Selective Gold Precipitation by a Tertiary Diamide Driven by Thermodynamic Control.

The simple diamide ligand L was previously shown to selectively precipitate gold from acidic solutions typical of e-waste leach streams, with precipitation of gallium, iron, tin, and platinum possible under more forcing conditions. Herein, we report direct competition experiments to afford the order of selectivity. Thermal analysis indicates that the gold-, gallium-, and iron-containing precipitates present as the most thermodynamically stable structures at room temperature, while the tin-containing structure does not. Computational modeling established that the precipitation process is thermodynamically driven, with ion exchange calculations matching the observed experimental selectivity ordering. Calculations also show that the stretched ligand conformation seen in the X-ray crystal structure of the gold-containing precipitate is more strained than in the structures of the other metal precipitates, indicating that intermolecular interactions likely dictate the selectivity ordering. This was confirmed through a combination of Hirshfeld, noncovalent interaction (NCI), and quantum theory of atoms in molecules (QTAIM) analyses, which highlight favorable halogen···halogen contacts between metalates and pseudo-anagostic C-H···metal interactions in the crystal structure of the gold-containing precipitate.

Discovery and Characterization of a Bicyclic Peptide (Bicycle) Binder to Thymic Stromal Lymphopoietin.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pro-inflammatory cytokine involved in the development of asthma and other atopic diseases. We used Bicycle Therapeutics' proprietary phage display platform to identify bicyclic peptides (Bicycles) with high affinity for TSLP, a target that is difficult to drug with conventional small molecules due to the extended protein-protein interactions it forms with both receptors. The hit series was shown to bind to TSLP in a hotspot, that is also used by IL-7Rα. Guided by the first X-ray crystal structure of a small peptide binding to TSLP and the identification of key metabolites, we were able to improve the proteolytic stability of this series in lung S9 fractions without sacrificing binding affinity. This resulted in the potent Bicycle 46 with nanomolar affinity to TSLP (KD = 13 nM), low plasma clearance of 6.4 mL/min/kg, and an effective half-life of 46 min after intravenous dosing to rats.

Family listening/circle program: The experience of community action projects to promote family and community wellness in three tribal communities in New Mexico.

Introduction: The Family Listening/Circle Program (FLCP) is a community-based participatory research (CBPR), culture-centered, intergenerational family strengthening program that was co-developed in partnership with the University of New Mexico's Center for Participatory Research (UNM-CPR) and three tribal communities (Pueblo of Jemez, Ramah Navajo, and Mescalero Apache) in New Mexico. The Family Listening/Circle Program brings together fourth and fifth graders, their parents, caregivers, and elders to reduce risky behaviors associated with the initiation of substance use among the youth, and to strengthen family communication and connectedness to culture and language as protective factors. Methods: The tribal research teams (TRTs) from each community worked with UNM-CPR to co-create, pilot, implement, and evaluate the tribally-specific FL/CP curricula centered in their own tribal histories, language, knowledge, visions, and actions for the future. A key component of the FL/CP involved the planning and completion of community action projects (CAPs) by participating families. During the final session of the program, the families present their community action projects on poster boards, with children leading the presentations. The TRTs and UNM team document narratives of what was shared and learned by the families. Results: The CAPs provide an empowerment and community benefit focus based on Paulo Freire's philosophy that people can become agents of change if they identify and work on issues that are important to them. The community action projects are also centered in Indigenous values and practices of reciprocity, responsibility, and being active members of the community. Discussion: The CAPs added unique contributions to the Family Listening/Circle Program as the participants' learnings were strengthened when they had the opportunity to give back to their communities. The CAPs were important to document as they illustrated the potential range of effectiveness with their capacity to empower participants to address challenges within their communities, strengthen cultural norms and values, and improve the wellbeing of community members.

Investigating the hydration of C3A in the presence of the potentially toxic element chromium-a route to remediation?

Pollution by hexavalent chromium is a growing, global problem. Its presence in public water systems is often the result of industrial activities, both past and present. In this study, tricalcium aluminate (C3A, Ca3Al2O6) is added to solutions of varying concentrations of potassium chromate (K2CrO4) and samples of both the solid and liquid are taken at various time intervals to monitor the removal of chromium from the solutions. Solution concentrations of 0.2 M, 0.1 M, 0.02 M, and 0.01 M are used, and the chromium concentration is found to reduce in all cases. For the 0.02 M solution the chromium concentration is reduced from 1040 ppm to 3.1 ppm in 1 week, and the chromium concentration of the 0.01 M solution is reduced from 520 ppm to 0.26 ppm in only one day of reaction with the C3A. The chromium removed from solution is identified in the solid products, which were fully characterised as being a mixture of ettringite (Ca6[Al(OH)6]2(CrO4)3·26H2O) and monochromate (Ca4[Al(OH)6]2CrO4·8H2O) phases from analysis of Powder X-ray Diffraction and Fourier Transform Infrared Spectroscopy data. The work presented here is a proof of concept study to investigate C3A as a potential material for the removal of hexavalent chromium from solution. The results from this study are initial steps towards development of this as a technology for hexavalent chromium remediation.

