Machine Learning-Driven Classification of Urease Inhibitors Leveraging Physicochemical Properties as Effective Filter Criteria.

Urease, a pivotal enzyme in nitrogen metabolism, plays a crucial role in various microorganisms, including the pathogenic Helicobacter pylori. Inhibiting urease activity offers a promising approach to combating infections and associated ailments, such as chronic kidney diseases and gastric cancer. However, identifying potent urease inhibitors remains challenging due to resistance issues that hinder traditional approaches. Recently, machine learning (ML)-based models have demonstrated the ability to predict the bioactivity of molecules rapidly and effectively. In this study, we present ML models designed to predict urease inhibitors by leveraging essential physicochemical properties. The methodological approach involved constructing a dataset of urease inhibitors through an extensive literature search. Subsequently, these inhibitors were characterized based on physicochemical properties calculations. An exploratory data analysis was then conducted to identify and analyze critical features. Ultimately, 252 classification models were trained, utilizing a combination of seven ML algorithms, three attribute selection methods, and six different strategies for categorizing inhibitory activity. The investigation unveiled discernible trends distinguishing urease inhibitors from non-inhibitors. This differentiation enabled the identification of essential features that are crucial for precise classification. Through a comprehensive comparison of ML algorithms, tree-based methods like random forest, decision tree, and XGBoost exhibited superior performance. Additionally, incorporating the "chemical family type" attribute significantly enhanced model accuracy. Strategies involving a gray-zone categorization demonstrated marked improvements in predictive precision. This research underscores the transformative potential of ML in predicting urease inhibitors. The meticulous methodology outlined herein offers actionable insights for developing robust predictive models within biochemical systems.

From Proteome to Potential Drugs: Integration of Subtractive Proteomics and Ensemble Docking for Drug Repurposing against Pseudomonas aeruginosa RND Superfamily Proteins.

Pseudomonas aeruginosa (P. aeruginosa) poses a significant threat as a nosocomial pathogen due to its robust resistance mechanisms and virulence factors. This study integrates subtractive proteomics and ensemble docking to identify and characterize essential proteins in P. aeruginosa, aiming to discover therapeutic targets and repurpose commercial existing drugs. Using subtractive proteomics, we refined the dataset to discard redundant proteins and minimize potential cross-interactions with human proteins and the microbiome proteins. We identified 12 key proteins, including a histidine kinase and members of the RND efflux pump family, known for their roles in antibiotic resistance, virulence, and antigenicity. Predictive modeling of the three-dimensional structures of these RND proteins and subsequent molecular ensemble-docking simulations led to the identification of MK-3207, R-428, and Suramin as promising inhibitor candidates. These compounds demonstrated high binding affinities and effective inhibition across multiple metrics. Further refinement using non-covalent interaction index methods provided deeper insights into the electronic effects in protein-ligand interactions, with Suramin exhibiting superior binding energies, suggesting its broad-spectrum inhibitory potential. Our findings confirm the critical role of RND efflux pumps in antibiotic resistance and suggest that MK-3207, R-428, and Suramin could be effectively repurposed to target these proteins. This approach highlights the potential of drug repurposing as a viable strategy to combat P. aeruginosa infections.

Unveiling Novel Urease Inhibitors for Helicobacter pylori: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations.

Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.

Implications of the microbiome and metabolic intermediaries produced by bacteria in breast cancer.

