Physical Modalities for the Treatment of Localized Provoked Vulvodynia: A Scoping Review of the Literature from 2010 to 2023.

Introduction: Localized provoked vulvodynia (LPV) is a prevalent sexual health condition with significant negative impacts on quality of life. There is a lack of consensus regarding effective management. Methods: We used Arksey and O'Malley's five-step method to identify, collate, and evaluate literature published between 2010 and 2023. The scoping review investigated the efficacy or effectiveness of interventions in the management of LPV. The aim of this paper is to map the literature on the efficacy or effectiveness of physical interventions. Results: The review produced 19 primary studies of physical interventions for LPV. These include acupuncture, laser therapy, physiotherapy, transcutaneous electrical nerve stimulation, low-intensity shockwave therapy, transcranial direct current stimulation, and vestibulectomy. Conclusion: Published studies that investigated a range of physical treatments for LPV showed some positive effects, except for transcranial direct-current stimulation. The remaining modalities demonstrated improved sexual pain and treatment satisfaction, when measured. Findings were mixed for non-sexual pain. There was insufficient evidence to draw conclusions regarding other outcomes. Researchers are encouraged to conduct larger, high-quality studies that sample more diverse patient populations and use patient-oriented outcomes to assess effectiveness of physical modalities.

Corrigendum: A structural connectivity atlas of limbic brainstem nuclei.

[This corrects the article DOI: 10.3389/fnimg.2022.1009399.].

A novel inhibitory BAK antibody enables assessment of non-activated BAK in cancer cells.

BAX and BAK are pro-apoptotic members of the BCL2 family that are required to permeabilize the mitochondrial outer membrane. The proteins can adopt a non-activated monomeric conformation, or an activated conformation in which the exposed BH3 domain facilitates binding either to a prosurvival protein or to another activated BAK or BAX protein to promote pore formation. Certain cancer cells are proposed to have high levels of activated BAK sequestered by MCL1 or BCLXL, thus priming these cells to undergo apoptosis in response to BH3 mimetic compounds that target MCL1 or BCLXL. Here we report the first antibody, 14G6, that is specific for the non-activated BAK conformer. A crystal structure of 14G6 Fab bound to BAK revealed a binding site encompassing both the α1 helix and α5-α6 hinge regions of BAK, two sites involved in the unfolding of BAK during its activation. In mitochondrial experiments, 14G6 inhibited BAK unfolding triggered by three diverse BAK activators, supporting crucial roles for both α1 dissociation and separation of the core (α2-α5) and latch (α6-α9) regions in BAK activation. 14G6 bound the majority of BAK in several leukaemia cell lines, and binding decreased following treatment with BH3 mimetics, indicating only minor levels of constitutively activated BAK in those cells. In summary, 14G6 provides a new means of assessing BAK status in response to anti-cancer treatments.

From pregnancy to the postpartum: Unraveling the complexities of symptom profiles among trauma-exposed women.

BACKGROUND: Many women experience new onset or worsening of existing posttraumatic stress disorder (PTSD) symptoms during pregnancy and the early postpartum period. However, perinatal PTSD symptom profiles and their predictors are not well understood. METHODS: Participants (N = 614 community adults) completed self-report measures across three methodologically similar longitudinal studies. Mixture modeling was used to identify latent subgroups of trauma-exposed women with distinct patterns of symptoms at pregnancy, 1-month, and 3-month postpartum. RESULTS: Mixture modeling demonstrated two classes of women with relatively homogenous profiles (i.e., low vs. high symptoms) during pregnancy (n = 237). At 1-month postpartum (n = 391), results suggested a five-class solution: low symptoms, PTSD only, depression with primary appetite loss, depression, and comorbid PTSD and depression. At 3-months postpartum (n = 488), three classes were identified: low symptoms, elevated symptoms, and primary PTSD. Greater degree of exposure to interpersonal trauma and reproductive trauma, younger age, and minoritized racial/ethnic identity were associated with increased risk for elevated symptoms across the perinatal period. LIMITATIONS: Only a subset of potential predictors of PTSD symptoms were examined. Replication with a larger and more racially and ethnically diverse sample of pregnant women is needed. CONCLUSIONS: Results highlight limitations of current perinatal mental health screening practices, which could overlook women with elevations in symptoms (e.g., intrusions) that are not routinely assessed relative to others (e.g., depressed mood), and identify important risk factors for perinatal PTSD symptoms to inform screening and referral.

