Identification of Fasnall as a therapeutically effective Complex I inhibitor.

Proliferating cancer cells actively utilize anabolic processes for biomass production, including de novo biosynthesis of amino acids, nucleotides, and fatty acids. The key enzyme of the fatty acid biosynthesis pathway, fatty acid synthase (FASN), is widely recognized as a promising therapeutic target in cancer and other health conditions1,2. Here, we establish a metabolic signature of FASN inhibition using a panel of pharmacological inhibitors (GSK2194069, TVB-2640, TVB-3166, C75, cerulenin, and Fasnall). We find that the activity of commonly used FASN inhibitors is inconsistent with the metabolic signature of FASN inhibition (accumulation of malonate, succinate, malonyl coenzyme A, succinyl coenzyme A, and other metabolic perturbations). Moreover, we show that one of these putative FASN inhibitors, Fasnall, is a respiratory Complex I inhibitor that mimics FASN inhibition through NADH accumulation and consequent depletion of the tricarboxylic acid cycle metabolites. We demonstrate that Fasnall impairs tumor growth in several oxidative phosphorylation-dependent cancer models, including combination therapy-resistant melanoma patient-derived xenografts. Fasnall administration does not reproduce neurological side effects in mice reported for other Complex I inhibitors3,4. Our results have significant implications for understanding the FASN role in human health and disease and provide evidence of therapeutic potential for Complex I inhibitors with fast systemic clearance. Our findings also highlight the continuing need for validation of small molecule inhibitors to distinguish high-quality chemical probes and to expand the understanding of their application.

Identifying Best Practices for Increasing HIV Pre-exposure Prophylaxis (PrEP) Use and Persistence in the United States: A Systematic Review.

A qualitative systematic review was conducted to evaluate pre-exposure prophylaxis (PrEP) interventions, describe characteristics of best practices for increasing PrEP use and persistence, and explore research gaps based on current PrEP interventions. We searched CDC's Prevention Research Synthesis (PRS) Project's cumulative HIV database (includes CINAHL, EMBASE, Global Health, MEDLINE, PsycInfo, and Sociological Abstracts) to identify PrEP intervention studies conducted in the U.S., published between 2000 and 2022 (last searched January 2023). Eligibility criteria include studies that evaluated PrEP interventions for persons testing negative for HIV infection, or for healthcare providers who prescribed PrEP; included comparisons between groups or pre/post; and reported at least one relevant PrEP outcome. Each eligible intervention was evaluated on the quality of study design, implementation, analysis, and strength of evidence (PROSPERO registration number: CRD42021256460). Of the 26 eligible interventions, the majority were focused on men who have sex with men (n = 18) and reported PrEP adherence outcomes (n = 12). Nine interventions met the criteria for Best Practices (i.e., evidence-based interventions, evidence-informed interventions). Five were digital health interventions while two implemented individual counseling, one offered motivational interviewing, and one provided integrated medical care with a PrEP peer navigator. Longer intervention periods may provide more time for intervention exposure to facilitate behavioral change, and engaging the community when developing, designing and implementing interventions may be key for effectiveness. For digital health interventions, two-way messaging may help participants feel supported. Research gaps included a lack of Best Practices for several populations (e.g., Black persons, Hispanic/Latino persons, persons who inject drugs, and women of color) and evidence for various intervention strategies (e.g., interventions for promoting provider's PrEP prescription behavior, peer support). These findings call for more collaborative work with communities to develop interventions that work and implement and disseminate Best Practices for increasing PrEP use and persistence in communities.

EpicTope: narrating protein sequence features to identify non-disruptive epitope tagging sites.

Epitope tagging is an invaluable technique enabling the identification, tracking, and purification of proteins in vivo. We developed a tool, EpicTope, to facilitate this method by identifying amino acid positions suitable for epitope insertion. Our method uses a scoring function that considers multiple protein sequence and structural features to determine locations least disruptive to the protein's function. We validated our approach on the zebrafish Smad5 protein, showing that multiple predicted internally tagged Smad5 proteins rescue zebrafish smad5 mutant embryos, while the N- and C-terminal tagged variants do not, also as predicted. We further show that the internally tagged Smad5 proteins are accessible to antibodies in wholemount zebrafish embryo immunohistochemistry and by western blot. Our work demonstrates that EpicTope is an accessible and effective tool for designing epitope tag insertion sites. EpicTope is available under a GPL-3 license from: https://github.com/FriedbergLab/Epictope.