The breast microbiome presents a diverse microbial community that could affects health and disease states, in the context of breast cancer. Sequencing technologies have allowed describing the diversity and abundance of microbial communities among individuals. The complex tumoral microenvironment that includes the microbial composition could influence tumor growth. The imbalance of diversity and abundance inside the microbial community, known as dysbiosis plays a crucial role in this context. One the most prevalent bacterial genera described in breast invasive carcinoma are Bacillus, Pseudomonas, Brevibacillus, Mycobacterium, Thermoviga, Acinetobacter, Corynebacterium, Paenibacillus, Ensifer, and Bacteroides. Paenibacills genus shows a relation with patient survival. When the Paenibacills genus increases its abundance in patients with breast cancer, the survival probability decreases. Within this dysbiotic environment, various bacterial metabolites could play a pivotal role in the progression and modulation of breast cancer. Key bacterial metabolites, such as cadaverine, lipopolysaccharides (LPS), and trimethylamine N-oxide (TMAO), have been found to exhibit potential interactions within breast tissue microenvironments. Understanding the intricate relationships between dysbiosis and these metabolites in breast cancer may open new avenues for diagnostic biomarkers and therapeutic targets. Further research is essential to unravel the specific roles and mechanisms of these microbial metabolites in breast cancer progression.

Availability of healthy foods, fruit and vegetable consumption, and cognition among urban older adults.

BACKGROUND: . Although prior studies have examined the associations between neighborhood characteristics and cognitive health, little is known about whether local food environments, which are critical for individuals' daily living, are associated with late-life cognition. Further, little is known about how local environments may shape individuals' health-related behaviors and impact cognitive health. The aim of this study is to examine whether objective and subjective measures of healthy food availability are associated with ambulatory cognitive performance and whether behavioral and cardiovascular factors mediate these associations among urban older adults. METHODS: . The sample consisted of systematically recruited, community-dwelling older adults (N = 315, mean age = 77.5, range = 70-91) from the Einstein Aging Study. Objective availability of healthy foods was defined as density of healthy food stores. Subjective availability of healthy foods and fruit/vegetable consumption were assessed using self-reported questionnaires. Cognitive performance was assessed using smartphone-administered cognitive tasks that measured processing speed, short-term memory binding, and spatial working memory performance 6 times a day for 14 days. RESULTS: . Results from multilevel models showed that subjective availability of healthy foods, but not objective food environments, was associated with better processing speed (estimate= -0.176, p = .003) and more accurate memory binding performance (estimate = 0.042, p = .012). Further, 14~16% of the effects of subjective availability of healthy foods on cognition were mediated through fruit and vegetable consumption. CONCLUSIONS: . Local food environments seem to be important for individuals' dietary behavior and cognitive health. Specifically, subjective measures of food environments may better reflect individuals' experiences regarding their local food environments not captured by objective measures. Future policy and intervention strategies will need to include both objective and subjective food environment measures in identifying impactful target for intervention and evaluating effectiveness of policy changes.

Longitudinal analyses indicate bidirectional associations between loneliness and health.

OBJECTIVES: To evaluate temporal dynamics between loneliness and both objective and subjective health (i.e. functional impairment and self-rated health) in mid- to late-adulthood. METHOD: We applied bivariate dual-change-score models to longitudinal data from 3 Swedish twin studies (N = 1,939) to explore dynamic associations between loneliness and health across 3 age ranges (50-69, 70-81, and 82+ years) to investigate whether associations between loneliness and health change with age due to increasing incidence of chronic health conditions and bereavement. RESULTS: Results showed bidirectional associations between loneliness and both objective and subjective health, with adverse impacts of loneliness observed on subsequent subjective and objective health beginning at age 70. Associations between health and subsequent loneliness were observed after age 82 and varied for subjective and objective health, with subjective health associated with less loneliness and objective health associated with greater loneliness. CONCLUSIONS: Our results indicate dynamic associations between loneliness and health with age in mid- to late-adulthood, with earlier impacts of loneliness on health and later impacts of health on loneliness that vary for objective and subjective measures of health. These findings suggest impacts of health on loneliness may arise later in life when worsening health or mobility interfere with social interaction.

CATSLife: A Study of Lifespan Behavioral Development and Cognitive Functioning.