Barriers and Enablers to a Hospital-to-Home, Combined Exercise and Nutrition, Self-Managed Program for Pre-Frail and Frail Hospitalised Older Adults.

INTRODUCTION: Self-managed exercise and nutrition interventions can alleviate pre-frailty and frailty but understanding of adherence to them is lacking. This study aimed to explore the experiences of, and barriers and enablers to, a hospital-to-home self-managed combined exercise and nutrition program for hospitalised older adults living with pre-frailty and frailty. METHODS: A hybrid approach to data- and theory-driven descriptive thematic analysis identified experiences, barriers, and enablers to participation in a 3-month, self-managed, exercise-nutrition, hospital-to-home frailty-support program. Pre-frail and frail older adult patients ≥ 65 years admitted to the acute medical unit at a South Australian tertiary hospital were recruited. Individual semi-structured interviews were audio-recorded, transcribed verbatim, and analysed descriptively, using the Theoretical Domains Framework. RESULTS: The nutrition component of the program found 11 common barriers and 18 common enablers. The exercise component included 14 barriers and 24 enablers. Intentions, Social influences, Environmental context/resource and Emotions served as primary barriers towards adherence to both components. Common enablers for both components included Knowledge, Social identity, Environmental context/resource, Social influences, and Emotions. CONCLUSIONS: This research revealed important factors affecting adherence to a self-managed exercise-nutrition program in pre-frail and frail older adults within the environment, resources, and emotion domains that should be considered when designing other intervention programs in this population group.

Distinctive retinal peri-arteriolar versus peri-venular amyloid plaque distribution correlates with the cognitive performance.

Introduction: The vascular contribution to Alzheimer's disease (AD) is tightly connected to cognitive performance across the AD continuum. We topographically describe retinal perivascular amyloid plaque (AP) burden in subjects with normal or impaired cognition. Methods: Using scanning laser ophthalmoscopy, we quantified retinal peri-arteriolar and peri-venular curcumin-positive APs in the first, secondary and tertiary branches in twenty-eight subjects. Perivascular AP burden among cognitive states was correlated with neuroimaging and cognitive measures. Results: Peri-arteriolar exceeded peri-venular AP count (p<0.0001). Secondary branch AP count was significantly higher in cognitively impaired (p<0.01). Secondary small and tertiary peri-venular AP count strongly correlated with clinical dementia rating, hippocampal volumes, and white matter hyperintensity count. Discussion: Our topographic analysis indicates greater retinal amyloid accumulation in the retinal peri-arteriolar regions overall, and distal peri-venular regions in cognitively impaired individuals. Larger longitudinal studies are warranted to understand the temporal-spatial relationship between vascular dysfunction and perivascular amyloid deposition in AD. Highlights: Retinal peri-arteriolar region exhibits more amyloid compared with peri-venular regions.Secondary retinal vascular branches have significantly higher perivascular amyloid burden in subjects with impaired cognition, consistent across sexes.Cognitively impaired individuals have significantly greater retinal peri-venular amyloid deposits in the distal small branches, that correlate with CDR and hippocampal volumes.

A world-first food service satisfaction questionnaire for use with family members of nursing home residents: expanding the toolkit of valid and reliable aged care food service satisfaction questionnaires.

OBJECTIVES: This study aimed to develop a valid and reliable food service satisfaction questionnaire for use by family members of residents in nursing homes. DESIGN: Questionnaire development and validation study conducted using COSMIN® benchmarks for excellence. SETTING: Nursing homes. PARTICIPANTS: Family members of residents in nursing homes. MEASUREMENTS: Content validity was established based on a review of the literature, qualitative interviews with family members (n = 9) and expert review (n = 10). Face validity was established in pilot testing with family members (n = 5). A 40-item questionnaire was developed for psychometric testing. Data from 414 family members was used to establish construct validity (Principal Components Analysis), with data from 101 of those family members used to evaluate reliability (internal consistency (Cronbach's alpha [α]) and temporal stability [weighted Kappa]). RESULTS: A two factor 24-item scale resulted, with excellent internal consistency (factor one: 11 items related to food and meals (α = 0.960); factor two: 13 items related to the mealtime experience (α = 0.907)). Temporal stability was moderate to near perfect (weighted Kappa: 0.461-0.875; p < 0.001). CONCLUSION: This world-first, valid and reliable, food service satisfaction questionnaire for use with family members of nursing home residents meets COSMIN® standards for excellence and complements the Flinders University resident and workforce food service satisfaction questionnaires also available for use in nursing homes.