A Community Guide Systematic Review: Digital HIV Pre-Exposure Prophylaxis Interventions.

INTRODUCTION: HIV preexposure prophylaxis (PrEP) is highly effective when taken as prescribed. Digital health adherence interventions have been identified as effective for improving antiretroviral therapy adherence among people with HIV, but limited evidence exists for PrEP adherence interventions among people without HIV. The purpose of this Community Guide systematic review was to present the characteristics and effectiveness of digital PrEP adherence interventions. METHODS: The author searched the CDC HIV Prevention Research Synthesis cumulative database for digital health interventions with PrEP adherence outcomes published in peer-reviewed journals from 2000 to 2022. Studies with comparison arms or pre-post data evaluating interventions in high-income countries were included. Two reviewers independently screened citations, extracted data, conducted risk of bias assessment, and resolved discrepancies through discussion. Summary effect estimates were calculated using median and interquartile interval. RESULTS: Nine studies were included and all focused on gay, bisexual, and other men who have sex with men. Eight studies were U.S.-based while the other was conducted in the Netherlands. Five were randomized control trials and four were pre-/post studies. All studies showed improved adherence in the intervention arms compared with comparison groups or preintervention data. One study also reported improvement in PrEP care retention. DISCUSSION: Digital health adherence interventions with different strategies to improve PrEP and HIV-related outcomes were identified. The small number of studies identified is a limitation. Findings from this review served as the basis for the Community Preventive Services Task Force recommendation to use these interventions to increase PrEP adherence to prevent HIV infection.

Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish.

Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic condition characterized by altered skeletal development and extraskeletal bone formation. All cases of FOP are caused by mutations in the type I bone morphogenetic protein (BMP) receptor gene ACVR1 that result in overactivation of the BMP signaling pathway. Activation of the wild-type ACVR1 kinase requires assembly of a tetrameric type I and II BMP receptor complex followed by phosphorylation of the ACVR1 GS domain by type II BMP receptors. Previous studies showed that the FOP-mutant ACVR1-R206H required type II BMP receptors and presumptive glycine/serine-rich (GS) domain phosphorylation for overactive signaling. Structural modeling of the ACVR1-R206H mutant kinase domain supports the idea that FOP mutations alter the conformation of the GS domain, but it is unclear how this leads to overactive signaling. Here we show, using a developing zebrafish embryo BMP signaling assay, that the FOP-mutant receptors ACVR1-R206H and -G328R have reduced requirements for GS domain phosphorylatable sites to signal compared to wild-type ACVR1. Further, ligand-independent and ligand-dependent signaling through the FOP-mutant ACVR1 receptors have distinct GS domain phosphorylatable site requirements. ACVR1-G328R showed increased GS domain serine/threonine requirements for ligand-independent signaling compared to ACVR1-R206H, whereas it exhibited reduced serine/threonine requirements for ligand-dependent signaling. Remarkably, while ACVR1-R206H does not require the type I BMP receptor partner, Bmpr1, to signal, a ligand-dependent GS domain mutant of ACVR1-R206H could signal independently of Bmpr1 only when Bmp7 ligand was overexpressed. Of note, unlike human ACVR1-R206H, the zebrafish paralog Acvr1l-R203H does not show increased signaling activity. However, in domain-swapping studies, the human kinase domain, but not the human GS domain, was sufficient to confer overactive signaling to the Acvr1l-R203H receptor. Together these results reflect the importance of GS domain activation and kinase domain functions in regulating ACVR1 signaling and identify mechanisms of reduced regulatory constraints conferred by FOP mutations. © 2023 American Society for Bone and Mineral Research (ASBMR).

Formation and characterization of BMP2/GDF5 and BMP4/GDF5 heterodimers.

