Loss of mGlu5 receptors in somatostatin-expressing neurons alters negative emotional states.

Subtype 5 metabotropic glutamate receptors (mGlu5) are known to play an important role in regulating cognitive, social and valence systems. However, it remains largely unknown at which circuits and neuronal types mGlu5 act to influence these behavioral domains. Altered tissue- or cell-specific expression or function of mGlu5 has been proposed to contribute to the exacerbation of neuropsychiatric disorders. Here, we examined how these receptors regulate the activity of somatostatin-expressing (SST+) neurons, as well as their influence on behavior and brain rhythmic activity. Loss of mGlu5 in SST+ neurons elicited excitatory synaptic dysfunction in a region and sex-specific manner together with a range of emotional imbalances including diminished social novelty preference, reduced anxiety-like behavior and decreased freezing during retrieval of fear memories. In addition, the absence of mGlu5 in SST+ neurons during fear processing impaired theta frequency oscillatory activity in the medial prefrontal cortex and ventral hippocampus. These findings reveal a critical role of mGlu5 in controlling SST+ neurons excitability necessary for regulating negative emotional states.

Breaking the Mucin Barrier: A New Affinity Chromatography-Mass Spectrometry Approach to Unveil Potential Cell Markers and Pathways Altered in Pseudomyxoma Peritonei.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare peritoneal mucinous carcinomatosis with largely unknown underlying molecular mechanisms. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is the only therapeutic option; however, despite its use, recurrence with a fatal outcome is common. The lack of molecular characterisation of PMP and other mucinous tumours is mainly due to the physicochemical properties of mucin. RESULTS: This manuscript describes the first protocol capable of breaking the mucin barrier and isolating proteins from mucinous tumours. Briefly, mucinous tumour samples were homogenised and subjected to liquid chromatography using two specific columns to reduce mainly glycoproteins, albumins and immunoglobulin G. The protein fractions were then subjected to mass spectrometry analysis and the proteomic profile obtained was analysed using various bioinformatic tools. Thus, we present here the first proteome analysed in PMP and identified a distinct mucin isoform profile in soft compared to hard mucin tumour tissues as well as key biological processes/pathways altered in mucinous tumours. Importantly, this protocol also allowed us to identify MUC13 as a potential tumour cell marker in PMP. CONCLUSIONS: In sum, our results demonstrate that this protein isolation protocol from mucin will have a high impact, allowing the oncology research community to more rapidly advance in the knowledge of PMP and other mucinous neoplasms, as well as develop new and effective therapeutic strategies.

The effects of eating a traditional high fat/high carbohydrate or a ketogenic diet on sensitivity of female rats to morphine.

Patients diagnosed with obesity are prescribed opioid medications at a higher rate than the general population; however, it is not known if eating a high fat diet might impact individual sensitivity to these medications. To explore the hypothesis that eating a high fat diet increases sensitivity of rats to the effects of morphine, 24 female Sprague-Dawley rats (n=8/diet) ate either a standard laboratory chow (17% kcal from fat), a high fat/low carbohydrate (ketogenic) chow (90.5% kcal from fat), or a traditional high fat/high carbohydrate chow (60% kcal from fat). Morphine-induced antinociception was assessed using a warm water tail withdrawal procedure, during which latency (in seconds) for rats to remove their tail from warm water baths was recorded following saline or morphine (0.32-56 mg/kg, IP) injections. Morphine was administered acutely and chronically, which involved 19 days of twice daily injections (increasing in 1/4 log dose increments every 3 days: 3.2-56 mg/kg, IP) to induce dependence and assess tolerance. The adverse effects of morphine (i.e., tolerance, withdrawal, changes in body temperature) were assessed throughout the study. Morphine induced comparable antinociception in rats eating different diets, and all rats developed tolerance following chronic morphine exposure. Additional adverse effects of morphine were also comparable among rats eating different diets; however, withdrawal-induced weight loss was less severe for rats eating ketogenic chow. These results suggest that dietary manipulation might modulate the severity of withdrawal-related weight loss, in ways that could be relevant for patients. Significance Statement The present study in female rats suggests that eating a high fat/low carbohydrate (ketogenic) or a traditional high fat/high carbohydrate diet does not impact the pain-relieving or adverse effects of opioids (i.e., tolerance or withdrawal). However, eating a ketogenic diet may have beneficial effects on opioid withdrawal-related weight loss. Individuals diagnosed with obesity taking opioids for pain-related conditions might therefore consider adopting a ketogenic diet when opioid administration is discontinued to potentially mitigate withdrawal-related weight loss.

