The gap between experts, farmers and non-farmers on perceived environmental vulnerability and the influence of values and beliefs.

Science has played a mixed role in guiding conservation and sustainability-oriented decision-making by individuals, policymakers, institutions, and governments. Not all science-based conservation and sustainability initiatives that address issues facing humanity and ecosystems and global problems have gained public support. Conservation decisions and policy prescriptions are and may be based on perceptions about and experiences with the environment, local land use, and ecosystems that may not align with or be grounded in science or evidence from experts in the field.

Local environment and individuals' beliefs: The dynamics shaping public support for sustainability policy in an agricultural landscape.

Agricultural landscapes are the leading edge in the advancement of sustainability and climate change adaptation. The purpose of this study is to endogenize culture as shaped by natural-cultural feedback into individuals' decision-making processes on sustainability policy support. We present an agent-based model in which an adaptive cultural decision-rule quantifies the probability of an agent deciding to support a wildlife area policy for the Smoky Hill River Watershed (SHRW) in Kansas, USA.

Spirometry quality predictors in a large multistate prospective study.

Background: The Gulf Long-Term Follow-up (GuLF) Study is a prospective cohort study of health effects associated with oil spill response and clean-up following the 2010 Deepwater Horizon Disaster (DWH). As part of the study, spirometry testing of lung function was carried out in home visits across multiple states. Few studies have described factors associated with spirometry test failure in field-based settings.

A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects.

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH group with phenyl (), methyl (), or 3'-furanyl [ ()] substituents demonstrated partial agonism with a lower efficacy than DAMGO or morphine in heterologous G-protein assays and synaptic physiology.

Predicted Mode of Binding to and Allosteric Modulation of the μ-Opioid Receptor by Kratom's Alkaloids with Reported Antinociception .

Pain management devoid of serious opioid adverse effects is still far from reach despite vigorous research and development efforts. Alternatives to classical opioids have been sought for years, and mounting reports of individuals finding pain relief with kratom have recently intensified research on this natural product. Although the composition of kratom is complex, the pharmacological characterization of its most abundant alkaloids has drawn attention to three molecules in particular, owing to their demonstrated antinociceptive activity and limited side effects .

High-resolution structures of multiple 5-HTR-setron complexes reveal a novel mechanism of competitive inhibition.

Serotonin receptors (5-HTR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HTR in complex with palonosetron, ondansetron, and alosetron.

Developing an Environmental Health Sciences COVID-19 Research Agenda: Results from the NIEHS Disaster Research Response (DR2) Work Group's Modified Delphi Method.

Leveraging the community of practice recently established through the U.S. National Institute of Environmental Health Sciences (NIEHS) Disaster Research Response (DR2) working group, we used a modified Delphi method to identify and prioritize environmental health sciences Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and associated Coronavirus Disease 2019 (COVID-19) research questions.

Mechanism of μ-Opioid Receptor-Magnesium Interaction and Positive Allosteric Modulation.

In the era of opioid abuse epidemics, there is an increased demand for understanding how opioid receptors can be allosterically modulated to guide the development of more effective and safer opioid therapies. Among the modulators of the μ-opioid (MOP) receptor, which is the pharmacological target for the majority of clinically used opioid drugs, are monovalent and divalent cations. Specifically, the monovalent sodium cation (Na) has been known for decades to affect MOP receptor signaling by reducing agonist binding, whereas the divalent magnesium cation (Mg) has been shown to have the opposite effect, notwithstanding the presence of sodium chloride.

Inclusion of enclosed hydration effects in the binding free energy estimation of dopamine D3 receptor complexes.

Confined hydration and conformational flexibility are some of the challenges encountered for the rational design of selective antagonists of G-protein coupled receptors. We present a set of C3-substituted (-)-stepholidine derivatives as potent binders of the dopamine D3 receptor. The compounds are characterized biochemically, as well as by computer modeling using a novel molecular dynamics-based alchemical binding free energy approach which incorporates the effect of the displacement of enclosed water molecules from the binding site.

Hidden bias in the DUD-E dataset leads to misleading performance of deep learning in structure-based virtual screening.

Recently much effort has been invested in using convolutional neural network (CNN) models trained on 3D structural images of protein-ligand complexes to distinguish binding from non-binding ligands for virtual screening. However, the dearth of reliable protein-ligand x-ray structures and binding affinity data has required the use of constructed datasets for the training and evaluation of CNN molecular recognition models. Here, we outline various sources of bias in one such widely-used dataset, the Directory of Useful Decoys: Enhanced (DUD-E).

Evaluating environmental change and behavioral decision-making for sustainability policy using an agent-based model: A case study for the Smoky Hill River Watershed, Kansas.