BACKGROUND: Proteins of the TGFß family, which are largely studied as homodimers, are also known to form heterodimers with biological activity distinct from their component homodimers. For instance, heterodimers of bone morphogenetic proteins, including BMP2/BMP7, BMP2/BMP6, and BMP9/BMP10, among others, have illustrated the importance of these heterodimeric proteins within the context of TGFß signaling. RESULTS: In this study, we have determined that mature GDF5 can be combined with mature BMP2 or BMP4 to form BMP2/GDF5 and BMP4/GDF5 heterodimer. Intriguingly, this combination of a BMP2 or BMP4 monomer, which exhibit high affinity to heparan sulfate characteristic to the BMP class, with a GDF5 monomer with low heparan sulfate affinity produces a heterodimer with an intermediate affinity. Using heparin affinity chromatography to purify the heterodimeric proteins, we then determined that both the BMP2/GDF5 and BMP4/GDF5 heterodimers consistently signaled potently across an array of cellular and in vivo systems, while the activities of their homodimeric counterparts were more context dependent. These differences were likely driven by an increase in the combined affinities for the type 1 receptors, Alk3 and Alk6. Furthermore, the X-ray crystal structure of BMP2/GDF5 heterodimer was determined, highlighting the formation of two asymmetric type 1 receptor binding sites that are both unique relative to the homodimers. CONCLUSIONS: Ultimately, this method of heterodimer production yielded a signaling molecule with unique properties relative to the homodimeric ligands, including high affinity to multiple type 1 and moderate heparan binding affinity.

Systematic Review of Social Determinants of Health Associated With HIV Testing Among Hispanic/Latino Gay, Bisexual, and Other Men Who Have Sex With Men in the United States.

This systematic review synthesized published literature (January 2008-October 2021) about the association between social determinants of health (SDOH) and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men (HLMSM), a group disproportionally affected by HIV. Having higher education than a high school diploma, health insurance and access to health care services, and visiting a health care provider in the past 12 months were some of the determinants associated with HIV testing, while limited English proficiency was associated with reduced odds of HIV-testing among HLMSM. More research is needed to understand the relationship of SDOH (especially neighborhood) and HIV testing, how SDOH may affect HIV testing among different HLMSM groups, and how to increase self-testing and use of e-health in this priority population. Additionally, culturally and linguistically appropriate multilevel interventions and health services for HLMSM are urgently needed to diagnose HIV as early as possible after infection.

Cell signaling pathways controlling an axis organizing center in the zebrafish.

Body axis formation in vertebrate development entails the remarkable feat of patterning a myriad of specialized cell types and organ progenitors from a field of unpatterned, multipotent cells. This feat is achieved largely by secreted cell-cell signaling molecules, enabling cells at different positions within the embryo to adopt distinct fates. During patterning of the vertebrate embryonic axes, a multitude of cell fates is induced by a surprisingly small set of signaling pathways: Wnt, Nodal, Bone Morphogenetic Protein (BMP), and Fibroblast Growth Factor (FGF) signaling. These signals function as morphogens, specifying multiple cell fates in a concentration-dependent mechanism, and must therefore be distributed non-uniformly throughout the embryo. A primary signaling center that sets up spatial asymmetries in these signaling pathways to break the symmetry of the vertebrate embryo is known as the dorsal organizer. Discovered nearly a century ago by Hilde Mangold and Hans Spemann in the newt, the organizer has the remarkable ability to induce a secondary body axis when grafted ectopically into a host embryo. Here, we review the cell-cell signaling pathways that control the establishment of the dorsal organizer and its inductive functions in the zebrafish Danio rerio, a vertebrate model highly amenable to genetic manipulation. The organizer's remarkable inductive abilities continue to provide a fascinating source of scientific inquiry in the field of developmental biology.

Stage Specific Transcriptomic Analysis and Database for Zebrafish Oogenesis.

Oogenesis produces functional eggs and is essential for fertility, embryonic development, and reproduction. The zebrafish ovary is an excellent model to study oogenesis in vertebrates, and recent studies have identified multiple regulators in oocyte development through forward genetic screens, as well as reverse genetics by CRISPR mutagenesis. However, many developmental steps in oogenesis, in zebrafish and other species, remain poorly understood, and their underlying mechanisms are unknown. Here, we take a genomic approach to systematically uncover biological activities throughout oogenesis. We performed transcriptomic analysis on five stages of oogenesis, from the onset of oocyte differentiation through Stage III, which precedes oocyte maturation. These transcriptomes revealed thousands of differentially expressed genes across stages of oogenesis. We analyzed trends of gene expression dynamics along oogenesis, as well as their expression in pair-wise comparisons between stages. We determined their functionally enriched terms, identifying uniquely characteristic biological activities in each stage. These data identified two prominent developmental phases in oocyte differentiation and traced the accumulation of maternally deposited embryonic regulator transcripts in the developing oocyte. Our analysis provides the first molecular description for oogenesis in zebrafish, which we deposit online as a resource for the community. Further, the presence of multiple gene paralogs in zebrafish, and the exclusive curation by many bioinformatic tools of the single paralogs present in humans, challenge zebrafish genomic analyses. We offer an approach for converting zebrafish gene name nomenclature to the human nomenclature for supporting genomic analyses generally in zebrafish. Altogether, our work provides a valuable resource as a first step to uncover oogenesis mechanisms and candidate regulators and track accumulating transcripts of maternal regulators of embryonic development.

