Search

Staphylococcus aureus is a microorganism with high morbidity and mortality due to antibiotic-resistant strains, making the search for new therapeutic options urgent. In this context, computational drug design can facilitate the drug discovery process, optimizing time and resources. In this work, computational methods involving ligand- and structure-based virtual screening were employed to identify potential antibacterial agents against the S. aureus MRSA and VRSA strains. To achieve this goal, tetrahydroxybenzofuran, a promising antibacterial agent according to in vitro tests described in the literature, was adopted as the pivotal molecule and derivative molecules were considered to generate a pharmacophore model, which was used to perform virtual screening on the Pharmit platform. Through this result, twenty-four molecules were selected from the MolPort® database. Using the Tanimoto Index on the BindingDB web server, it was possible to select eighteen molecules with greater structural similarity in relation to commercial antibiotics (methicillin and oxacillin). Predictions of toxicological and pharmacokinetic properties (ADME/Tox) using the eighteen most similar molecules, showed that only three exhibited desired properties (LB255, LB320 and LB415). In the molecular docking study, the promising molecules LB255, LB320 and LB415 showed significant values in both molecular targets. LB320 presented better binding affinity to MRSA (−8.18 kcal/mol) and VRSA (−8.01 kcal/mol) targets. Through PASS web server, the three molecules, specially LB320, showed potential for antibacterial activity. Synthetic accessibility (SA) analysis performed on AMBIT and SwissADME web servers showed that LB255 and LB415 can be considered difficult to synthesize and LB320 is considered easy. In conclusion, the results suggest that these ligands, particularly LB320, may bind strongly to the studied targets and may have appropriate ADME/Tox properties in experimental studies.

In this article, we draw on various critical perspectives to theorize neoliberal choice and examine how it has been deployed to market new educational reforms in Ontario. We begin by offering a contemporary framing of neoliberalism that looks at its core elements as well as its chameleon-like tendencies to draw on neoconservative elements as needed. We also furnish critiques of neoliberalism by engaging Adams et al.'s (2019) description of neoliberal "choice" as one component of a larger psychological exercise in support of capitalism. We then examine how the language of choice has been used to position three recent Ontario education reforms: (a) mandatory e-learning; (b) growth of international students; and (c) the revision of curricula according to economic ends. Finally, we argue that the implementation of these reforms ironically has produced less choice for stakeholders through austerity and standardization.

Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the hosts genome (∼0.005%) should be corrected to: Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the hosts genome (∼0.5%).

Biomarkers that aid in early detection of neurodegeneration are needed to enable early symptomatic treatment and enable identification of people who may benefit from neuroprotective interventions. Increasing evidence suggests that sleep biomarkers may be useful, given the bi-directional relationship between sleep and neurodegeneration and the prominence of sleep disturbances and altered sleep architectural characteristics in several neurodegenerative disorders. This study aimed to demonstrate that sleep can accurately characterize specific neurodegenerative disorders (NDD). A four-class machine-learning algorithm was trained using age and nine sleep biomarkers from patients with clinically-diagnosed manifest and prodromal NDDs, including Alzheimers disease dementia (AD = 27), Lewy body dementia (LBD = 18), and isolated REM sleep behavior disorder (iRBD = 15), as well as a control group (CG = 58). The algorithm was validated in a total of 381 recordings, which included the training data set plus an additional AD = 10, iRBD = 18, Parkinson disease without dementia (PD = 29), mild cognitive impairment (MCI = 78) and CG = 128. Test-retest consistency was then assessed in LBD = 10, AD = 9, and CG = 46. The agreement between the NDD profiles and their respective clinical diagnoses exceeded 75% for the AD, LBD, and CG, and improved when NDD participants classified Likely Normal with NDD indications consistent with their clinical diagnosis were considered. Profiles for iRBD, PD and MCI participants were consistent with the heterogeneity of disease severities, with the majority of overt disagreements explained by normal sleep characterization in 27% of iRBD, 21% of PD, and 26% of MCI participants. For test-retest assignments, the same or similar NDD profiles were obtained for 88% of LBD, 86% in AD, and 98% of CG participants. The potential utility for NDD subtyping based on sleep biomarkers demonstrates promise and requires further prospective development and validation in larger NDD cohorts.

The drugs activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a presurgical study of alternative exemestane schedules. Postmenopausal women candidates for breast surgery for estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg once daily (QD), 25 mg 3 times/week (TIW), or 25 mg per week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in nonmalignant tissue. Estradiol was nearly suppressed in all groups in the nonmalignant tissue (QD vs TIW P = .364 and QD vs QW P = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in nonmalignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy. Trial Registration: Clinical Trials.gov NCT02598557 and EudraCT 2015-005063-1.