Vulnerability of Eastern Tropical Pacific chondrichthyan fish to climate change.

Climate change is an environmental emergency threatening species and ecosystems globally. Oceans have absorbed about 90% of anthropogenic heat and 20%-30% of the carbon emissions, resulting in ocean warming, acidification, deoxygenation, changes in ocean stratification and nutrient availability, and more severe extreme events. Given predictions of further changes, there is a critical need to understand how marine species will be affected. Here, we used an integrated risk assessment framework to evaluate the vulnerability of 132 chondrichthyans in the Eastern Tropical Pacific (ETP) to the impacts of climate change. Taking a precautionary view, we found that almost a quarter (23%) of the ETP chondrichthyan species evaluated were highly vulnerable to climate change, and much of the rest (76%) were moderately vulnerable. Most of the highly vulnerable species are batoids (77%), and a large proportion (90%) are coastal or pelagic species that use coastal habitats as nurseries. Six species of batoids were highly vulnerable in all three components of the assessment (exposure, sensitivity and adaptive capacity). This assessment indicates that coastal species, particularly those relying on inshore nursery areas are the most vulnerable to climate change. Ocean warming, in combination with acidification and potential deoxygenation, will likely have widespread effects on ETP chondrichthyan species, but coastal species may also contend with changes in freshwater inputs, salinity, and sea level rise. This climate-related vulnerability is compounded by other anthropogenic factors, such as overfishing and habitat degradation already occurring in the region. Mitigating the impacts of climate change on ETP chondrichthyans involves a range of approaches that include addressing habitat degradation, sustainability of exploitation, and species-specific actions may be required for species at higher risk. The assessment also highlighted the need to further understand climate change's impacts on key ETP habitats and processes and identified knowledge gaps on ETP chondrichthyan species.

El cambio climático es una emergencia medioambiental que amenaza a especies y ecosistemas en todo el mundo. Los océanos han absorbido alrededor del 90% del calor antropogénico y entre el 20% y el 30% de las emisiones de carbono, lo que ha provocado su calentamiento, acidificación, desoxigenación, cambios en la estratificación de los océanos y en la disponibilidad de nutrientes, así como fenómenos extremos más pronunciados. Dadas las predicciones de cambios, hay una importante necesidad de entender cómo las especies marinas se verán afectadas. En este estudio utilizamos una Evaluación Integrada de Riesgos para evaluar la vulnerabilidad de 132 condrictios del Pacífico Tropical Oriental (PTO) a los impactos del cambio climático. Adoptando un enfoque preventivo, estimamos que la vulnerabilidad general al cambio climático es Alta para casi una cuarta parte (23%) de las especies de condrictios del PTO evaluadas y Moderada para gran parte del resto (76%). La mayoría de las especies altamente vulnerables son batoideos (77%), y una gran proporción de éstas (90%) son especies costeras o especies pelágicas que utilizan los hábitats costeros como áreas de crianza. Seis especies de batoideos tuvieron una vulnerabilidad Alta en los tres componentes de la evaluación. Esta evaluación indica que las especies costeras, en particular las que dependen de áreas de crianza costeras, son las más vulnerables al cambio climático. Es probable que el calentamiento de los océanos, junto con la acidificación y la posible desoxigenación, tenga efectos generalizados sobre las especies de condrictios del PTO, pero las especies costeras se verán también afectadas por los cambios en los aportes de agua dulce, la salinidad y el aumento del nivel del mar. Esta vulnerabilidad relacionada con el clima se ve agravada por otros factores antropogénicos que ya se están produciendo en la región, como la sobrepesca y la degradación del hábitat. La mitigación de los impactos del cambio climático sobre los condrictios del PTO implica medidas que incluyan abordar la degradación del hábitat y la sostenibilidad de la explotación pesquera, y acciones para las especies de mayor riesgo son necesarias. Esta evaluación también destaca la necesidad de comprender mejor los impactos del cambio climático en los hábitats y procesos clave del PTO y las lagunas de conocimiento identificadas en relación con las especies de condrictios del PTO.