A proteomics approach identifies novel resident zebrafish Balbiani body proteins Cirbpa and Cirbpb.

The Balbiani body (Bb) is the first marker of polarity in vertebrate oocytes. The Bb is a conserved structure found in diverse animals including insects, fish, amphibians, and mammals. During early zebrafish oogenesis, the Bb assembles as a transient aggregate of mRNA, proteins, and membrane-bound organelles at the presumptive vegetal side of the oocyte. As the early oocyte develops, the Bb appears to grow slowly, until at the end of stage I of oogenesis it disassembles and deposits its cargo of localized mRNAs and proteins. In fish and frogs, this cargo includes the germ plasm as well as gene products required to specify dorsal tissues of the future embryo. We demonstrate that the Bb is a stable, solid structure that forms a size exclusion barrier similar to other biological hydrogels. Despite its central role in oocyte polarity, little is known about the mechanism behind the Bb's action. Analysis of the few known protein components of the Bb is insufficient to explain how the Bb assembles, translocates, and disassembles. We isolated Bbs from zebrafish oocytes and performed mass spectrometry to define the Bb proteome. We successfully identified 77 proteins associated with the Bb sample, including known Bb proteins and novel RNA-binding proteins. In particular, we identified Cirbpa and Cirbpb, which have both an RNA-binding domain and a predicted self-aggregation domain. In stage I oocytes, Cirbpa and Cirbpb localize to the Bb rather than the nucleus (as in somatic cells), indicating that they may have a specialized function in the germ line. Both the RNA-binding domain and the self-aggregation domain are sufficient to localize to the Bb, suggesting that Cirbpa and Cirbpb interact with more than just their mRNA targets within the Bb. We propose that Cirbp proteins crosslink mRNA cargo and proteinaceous components of the Bb as it grows. Beyond Cirbpa and Cirbpb, our proteomics dataset presents many candidates for further study, making it a valuable resource for building a comprehensive mechanism for Bb function at a protein level.

Strategies to improve HIV care outcomes for people with HIV who are out of care.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of five intervention strategies: patient navigation, appointment help/alerts, psychosocial support, transportation/appointment accompaniment, and data-to-care on HIV care outcomes among persons with HIV (PWH) who are out of care (OOC). DESIGN: A systematic review with meta-analysis. METHODS: We searched CDC's Prevention Research Synthesis (PRS) Project's cumulative HIV database to identify intervention studies conducted in the U.S., published between 2000 and 2020 that included comparisons between groups or prepost, and reported at least one relevant outcome (i.e. re-engagement or retention in HIV care, and viral suppression). Effect sizes were meta-analyzed using random-effect models to assess intervention effectiveness. RESULTS: Thirty-nine studies reporting on 42 unique interventions met the inclusion criteria. Overall, intervention strategies are effective in improving re-engagement in care [odds ratio (OR) = 1.79;95% confidence interval (95% CI): 1.36-2.36, k = 14], retention in care (OR = 2.01; 95% CI: 1.64-2.64, k = 22), and viral suppression (OR = 2.50;95% CI: 1.87-3.34, k = 27). Patient navigation, appointment help/alerts, psychosocial support, and transportation/appointment accompaniment improved all three HIV care outcomes. Data-to-care improved re-engagement and retention but had insufficient evidence for viral suppression. CONCLUSION: Several strategies are effective for improving HIV care outcomes among PWH who are OOC. More work is still needed for consistent definitions of OOC and HIV care outcomes, better reporting of intervention and cost data, and identifying how best to implement and scale-up effective strategies to engage and retain OOC PWH in care and reach the ending the HIV epidemic goals.