The purpose of this update is to provide the most current information about both the Colorado Adoption Project (CAP) and the Longitudinal Twin Study (LTS) and to introduce the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife), a product of their merger and a unique study of lifespan behavioral development and cognitive aging. The primary objective of CATSLife is to assess the unique saliency of early childhood genetic and environmental factors to adult cognitive maintenance and change, as well as proximal influences and innovations that emerge across development. CATSLife is currently assessing up to 1600 individuals on the cusp of middle age, targeting those between 30 and 40 years of age. The ongoing CATSLife data collection is described as well as the longitudinal data available from the earlier CAP and LTS assessments. We illustrate CATSLife via current projects and publications, highlighting the measurement of genetic, biochemical, social, sociodemographic and environmental indices, including geospatial features, and their impact on cognitive maintenance in middle adulthood. CATSLife provides an unparalleled opportunity to assess prospectively the etiologies of cognitive change and test the saliency of early childhood versus proximal influences on the genesis of cognitive decline.

The influence of social support and perceived stress on response time inconsistency.

OBJECTIVES: Lack of social support and high levels of stress represent potentially modifiable risk factors for cognitive aging. In this study we examined the relationships between these two risk factors and response time inconsistency (RTI), or trial-to-trial variability in choice response time tasks. RTI is an early indicator of declining cognitive health, and examining the influence of modifiable psychosocial risk factors on RTI is important for understanding and promoting cognitive health during adulthood and old age. METHODS: Using data from a community sample study (n = 317; Mage = 49, range = 19-83), we examined the effects of social support, including size of network and satisfaction with support, global perceived stress, and their interactions on RTI. RESULTS: Neither size of network nor satisfaction with support was associated with RTI independent of perceived stress. Stress was positively associated with increased RTI on all tasks, independent of social support. Perceived stress did not interact with either dimension of social support to predict RTI, and perceived stress effects were invariant across age and sex. CONCLUSION: Perceived stress, but not social support, may be a unique and modifiable risk factor for normal and pathological cognitive aging. Discussion focuses on the importance of perceived stress and its impact on RTI in supporting cognitive health in adulthood and old age.

Genetic and environmental factors associated with delirium severity in older adults with dementia.

OBJECTIVE: To determine (1) whether delirium severity was associated with Apolipoprotein E (APOE) genotype status and occupational complexity, a measure of cognitive reserve, in individuals with delirium superimposed on dementia; and (2) whether decline in delirium severity was associated with these same factors over a post-acute care (PAC) stay. METHODS: Control group data (n = 142) from a completed randomized clinical trial were used to address the aims of the study. Delirium severity was calculated by combining items from the Confusion Assessment Method and the Montreal Cognitive Assessment. APOE ε4 carriers versus non-carriers were considered. Occupational complexity, a measure of cognitive reserve, was derived from the Lifetime of Experiences Questionnaire. Covariates examined included age, gender, education, Clinical Dementia Rating Scale, and the Charlson comorbidity score. Data were nested (i.e., days nested within persons) and analyzed using multilevel models. RESULTS: The presence of an APOE ε4 allele and higher Clinical Dementia Rating Scale were associated with greater delirium severity at baseline. The presence of an APOE ε4 allele was also associated with greater delirium severity averaged across the PAC stay. Occupational complexity was not associated with baseline delirium severity or average daily delirium severity; however, individuals with low occupational complexity showed a significant decreased in delirium severity during the course of their PAC stay. CONCLUSIONS: Individual differences, including genetic factors and level of cognitive reserve, contribute to the severity of delirium in older adults with dementia. Copyright © 2016 John Wiley & Sons, Ltd.

Subjective cognitive impairment and quality of life: a systematic review.