Parent-provider communication dynamics during the pediatric oncology diagnostic process in Guatemala: A qualitative study.

BACKGROUND: Effective communication is founded on bidirectional participation from families and healthcare providers. In adult medicine, bidirectional communication promotes treatment adherence and builds the family-provider relationship. However, the relationship between communication styles in pediatrics remains poorly understood, particularly in culturally diverse settings. This study aims to investigate parent-provider communication dynamics and parental involvement during diagnostic cancer communication in Guatemala. PROCEDURE: This qualitative study included 20 families of children with cancer and 10 providers at Unidad Nacional de Oncología Pediátrica in Guatemala. Psychoeducation and diagnostic conversations between parents, psychologists, and oncologists were recorded and thematically analyzed using a priori and novel codes exploring communication behaviors, parental engagement, and interpersonal dynamics. RESULTS: Participating parents had children with various diagnoses. Only 15% of fathers and 5% of mothers reported education beyond primary school. Providers spoke 68% of words during psychoeducation and 85% of words during diagnosis conversations. Providers used supportive communication behaviors providing explanations, demonstrating verbal attentiveness, and soliciting questions and non-supportive behaviors including paternalistic talk. Parental participation was considered active when they asked questions, expressed hopes or concerns, or asserted their opinions, and non-active when participation was limited to brief responses to closed-ended questions. Supportive provider communication often encouraged active participation; non-supportive communication did not. Furthermore, active parental participation prompted supportive communication from providers, while non-active participation did not. CONCLUSIONS: Our findings highlight the bidirectional nature of effective communication, establishing that provider communication styles both influence and are influenced by parental participation, and emphasizing the importance of supportive provider communication for patient-centered care.

Etiological diagnosis of recurrent acute pancreatitis.

Acute pancreatitis is the leading cause of inpatient care among gastrointestinal conditions. Despite early intervention, one-third of patients experience recurrent acute pancreatitis (RAP). A comprehensive diagnostic approach is warranted to identify and treat underlying factors in order to prevent recurrence. RAP is most frequent among men aged 30-40, smokers, and in those with excessive alcohol consumption. To identify the etiology is paramount to stratify patients according to their individual risk of RAP and for predicting an eventual evolution to chronic pancreatitis. Although the initial management of acute pancreatitis is widely homogeneous according to established guidelines, there are no defined protocols to investigate RAP. In the present editorial article we propose a structured algorithm with precise recommendations to investigate the etiology RAP as part of routine clinical practice. Although there are relevant knowledge gaps in this disease, we believe that our guidance would contribute for a more homogenous diagnostic approach of RAP in clinical practice.

Revisiting the Heider and Simmel experiment for social meaning attribution in virtual reality.

