes were observed, with vacuolization around the germinal vesicle and disorganization of the pedicular cells, suggesting an interference in the normal embryogenic formation of the larvae. These results demonstrate that T. patula extracts interfere at all stages of development of the ixodid, from eggs to adults forms, and have a pronounced repellent effect. In addition, the results of the cytotoxicity assays performed on keratinocytes, as well as previous information on oral and dermal acute toxicity (LD50 > 4000 mg kg−1), attest that T. patula can be a safe alternative for ectoparasitic control, representing an alternative for development of a formulation used to help control populations of ticks in the field.

Introduction: Exercise is an important therapeutic strategy for preventing and treating myocardial infarction (MI)-induced cardiac remodeling and heart failure. However, the myocardial effects of resistance exercise on infarcted hearts are not completely established. In this study, we investigated the effects of resistance exercise on structural, functional, and molecular cardiac alterations in infarcted rats. Methods: Three months after MI induction or simulated surgery, Wistar rats were assigned into three groups: Sham (n = 14); MI (n = 9); and exercised MI (MI-Ex, n = 13). Exercised rats performed, 3 times a week for 12 weeks, four climbs on a ladder with progressive loads. Cardiac structure and left ventricle (LV) function were analyzed by echocardiogram. Myocyte diameters were evaluated in hematoxylin- and eosin-stained histological sections as the smallest distance between borders drawn across the nucleus. Myocardial energy metabolism, lipid hydroperoxide, malondialdehyde, protein carbonylation, and antioxidant enzyme activities were evaluated by spectrophotometry. Gene expressions of NADPH oxidase subunits were evaluated by RT-PCR. Statistical analyses were performed using ANOVA and Tukey or Kruskal–Wallis and Dunn’s test. Results: Mortality did not differ between the MI-Ex and MI groups. MI had dilated left atrium and LV, with LV systolic dysfunction. Exercise increased the maximum load-carrying capacity, with no changes in cardiac structure or LV function. Myocyte diameters were lower in MI than in Sham and MI-Ex. Lactate dehydrogenase and creatine kinase activity were lower in MI than in Sham. Citrate synthase and catalase activity were lower in MI and MI-Ex than in Sham. Lipid hydroperoxide concentration was lower in MI-Ex than in MI. Nox2 and p22phox gene expressions were higher in MI-Ex than in Sham. Gene expression of Nox4 was higher in MI and MI-Ex than in Sham, and p47phox was lower in MI than in Sham. Conclusion: Late resistance exercise was safe in infarcted rats. Resistance exercise improved maximum load-carrying capacity, reduced myocardial oxidative stress, and preserved myocardial metabolism, with no changes in cardiac structure or left ventricle function in infarcted rats.

Abstract Regardless of family configurations, few studies address the concomitant assessment of mothers and fathers regarding their children’s behaviors and parenting practices. The objective was to compare and correlate the assessment of biological mothers and fathers of intact nuclear families on their parental practices and behavioral problems of their school-aged children. Fourth-two intact nuclear families answered to the following instruments: General Questionnaire, Parenting Style Inventory, Strengths and Difficulties Questionnaire and Raven Progressive Matrices Test - Special Scale. The quantitative analysis showed that mothers and fathers presented similar assessments regarding the behavior of their children, though mothers reported more positive practices than fathers. Negative parenting styles were positively correlated with child behavioral problems. These findings contribute to the planning of preventive strategies and interventions directed to families. Resumo Independente da configuração familiar, poucos estudos têm abordado as avaliações concomitantes de mães e pais sobre os comportamentos e práticas educativas adotadas com seus filhos. Objetivou-se comparar e correlacionar a avaliação de mães e pais biológicos, de famílias nucleares intactas, sobre suas práticas educativas e problemas comportamentais de seus filhos, em idade escolar. Foram avaliadas 42 famílias nucleares intactas, que responderam aos seguintes instrumentos: Questionário Geral, Inventário de Estilos Parentais, Questionário de Capacidades e Dificuldades da Criança e Teste das Matrizes Progressivas de Raven - Escala Especial. Por meio de análise quantitativa, verificou-se que mães e pais apresentaram semelhanças quanto às avaliações sobre o comportamento dos filhos e que mães referiram mais práticas positivas do que pais. As práticas parentais negativas correlacionaram-se positivamente com os problemas de comportamento. Tais achados contribuem para o planejamento de estratégias de prevenção e intervenção com famílias. Resumen Independiente de la configuración familiar, pocos estudios han abordado las evaluaciones concomitantes de madres y padres sobre los comportamientos y prácticas educativas adoptadas con sus hijos. Se tuvo como objetivo comparar y correlacionar la evaluación de madres y padres biológicos, de familias nucleares intactas, sobre las prácticas educativas y problemas comportamentales de sus hijos en edad escolar. Fueron evaluadas 42 familias nucleares intactas, que respondieron a los siguientes instrumentos: Cuestionario General, Inventario de Estilos Parentales, Cuestionario de Capacidades y Dificultades del Niño y Test de las Matrices Progresivas de Raven - Escala Especial. Por medio de un análisis cuantitativo, se verificó que madres y padres presentaron semejanzas con relación a las evaluaciones sobre el comportamiento de los hijos y que las madres mencionaron más prácticas positivas que los padres. Las prácticas parentales negativas se correlacionan positivamente con los problemas de comportamiento. Estos resultados contribuyen para la planificación de estrategias de prevención e intervención con las familias.