BACKGROUND: Older adults with subjective cognitive impairment (SCI) experience increased affective symptoms, reduced engagement in a range of activities, as well as more functional problems when compared to those without SCI. These associations suggest that SCI may be detrimental to older adults' quality of life (QoL). The purpose of this paper is to advance understanding of the SCI-QoL relationship through a comprehensive review of the empirical literature relating SCI and QoL. METHODS: A systematic literature review was conducted in CINAHL, PsycINFO, and PubMed per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Eligible articles were appraised using the weight of evidence (WoE) framework to evaluate methodological quality, methodological relevance, and topic relevance. A narrative synthesis of results was conducted, based on conceptual definitions of QoL. RESULTS: Eleven articles were identified that met eligibility criteria. WoE ratings ranged from low to high scores. Studies reviewed reported that the presence, greater frequency, or greater severity of SCI is associated with lower QoL regardless of methodological quality rating, sample characteristics (e.g. geographic location, clinical vs. community settings), study design (e.g. cross-sectional vs. longitudinal), and operationalization of SCI or QoL. CONCLUSION: Across studies, QoL was negatively associated with SCI. However, a frequent limitation of the reviewed literature was the mismatch between the conceptual and operational definitions of SCI and QoL. Similarly, SCI measures varied in quality across the reviewed literature. This suggests future empirical work should focus on the appropriate strategies for conceptually and operationally defining these constructs.

The Effects of Stress on Cognitive Aging, Physiology and Emotion (ESCAPE) Project.

BACKGROUND: Despite evidence that psychological stress is an important risk factor for age-related cognitive loss, little research has directly evaluated psychological and physiological mediators of the relationship between stressful experiences and cognitive function. A key objective of the ESCAPE (Effects of Stress on Cognitive Aging, Physiology, and Emotion) project is to evaluate whether engaging in stress-related unconstructive repetitive thought (URT) is a pathway through which stressful experiences negatively affect cognitive health over the short- and long-term. Over the short-term, we hypothesize that engaging in URT will deplete attentional resources and result in worse cognitive performance in daily life. Over the long-term, we expect that the effects of chronic stress, from repeated exposure to stressors and regular engagement in URT, will be apparent in dysregulated hypothalamic-pituitary-adrenal (HPA) axis function and inflammation. Over time, stress-related physiological dysregulation will result in accelerated cognitive decline. METHODS/DESIGN: This study utilizes a prospective longitudinal measurement-burst design. A systematic probability sample of participants aged 25 to 65 is recruited from residents of the Bronx, NY. Consenting participants complete a baseline assessment and follow-up waves at 9, 18, and 27 months post-baseline. At each wave, participants complete a 14 day measurement burst of brief surveys and cognitive assessments delivered via study smartphones during daily life. Participants provide saliva samples four times each day for five days during the measurement burst and fasting blood samples at the end of each burst from which cortisol and dehydroepiandrosterone sulfate (DHEAS), circulating inflammatory markers, and stimulated inflammatory responses to lipopolysaccharide in whole blood are determined. DISCUSSION: This study takes a multi-pronged approach to assessing stress (i.e., early adversity, chronic strains, major events, daily hassles), psychological mediators (e.g., URT), biological mechanisms (i.e., HPA function, inflammation) and outcomes across different time-scales (i.e., momentary cognitive performance, cognitive decline across years). The systematic probability sample is locally representative and can be compared with national norms on key markers of health and well-being. The findings will improve our understanding of how environmental, psychological, and physiological stress-related influences accumulate to affect cognitive health and identify potential targets (e.g., URT, inflammation) for prevention and intervention promoting cognitive health.

Assessment of subjective cognitive impairment among older adults.

Subjective cognitive impairment (SCI) refers to an individual's everyday concerns related to cognitive functioning, which can exist even in the absence of objectively assessed impairment. SCI is common among older adults, and although symptoms may be mild, SCI is associated with subsequent cognitive decline as well as significant negative effects on everyday functional ability, mood, and social engagement. Despite the potential consequences, SCI is often underreported and undetected. Thus, it is critical to consider assessing for SCI among older adults to determine cognitive impairment risk and support early intervention to promote functional well-being and health management. The current article reviews factors related to SCI, evaluates existing methods for the assessment of SCI, and proposes a person-centered framework for enhancing assessment. Application of the framework is further illustrated through the use of clinical examples.

Mitigating Weight Bias in the Clinical Setting: A New Approach to Care.