In their seminal experiment in 1944, Heider and Simmel revealed that humans have a pronounced tendency to impose narrative meaning even in the presence of simple animations of geometric shapes. Despite the shapes having no discernible features or emotions, participants attributed strong social context, meaningful interactions, and even emotions to them. This experiment, run on traditional 2D displays has since had a significant impact on fields ranging from psychology to narrative storytelling. Virtual Reality (VR), on the other hand, offers a significantly new viewing paradigm, a fundamentally different type of experience with the potential to enhance presence, engagement and immersion. In this work, we explore and analyze to what extent the findings of the original experiment by Heider and Simmel carry over into a VR setting. We replicate such experiment in both traditional 2D displays and with a head mounted display (HMD) in VR, and use both subjective (questionnaire-based) and objective (eye-tracking) metrics to record the observers' visual behavior. We perform a thorough analysis of this data, and propose novel metrics for assessing the observers' visual behavior. Our questionnaire-based results suggest that participants who viewed the animation through a VR headset developed stronger emotional connections with the geometric shapes than those who viewed it on a traditional 2D screen. Additionally, the analysis of our eye-tracking data indicates that participants who watched the animation in VR exhibited fewer shifts in gaze, suggesting greater engagement with the action. However, we did not find evidence of differences in how subjects perceived the roles of the shapes, with both groups interpreting the animation's plot at the same level of accuracy. Our findings may have important implications for future psychological research using VR, especially regarding our understanding of social cognition and emotions.

Modeling the Impact of Head-Body Rotations on Audio-Visual Spatial Perception for Virtual Reality Applications.

Humans perceive the world by integrating multimodal sensory feedback, including visual and auditory stimuli, which holds true in virtual reality (VR) environments. Proper synchronization of these stimuli is crucial for perceiving a coherent and immersive VR experience. In this work, we focus on the interplay between audio and vision during localization tasks involving natural head-body rotations. We explore the impact of audio-visual offsets and rotation velocities on users' directional localization acuity for various viewing modes. Using psychometric functions, we model perceptual disparities between visual and auditory cues and determine offset detection thresholds. Our findings reveal that target localization accuracy is affected by perceptual audio-visual disparities during head-body rotations, but remains consistent in the absence of stimuli-head relative motion. We then showcase the effectiveness of our approach in predicting and enhancing users' localization accuracy within realistic VR gaming applications. To provide additional support for our findings, we implement a natural VR game wherein we apply a compensatory audio-visual offset derived from our measured psychometric functions. As a result, we demonstrate a substantial improvement of up to 40% in participants' target localization accuracy. We additionally provide guidelines for content creation to ensure coherent and seamless VR experiences.

A GMR enzymatic assay for quantifying nuclease and peptidase activity.

Hydrolytic enzymes play crucial roles in cellular processes, and dysregulation of their activities is implicated in various physiological and pathological conditions. These enzymes cleave substrates such as peptide bonds, phosphodiester bonds, glycosidic bonds, and other esters. Detecting aberrant hydrolase activity is vital for understanding disease mechanisms and developing targeted therapeutic interventions. This study introduces a novel approach to measuring hydrolase activity using giant magnetoresistive (GMR) spin valve sensors. These sensors change resistance in response to magnetic fields, and here, they are functionalized with specific substrates for hydrolases conjugated to magnetic nanoparticles (MNPs). When a hydrolase cleaves its substrate, the tethered magnetic nanoparticle detaches, causing a measurable shift in the sensor's resistance. This design translates hydrolase activity into a real-time, activity-dependent signal. The assay is simple, rapid, and requires no washing steps, making it ideal for point-of-care settings. Unlike fluorescent methods, it avoids issues like autofluorescence and photobleaching, broadening its applicability to diverse biofluids. Furthermore, the sensor array contains 80 individually addressable sensors, allowing for the simultaneous measurement of multiple hydrolases in a single reaction. The versatility of this method is demonstrated with substrates for nucleases, Bcu I and DNase I, and the peptidase, human neutrophil elastase. To demonstrate a clinical application, we show that neutrophil elastase in sputum from cystic fibrosis patients hydrolyze the peptide-GMR substrate, and the cleavage rate strongly correlates with a traditional fluorogenic substrate. This innovative assay addresses challenges associated with traditional enzyme measurement techniques, providing a promising tool for real-time quantification of hydrolase activities in diverse biological contexts.

