"And Now that I Feel Safe I'm Coming Out of Fight or Flight": A Qualitative Exploration of Challenges and Opportunities for Residents' Mental Health in Substance Use Recovery Housing.

Co-occurring mental health concerns are prevalent among substance use recovery housing residents. We sought to explore how residents with co-occurring mental health and substance use needs experience recovery housing. We conducted semi-structured interviews with residents (N = 92) in recovery homes across Texas and developed themes through thematic analysis. Residents note that living in a group home can exacerbate anxiety and paranoia, especially during periods of high turnover. Overwhelmingly, however, residents believe recovery housing improves their mental health. Residents use their shared lived experiences to support one another. Residents also express appreciation for the transition period offered by recovery housing, allowing them to solidify their recoveries before fully re-entering society. Participants describe recovery homes as a critical support for their co-occurring mental health and substance use concerns. These results provide key insights on how to better support mental health in recovery housing.

Conformational study into N-alkyl-N'-aryl ureas to inform drug discovery.

Ureas are an important functional group in small molecule drugs as well as having wider applications in organic chemistry. Understanding of their conformation is of critical importance for rational design of urea-containing bioactive compounds. Whilst the conformational preferences of biaryl ureas have been extensively studied, very little attention has been paid to alkylated analogues. We carried out a systematic study of N-aryl (phenyl and pyridyl)-N'-cyclopentyl ureas with differing N-methylation patterns using Well Tempered Metadynamics at a semi-empirical level in implicit water (GBSA) using Well-Tempered Metadynamics to generate their conformational free-energy landscapes. Geometries and energetics of the most relevant configurations are further refined using DFT level of theory. Validation for the computation was obtained by synthesis of all 8 analogues followed by conformational studies by X-ray crystallography and NMR. These findings reveal that the methylation pattern significantly affects the conformational preference of the system. Most notably, N-phenyl-N'-cyclopentyl urea is shown to adopt both the trans-trans, and cis-trans conformations with equal energy and that the cis-trans conformation can be significantly stabilised by the presence of an internal hydrogen bond to the N'-hydrogen. This study will be of utility for the design of N-alkyl-N'-aryl ureas as drug candidates.

Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery.

In recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2-rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three-dimensional scaffolds. Herein, we report step-efficient routes to a number of biologically relevant, fragment-like heterocyclic spirocycles. The use of both electron-deficient and electron-rich 2-atom donors was explored in complexity-generating [3+2]-cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses.

Semi-syntheses of the 11-hydroxyrotenoids sumatrol and villosinol.

We describe semi-syntheses of the 11-hydroxyrotenoids sumatrol (1) and villosinol (2), starting from rotenone (5), using an oxime-directed C11-H functionalisation approach. Thus, rotenone (5) was converted into rotenone oxime (6), which gave dimeric palladacycle 7 following reaction with Na2PdCl4·3H2O. Controlled, divergent, oxidation of palladacycle 7 with either Pb(OAc)4 or K2Cr2O7 afforded the 11-acetoxylated intermediates 9 and 13, respectively, which were transformed into sumatrol (1) and villosinol (2).

"Nobody does checkups back there": A qualitative study of refugees' healthcare needs in the United States from stakeholders' perspectives.

The number of refugees globally grew to 35.3 million in 2022, and many refugees are exposed to various health risks along their migration journey. As a result, they may arrive in host communities with numerous health issues, including communicable diseases and chronic and mental health conditions. Navigating the healthcare system in a host country proves to be a significant challenge for them, leading to delayed care. This qualitative study explored the convolute healthcare needs of refugees in the United States by soliciting insights from stakeholders involved in refugee resettlement and healthcare. In-depth interviews were conducted with fifteen stakeholders who work closely with refugees, including healthcare providers, cultural/clinical health navigators supporting refugees, staff from refugee resettlement agencies and governmental entities, and researchers studying refugee health. Following informed consent, interviews were audio-recorded, transcribed verbatim, and imported into MAXQDA 2022 (VERBI Software) for thematic analysis. The results revealed key themes, including the heterogeneity of refugee populations, limited awareness of preventive healthcare, high prevalence and suboptimal management of chronic conditions, complexity of the healthcare system, lack of follow-up, and language barriers. Further research is warranted concerning the long-term health of refugee populations in the United States. Additionally, more tailored programs involving peer educators are recommended to support refugee communities in navigating the complex healthcare system in the host country.

"Being here is saving my life": Resident experiences of living in recovery residences for people taking medication for an opioid use disorder.