BACKGROUND: Clinical trials are increasingly using Bayesian methods for their design and analysis. Inference in Bayesian trials typically uses simulation-based approaches such as Markov Chain Monte Carlo methods. Markov Chain Monte Carlo has high computational cost and can be complex to implement. The Integrated Nested Laplace Approximations algorithm provides approximate Bayesian inference without the need for computationally complex simulations, making it more efficient than Markov Chain Monte Carlo. The practical properties of Integrated Nested Laplace Approximations compared to Markov Chain Monte Carlo have not been considered for clinical trials. Using data from a published clinical trial, we aim to investigate whether Integrated Nested Laplace Approximations is a feasible and accurate alternative to Markov Chain Monte Carlo and provide practical guidance for trialists interested in Bayesian trial design. METHODS: Data from an international Bayesian multi-platform adaptive trial that compared therapeutic-dose anticoagulation with heparin to usual care in non-critically ill patients hospitalized for COVID-19 were used to fit Bayesian hierarchical generalized mixed models. Integrated Nested Laplace Approximations was compared to two Markov Chain Monte Carlo algorithms, implemented in the software JAGS and stan, using packages available in the statistical software R. Seven outcomes were analysed: organ-support free days (an ordinal outcome), five binary outcomes related to survival and length of hospital stay, and a time-to-event outcome. The posterior distributions for the treatment and sex effects and the variances for the hierarchical effects of age, site and time period were obtained. We summarized these posteriors by calculating the mean, standard deviations and the 95% equitailed credible intervals and presenting the results graphically. The computation time for each algorithm was recorded. RESULTS: The average overlap of the 95% credible interval for the treatment and sex effects estimated using Integrated Nested Laplace Approximations was 96% and 97.6% compared with stan, respectively. The graphical posterior densities for these effects overlapped for all three algorithms. The posterior mean for the variance of the hierarchical effects of age, site and time estimated using Integrated Nested Laplace Approximations are within the 95% credible interval estimated using Markov Chain Monte Carlo but the average overlap of the credible interval is lower, 77%, 85.6% and 91.3%, respectively, for Integrated Nested Laplace Approximations compared to stan. Integrated Nested Laplace Approximations and stan were easily implemented in clear, well-established packages in R, while JAGS required the direct specification of the model. Integrated Nested Laplace Approximations was between 85 and 269 times faster than stan and 26 and 1852 times faster than JAGS. CONCLUSION: Integrated Nested Laplace Approximations could reduce the computational complexity of Bayesian analysis in clinical trials as it is easy to implement in R, substantially faster than Markov Chain Monte Carlo methods implemented in JAGS and stan, and provides near identical approximations to the posterior distributions for the treatment effect. Integrated Nested Laplace Approximations was less accurate when estimating the posterior distribution for the variance of hierarchical effects, particularly for the proportional odds model, and future work should determine if the Integrated Nested Laplace Approximations algorithm can be adjusted to improve this estimation.

There is a growing interest within higher education to engage with students as partners to reposition students from consumers to producers of knowledge. The purpose of this study was to gather insights into the benefits, barriers/challenges, and best practices for engaging in student-faculty partnership activities for science faculty members. Supervising or working with graduate teaching assistants, working with students on university committees, collaborating with undergraduate or graduate students on a new or existing research project, and co-authoring manuscripts with graduate students were regarded as the most impactful partnership activities. Common benefits of student partnership activities included: collaboration and relationship building, broadening perspectives and gaining feedback, personal satisfaction, and institutional and career-related benefits. Common barriers/challenges reported were interpersonal dynamics and maintaining relationships, student management, and external influences. Best practices consisted of planning and setting expectations, developing students' agency, using open communication, and facilitating peer-to-peer collaboration and peer mentoring.

