Culturally adapted cognitive behavioral therapy for psychosis (CaCBTp): A review of key features of cultural adaptation and considerations for psychologists.

Cognitive behavioral therapy for psychosis is an effective treatment for psychosis. However, psychosis presents differentially according to an individual's cultural context, and it is currently unclear which methods have been used to formulate culturally adapted cognitive behavioral therapy for psychosis (CaCBTp). The current systematic review examines the approaches to CaCBTp that have been evaluated to date and comments on preliminary evidence for the efficacy of CaCBTp. Key features of CaCBTp interventions are discussed in reference to broader cultural adaptations of psychosocial interventions for psychosis and culturally adapted cognitive behavioral therapy for other disorders. Overall, our results identified 12 studies and highlighted five overarching themes of cultural adaptation that clinicians should integrate into the design of future CaCBTp interventions, including family members in treatment, targeting stigma, relying on spiritual leaders, using multifaceted models of mental health, and ensuring adequate language match. The results of this review also highlight the paucity of literature in global CaCBTp interventions, as only 10 studies examining CaCBTp interventions were found. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Subcellular imaging of lipids and sugars using genetically encoded proximity sensors.

Live cell imaging of lipids and other metabolites is a long-standing challenge in cell biology. Bioorthogonal labeling tools allow for the conjugation of fluorophores to several phospholipid classes, but cannot discern their trafficking between adjacent organelles or asymmetry across individual membrane leaflets. Here we present fluorogen-activating coincidence sensing (FACES), a chemogenetic tool capable of quantitatively imaging subcellular lipid pools and reporting their transbilayer orientation in living cells. FACES combines bioorthogonal chemistry with genetically encoded fluorogen-activating proteins (FAPs) for reversible proximity sensing of conjugated molecules. We first validate this approach for quantifying discrete phosphatidylcholine pools in the ER and mitochondria that are trafficked by lipid transfer proteins. We then show that transmembrane domain-containing FAPs can be used to reveal the membrane asymmetry of multiple lipid classes that are generated in the trans-Golgi network. Lastly, we demonstrate that FACES is a generalizable tool for subcellular bioorthogonal imaging by measuring changes in mitochondrial N -acetylhexosamine levels. These results demonstrate the use of fluorogenic tags for spatially-defined molecular imaging.

Predicting CBT modality, treatment participation, and reliable improvements for individuals with anxiety and depression in a specialized mental health centre: a retrospective population-based cohort study.

BACKGROUND: Cognitive Behaviour Therapy (CBT) is one of the most successful therapeutic approaches for treating anxiety and depression. Clinical trials show that for some clients, internet-based CBT (eCBT) is as effective as other CBT delivery modes. However, the fidelity of these effects may be weakened in real-world settings where clients and providers have the freedom to choose a CBT delivery mode and switch treatments at any time. The purpose of this study is to measure the CBT attendance rate and identify client-level characteristics associated with delivery mode selection and having reliable and clinically significant improvement (RCSI) of treatment in each delivery mode in a real-world CBT outpatient program. METHODS: This is a retrospective cohort analysis of electronic medical records collected between May 1, 2019, and March 31, 2022, at Ontario Shores Centre for Mental Health Sciences. Regression models were used to investigate the impact of individual client characteristics on participation and achieving RCSI of different CBT delivery modes. RESULTS: Our data show a high attendance rate for two and more CBT sessions across all modalities (98% of electronic, 94% of group, 100% of individual, and 99% of mixed CBT). Individuals were more likely to enter mixed and group CBT modality if they were younger, reported being employed, and reported higher depression severity at the baseline. Among the four modalities of CBT delivery, group CBT clients were least likely to have RCSI. Of those who started sessions, clients were significantly more likely to experience RCSI on the Patient Health Questionnaire (PHQ)-9 and the Generalized Anxiety Disorder (GAD)-7 if they were employed, reported more severe symptoms at baseline, and were living in the most deprived neighborhoods. CONCLUSIONS: This study will contribute to the body of knowledge about the implementation and treatment planning of different CBT delivery modes in real-world settings. With the changing clinical environment, it is possible to advocate for the adoption of the eCBT intervention to improve therapy practices and achieve better treatment success. The findings can help guide future CBT program planning based on client socio-demographic characteristics, allowing the optimal therapy type to be targeted to the right client at the right time.

Borderline personality disorder stigma: Examining the effects of diagnostic disclosure, behavior, and gender as sources of stigma in the general population.

