Cysteine Oxidation in Human Galectin-1 Occurs Sequentially via a Folded Intermediate to a Fully Oxidized Unfolded Form.

Galectins are multifunctional effectors in cellular homeostasis and dysregulation. Oxidation of human galectin-1 (Gal-1) with its six sulfhydryls produces a disulfide-bridged oxidized form that lacks normal lectin activity yet gains new glycan-independent functionality. Nevertheless, the mechanistic details as to how Gal-1 oxidation occurs remain unclear. Here, we used 15N and 13C HSQC NMR spectroscopy to gain structural insight into the CuSO4-mediated path of Gal-1 oxidation and identified a minimum two-stage conversion process. During the first phase, disulfide bridges form slowly between C16-C88 and/or C42-C66 to produce a partially oxidized, conformationally flexible intermediate that retains the ability to bind lactose. Site-directed mutagenesis of C16 to S16 impedes the onset of this overall slow process. During the second phase, increased motional dynamics of the intermediate enable the relatively distant C2 and C130 residues to form the third and final disulfide bond, leading to an unfolded state and consequent dimer dissociation. This fully oxidized end state loses the ability to bind lactose, as shown by the hemagglutination assay. Consistent with this model, we observed that the Gal-1 C2S mutant maintains intermediate-state structural features with a free sulfhydryl group at C130. Incubation with dithiothreitol reduces all disulfide bonds and allows the lectin to revert to its native state. Thus, the sequential, non-random formation of three disulfide bridges in Gal-1 in an oxidative environment acts as a molecular switch for fundamental changes to its functionality. These data inspire detailed bioactivity analysis of the structurally defined oxidized intermediate in, e.g., acute and chronic inflammation.

Health Equity and Perinatal Mental Health.

PURPOSE OF REVIEW: Pregnancy and the postpartum period are vulnerable times to experience psychiatric symptoms. Our goal was to describe existing inequities in perinatal mental health, especially across populations, geography, and in the role of childbirth. RECENT FINDINGS: People of color are at an increased risk for perinatal mental health difficulties and more likely to experience neglect, poor communication, and racial discrimination. LGBTQ + individuals encounter unique challenges, implicating the role of heteronormativity, cisnormativity, and gender dysphoria through pregnancy-related processes. Rural-dwelling women are significantly less likely to seek care, be screened for, or receive treatment for perinatal mental health conditions. Trauma-informed, comprehensive mental health support must be provided to all patients during pregnancy, childbirth, and the postpartum period, especially for racially and ethnically minoritized individuals that have often been omitted from care. Future research needs to prioritize inclusion of perinatal populations not well represented in the literature, including rural-dwelling individuals.

Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities.

Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen-binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.

Pre-Frailty and Frailty in Hospitalized Older Adults: A Comparison Study in People with and without a History of Cancer in an Acute Medical Unit.

A prospective observational study was conducted in a cohort of older adults ≥65 years (n = 329), admitted to the acute medical unit (AMU) of a tertiary hospital, to describe and compare characteristics including frailty status and clinical outcomes. Multivariable models compared older adults with and without a history of cancer to determine characteristics associated with frailty and pre-frailty. An adjusted Poisson regression model was used to compare the length of hospital stay (LOS) between the two groups. About one-fifth (22%) of the cohort had a history of cancer. The most common cancer types were prostate (n = 20), breast (n = 13), lung (n = 8) and gastrointestinal (n = 8). There was no difference in the prevalence of pre-frailty/frailty among patients with or without a history of cancer (58% vs. 57%, p > 0.05). Pre-frailty/frailty was associated with polypharmacy (OR 8.26, 95% CI: 1.74 to 39.2) and malnutrition (OR 8.91, 95% CI: 2.15 to 36.9) in patients with a history of cancer. Adjusted analysis revealed that the risk of having a longer LOS was 24% higher in older adults with a history of cancer than those without (IRR 1.24, 95% CI 1.10 to 1.41, p < 0.001). Clinicians in the AMU should be aware that older adults with a history of cancer have a higher risk of a longer LOS compared to those without.

Retinal peri-arteriolar versus peri-venular amyloidosis, hippocampal atrophy, and cognitive impairment: exploratory trial.

The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort (P < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired (P < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.

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.

A panel network analysis of posttraumatic stress disorder and obsessive-compulsive disorder symptoms across the perinatal period.

The perinatal period is marked by a higher risk of experiencing depressive, anxiety, and/or trauma-related symptoms, a phenomenon that affects millions of individuals each year. Obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) symptoms commonly co-occur but have rarely been examined together beyond prevalence estimates in the perinatal period. Our study aimed to explore patterns of associations among OCD and PTSD symptoms to elucidate within- and between-person effects and how these effects may change over time. Participants (N = 270) were recruited during pregnancy from an academic medical center affiliated with a midwestern university. PTSD, OCD, and depressive symptoms were assessed at pregnancy, 4, 8, and 12 weeks postpartum. A panel graphical vector autoregression model was used to estimate networks. The temporal network provided information regarding directed predictive effects between symptoms, and hyperarousal, neutralizing, and ordering were the most stable and predictive symptoms across time. The contemporaneous network, which yields undirected partial correlations between symptoms at a given moment, indicated that there were positive associations between intrusions and avoidance, hyperarousal and negative alterations in cognitions and mood, as well as between hyperarousal and dysphoria. This study identified hyperarousal and neutralizing as the PTSD and OCD symptoms with the strongest stability, predictive power, and association with other symptoms. Clinically, this indicates that screening for hyperarousal and neutralizing symptoms may identify individuals who could maximally benefit from treatment in the perinatal period. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Corrigendum: A structural connectivity atlas of limbic brainstem nuclei.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.