Research Synthesis, HIV Prevention Response, and Public Health: CDC's HIV/AIDS Prevention Research Synthesis Project.

OBJECTIVE: Research synthesis, through qualitative or quantitative systematic reviews, allows for integrating results of primary research to improve public health. We examined more than 2 decades of work in HIV prevention by the Centers for Disease Control and Prevention's (CDC's) HIV/AIDS Prevention Research Synthesis (PRS) Project. We describe the context and contributions of research synthesis, including systematic reviews and meta-analyses, through the experience of the PRS Project. METHODS: We reviewed PRS Project publications and products and summarized PRS contributions from 1996 to July 2020 in 4 areas: synthesis of interventions and epidemiologic studies, synthesis methods, prevention programs, and prevention policy. RESULTS: PRS Project publications summarized risk behaviors and effects of prevention interventions (eg, changing one's perception of risk, teaching condom negotiation skills) across populations at risk for HIV infection and intervention approaches (eg, one-on-one or group meetings) as the HIV/AIDS epidemic and science evolved. We used the PRS Project cumulative database and intervention efficacy reviews to contribute to prevention programs and policies through identification of evidence-based interventions and development of program guidance. Subject matter experts and scientific evidence informed PRS Project products and contributions, which were implemented through strategic programmatic partnerships. CONCLUSIONS: The contributions of the PRS Project to HIV prevention and public health efforts in the United States can be credited to CDC's long-standing support of the project and its context within a federal prevention agency, where HIV programs and policies were developed and implemented. The effect of the PRS Project was likely facilitated by opportunities to directly influence program and policy because of connections with other research translation activities and program and policy decision making within CDC.

HIV care outcomes among transgender persons with HIV infection in the United States, 2006-2021.

OBJECTIVES: HIV prevalence is an estimated 14% among transgender women (TW) and 3% among transgender men (TM). HIV care is vital for viral suppression but is hindered by transphobia and HIV stigma. We assessed HIV care outcomes among transgender persons (TG) with HIV in the United States. DESIGN: Systematic review and meta-analysis of peer-reviewed journal articles. METHODS: We searched multiple electronic databases and Centers for Disease Control and Prevention's HIV Prevention Research Synthesis database for 2006-September 2020. Eligible reports were US-based studies that included TG and reported HIV care outcomes. Random-effects models were used to calculate HIV care outcome rates. The protocol is registered with PROSPERO (CRD42018079564). RESULTS: Few studies reported outcomes for TM; therefore, only TW meta-analysis results are reported. Fifty studies were identified having low-to-medium risk-of-bias scores. Among TW with HIV, 82% had ever received HIV care; 72% were receiving care, and 83% of those were retained in HIV care. Sixty-two percent were currently virally suppressed. Among those receiving HIV care or antiretroviral therapy (ART), 67% were virally suppressed at last test. Sixty-five percent were linked to HIV care 3 months or less after diagnosis. Seventy-one percent had ever been prescribed ART. Approximately 66% were taking ART, and 66% were ART-adherent. Only 56% were currently adherent the previous year. CONCLUSIONS: HIV care outcomes for TW were not ideal, and research gaps exists for TM. High heterogeneity was observed; therefore, caution should be taken interpreting the findings. Integrating transgender-specific health needs are needed to improve outcomes of transgender persons across the HIV care continuum.

The zebrafish issue: 25†years on.

In the 1990s, labs on both sides of the Atlantic performed the largest genetic mutagenesis screen at that time using an emerging model organism: the zebrafish. Led by Christiane Nüsslein-Volhard in Tübingen, Germany, and Wolfgang Driever in Boston, USA, these colossal screens culminated in 1996 with the publication of 37 articles in a special issue of Development, which remains the journal's largest issue to this day. To celebrate the anniversary of the zebrafish issue and reflect on the 25 years since its publication, five zebrafish researchers share what the issue means to them, how it has contributed to their career and its impact on the zebrafish community.

Microinjection Method for Analyzing Zebrafish Early Stage Oocytes.