Borderline personality disorder (BPD) is a severe mental disorder characterized by a pervasive pattern of emotional and behavioral dysregulation. Dysfunction and distress may be compounded by stigmatizing beliefs held by members of the community. There is a lack of research focusing on stigmatizing beliefs about BPD held by the general population. This study addressed this gap by examining the relationship between BPD and a variety of stigma domains in a community sample. The current study explored whether (a) stigma is more strongly related to BPD symptomatic behavior or the diagnostic label of BPD, (b) attaching a diagnosis of BPD to symptomatic behavior or nonclinical behavior influences stigma, and (c) the gender of a vignette character influences the stigmatization of BPD. A total of 295 participants read vignettes and completed questionnaires assessing stigma type and intensity. Findings from the current study suggest that stigma is higher for BPD symptomatic behavior than for the diagnosis itself. Attaching a diagnostic label of BPD to BPD symptomatic behavior did not significantly impact the resultant stigma; however, the diagnosis was found to increase stigma for nonclinical behavior. Findings concerning BPD stigma and gender are in line with broader gender stereotypes. Specifically, there was greater pity for women displaying BPD behavior, whereas there was greater anger for men displaying the same behavior. BPD symptomatic behavior vignettes depicting a man also received a higher level of dangerousness and fear. Study limitations and future directions are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Probing Glycerolipid Metabolism using a Caged Clickable Glycerol-3-Phosphate Probe.

In this study, we present the probe SATE-G3P-N3 as a novel tool for metabolic labeling of glycerolipids (GLs) to investigate lipid metabolism in yeast cells. By introducing a clickable azide handle onto the glycerol backbone, this probe enables general labeling of glycerolipids. Additionally, this probe contains a caged phosphate moiety at the glycerol sn-3 position to not only facilitate probe uptake by masking negative charge but also to bypass the phosphorylation step crucial for initiating phospholipid synthesis, thereby enhancing phospholipid labeling. The metabolic labeling activity of the probe was thoroughly assessed through cellular fluorescence microscopy, mass spectrometry (MS), and thin-layer chromatography (TLC) experiments. Fluorescence microscopy analysis demonstrated successful incorporation of the probe into yeast cells, with labeling predominantly localized at the plasma membrane. LCMS analysis confirmed metabolic labeling of various phospholipid species (PC, PS, PA, PI, and PG) and neutral lipids (MAG, DAG, and TAG), and GL labeling was corroborated by TLC. These results showcased the potential of the SATE-G3P-N3 probe in studying GL metabolism, offering a versatile and valuable approach to explore the intricate dynamics of lipids in yeast cells.

The small molecule CBR-5884 inhibits the Candida albicans phosphatidylserine synthase.

Systemic infections by Candida spp. are associated with high mortality rates, partly due to limitations in current antifungals, highlighting the need for novel drugs and drug targets. The fungal phosphatidylserine synthase, Cho1, from Candida albicans is a logical antifungal drug target due to its importance in virulence, absence in the host, and conservation among fungal pathogens. Inhibitors of Cho1 could serve as lead compounds for drug development, so we developed a target-based screen for inhibitors of purified Cho1. This enzyme condenses serine and cytidyldiphosphate-diacylglycerol (CDP-DAG) into phosphatidylserine (PS) and releases cytidylmonophosphate (CMP). Accordingly, we developed an in vitro nucleotidase-coupled malachite-green-based high throughput assay for purified C. albicans Cho1 that monitors CMP production as a proxy for PS synthesis. Over 7,300 molecules curated from repurposing chemical libraries were interrogated in primary and dose-responsivity assays using this platform. The screen had a promising average Z' score of ~0.8, and seven compounds were identified that inhibit Cho1. Three of these, ebselen, LOC14, and CBR-5884, exhibited antifungal effects against C. albicans cells, with fungicidal inhibition by ebselen and fungistatic inhibition by LOC14 and CBR-5884. Only CBR-5884 showed evidence of disrupting in vivo Cho1 function by inducing phenotypes consistent with the cho1∆∆ mutant, including a reduction of cellular PS levels. Kinetics curves and computational docking indicate that CBR-5884 competes with serine for binding to Cho1 with a Ki of 1,550 ± 245.6 nM. Thus, this compound has the potential for development into an antifungal compound. IMPORTANCE: Fungal phosphatidylserine synthase (Cho1) is a logical antifungal target due to its crucial role in the virulence and viability of various fungal pathogens, and since it is absent in humans, drugs targeted at Cho1 are less likely to cause toxicity in patients. Using fungal Cho1 as a model, there have been two unsuccessful attempts to discover inhibitors for Cho1 homologs in whole-cell screens prior to this study. The compounds identified in these attempts do not act directly on the protein, resulting in the absence of known Cho1 inhibitors. The significance of our research is that we developed a high-throughput target-based assay and identified the first Cho1 inhibitor, CBR-5884, which acts both on the purified protein and its function in the cell. This molecule acts as a competitive inhibitor with a Ki value of 1,550 ± 245.6 nM and, thus, has the potential for development into a new class of antifungals targeting PS synthase.