INTRODUCTION: Medications for opioid use disorder (MOUD) are an effective treatment for addressing opioid use disorder. Despite MOUD's demonstrated effectiveness, MOUD-related stigma is prevalent throughout many recovery communities and subsequently limits persons taking MOUD access to recovery supports, including recovery housing. While recovery residences that serve people taking MOUD could be a critical recovery support, they are limited in number and understudied. METHODS: We conducted in-depth interviews with 47 residents in medication-assisted recovery (MAR) living in 11 Texas-based recovery residences serving people taking MOUD to characterize residents' experiences and understand the impact that these homes had on their recovery. RESULTS: We found that many participants could not previously access recovery housing and other recovery supports due to MOUD-related stigma, thus recovery homes that supported people in MAR were considered a groundbreaking opportunity. Recovery residences provided participants with a space in which they did not feel judged for taking MOUD, which facilitated participants' connections with their fellow housemates. Subsequently, participants no longer had to hide their MAR pathway and could be transparent about taking MOUD among their recovery residence community. Last, recovery homes provided a supportive environment in which participants' internalized MOUD-related stigma could evolve into acceptance of their MAR pathway. CONCLUSIONS: Recovery residences that serve people in MAR provide a supportive, safe, nonjudgmental recovery environment in which residents develop relationships with other peers taking MOUD, share openly about their MAR, and are empowered to embrace their recovery pathway. These findings highlight the need for more recovery residences that are supportive of people taking MOUD as part of their recovery.

Leveraging qualitative approaches to guide sustainable international research collaborations.

Qualitative research approaches were used to launch an international research collaboration between the U. S. and Cambodia. Cambodian officials requested assistance in learning qualitative approaches to complement the research skills of Cambodian mental health providers. This article provides a description of how U. S. researchers responded to that request and engaged with Cambodian psychiatrists to explore mental health needs and interventions in both countries and initiate a sustainable relationship. The early focus on qualitative research methodologies may be an avenue that mitigates some of the challenges that can characterize international research. In this study, early communications involved developing a plan to teach qualitative methods while also collecting and analyzing data in both countries that would address the mental health concerns experienced by respective care providers. A case study exemplar was embedded with a scripted focus group guide to collect data from U. S. focus groups, then share with Cambodian psychiatrists. Components of hermeneutic phenomenological interviewing and descriptive content analysis were used to simultaneously teach and enact the research methods, gather data in both countries to analyze, and inspire participants to replicate the methods in their ongoing work. Cambodian psychiatrists were able to demonstrate competence in facilitating focus groups after being participant-observers. Researcher/practitioners from both U. S. and Cambodian teams gained new understandings about the mental health needs of their patients. The mutual engagement of a research focus is an effective way to establish cross-cultural relationships. The challenges of staying with stable teams over times remain, but the content shared and learned in a participatory structure yields understandings that cross cultural boundaries. Anticipated and unexpected challenges may be offset by an intention of reciprocity and mutual engagement. The use of qualitative methodologies, early and repeatedly, can facilitate relational understanding.

Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the ß-position of the Michael acceptor, via an addition-elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU. This work establishes that acrylates can be used to release conjugated molecules upon covalent binding to proteins and could be used to develop targeted therapeutics.

Build-Couple-Transform: A Paradigm for Lead-like Library Synthesis with Scaffold Diversity.

High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types. We address this problem through a "build-couple-transform" paradigm for the generation of lead-like libraries with scaffold diversity. Nineteen transformations of a 4-oxo-2-butenamide scaffold template were optimized, including 1,4-cyclizations, 3,4-cyclizations, reductions, and 1,4-additions. A pool-transformation approach efficiently explored the scope of these transformations for nine different building blocks and synthesized a >170-member library with enhanced chemical space coverage and favorable drug-like properties. Screening revealed hits against CDK2. This work establishes the build-couple-transform concept for the synthesis of lead-like libraries and provides a differentiated approach to libraries with significantly enhanced scaffold diversity.

Streamlining behaviour of the red urchin Strongylocentrotus franciscanus in response to flow.

This work was motivated by subtidal observations of red urchins (Strongylocentrotus franciscanus) moving their spines into streamlined positions as water current increased in the field. Trials in a flume across flow speeds from 0 to 65 cm s(-1) enabled us to observe the change in overall shape of the urchins and quantify the decrease in spine angle that occurred as flow speeds increased. The effect of this behaviour on drag and lift was measured with physical models made from urchin tests with spines in the `up' position (typical in stagnant and slow velocities) and in the `down' position (typical of posture in high velocities). Streamlining spines decreased the drag, but increased the lift experienced by urchin models at flow speeds between 10 and 40 cm s(-1), current velocities that are commonly encountered by these animals in the field in Washington, USA. Total force (combination of drag and lift) was similar for `up' and `down' models at all flow speeds, lift comprising the majority of the force for `down' models, and drag slightly higher for `up' models. Live urchins in the field routinely adopt a streamlined `down' posture in flow, suggesting that they may be better able to cope with lift than drag. This behaviour, although affecting hydrodynamic forces and enabling S. franciscanus to remain attached to the substratum in high currents, may lead to reduced capture of drift kelp, which is entrapped on upright spines and then eaten, delivery of which is positively related to flow speed. Urchins living in deep subtidal habitats rely on drift kelp capture but must stay attached to the substratum to be successful in a habitat. Therefore, this streamlining behaviour may be an important factor enabling S. franciscanus to persist in deep, high-current areas.