Weight bias toward patients in larger bodies is pervasive among health care providers and can negatively influence provider-patient communication, as well as patients' behavior and health outcomes. Weight bias has historical roots that perpetuate thinness and Whiteness as the cultural norm. Although weight bias remains socially acceptable in US culture, contributing factors to an individual's body size are complex and multifactorial. Providers and health care systems also consistently use body mass index (BMI) as an indicator of health status, despite its limitations and harmful effects in the clinical setting. This state of the science review presents 8 evidence-based strategies that demonstrate how to mitigate harm from weight bias and improve quality of care and health outcomes for patients living in larger bodies. Person-centered approaches to care include (1) eliminating clinical recommendations to lose weight; (2) shifting from a focus on weight to health; (3) implementing a size and weight-inclusive approach; (4) engaging in weight bias self-evaluation; (5) creating a welcoming environment for patients of all sizes; (6) seeking permission and learning the patient's story; (7) using weight-inclusive language; and (8) re-evaluating clinical guidelines and policies based on BMI. Midwives and other health care providers may benefit from training that re-imagines the delivery of health care to patients in larger bodies.

History of Midwifery at Tuskegee: Vanguards of Midwifery Education.

Tuskegee, in Macon County, Alabama, has played an important role in Alabama's midwifery legacy and was home to 2 different midwifery education programs from the 1920s through the 1940s. In response to a 1918 state law requiring midwives to pass an examination to receive a practice permit in their county, stakeholders developed a four-week course for Black Alabamian midwives on the grounds of Tuskegee Institute at the John A. Andrew Memorial Hospital. In the 1940s, in the same location on the grounds of Tuskegee Institute, the Tuskegee School of Nurse-Midwifery educated Black nurse-midwives to improve Black maternal and neonatal outcomes in the South.

An examination of early socioeconomic status and neighborhood disadvantage as independent predictors of antisocial behavior: A longitudinal adoption study.

The present study examined early socioeconomic status (SES) and neighborhood disadvantage (ND) as independent predictors of antisocial behavior (ASB) and addressed the etiology of the associations (i.e., genes versus the environment) using a longitudinal adoption design. Prospective data from the Colorado Adoption Project (435 adoptees, 598 nonadopted children, 526 biological grandparents of adoptees, 481 adoptive parents, and 617 nonadoptive parents including biological parents of unrelated siblings of adoptees) were examined. SES and ND were assessed during infancy and ASB was evaluated from ages four through 16 using parent and teacher report. Associations between predictors and ASB were compared across adoptive and nonadoptive families and sex. Early SES was a nominally significant, independent predictor of antisocial ASB, such that lower SES predicted higher levels of ASB in nonadoptive families only. ND was not associated with ASB. Associations were consistent across aggression and delinquency, and neither SES nor ND was associated with change in ASB over time. Nominally significant associations did not remain significant after controlling for multiple testing. As such, despite nonsignificant differences in associations across sex or adoptive status, we were unable to make definitive conclusions regarding the genetic versus environmental etiology of or sex differences in the influence of SES and ND on ASB. Despite inconclusive findings, in nonadoptees, results were consistent-in effect size and direction-with previous studies in the literature indicating that lower SES is associated with increased risk for ASB.

Exposure to neighborhood violence, and laboratory-based and ambulatory cognitive task performance in adulthood.

OBJECTIVE: Exposure to neighborhood violence may have negative implications for adults' cognitive functioning, but the ecological sensitivity of these effects has yet to be determined. We first evaluated the link between exposure to neighborhood violence and two latent constructs of cognitive function that incorporated laboratory-based and ambulatory, smartphone-based, cognitive assessments. Second, we examined whether the effect of exposure to violence was stronger for ambulatory assessments compared to in-lab assessments. METHODS: We used data from 256 urban-dwelling adults between 25 and 65 years old (M = 46.26, SD = 11.07); 63.18% non-Hispanic Black, 9.21% non-Hispanic White, 18.41% Hispanic White, 5.02% Hispanic Black, and 4.18% other. Participants completed baseline surveys on neighborhood exposures, cognitive assessments in a laboratory/research office, and ambulatory smartphone-based cognitive assessments five-times a day for 14 days. RESULTS: Exposure to neighborhood violence was associated with poorer performance in a latent working memory construct that incorporated in-lab and ambulatory assessments, but was not associated with the perceptual speed construct. The effect of exposure to neighborhood violence on the working memory construct was explained by its effect on the ambulatory working memory task and not by the in-lab cognitive assessments. CONCLUSION: This study shows the negative effect that exposure to neighborhood violence may have on everyday working memory performance in urban-dwelling adults in midlife. Results highlight the need for more research to determine the sensitivity of ambulatory assessments to quantify the effects of neighborhood violence on cognitive function.