Multimodal and Interdisciplinary Interventions for the Treatment of Localized Provoked Vulvodynia: A Scoping Review of the Literature from 2010 to 2023.

Introduction: Localized provoked vulvodynia (LPV) is a chronic condition characterized by pain in the vulvar vestibule, which can be provoked by pressure or touch and which is not tied to a clear underlying cause. Research into the etiology of and most appropriate treatment strategy for LPV is still limited. Methods: Using Arksey and O'Malley's model for scoping reviews, we evaluated the research question: what is the current evidence regarding the efficacy/effectiveness of multimodal or interdisciplinary interventions for the treatment of LPV? We collated and analyzed articles from 2010 to 2023 to capture the current research landscape. Results: Our review identified 27 studies, which either compared treatments between classes (eg pharmacologic versus psychologic modalities) or described interdisciplinary treatment programs. We identify several trends in the literature. First, outcome measures are inconsistent between studies, often unvalidated, and may not adequately mirror patient concerns. Second, the absence of appropriate comparator groups in many studies restricts providers' ability to appraise which treatments may be most efficacious. Third, selection bias and demographic homogeneity limit generalizability. Finally, we highlight the need for head-to-head trials of vestibulectomy with other treatments considered first line for vulvodynia management. Conclusion: There is insufficient evidence to suggest the superiority of one treatment modality for LPV relative to others or to recommend a particular interdisciplinary management strategy. Future research should use a head-to-head design where sham control is impossible, incorporate patient-centered outcome measures, and investigate impacts of treatment among diverse samples of LPV patients.

Experiential avoidance as a mediator of risk factors for higher order internalizing psychopathology in the perinatal period.

OBJECTIVES: Perinatal psychopathology can be damaging. This study examined the strength of the associations between risk factors and all perinatal mood and anxiety disorder symptoms while assessing the mediating effect of experiential avoidance. METHOD: Participants (N = 246) completed assessments during pregnancy (28-32 weeks) and the postpartum (6-8 weeks). Structural equation modeling (SEM) was used to examine associations between risk factors and latent factors: distress (composed of depression, generalized anxiety, irritability, and panic symptoms); fear (social anxiety, agoraphobia, specific phobia, and obsessive-compulsive); and bipolar (mania and obsessive-compulsive). RESULTS: During pregnancy, past psychiatric history, anxiety sensitivity, maladaptive coping, and age were significant risk factors. In the postpartum, negative maternal attitudes and past psychiatric history were only risk factors for symptoms that composed distress. Experiential avoidance mediated the relation between maladaptive coping and symptoms that composed fear. CONCLUSION: It is important to assess for psychological risk factors starting in pregnancy. This study identified critical risk factors that are associated with the underlying commonality among perinatal mood and anxiety symptoms. Some of the risk factors as well as the mediator are malleable (negative maternal attitudes, experiential avoidance), creating new possibilities for prevention and treatment of perinatal mood and anxiety disorder symptoms.

Isomerization of proline-46 in the N-terminal tail of galectin-3 enhances T cell apoptosis via the ROS-ERK pathway.

Galectin-3 (Gal-3) is unique in the galectin family, due to the presence of a long N-terminal tail (NT) arising from its conserved carbohydrate recognition domain (CRD). Although functional significance of the NT has remained elusive, our previous studies demonstrated the importance of NT prolines to Gal-3 function. Here, we show that during the time Gal-3 stands in solution for three or more days, Gal-3 NT undergoes a slow, intra-molecular, time-dependent conformational/dynamical change associated with proline cis-trans isomerization. From initial dissolution of Gal-3 in buffer to three days in solution, Gal-3-mediated T cell apoptosis is enhanced from 23 % to 37 %. Western blotting and flow cytometry show that the enhancement occurs via the ROS-ERK pathway, and not by the PKC-ERK pathway. To assess which proline(s) is (are) responsible for this effect, we individually mutated all 14 NT prolines within the first 68 residues to alanines, and assessed their effect on ROS production. Our study shows that isomerization of P46 alone is responsible for the upregulation of ROS and T cell apoptosis. NMR studies show that this unique effect is mediated by a change in dynamic interactions between the NT and CRD F-face, which in turn leads to this change in Gal-3 function.

A transboundary agenda for nature-based solutions across sectors, scales and disciplines: Insights from carbon projects in Southeast Asia.