Maternal factors which accumulate and establish oocyte polarity during the early stages of oogenesis play key roles in embryonic development, as well as germ cell formation. However, vertebrate oogenesis, especially early stages of oogenesis, is not well understood due to the difficulty of accessing these oocytes and the lack of analytical methods. Here, we report on a microinjection method for analyzing zebrafish early-stage oocytes and some artifacts to be aware of when performing oocyte injections or analyzing oocytes. Using this method, we successfully injected mRNAs encoding fluorescent-tagged proteins into early-stage oocytes and observed subcellular localization in the live oocytes. This method is expected to advance the functional analysis of genes involved in oogenesis.

Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.

Numerous stages of organismal development rely on the cellular interpretation of gradients of secreted morphogens including members of the Bone Morphogenetic Protein (BMP) family through transmembrane receptors. Early gradients of BMPs drive dorsal/ventral patterning throughout the animal kingdom in both vertebrates and invertebrates. Growing evidence in Drosophila, zebrafish, murine and other systems suggests that BMP ligand heterodimers are the primary BMP signaling ligand, even in systems in which mixtures of BMP homodimers and heterodimers are present. Signaling by heterodimers occurs through a hetero-tetrameric receptor complex comprising of two distinct type one BMP receptors and two type II receptors. To understand the system dynamics and determine whether kinetic assembly of heterodimer-heterotetramer BMP complexes is favored, as compared to other plausible BMP ligand-receptor configurations, we developed a kinetic model for BMP tetramer formation based on current measurements for binding rates and affinities. We find that contrary to a common hypothesis, heterodimer-heterotetramer formation is not kinetically favored over the formation of homodimer-tetramer complexes under physiological conditions of receptor and ligand concentrations and therefore other mechanisms, potentially including differential kinase activities of the formed heterotetramer complexes, must be the cause of heterodimer-heterotetramer signaling primacy. Further, although BMP complex assembly favors homodimer and homomeric complex formation over a wide range of parameters, ignoring these signals and instead relying on the heterodimer improves the range of morphogen interpretation in a broad set of conditions, suggesting a performance advantage for heterodimer signaling in patterning multiple cell types in a gradient.

A Rapid Review of Disparities in HIV Prevention and Care Outcomes Among Hispanic/Latino Men Who Have Sex With Men in the United States.

In the United States, Hispanic/Latino men who have sex with men (HLMSM) are disproportionally affected by HIV. We conducted a rapid review of national surveillance data to examine disparities in HIV prevention and care outcomes among HLMSM. Thirteen reports provided relevant data from 2011 to 2018. Compared to White MSM, a higher percentage of HIV-negative HLMSM reported not taking PrEP and engaging in condomless sex; a lower percentage of HIV-negative HLMSM at risk for HIV reported PrEP awareness and use; and a lower percentage of HIV-positive HLMSM were aware of their status, linked to HIV care, and virally suppressed. Viral suppression rates in HLMSM were better among Ryan White clients than the national rates, suggesting that access to comprehensive care/services reduces disparities. Findings also call for identifying individual, social, and structural factors contributing to condomless sex without PrEP use and HIV status unawareness and identifying best approaches for scaling up comprehensive care/services.

Diversity and robustness of bone morphogenetic protein pattern formation.

Pattern formation by bone morphogenetic proteins (BMPs) demonstrates remarkable plasticity and utility in several contexts, such as early embryonic development, tissue patterning and the maintenance of stem cell niches. BMPs pattern tissues over many temporal and spatial scales: BMP gradients as short as 1-2 cell diameters maintain the stem cell niche of the Drosophila germarium over a 24-h cycle, and BMP gradients of several hundred microns establish dorsal-ventral tissue specification in Drosophila, zebrafish and Xenopus embryos in timescales between 30 min and several hours. The mechanisms that shape BMP signaling gradients are also incredibly diverse. Although ligand diffusion plays a dominant role in forming the gradient, a cast of diffusible and non-diffusible regulators modulate gradient formation and confer robustness, including scale invariance and adaptability to perturbations in gene expression and growth. In this Review, we document the diverse ways that BMP gradients are formed and refined, and we identify the core principles that they share to achieve reliable performance.

Cannabis dabbing: An emerging trend.

ABSTRACT: Cannabis dabbing refers to the recreational inhalation of extremely concentrated tetrahydrocannabinol, the main psychotropic cannabinoid derived from the marijuana plant. The practice carries significant health and legal risks. This article discusses what nurses need to know about dabbing and how they can educate patients who may be engaging in risky behavior.