Intrusive Thoughts Mediate the Association between Neuroticism and Cognitive Function.

Although research has established a negative association between trait neuroticism and cognition, little is known about the mechanisms that underlie this relationship. We examined the tendency to experience intrusive thoughts and negative affect as potential mediators of the relationship between neuroticism and cognitive performance. We hypothesized that the tendency to experience intrusive thoughts reflects ineffective attentional control and would account for the relationship between neuroticism and cognitive performance over and above the mediating effect of negative affect. Three hundred seventeen adults (Mage =49.43) completed a series of attention-demanding cognitive tasks as well as self-report measures of intrusive thoughts, negative affect, and neuroticism. Intrusive thoughts mediated the association between trait neuroticism and cognitive performance beyond negative affect. These findings are consistent with the hypothesis that the tendency to experience intrusive thoughts is a mechanism through which trait neuroticism influences cognitive performance.

The Association of Glucose Variability and Dementia Incidence in Latinx Adults with Type 2 Diabetes: A Retrospective Study.

Latinx adults with both cognitive dysfunction and type 2 diabetes mellitus (T2DM) are significantly more likely than Latinx adults with diabetes alone to have complications such as cardiovascular disease. Glucose variability may be a risk for dementia, but the course of glucose variability in the time before a dementia diagnosis for Latinx adults with T2DM has not been examined. We used a 10-year retrospective cohort of medical records of Latinx patients with T2DM who had at least one use of a continuous glucose monitor. The objective was to examine how glucose variability was associated with future dementia diagnoses. A total of 116 charts were included. Mean of daily differences and mean amplitude of glycemic excursions were more strongly associated with dementia diagnoses than other variability indices (p < .01). Understanding the relationships between cognitive function, glucose variability, and barriers to health care can translate into improved interventions to enhance diabetes care.

Neighborhood Cohesion Across the Life Course and Effects on Cognitive Aging.

OBJECTIVES: Greater neighborhood cohesion is associated with better cognitive function in adulthood and may serve as a protective factor against cognitive impairment and decline. We build on prior work by examining the effects of perceived neighborhood cohesion across the life course on level and change in cognitive function in adulthood. METHODS: Utilizing longitudinal data from the Health and Retirement Study (1998-2016) and its Life History Mail Survey, we leveraged data from 3,599 study participants (baseline age: 51-89) who participated in up to 10 waves. Respondents provided retrospective ratings of neighborhood cohesion at childhood (age 10), young adulthood (age at the first full-time job), early midlife (age 40), and concurrently at baseline (i.e., late midlife/adulthood); they completed the modified version of the Telephone Interview for Cognitive Status. We fit a univariate latent growth curve model of change in cognitive function across waves and tested whether neighborhood cohesion during each recollected life stage predicted level and change in cognitive function. RESULTS: Greater neighborhood cohesion during childhood and late midlife/adulthood each predicted higher cognitive function at baseline but not the rate of cognitive decline. The final model showed that greater neighborhood cohesion in childhood and in late midlife/adulthood remained significantly associated with higher baseline cognitive function, even after accounting for one another. DISCUSSION: Findings provide insight into life-course neighborhood contextual influences on cognitive aging. Our results emphasize the need for more research to understand the life-course dynamics between neighborhood environments and cognitive aging.