Nuclear phosphoinositide signaling promotes YAP/TAZ-TEAD transcriptional activity in breast cancer.

The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ-TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ-TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding. Here, we report that nuclear phosphoinositides function as cofactors that mediate the binding of YAP/TAZ to TEADs. The enzymatic products of phosphoinositide kinases PIPKIα and IPMK, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (P(I3,4,5)P3), bridge the binding of YAP/TAZ to TEAD. Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer.

Examining the effects of diagnostic awareness, positive symptoms, and negative symptoms on stigmatizing attitudes and social exclusion towards schizophrenia.

BACKGROUND: Social exclusion towards schizophrenia can occur as a response to symptom presentations and/or diagnostic knowledge. The present study examined stigma towards schizophrenia as a function of diagnostic awareness, positive symptoms, and negative symptoms. METHODS: 559 participants were presented with one of eight vignettes depicting an individual in a social situation based on a 2 (label: present, absent) x 2 (positive symptoms: present, absent) x 2 (negative symptoms: present, absent) design. Participants then completed various measures of social exclusion and stigmatizing attitudes. RESULTS: A significant three-way interaction between positive symptoms, negative symptoms, and a diagnostic label was found for stigmatizing attitudes such that knowledge of diagnosis was associated with less stigma when symptoms were present but resulted in more stigma when symptoms were absent. A significant interaction between diagnostic label and negative symptoms was found on social distance such that knowledge of diagnosis increased desire for social distance when negative symptoms were present. CONCLUSION: Diagnostic awareness increases stigmatizing attitudes and social distance when symptoms are not present. However, when contextualized with the presence of symptoms, diagnostic awareness may reduce exclusion by providing an explanation for those symptoms. Determining when and to whom to disclose one's diagnosis may be helpful to improve social functioning in schizophrenia.

Examining the influence of self-referential thinking on aberrant salience and jumping to conclusions bias in individuals with schizophrenia-spectrum disorders.

BACKGROUND AND OBJECTIVES: Cognitive processes such as aberrant salience and the jumping to conclusions (JTC) bias are implicated in the development of delusions. Self-referential thinking is implicated in this process; however, it is unknown how it may interact with aberrant salience and JTC bias in individuals with schizophrenia-spectrum disorders (SSDs). This study examined associations of self-referential thinking with aberrant salience, JTC bias, and delusion severity, and whether self-referential stimuli led to an increase in aberrant salience and JTC bias in SSDs (n = 20) relative to psychiatrically healthy controls (n = 20). METHODS: To assess aberrant salience and JTC bias, participants were asked to complete both self-referential and neutral versions of the Salience Attribution Test (SAT) and the Beads Task, as well as self-report measures of aberrant salience and JTC bias. RESULTS: Self-referential task condition interacted with clinical group to predict JTC beads task scores, such that participants with SSDs exhibited greater levels of JTC bias than psychiatrically healthy controls during the neutral task condition, when controlling for levels of motivation, cognitive insight, and functioning. Self-referential thinking was significantly associated with aberrant salience, JTC bias, and delusion severity. LIMITATIONS: This experiment examined trait-level relationships between variables, so does not provide information about state-level interrelationships and would benefit from replication using more dynamic methods such as ecological momentary assessment. CONCLUSIONS: These findings highlight the interrelationships between self-referential thinking, JTC bias, aberrant salience, and delusion severity, in individuals with SSDs, and support the interactive role of self-referential thinking in predicting JTC bias.

Examining the Role of Failure and Success Experiences on Task Persistence and Neurocognition in Schizophrenia-Spectrum Disorders.