Body composition and resting energy expenditure in a group of children with achondroplasia.

BACKGROUND: Persons with achondroplasia develop early obesity, which is a comorbidity associated with other complications. Currently, there are no validated specific predictive equations to estimate resting energy expenditure in achondroplasia. METHODS: We analyzed the influence of body composition on this parameter and determined whether predictive models used for children with standard height are adjusted to achondroplasia. In this cross-sectional study, we measured anthropometric parameters in children with achondroplasia. Fat mass was obtained using the Slaughter skinfold-thickness equation and resting energy expenditure was determined with a Fitmate-Cosmed calorimeter and with predictive models validated for children with average height (Schofield, Institute of Medicine, and Tverskaya). RESULTS: All of the equations yielded a lower mean value than resting energy expenditure with indirect calorimetry (1256±200 kcal/day [mean±SD]) but the closest was the Tverskaya equation (1017 ± 64 kcal/day), although the difference remained statistically significant. We conclude that weight and height have the greatest influence on resting energy expenditure. CONCLUSION: We recommend studying the relationship between body composition and energy expenditure in achondroplasia in more depth. In the absence of valid predictive models suitable for clinical use to estimate body composition and resting energy expenditure in achondroplasia, it is recommended to use the gold standard methods by taking into account certain anthropometric parameters.

Studying the Effect of Material and Geometry on Perceptual Outdoor Illumination.

Understanding and modeling perceived properties of sky-dome illumination is an important but challenging problem due to the interplay of several factors such as the materials and geometries of the objects present in the scene being observed. Existing models of sky-dome illumination focus on the physical properties of the sky. However, these parametric models often do not align well with the properties perceived by a human observer. In this work, drawing inspiration from the Hosek-Wilkie sky-dome model, we investigate the perceptual properties of outdoor illumination. For this purpose, we perform a large-scale user study via crowdsourcing to collect a dataset of perceived illumination properties (scattering, glare, and brightness) for different combinations of geometries and materials under a variety of outdoor illuminations, totaling 5,000 distinct images. We perform a thorough statistical analysis of the collected data which reveals several interesting effects. For instance, our analysis shows that when there are objects in the scene made of rough materials, the perceived scattering of the sky increases. Furthermore, we utilize our extensive collection of images and their corresponding perceptual attributes to train a predictor. This predictor, when provided with a single image as input, generates an estimation of perceived illumination properties that align with human perceptual judgments. Accurately estimating perceived illumination properties can greatly enhance the overall quality of integrating virtual objects into real scene photographs. Consequently, we showcase various applications of our predictor. For instance, we demonstrate its utility as a luminance editing tool for showcasing virtual objects in outdoor scenes.

Applying andragogy for integrating a MOOC into a formal online learning experience in computer engineering.

In this paper, we present the results of a research experience of implementing andragogy in a learning environment designed to better meet the needs of adult learners studying part-time at a distance university. The learning environment was composed of a learning experience on a formal distance university online course that has been enriched with a non-formal component based on students' participation in a Massive Online Open Course (MOOC) related to the same topic. The non-formal experience was designed to consolidate the learning of specific content that involved difficult concepts and foster collaborative skills. The university online course is in the field of computer science and human-computer interaction. The instructional design, including the course assignments, has been guided by Knowles' principles of andragogy. Results from the data analysis of five years of academic results and student satisfaction has helped to understand the learning experience from including a MOOC in adult distance formal learning.

Unveiling the kinetic versatility of aryl-alcohol oxidases with different electron acceptors.

