Mitigating Molecular Aggregation in Drug Discovery with Predictive Insights from Explainable AI

As the importance of high-throughput screening (HTS) continues to grow due to its value in early stage drug discovery and data generation for training machine learning models, there is a growing need for robust methods for pre-screening compounds to identify and prevent false-positive hits. Small, colloidally aggregating molecules are one of the primary sources of false-positive hits in high-throughput screens, making them an ideal candidate to target for removal from libraries using predictive pre-screening tools. However, a lack of understanding of the causes of molecular aggregation introduces difficulty in the development of predictive tools for detecting aggregating molecules. Herein, we present an examination of the molecular features differentiating datasets of aggregating and non-aggregating molecules, as well as a machine learning approach to predicting molecular aggregation. Our method uses explainable graph neural networks and counterfactuals to reliably predict and explain aggregation, giving additional insights and design rules for future screening. The integration of this method in HTS approaches will help combat false positives, providing better lead molecules more rapidly and thus accelerating drug discovery cycles.Comment: 17 pages, plus S

Walking and Walkability: Is Wayfinding a Missing Link? Implications for Public Health Practice

Research on walking and walkability has yet to focus on wayfinding, the interactive, problem-solving process by which people use environmental information to locate themselves and navigate through various settings

The impact of the cost of living crisis and food insecurity on food purchasing behaviours and food preparation practices in people living with obesity.

Lower income households are at greater risk of food insecurity and poor diet quality than higher income households. In high-income countries, food insecurity is associated with high levels of obesity, and in the UK specifically, the cost of living crisis (i.e., where the cost of everyday essentials has increased quicker than wages) is likely to have exacerbated existing dietary inequalities. There is currently a lack of understanding of the impact of the current UK cost of living crisis on food purchasing and food preparation practices of people living with obesity (PLWO) and food insecurity, however this knowledge is critical in order to develop effective prevention and treatment approaches to reducing dietary inequalities. Using an online survey (N=583) of adults residing in England or Scotland with a body mass index (BMI) of ≥30 kg/m2, participants self-reported on food insecurity, diet quality, perceived impact of the cost of living crisis, and their responses to this in terms of food purchasing behaviours and food preparation practices. Regression analyses found that participants adversely impacted by the cost of living crisis reported experiencing food insecurity. Additionally, food insecurity was associated with use of specific purchasing behaviours (i.e., use of budgeting, use of supermarket offers) and food preparation practices (i.e., use of energy-saving appliances, use of resourcefulness). Exploratory analyses indicated that participants adversely impacted by the cost of living crisis and who used budgeting had low diet quality, whereas use of meal planning was associated with high diet quality. These findings highlight the fragility of food budgets and the coping strategies used by PLWO and food insecurity during the cost of living crisis. Policy measures and interventions are urgently needed that address the underlying economic factors contributing to food insecurity, to improve access to and affordability of healthier foods for all

Mobility Disability in Older Adults: At the Intersection of People and Places

Mobility disability is associated with poor lower body function among older adults. This study examines whether specific types of neighborhood characteristics moderate that association

Inaccuracies of Nitric Oxide Measurement Methods in Biological Media

Despite growing reports on the biological action of nitric oxide (NO) as a function of NO payload, the validity of such work is often questionable due to the manner in which NO is measured and/or the solution composition in which NO is quantified. To highlight the importance of measurement technique for a given sample type, NO produced from a small molecule NO donor (N-diazeniumdiolated l-proline, PROLI/NO) and a NO-releasing xerogel film were quantified in a number of physiological buffers and fluids, cell culture media, and bacterial broth using the Griess assay, a chemiluminescence analyzer, and an amperometric NO sensor. Despite widespread use, the Griess assay proved to be inaccurate for measuring NO in many of the media tested. In contrast, the chemiluminescence analyzer provided superb kinetic information in most buffers, but was impractical for NO analysis in proteinaceous media. The electrochemical NO sensor enabled greater flexibility across the various media with potential for spatial resolution, albeit at lower than expected NO totals versus either the Griess assay or chemiluminescence. The results of this study highlight the importance of measurement strategy for accurate NO analysis and reporting NO-based biological activity

A Pilot Study Comparing the Efficacy of Lactate Dehydrogenase Levels Versus Circulating Cell-Free microRNAs in Monitoring Responses to Checkpoint Inhibitor Immunotherapy in Metastatic Melanoma Patients.