BACKGROUND: Recent theoretical models suggest that a variety of psychological and contextual factors account for a significant proportion of the observed neurocognitive impairment in schizophrenia-spectrum disorders (SSD). Numerous non-neurocognitive mechanisms of neurocognitive functioning have been proposed that warrant investigation; however, few studies have empirically examined these factors. This cross-over study examined whether the experience of failure or success affects task persistence and neurocognition differentially between individuals with SSD and healthy controls. METHODS: Twenty-nine participants with SSD and 30 healthy controls (Mage = 29.33, SD = 10.72) completed success and failure inductions, psychological questionnaires, an anagram persistence task, and brief neurocognitive testing remotely at two time-points. RESULTS: Both groups demonstrated significantly lower persistence and worse decision-making skills in the failure condition relative to the success condition. Individuals with SSD demonstrated slower processing speed, but this was not affected by prior failure or success. CONCLUSIONS: This study demonstrates that the experience of failure is similarly detrimental to persistence and decision-making in healthy controls and individuals with SSD but does not contribute to processing speed performance. This suggests that higher-order executive functions are more susceptible to manipulation by contextual factors compared to lower-order cognitive functions.

Community-Centered Assessment to Inform Pandemic Response in Georgia (US).

The Georgia Community Engagement Alliance (CEAL) Against COVID-19 Disparities Project conducts community-engaged research and outreach to address misinformation and mistrust, to promote inclusion of diverse racial and ethnic populations in clinical trials and increase testing and vaccination uptake. Guided by its Community Coalition Board, The GEORGIA CEAL Survey was administered among Black and Latinx Georgia 18 years and older to learn about community knowledge, perceptions, understandings, and behaviors regarding COVID-19 testing and vaccines. Survey dissemination occurred using survey links generated through Qualtrics and disseminated among board members and other statewide networks. Characteristics of focus counties were (a) highest proportion of 18 years and older Black and Latinx residents; (b) lowest COVID-19 testing rates; and (c) highest SVI values. The final sample included 2082 surveyed respondents. The majority of participants were men (57.1%) and Latinx (62.8%). Approximately half of the sample was aged 18-30 (49.2%); the mean age of the sample was 33.2 years (SD = 9.0), ranging from 18 to 82 years of age. Trusted sources of COVID-19 information that significantly predicted the likelihood of vaccination included their doctor/health care provider (p-value: 0.0054), a clinic (p-value: 0.006), and university hospitals (p-value: 0.0024). Latinx/non-Latinx, Blacks vs. Latinx, Whites were significantly less likely to get tested and/or vaccinated. Non-Latinx, Blacks had higher mean knowledge scores than Latinx, Whites (12.1 vs. 10.9, p < 0.001) and Latinx, Blacks (12.1 vs. 9.6, respectively, p < 0.001). The mean knowledge score was significantly lower in men compared to women (10.3 vs. 11.0, p = 0.001), in those who had been previously tested for COVID-19 compared to those who had never been tested (10.5 vs. 11.5, respectively, p = 0.005), and in those who did not receive any dose of vaccination compared to those who were fully vaccinated (10.0 vs. 11.0, respectively, p < 0.001). These data provide a benchmark for future comparisons of the trajectory of public attitudes and practices related to the COVID-19 pandemic. They also point to the importance of tailoring communication strategies to specific cultural, racial, and ethnic groups to ensure that community-specific barriers to and determinants of health-seeking behaviors are appropriately addressed.

Development of a bis-pyrene phospholipid probe for fluorometric detection of phospholipase A2 inhibition.

In this work, we report the design, synthesis, and application of a bis-pyrene phospholipid probe for detection of phospholipase A2 action through changes in pyrene monomer and excimer fluorescence intensities. Continuous fluorometric assays enabled detection of the activities of multiple PLA2 enzymes as well as the decrease in catalysis by PLA2 from honey bee venom caused by the inhibitor p-bromo phenacylbromide. Thin-layer chromatography and mass spectrometry analysis were also used to validate probe hydrolysis by PLA2. Mass spectrometry data also supported cleavage of the probe by phospholipase C and D enzymes, although changes in fluorescence were not observed in these cases. Nevertheless, the bis-pyrene phospholipid probe developed in this work is effective for detection of PLA2 enzyme activity through an assay that enables screening for inhibitor development.

Efficacy of Remotely Delivered Evidence-Based Psychosocial Treatments for Schizophrenia-Spectrum Disorders: A Series of Systematic Reviews and Meta-Analyses.