Nature-based Solutions (NbS) are integral to efforts to keep global warming below 2°C in accordance with the United Nations' 2015 Paris Agreement on Climate Change. Yet the transboundary governance dimensions of NbS remain unclear and largely undocumented. In Southeast Asia, NbS have emphasised the conservation and/ or sustainable commodification of carbon sinks found in terrestrial and mangrove forests, seagrass meadows, peatlands and agricultural soils. Mostly project-driven and fixed-term, these "solutions" have often failed to meet their social and ecological objectives. Increasingly, they have added to cross-border problems of: (1) displaced carbon emissions; and (2) economic migration and societal dispossession. This perspective paper delineates a transboundary governance research agenda to mitigate these trade-offs and enhance the co-benefits of NbS in carbon sinks. Building on NbS literature, it identifies cross-sector, multi-scalar and interdisciplinary pathways to improve transboundary cooperation, inclusion and equity in carbon sink governance in varying Southeast Asian contexts.

Obsessive-compulsive disorder symptoms and intrusive thoughts in the postpartum period: Associations with trauma exposure and PTSD symptoms.

In a community sample of trauma-exposed postpartum individuals (N = 167; mean age = 30, 90% White; 61.7% completed bachelor's degree or higher) longitudinally completed self-report measures on PTSD, depressive, and Obsessive-compulsive disorder (OCD) symptoms (specifically checking, ordering, washing, and obsessing symptoms), preoccupation with intrusive postpartum thoughts/neutralising strategies, and trauma exposure at 4 and 12 weeks postpartum. PTSD symptoms were strongly associated with all OCD symptoms (r = 0.32- 0.49, p < 0.001), preoccupation with postpartum-specific intrusive thoughts (r = 0.32-0.45, p < 0.001), and preoccupation with neutralising strategies (r = 0.21-0.29, p < 0.05) at both time points. PTSD symptoms were also predictive of checking and obsessing symptoms. This study identified PTSD symptoms as a new correlate for preoccupation with postpartum-specific intrusive thoughts and neutralising strategies in the postpartum period in a community sample. These findings add to the evidence suggesting a strong association between PTSD and OCD symptoms across the lifespan, including in non-clinical samples. Future research should examine best practices to assess and treat a variety of postpartum psychopathology symptoms, not just depression.

The energetics and evolution of oxidoreductases in deep time.

The core metabolic reactions of life drive electrons through a class of redox protein enzymes, the oxidoreductases. The energetics of electron flow is determined by the redox potentials of organic and inorganic cofactors as tuned by the protein environment. Understanding how protein structure affects oxidation-reduction energetics is crucial for studying metabolism, creating bioelectronic systems, and tracing the history of biological energy utilization on Earth. We constructed ProtReDox (https://protein-redox-potential.web.app), a manually curated database of experimentally determined redox potentials. With over 500 measurements, we can begin to identify how proteins modulate oxidation-reduction energetics across the tree of life. By mapping redox potentials onto networks of oxidoreductase fold evolution, we can infer the evolution of electron transfer energetics over deep time. ProtReDox is designed to include user-contributed submissions with the intention of making it a valuable resource for researchers in this field.

Iatrogenic Cerebrospinal Fluid Breast Augmentation: Rare Complication of Ventriculoperitoneal Shunts and Management Strategies.

BACKGROUND: Ventriculoperitoneal shunt is one of the most common neurosurgical procedures in the treatment of hydrocephalus. There are reports of migration of the distal catheter to the breast pocket where cerebrospinal fluid then collects and can develop into a pseudocyst. There exist case reports in the literature of patients with prior breast augmentation who present with distal catheter migration from the peritoneal space into the breast tissue. We present a case series of 3 patients with preexisting breast augmentation who returned with unilateral breast enlargement after ventriculoperitoneal shunt. In all 3 patients, the distal catheter migrated out of the peritoneal space and was found to be coiled around the breast prosthesis. Additionally, we offer recommendations for managing these complications and a review of the literature. METHODS: We performed a systematic review without meta-analysis of studies involving management of shunt migration in the setting of preexisting breast implants. We present a case series of 3 patients whom we treated with breast cerebrospinal pseudocyst after migration of the distal catheter into the breast tissue. RESULTS: A total of 17 studies, dating from 2002 to 2022, met our inclusion and exclusion criteria and were selected for full review. Catheter migration occurred between 2 weeks and 9 months of initial shunt placement. All patients presented with unilateral breast enlargement and cerebrospinal fluid pseudocyst formation. All patients underwent revision shunt surgery. Surgical treatment strategies used included reimplantation of the distal catheter into the pleural space or ipsilateral or contralateral peritoneal space or complete removal of the entire shunt system. CONCLUSIONS: Breast-related ventriculoperitoneal shunt complication is a rare entity that is increasingly seen as more patients receive breast augmentation. Breast-related shunt complications most commonly present with cerebrospinal fluid pseudocyst formation in the breast. It is important for neurosurgeons to be aware of an underlying breast implant before placing a ventriculoperitoneal shunt. For patients who have migration of the distal catheter into the breast, a protocol for managing these situations should be followed to ensure no shunt infection and avoidance of future catheter migration complications with subsequent shunt revisions.