In the context of education, the issues of integrating artificial intelligence (AI) into teaching and maintaining academic integrity in students' use of AI are particularly relevant. This paper empirically examined the issue of ChatGPT usage for writing homework from the perspectives of students and professors. Study research methods included both quantitative and qualitative approaches. In Study 1, an anonymous questionnaire was administered to 350 Croatian students, users of ChatGPT, to investigate their perceptions, attitudes, habits, and intentions regarding ChatGPT usage for homework assignments. In Study 2, twelve faculty members were tested on their accuracy of distinguishing between original students' papers and ChatGPT-generated papers. For this purpose, 25 different versions of papers for 8 different courses were prepared. The results of the students' survey showed that most students still do not use ChatGPT regularly and have neutral attitudes about its usefulness, ease of use, risks, and intentions for future use. In addition, they were moderately concerned about ethical issues around its usage. Differences across gender and field of study were found. Professors, on the other hand, reported having average self-efficacy in appraising authorship, which is in line with their low average accuracy of 53%. Accuracy in distinguishing was lowest when ChatGPT was instructed to write a paper as a student. These results strongly suggest the necessity for clear guidelines, plagiarism detection tools, and educational initiatives to promote ethical use of AI technology.

Background: Upper elementary grade students encounter increasingly complex texts with abundant morphologically complex words. Despite the positive effects of morphology-based vocabulary instruction, emergent bilinguals with limited word reading skills may need additional support. Methods: This study investigated the effects of morphological analysis and morphophonemic analysis instruction on the orthographic and semantic learning of morphologically complex academic words. Fourth- and fifth-grade Spanish-English bilingual students (N = 30) in the United States participated in two learning tasks. In learning task one, participants learned two sets of carefully matched derivational words under morphological and whole-word learning conditions. In learning task two, the same participants learned two other sets of words under morphophonemic and whole-word learning conditions. Each learning task included two learning sessions interweaved by meaning recall and spelling production assessments. Cross-classified multilevel regression was used to assess the effects of intervention conditions, child and item predictors, as well as cross-level interactions. Results: Findings showed no significant difference in meaning recall and spelling measures between morphological and whole-word conditions. Students performed significantly better in the morphophonemic condition than in the whole-word condition for both meaning and affix spelling outcomes. The effect of morphophonemic intervention over whole word condition was stronger for younger students and words of lower base frequencies. Student meaning and spelling performance was significantly predicted by their word reading skills. Conclusions: Morphophonemic analysis instruction enhances word meaning recall and spelling of complex derivative words.

While intergroup contacts and social norms both have important roles in regulating intergroup relations, their effects on intergroup outcomes have mostly been examined independently from each other. The purpose of this longitudinal study was to explore the role of perceived ingroup norms about intergroup contact in the relationships between both direct and extended intergroup friendships and positive and negative outgroup orientations. To provide a more comprehensive normative perspective of intergroup contact, we tested for both cross-sectional and longitudinal, as well as moderation and mediation effects of perceived peer, parental, and school contact norms. The research was carried out in two waves on a sample of 1,128 majority and minority adolescents from four multiethnic communities in the Republic of Croatia. The results indicated that all three types of perceived ingroup contact norms exclusively mediate the cross-sectional, but not longitudinal, relationships between both forms of friendships and positive and negative outgroup orientations, highlighting the importance and consistency of perceived parental and school normative influences.

Introduction: The emergency department (ED) is a safety net, caring for families who lack adequate access to food and other basic needs. The COVID-19 pandemic caused a dramatic rise in food insecurity (FI) nationally; however, little is known about the prevalence of FI among families seen in pediatric EDs (PED). In this study we aimed to determine the prevalence of FI, as well as awareness and utilization of supplemental food services, among families seen in an urban PED during the COVID-19 pandemic using an electronic screening survey.Methods: This was a cross-sectional survey of families screened for FI in an urban PED. An electronic survey was advertised to all families via posters placed in patient rooms and other locations in the PED between February–October 2022. Surveys in English and Spanish were accessed on personal electronic devices via QR codes. Six validated US Department of Agriculture household food security questions and sociodemographic questions were included. We calculated respondents’ food security and performed descriptive and bivariate analyses of patient sociodemographics and responses to FI questions.Results: Of 42,697 PED visits, 612 surveys were completed and analyzed (1.4%). Nearly 50% of respondents identified as White and non-Hispanic, with approximately 80% female. Thirty percent had a household income of

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Given its aim to examine the impact of adversity and protective factors on childrens outcomes, the recruitment and retention of families who have a wide diversity in experiences are essential. However, the unfortunate history of inequitable treatment of underrepresented families in research and the risks with which some participants will contend (e.g., substance use) makes their recruitment and retention in social science and neuroscience research particularly challenging. This article explores strategies that the HBCD Study has developed to recruit and retain participants, including marginalized, underserved, and hard-to-reach populations, capitalizing on the extant literature and the researchers own experiences. In this paper, we address strategies to recruit and retain families within HBCD, including: 1) creating experiences that engender trust and promote relationships; 2) maintaining connections with participants over time; 3) ensuring appropriate compensation and supports; 4) considerations for study materials and procedures; and 5) community engagement. The implementation of these strategies may increase representation and inclusiveness, as well as improve the quality of the resulting data.