BACKGROUND: Schizophrenia is among the most persistent and debilitating mental health conditions worldwide. The American Psychological Association (APA) has identified 10 psychosocial treatments with evidence for treating schizophrenia and these treatments are typically provided in person. However, in-person services can be challenging to access for people living in remote geographic locations. Remote treatment delivery is an important option to increase access to services; however, it is unclear whether evidence-based treatments for schizophrenia are similarly effective when delivered remotely. STUDY DESIGN: The current study consists of a series of systematic reviews and meta-analyses examining the evidence-base for remote-delivery of each of the 10 APA evidence-based treatments for schizophrenia. RESULTS: Of the 10 treatments examined, only cognitive remediation (CR), cognitive-behavioral therapy (CBT), and family psychoeducation had more than 2 studies examining their efficacy for remote delivery. Remote delivery of CBT produced moderate effects on symptoms (g = 0.43) and small effects on functioning (g = 0.26). Remote delivery of CR produced small-moderate effects on neurocognition (g = 0.35) and small effects on functioning (g = 0.21). There were insufficient studies of family psychoeducation with equivalent outcome measures to assess quantitatively, however, studies of remotely delivered family psychoeducation suggested that it is feasible, acceptable, and potentially effective. CONCLUSIONS: Overall, the evidence-base for remotely delivered treatment for schizophrenia is limited. Studies to date suggest that remote adaptations may be effective; however, more rigorous trials are needed to assess efficacy and methods of remote delivery that are most effective.

Examining Cognitive Biases Uniquely Associated with Schizotypy.

INTRODUCTION: Individuals with schizotypy can experience a number of cognitive biases that may increase their risk in developing schizophrenia-spectrum psychopathology. However, cognitive biases are also present in mood and anxiety disorders, and it is currently unclear which biases are specific to schizotypy and which may be a result of comorbid depression and/or anxiety. METHODS: 462 participants completed measures of depression, anxiety, cognitive biases, cognitive schemas, and schizotypy. Correlation analyses were conducted to examine the relationship between these constructs. Three hierarchical regression analyses were conducted to examine if schizotypy, depression, and anxiety explained a statistically significant amount of variance in cognitive biases after controlling for depression and anxiety, schizotypy and anxiety, and schizotypy and depression, respectively. Moderated regression analyses were also conducted to investigate the moderating role of biological sex and ethnicity in the association between cognitive biases and schizotypy. RESULTS: Self-referential processing, belief inflexibility, and attention for threat were associated with schizotypy. The belief inflexibility bias and social cognition problems were specifically associated with schizotypy after controlling for depression and anxiety and were not directly associated with either depression or anxiety. These associations were not moderated by biological sex or ethnicity. CONCLUSION: The belief inflexibility bias may be an important cognitive bias underlying schizotypal personality, and further research will be important to determine whether this bias is also associated with an increased likelihood of transitioning to psychosis.

Harnessing Clickable Acylated Glycerol Probes as Chemical Tools for Tracking Glycerolipid Metabolism.

We report the use of clickable monoacylglycerol (MAG) analogs as probes for the labeling of glycerolipids during lipid metabolism. Incorporation of azide tags onto the glycerol region was pursued to develop probes that would label glycerolipids, in which the click tag would not be removed through processes including acyl chain and headgroup remodeling. Analysis of clickable MAG probes containing acyl chains of different length resulted in widely variable cell imaging and cytotoxicity profiles. Based on these results, we focused on a probe bearing a short acyl chain (C4 -MAG-N3 ) that was found to infiltrate natural lipid biosynthetic pathways to produce click-tagged versions of both neutral and phospholipid products. Alternatively, strategic blocking of the glycerol sn-3 position in probe C4 -MEG-N3 served to deactivate phospholipid tagging and focus labeling on neutral lipids. This work shows that lipid metabolic labeling profiles can be tuned based on probe structures and provides valuable tools for evaluating alterations to lipid metabolism in cells.

Cellular Labeling of Phosphatidylserine Using Clickable Serine Probes.

Phosphatidylserine (PS) is a key lipid that plays important roles in disease-related biological processes, and therefore, the means to track PS in live cells are invaluable. Herein, we describe the metabolic labeling of PS in Saccharomyces cerevisiae cells using analogues of serine, a PS precursor, derivatized with azide moieties at either the amino (N-l-SerN3) or carbonyl (C-l-SerN3) groups. The conservative click tag modification enabled these compounds to infiltrate normal lipid biosynthetic pathways, thereby producing tagged PS molecules as supported by mass spectrometry studies, thin-layer chromatography (TLC) analysis, and further derivatization with fluorescent reporters via click chemistry to enable imaging in yeast cells. This approach shows strong prospects for elucidating the complex biosynthetic and trafficking pathways involving PS.