An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase.

NF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest in the treatment of a variety of diseases including cancer. Validation of NIK as a drug target requires potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, unique within the kinome. Analysis of existing inhibitor scaffolds and early structure-activity relationships (SARs) led to the design of C444-targeting covalent inhibitors based on alkynyl heterocycle warheads. Mass spectrometry provided proof of the covalent mechanism, and the SAR was rationalized by computational modeling. Profiling of more potent analogues in tumor cell lines with constitutively activated NIK signaling induced a weak antiproliferative effect, suggesting that kinase inhibition may have limited impact on cancer cell growth. This study shows that alkynyl heterocycles are potential cysteine traps, which may be employed where common Michael acceptors, such as acrylamides, are not tolerated.

An efficient, stereocontrolled and versatile synthetic route to bicyclic partially saturated privileged scaffolds.

Herein, we describe the development of a simple, high yielding and stereocontrolled strategy for the synthesis of a series of triazolopiperazines and other biologically relevant fused scaffolds from optically active amino acids. This route was applied to the synthesis of 22 scaffolds containing new, previously inaccessible vectors and used to access a novel analogue of ganaplacide.

Quantification of symbiotic contributions to lower termite lignocellulose digestion using antimicrobial treatments.

Animal-microbe co-evolution and symbiosis are broadly distributed across the animal kingdom. Insects form a myriad of associations with microbes ranging from vectoring of pathogens to intracellular, mutualistic relationships. Lower termites are key models for insect-microbe symbiosis because of the diversity, complexity and functionality of their unique tripartite symbiosis. This collaboration allows termites to live on a diet of nitrogen-poor lignocellulose. Recent functional investigations of lignocellulose digestion in lower termites have primarily focused on the contributions of the eukaryotic members of the termite holobiont (termite and protist). Here, using multiple antimicrobial treatments, we induced differing degrees of dysbiosis in the termite gut, leading to variably altered symbiont abundance and diversity, and lignocellulolytic capacity. Although protists are clearly affected by antimicrobial treatments, our findings provide novel evidence that the removal of distinct groups of bacteria partially reduces, but does not abolish, the saccharolytic potential of the termite gut holobiont. This is specifically manifested by reductions of 23-47% and 30-52% in glucose and xylose yields respectively from complex lignocellulose. Thus, all members of the lower termite holobiont (termite, protist and prokaryotes) are involved in the process of efficient, sustained lignocellulase activity. This unprecedented quantification of the relative importance of prokaryotes in this system emphasizes the collaborative nature of the termite holobiont, and the relevance of lower termites as models for inter-domain symbioses.

Dispensing apparatus for use in a cued food delivery task.

Neurobiological models of obesity postulate that obese individuals have difficulty regulating food intake partly because they attribute excessive salience to stimuli signaling food availability. Typically, human studies that investigate the relationship between brain responses to food-related stimuli and obesity present food cues without subsequent delivery of food. However, in order to identify the brain correlates of cue reactivity, we must record brain responses to food-related cues signaling food availability. Therefore, we have developed a dispensing apparatus for use in a cued-food delivery task in which event-related potentials (ERPs) to food-related images predicting food delivery and images not predicting food delivery can be recorded. Here, we describe a method where:•The experimental apparatus dispenses an edible item (i.e., a chocolate candy) which may or may not be eaten, or a non-edible control item (e.g., a plastic bead).•Deposit boxes are available to store uneaten candies and the non-edible control items.•The dispensing mechanism is capable of recording the exact timestamp when each delivery event occurs (e.g., release from the dispenser, arrival in the receptacle, storage in the deposit box).

The role of spatial and ontogenetic morphological variation in the expansion of the geographic range of the tropical brown alga, Turbinaria ornata.

Like many reefs worldwide, reefs in French Polynesia are experiencing a shift from coral-dominated to algal-dominated systems. The macroalga Turbinaria ornata comprises the majority of the increasing algal biomass on the barrier reefs surrounding these islands, and its distribution is increasing throughout this region. Aspects of the ecomorphology of Turbinaria make it ideally suited to thrive under the physical conditions found across barrier reefs throughout French Polynesia. Spatial morphological variation allows Turbinaria to produce morphotypes that are suited either to the calm, unidirectional, slowly flowing water in the backreef or to the high-energy wave-driven flow of the forereef. Backreef plants are flexible and produce airbladders that make them buoyant, whereas forereef plants are not buoyant, but strong and stiff. Production of bladders and resulting buoyancy has been found to be a phenotypically plastic trait in response to movement of water and confers advantages to backreef plants and plays an important role in dispersal. Ontogenetic variation of buoyancy, material properties, and reproductive capacity is part of a dispersal strategy whereby fertile, buoyant fronds drift between oceanic islands and form new populations, thereby contributing to the recent expansion of range of T. ornata across French Polynesia.