Sequence differences between BAX and BAK core domains manifest as differences in their interactions with lipids.

The B-cell lymphoma 2 (BCL2) family members, BCL2-associated protein X (BAX) and BCL2 homologous antagonist killer (BAK), are required for programmed cell death via the mitochondrial pathway. When cells are stressed, damaged or redundant, the balance of power between the BCL2 family of proteins shifts towards BAX and BAK, allowing their transition from an inactive, monomeric state to a membrane-active oligomeric form that releases cytochrome c from the mitochondrial intermembrane space. That oligomeric state has an essential intermediate, a symmetric homodimer of BAX or BAK. Here we describe crystal structures of dimers of the core domain of BAX, comprising its helices α2-α5. These structures provide an atomic resolution description of the interactions that drive BAX homo-dimerisation and insights into potential interaction between core domain dimers and membrane lipids. The previously identified BAK lipid-interacting sites are not conserved with BAX and are likely to determine the differences between them in their interactions with lipids. We also describe structures of heterodimers of BAK/BAX core domains, yielding further insight into the differences in lipid binding between BAX and BAK.

Sleep and cardiovascular disease.

This review centres around the recent evidence in examining the intersection of sleep and cardiovascular disease (CVD). Sleep in this review will be further subdivided to consider both sleep quantity and quality along and will also consider some of the more common sleep disorders, such as insomnia and obstructive sleep apnoea, in the context of CVD. Sleep disorders have been further explored in several specific populations which are both at risk of sleep disorders and CVD. Secondly, the review will present some of the risk factors for CVD that are affected by sleep and sleep disorders which include hypertension, diabetes, and obesity. It will also examine the potential underlying mechanisms including inflammation, appetite control, endocrine, and genetic processes that are affected by sleep and sleep disorders leading to increased risk of CVD development. In addition, we will consider the observed bi-directional relationships between sleep and cardiovascular risk factors. For example, obesity, a risk factor for CVD can be affected by sleep, but in turn can increase the risk of certain sleep disorder development which disrupts sleep, leading to further risk of obesity development and increased CVD risk. Finally, the review will explore emerging evidence around lifestyle interventions that have included a sleep component and how it impacts the management of CVD risk factor. The need for increased awareness of the health effects of poor sleep and sleep disorders will be discussed alongside the need for policy intervention to improve sleep to facilitate better health and well-being.

Time for bed: diet, sleep and obesity in children and adults.

Sufficient sleep is necessary for optimal health, daytime performance and wellbeing and the amount required is age-dependent and decreases across the lifespan. Sleep duration is usually affected by age and several different cultural, social, psychological, behavioural, pathophysiological and environmental factors. This review considers how much sleep children and adults need, why this is important, what the consequences are of insufficient sleep and how we can improve sleep. A lack of the recommended amount of sleep for a given age group has been shown to be associated with detrimental effects on health including effects on metabolism, endocrine function, immune function and haemostatic pathways. Obesity has increased worldwide in the last few decades and the WHO has now declared it a global epidemic. A lack of sleep is associated with an increased risk of obesity in children and adults, which may lead to future poor health outcomes. Data from studies in both children and adults suggest that the relationship between sleep and obesity may be mediated by several different mechanisms including alterations in appetite and satiety, sleep timing, circadian rhythm and energy balance. Moreover, there is evidence to suggest that improvements in sleep, in both children and adults, can be beneficial for weight management and diet and certain foods might be important to promote sleep. In conclusion this review demonstrates that there is a wide body of evidence to suggest that sleep and obesity are causally related and recommends that further research is required to inform policy, and societal change.

Seizure outcomes following single-fraction versus hypofractionated radiosurgery for brain metastases: a single-center experience.