Development of GTP-responsive liposomes by exchanging the metal-DPA binding site in a synthetic lipid switch.

We report stimuli-responsive liposomes that selectively release encapsulated contents upon treatment with guanosine triphosphate (GTP) over a wide variety of phosphorylated metabolites, validated by fluorescence-based leakage assays. Significant changes in liposome self-assembly properties were also observed. Our results showcase the potential of this platform for triggered release applications.

Copper-responsive liposomes for triggered cargo release employing a picolinamide-lipid conjugate.

In this work, we report triggered content release from liposomes brought about by copper chelation to a synthetic lipid switch containing a picolinamide headgroup. Fluorescence-based dye-leakage assays showcase release of carboxyfluorescein dye cargo upon copper treatment and control of liposomal release based on copper abundance. Our results additionally show that this platform is selective for copper and is accompanied by significant changes to liposome properties upon treatment with this ion.

Sticking the Landing: Enhancing Liposomal Cell Delivery using Reversible Covalent Chemistry and Caged Targeting Groups.

Liposomes are highly effective nanocarriers for encapsulating and delivering a wide range of therapeutic cargo. While advancements in liposome design have improved several pharmacological characteristics, an important area that would benefit from further progress involves cellular targeting and entry. In this concept article, we will focus on recent progress utilizing strategies including reversible covalent bonding and caging groups to activate liposomal cell entry. These approaches take advantage of advancements that have been made in complementary fields including molecular sensing and chemical biology and direct this technology toward controlling liposome cell delivery properties. The decoration of liposomes with groups including boronic acids and cyclic disulfides is presented as a means for driving delivery through reaction with functional groups on cell surfaces. Additionally, caging groups can be exploited to activate cell delivery only upon encountering a target stimulus. These approaches provide promising new avenues for controlling cell delivery in the development of next-generation liposomal therapeutic nanocarriers.

Metabolite-Responsive Liposomes Employing Synthetic Lipid Switches Driven by Molecular Recognition Principles.

The ability to exert control over lipid properties, including structure, charge, function, and self-assembly characteristics is a powerful tool that can be implemented to achieve a wide range of biomedical applications. Examples in this arena include the development of caged lipids for controlled activation of signaling properties, metabolic labeling strategies for tracking lipid biosynthesis, lipid activity probes for identifying cognate binding partners, approaches for in situ membrane assembly, and liposome triggered release strategies. In this Account, we describe recent advancements in the latter area entailing the development of stimuli-responsive liposomes through programmable changes to lipid self-assembly properties, which can be harnessed to drive the release of encapsulated contents toward applications including drug delivery. We will focus on an emerging paradigm involving liposomal platforms that are sensitized toward chemical agents ranging from metal cations to small organic molecules that exhibit dysregulation in disease states. This has been achieved by developing synthetic lipid switches that are designed to undergo programmed conformational changes upon the recognition of specific target analytes. These structural alterations are leveraged to perturb the packing of lipids within the membrane and thereby drive the release of encapsulated contents.We provide an overview of the inspiration, design, and characterization of liposomes that selectively respond to wide-ranging target analytes. This series of studies began with the development of calcium-responsive liposomes utilizing a lipid switch inspired by sensors including indo-1. Following this successful demonstration, we next showed that the selectivity of the lipid switch could be altered among different metal cations by producing a liposomal platform for which release is induced through zinc binding. Our next goal was to develop metabolite-responsive liposomes in which switching is driven by molecular recognition events involving phosphorylated small molecules. In this work, screening of lipid switches designed to interact with phosphorylated metabolites led to the identification of liposomal formulations that selectivity release contents in the presence of adenosine triphosphate (ATP). Finally, we were able to modulate the metabolite selectivity by rationally designing a modified lipid switch structure that is activated through complexation of inositol-(1,4,5)-trisphosphate (IP3). These projects show the progression of our approaches for liposome release triggered by molecular recognition principles, building from ion-responsive lipid switches to structures that are activated by small molecules. These "smart" liposomal platforms provide an important addition to the toolbox for controlled cargo release since they respond to ions or small molecules that are commonly overproduced by diseased cells.