Sustainability has been at the forefront of the environmental research agenda of the integrated anthroposphere, hydrosphere, and biosphere since the last century and will continue to be critically important for future environmental science. However, linking humans and the environment through effective policy remains a major challenge for sustainability research and practice. Here we address this gap using an agent-based model (ABM) for a coupled natural and human systems in the Smoky Hill River Watershed (SHRW), Kansas, USA.

Developing Large-Scale Research in Response to an Oil Spill Disaster: a Case Study.

Research conducted in the wake of a disaster can provide information to help mitigate health consequences, support future recovery efforts, and improve resilience. However, a number of barriers have prevented time-sensitive research responses following previous disasters. Furthermore, large-scale disasters present their own special challenges due to the number of people exposed to disaster conditions, the number of groups engaged in disaster response, and the logistical challenges of rapidly planning and implementing a large study.

New Dopamine D3-Selective Receptor Ligands Containing a 6-Methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol Motif.

A series of analogues featuring a 6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol unit as the arylamine "head" group of a classical D3 antagonist core structure were synthesized and evaluated for affinity at dopamine D1, D2, and D3 receptors (D1R, D2R, D3R). The compounds generally displayed strong affinity for D3R with very good D3R selectivity. Docking studies at D2R and D3R crystal structures revealed that the molecules are oriented such that their arylamine units are positioned in the orthosteric binding pocket of D3R, with the arylamide "tail" units residing in the secondary binding pocket.

Water Pharmacophore: Designing Ligands using Molecular Dynamics Simulations with Water.

In this study, we demonstrate a method to construct a water-based pharmacophore model which can be utilized in the absence of known ligands. This method utilizes waters found in the binding pocket, sampled through molecular dynamics. Screening of compound databases against this water-based pharmacophore model reveals that this approach can successfully identify known binders to a target protein.

Solvation Structure and Thermodynamic Mapping (SSTMap): An Open-Source, Flexible Package for the Analysis of Water in Molecular Dynamics Trajectories.

We have developed SSTMap, a software package for mapping structural and thermodynamic water properties in molecular dynamics trajectories. The package introduces automated analysis and mapping of local measures of frustration and enhancement of water structure. The thermodynamic calculations are based on Inhomogeneous Fluid Solvation Theory (IST), which is implemented using both site-based and grid-based approaches.

Synthesis and evaluation of C9 alkoxy analogues of (-)-stepholidine as dopamine receptor ligands.

Tetrahydroprotoberberine alkaloids have shown interesting polypharmacological actions at dopamine receptors and are a unique template from which to mine novel molecules with dual selective actions at D1 and D3 receptors. Such compounds will be valuable to evaluate as anti-cocaine therapeutics. Towards that eventual goal, we engaged an SAR study in which a series of C9 alkoxy analogues of the D1/D2/D3 ligand (-)-stepholidine that possessed or lacked a C12 bromo functionality, were synthesized and evaluated for affinity at dopamine D1, D2 and D3 receptors.

Solvation thermodynamic mapping of molecular surfaces in AmberTools: GIST.

The expulsion of water from surfaces upon molecular recognition and nonspecific association makes a major contribution to the free energy changes of these processes. In order to facilitate the characterization of water structure and thermodynamics on surfaces, we have incorporated Grid Inhomogeneous Solvation Theory (GIST) into the CPPTRAJ toolset of AmberTools. GIST is a grid-based implementation of Inhomogeneous Fluid Solvation Theory, which analyzes the output from molecular dynamics simulations to map out solvation thermodynamic and structural properties on a high-resolution, three-dimensional grid.

Enthalpic Breakdown of Water Structure on Protein Active-Site Surfaces.

The principles underlying water reorganization around simple nonpolar solutes are well understood and provide the framework for the classical hydrophobic effect, whereby water molecules structure themselves around solutes so that they maintain favorable energetic contacts with both the solute and the other water molecules. However, for certain solute surface topographies, water molecules, due to their geometry and size, are unable to simultaneously maintain favorable energetic contacts with both the surface and neighboring water molecules. In this study, we analyze the solvation of ligand-binding sites for six structurally diverse proteins using hydration site analysis and measures of local water structure, in order to identify surfaces at which water molecules are unable to structure themselves in a way that maintains favorable enthalpy relative to bulk water.

Tetrahydroprotoberberine alkaloids with dopamine and σ receptor affinity.

Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n-alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues (10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity.

Evaluation of a model training program for respiratory-protection preparedness at local health departments.

Respiratory-protection programs have had limited application in local health departments and have mostly focused on protecting employees against exposure to tuberculosis (TB). The need to provide the public health workforce with effective respiratory protection has, however, been underscored by recent concerns about emerging infectious diseases, bioterrorism attacks, drug-resistant microbes, and environmental exposures to microbial allergens (as in recent hurricane flood waters). Furthermore, OSHA has revoked the TB standard traditionally followed by local health departments, replacing it with a more stringent regulation.