OBJECTIVE: Although seizures are a relatively common phenomenon in the setting of brain metastases (BMs), there are no discrete recommendations regarding the use of antiepileptic drugs (AEDs) in this population, either in general or in the context of treatment. The authors' aim was to better understand the underlying pathological factors as well as the therapeutic techniques that may lead to seizures following the radiosurgical treatment of BMs with the goal of guiding appropriate AED prophylaxis. METHODS: Adult patients with BMs diagnosed from 2013 to 2020 at a single academic institution and treated with radiation therapy were included in this study. The authors evaluated factors associated with the incidence of seizures throughout the disease course, with a focus on seizures in the 90-day period following stereotactic radiosurgery (SRS). RESULTS: Four hundred forty-four patients with newly diagnosed BMs were identified, 10% of whom had seizures at the time of presentation and 28% of whom had a seizure at any point during the study period. Tumor histology was significantly associated with initial seizure risk. AED use was highly variable. In the 90-day post-SRS period, the summed total planning target volume (PTV) was independently predictive of post-SRS seizures, regardless of the fractionation scheme (single fraction vs hypofractionated) and other clinical factors. The number of supratentorial BMs was not predictive of post-SRS seizures. CONCLUSIONS: PTV is a superior predictor of post-SRS seizures relative to the number of supratentorial BMs, as it serves as a volumetric proxy for intracranial disease burden. A larger PTV, alongside tumor histology and prior seizure history, should be considered in the decision-making process for AED use following radiosurgery.

Validation of Anti-Adeno Associated Virus Serotype rh10 (AAVrh.10) Total and Neutralizing Antibody Immunogenicity Assays.

Immunogenicity assessment of Adeno-Associated Virus (AAV) vectors is a critical part of gene therapy drug development. Whether the assays are used for inclusion/exclusion criteria or to monitor the safety and efficacy of the gene therapy, they are critical bioanalytical assessments. While total anti-AAV assays are perceived as easier to develop and implement than neutralizing anti-AAV assays, the gene therapy field is still nascent, and it is not yet clear which of the assays should be implemented at what stage of drug development. Recently AAVrh.10 has gained interest for use in gene therapies targeting cardiac, neurological, and other diseases due to its enhanced transduction efficiency. There is limited information on anti-AAVrh.10 antibodies and their clinical impact; thus, the information presented herein documents the validation of both a total antibody assay (TAb) and a neutralizing antibody (NAb) assay for anti-AAVrh.10 antibodies. In this manuscript, the validation was performed in accordance with the 2019 FDA immunogenicity guidance with additional evaluations to comply with CLIA where applicable. The AAVrh.10 TAb and NAb assays were compared in terms of sensitivity, drug tolerance, and precision, along with a concordance analysis using the same individual serum samples. This comparison gave insight into the utility of each format as a screening assay for inclusion into clinical studies.

Molecular basis for cellular retinoic acid-binding protein 1 in modulating CaMKII activation.

Introduction: Cellular retinoic acid (RA)-binding protein 1 (CRABP1) is a highly conserved protein comprised of an anti-parallel, beta-barrel, and a helix-turn-helix segment outside this barrel. Functionally, CRABP1 is thought to bind and sequester cytosolic RA. Recently, CRABP1 has been established as a major mediator of rapid, non-genomic activity of RA in the cytosol, referred to as "non-canonical" activity. Previously, we have reported that CRABP1 interacts with and dampens the activation of calcium-calmodulin (Ca2+-CaM)-dependent kinase 2 (CaMKII), a major effector of Ca2+ signaling. Through biophysical, molecular, and cellular assays, we, herein, elucidate the molecular and structural mechanisms underlying the action of CRABP1 in dampening CaMKII activation. Results: We identify an interaction surface on CRABP1 for CaMKII binding, located on the beta-sheet surface of the barrel, and an allosteric region within the helix segment outside the barrel, where both are important for interacting with CaMKII. Molecular studies reveal that CRABP1 preferentially associates with the inactive form of CaMKII, thereby dampening CaMKII activation. Alanine mutagenesis of residues implicated in the CaMKII interaction results in either a loss of this preference or a shift of CRABP1 from associating with the inactive CaMKII to associating with the active CaMKII, which corresponds to changes in CRABP1's effect in modulating CaMKII activation. Conclusions: This is the first study to elucidate the molecular and structural basis for CRABP1's function in modulating CaMKII activation. These results further shed insights into CRABP1's functional involvement in multiple signaling pathways, as well as its extremely high sequence conservation across species and over evolution.