Immunoprevention is an emerging consideration for solid tumors, including pancreatic ductal adenocarcinoma (PDAC). We and others have shown that Kras mutations in genetic models of spontaneous pancreatic intraepithelial neoplasia (PanIN), which is a precursor to PDAC, results in CD73 expression in the neoplastic epithelium and some populations of infiltrating immune cells, including macrophages and CD8 T cells. CD73 is an ecto-enzyme that converts extracellular adenosine monophosphate to adenosine, a critical immune inhibitory molecule in PDAC. We hypothesized inhibition of CD73 would reduce the incidence of PanIN formation and alter the immune microenvironment. To test our hypothesis, we used the KrasG12D; PdxCre1 (KC) genetically engineered mouse model and tested the utility of AB-680, a small molecule inhibitor targeting CD73, to inhibit PanIN progression. AB-680, or vehicle control, was administered using oral gavage delivery 3 days/week at 10 mg/kg, beginning when the mice were 2 months old and lasting 3 months. We euthanized the mice at 5 months old. In the KC model, we quantified significantly less pancreatitis, early and advanced PanIN, and quantified a significant increase in M1 macrophages in AB-680-treated mice. Single-cell RNA sequencing (scRNA-seq) of pancreata of AB-680-treated mice revealed increased infiltration of CD4+ T cells, CD8+ T cells, and mature B cells. The scRNA-seq analysis showed that CD73 inhibition reduced M2 macrophages, acinar, and PanIN cell populations. CD73 inhibition enhanced immune surveillance and expanded unique clonotypes of TCR and BCR, indicating that inhibition of CD73 augments adaptive immunity early in the neoplastic microenvironment. Prevention Relevance: Previous studies found PanIN lesions in healthy pancreata. Not all progress to PDAC, suggesting a window for enhanced antitumor immunity through immunoprevention therapy. CD73 inhibition in our study prevents PanIN progression, reduces immune-suppressive macrophages and expands TCR and BCR unique clonotypes, highlighting an encouraging therapeutic avenue for high-risk individuals.

The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinsons disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1741 participants had SAA data and of these 1030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary.

Wildlife tagging provides critical insights into animal movement ecology, physiology, and behavior amid global ecosystem changes. However, the stress induced by capture, handling, and tagging can impact post-release locomotion and activity and, consequently, the interpretation of study results. Here, we analyze post-tagging effects on 1585 individuals of 42 terrestrial mammal species using collar-collected GPS and accelerometer data. Species-specific displacements and overall dynamic body acceleration, as a proxy for activity, were assessed over 20 days post-release to quantify disturbance intensity, recovery duration, and speed. Differences were evaluated, considering species-specific traits and the human footprint of the study region. Over 70% of the analyzed species exhibited significant behavioral changes following collaring events. Herbivores traveled farther with variable activity reactions, while omnivores and carnivores were initially less active and mobile. Recovery duration proved brief, with alterations diminishing within 4-7 tracking days for most species. Herbivores, particularly males, showed quicker displacement recovery (4 days) but slower activity recovery (7 days). Individuals in high human footprint areas displayed faster recovery, indicating adaptation to human disturbance. Our findings emphasize the necessity of extending tracking periods beyond 1 week and particular caution in remote study areas or herbivore-focused research, specifically in smaller mammals.

BACKGROUND AND OBJECTIVES: It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies. METHODS: Participants from the Parkinsons Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score

We lack the fundamental information needed to understand how DNA damage in the brain is generated and how it is controlled over a lifetime in the absence of replication check points. To address these questions, here, we integrate cell-type and region-specific features of DNA repair activity in the normal brain. The brain has the same repair proteins as other tissues, but normal, canonical repair activity is unequal and is characterized by high base excision repair (BER) and low double strand break repair (DSBR). The natural imbalance creates conditions where single strand breaks (SSBs) can convert to double strand breaks (DSBs) and reversibly switch between states in response to oxidation both in vivo and in vitro. Our data suggest that, in a normal background of repair, SSBs and DSBs are in an equilibrium which is pushed or pulled by metabolic state. Interconversion of SSB to DSBs provides a physiological check point, which would allow the formation of unrepaired DSBs for productive functions, but would also restrict them from exceeding tolerable limits.