Serum lactate dehydrogenase (LDH) is a standard prognostic biomarker for stage IV melanoma patients. Often, LDH levels do not provide real-time information about the metastatic melanoma patients\u27 disease status and treatment response. Therefore, there is a need to find reliable blood biomarkers for improved monitoring of metastatic melanoma patients who are undergoing checkpoint inhibitor immunotherapy (CII). The objective in this prospective pilot study was to discover circulating cell-free microRNA (cfmiR) signatures in the plasma that could assess melanoma patients\u27 responses during CII. The cfmiRs were evaluated by the next-generation sequencing (NGS) HTG EdgeSeq microRNA (miR) Whole Transcriptome Assay (WTA; 2083 miRs) in 158 plasma samples obtained before and during the course of CII from 47 AJCC stage III/IV melanoma patients\u27 and 73 normal donors\u27 plasma samples. Initially, cfmiR profiles for pre- and post-treatment plasma samples of stage IV non-responder melanoma patients were compared to normal donors\u27 plasma samples. Using machine learning, we identified a 9 cfmiR signature that was associated with stage IV melanoma patients being non-responsive to CII. These cfmiRs were compared in pre- and post-treatment plasma samples from stage IV melanoma patients that showed good responses. Circulating miR-4649-3p, miR-615-3p, and miR-1234-3p demonstrated potential prognostic utility in assessing CII responses. Compared to LDH levels during CII, circulating miR-615-3p levels were consistently more efficient in detecting melanoma patients undergoing CII who developed progressive disease. By combining stage III/IV patients, 92 and 17 differentially expressed cfmiRs were identified in pre-treatment plasma samples from responder and non-responder patients, respectively. In conclusion, this pilot study demonstrated cfmiRs that identified treatment responses and could allow for real-time monitoring of patients receiving CII

S-Nitrosothiol-modified nitric oxide-releasing chitosan oligosaccharides as antibacterial agents

S-nitrosothiol-modified chitosan oligosaccharides were synthesized by reaction with 2-iminothiolane hydrochloride and 3-acetamido-4,4-dimethylthietan-2-one, followed by the thiol nitrosation. The resulting nitric oxide (NO)-releasing chitosan oligosaccharides stored ~0.3 μmol NO/mg chitosan. Both the chemical structure of the nitrosothiol (i.e., primary and tertiary) and the use of ascorbic acid as a trigger for NO donor decomposition were used to control the NO-release kinetics. With ascorbic acid, the S-nitrosothiol-modified chitosan oligosaccharides elicited a 4-log reduction in Pseudomonas aeruginosa (P. aeruginosa) viability. Confocal microscopy indicated that the primary S-nitrosothiol-modified chitosan oligosaccharides associated more with the bacteria relative to the tertiary S-nitrosothiol system. The primary S-nitrosothiol-modified chitosan oligosaccharides elicited minimal toxicity towards L929 mouse fibroblast cells at the concentration necessary for a 4-log reduction in bacterial viability, further demonstrating the potential of S-nitrosothiol-modified chitosan oligosaccharides as NO-release therapeutics

A two-species continuum model for aeolian sand ripples

We formulate a continuum model for aeolian sand ripples consisting of two species of grains: a lower layer of relatively immobile clusters, with an upper layer of highly mobile grains moving on top. We predict analytically the ripple wavelength, initial ripple growth rate and threshold saltation flux for ripple formation. Numerical simulations show the evolution of realistic ripple profiles from initial surface roughness via ripple growth and merger.Comment: 9 pages, 3 figure

Direct detection of blood nitric oxide reveals a burn-dependent decrease of nitric oxide in response to Pseudomonas aeruginosa infection

Burn injury is associated with severe immune dysfunction, including an anti-inflammatory state that occurs late after burn injury. While increased nitric oxide (NO) production is associated with severe infection and sepsis, the effect of burn trauma on these levels during a non-lethal infection remains unknown. We hypothesized that in a mouse model, 1) NO levels would be increased after infection without trauma and 2) burn injury would lead to decreased NO production even during infection

The Effect of a Food Addiction Explanation Model for Weight Control and Obesity on Weight Stigma

There is increasing scientific and public support for the notion that some foods may be addictive, and that poor weight control and obesity may, for some people, stem from having a food addiction. However, it remains unclear how a food addiction model (FAM) explanation for obesity and weight control will affect weight stigma. In two experiments (N = 530 and N = 690), we tested the effect of a food addiction explanation for obesity and weight control on weight stigma. In Experiment 1, participants who received a FAM explanation for weight control and obesity reported lower weight stigma scores (e.g., less dislike of 'fat people', and lower personal willpower blame) than those receiving an explanation emphasizing diet and exercise (F(4,525) = 7.675, p = 0.006; and F(4,525) = 5.393, p = 0.021, respectively). In Experiment 2, there was a significant group difference for the dislike of 'fat people' stigma measure (F(5,684) = 5.157, p = 0.006), but not for personal willpower weight stigma (F(5,684) = 0.217, p = 0.81). Participants receiving the diet and exercise explanation had greater dislike of 'fat people' than those in the FAM explanation and control group (p values 0.05). The FAM explanation for weight control and obesity did not increase weight stigma and resulted in lower stigma than the diet and exercise explanation that attributes obesity to personal control. The results highlight the importance of health messaging about the causes of obesity and the need for communications that do not exacerbate weight stigma