Discovery by Virtual Screening of an Inhibitor of CDK5-Mediated PPARγ Phosphorylation.

Thiazolidinedione PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetic drugs, but side effects have limited their use. It has been posited that their positive antidiabetic effects are mainly mediated by the inhibition of the CDK5-mediated Ser273 phosphorylation of PPARγ, whereas the side effects are linked to classical PPARγ agonism. Thus compounds that inhibit PPARγ Ser273 phosphorylation but lack classical PPARγ agonism have been sought as safer antidiabetic therapies. Herein we report the discovery by virtual screening of 10, which is a potent PPARγ binder and in vitro inhibitor of the CDK5-mediated phosphorylation of PPARγ Ser273 and displays negligible PPARγ agonism in a reporter gene assay. The pharmacokinetic properties of 10 are compatible with oral dosing, enabling preclinical in vivo testing, and a 7 day treatment demonstrated an improvement in insulin sensitivity in the ob/ob diabetic mouse model.

Dissemination of an American Indian Culturally Centered Community-Based Participatory Research Family Listening Program: Implications for Global Indigenous Well-Being.

We introduce a culture-centered indigenous program called the Family Listening Program (FLP), which was developed through a long-standing community-based participatory research (CBPR) partnership involving tribal research teams (TRTs) from three American Indian communities (Apache, Navajo, and Pueblo) with the University of New Mexico's Center for Participatory Research (UNM-CPR). This paper provides background information on the TRT/UNM-CPR multi-generational FLP intervention funded by the National Institute on Drug Abuse and how it is poised to take the next steps of dissemination and implementation (D&I). In preparing for the next steps, the TRT/UNM-CPR team piloted two FLP dissemination activities, first at the state-level and then nationally; this paper describes these activities. Based on the learnings from the pilot dissemination, the TRT/UNM-CPR team developed an innovative D&I model by integrating a community-based participatory research culture-centered science (CBPR-CCS) approach with the Interactive Systems Framework (ISF) to examine the uptake, cultural acceptance, and sustainability of the FLP as an evidence-based indigenous family program.

A class of highly selective inhibitors bind to an active state of PI3Kγ.

We have discovered a class of PI3Kγ inhibitors exhibiting over 1,000-fold selectivity over PI3Kα and PI3Kß. On the basis of X-ray crystallography, hydrogen-deuterium exchange-mass spectrometry and surface plasmon resonance experiments we propose that the cyclopropylethyl moiety displaces the DFG motif of the enzyme away from the adenosine tri-phosphate binding site, inducing a large conformational change in both the kinase- and helical domains of PI3Kγ. Site directed mutagenesis explained how the conformational changes occur. Our results suggest that these cyclopropylethyl substituted compounds selectively inhibit the active state of PI3Kγ, which is unique to these compounds and to the PI3Kγ isoform, explaining their excellent potency and unmatched isoform selectivity that were confirmed in cellular systems. This is the first example of a Class I PI3K inhibitor achieving its selectivity by affecting the DFG motif in a manner that bears similarity to DFG in/out for type II protein kinase inhibitors.

The piloting of a culturally centered American Indian family prevention program: a CBPR partnership between Mescalero Apache and the University of New Mexico.

The Mescalero Apache Family Listening Program (MAFLP) is a culturally centered family prevention program with third, fourth, and fifth graders; a parent/caregiver; and a family elder. The program follows a positive youth development model to develop stronger communication and shared cultural practices between elders, parents, and youth in the tribe to reduce substance initiation of use among the youth. The MAFLP was created using a community-based participatory research (CBPR) approach in partnership with the University of New Mexico. The research focus of MAFLP is centered on the adaptation of a family curriculum from a Navajo and Pueblo version of the Family Listening Program to an Apache version, the establishment of a (Apache) Tribal Research Team, and the piloting of the curriculum with Apache families. MAFLP was piloted twice, and evaluation measures were collected focused on formative and impact evaluation. This article provides a background on Mescalero Apache then introduces the Navajo and Pueblo version of a Family Listening and Family Circle Program, respectively, next, the CBPR research partnership between Mescalero Apache and the University of New Mexico and the creation of a Mescalero Apache Tribal Research Team followed by the development and adaptation of a Mescalero Apache Family Listening Program including implementation and evaluation, and concluding with preliminary findings.