Introduction: Aryl-alcohol oxidase (AAO) shows a pronounced duality as oxidase and dehydrogenase similar to that described for other glucose-methanol-choline (GMC) oxidase/dehydrogenase superfamily proteins involved in lignocellulose decomposition. In this work, we detail the overall mechanism of AAOs from Pleurotus eryngii and Bjerkandera adusta for catalyzing the oxidation of natural aryl-alcohol substrates using either oxygen or quinones as electron acceptors and describe the crystallographic structure of AAO from B. adusta in complex with a product analogue. Methods: Kinetic studies with 4-methoxybenzyl and 3-chloro-4- methoxybenzyl alcohols, including both transient-state and steady-state analyses, along with interaction studies, provide insight into the oxidase and dehydrogenase mechanisms of these enzymes. Moreover, the resolution of the crystal structure of AAO from B. adusta allowed us to compare their overall folding and the structure of the active sites of both AAOs in relation to their activities. Results and Discussion: Although both enzymes show similar mechanistic properties, notable differences are highlighted in this study. In B. adusta, the AAO oxidase activity is limited by the reoxidation of the flavin, while in P. eryngii the slower step takes place during the reductive half-reaction, which determines the overall reaction rate. By contrast, dehydrogenase activity in both enzymes, irrespective of the alcohol participating in the reaction, is limited by the hydroquinone release from the active site. Despite these differences, both AAOs are more efficient as dehydrogenases, supporting the physiological role of this activity in lignocellulosic decay. This dual activity would allow these enzymes to adapt to different environments based on the available electron acceptors.

Inhibition of Kv2.1 potassium channels by the antidepressant drug sertraline.

Sertraline is a commonly used antidepressant of the selective serotonin reuptake inhibitors (SSRIs) class. In this study, we have used the patch-clamp technique to assess the effects of sertraline on Kv2.1 channels heterologously expressed in HEK-293 cells and on the voltage-gated potassium currents (IKv) of Neuro 2a cells, which are predominantly mediated by Kv2.1 channels. Our results reveal that sertraline inhibits Kv2.1 channels in a concentration-dependent manner. The sertraline-induced inhibition was not voltage-dependent and did not require the channels to be open. The kinetics of activation and deactivation were accelerated and decelerated, respectively, by sertraline. Moreover, the inhibition by this drug was use-dependent. Notably, sertraline significantly modified the inactivation mechanism of Kv2.1 channels; the steady-state inactivation was shifted to hyperpolarized potentials, the closed-state inactivation was enhanced and accelerated, and the recovery from inactivation was slowed, suggesting that this is the main mechanism by which sertraline inhibits Kv2.1 channels. Overall, this study provides novel insights into the pharmacological actions of sertraline on Kv2.1 channels, shedding light on the intricate interaction between SSRIs and ion channel function.

Short-Term Panax Ginseng Extract Supplementation Reduces Fasting Blood Triacylglycerides and Oxygen Consumption during Sub-Maximal Aerobic Exercise in Male Recreational Athletes.

Ginseng, a popular herbal supplement among athletes, is believed to enhance exercise capacity and performance. This study investigated the short-term effects of Panax ginseng extract (PG) on aerobic capacity, lipid profile, and cytokines. In a 14-day randomized, double-blind trial, male participants took 500 mg of PG daily. Two experiments were conducted: one in 10 km races (n = 31) and another in a laboratory-controlled aerobic capacity test (n = 20). Blood lipid and cytokine profile, ventilation, oxygen consumption, hemodynamic and fatigue parameters, and race time were evaluated. PG supplementation led to reduced total blood lipid levels, particularly in triacylglycerides (10 km races -7.5 mg/dL (95% CI -42 to 28); sub-maximal aerobic test -14.2 mg/dL (95% CI -52 to 23)), while post-exercise blood IL-10 levels were increased (10 km 34.0 pg/mL (95% CI -2.1 to 70.1); sub-maximal aerobic test 4.1 pg/mL (95% CI -2.8 to 11.0)), and oxygen consumption decreased during the sub-maximal aerobic test (VO2: -1.4 mL/min/kg (95% CI -5.8 to -0.6)). No significant differences were noted in race time, hemodynamic, or fatigue parameters. Overall, PG supplementation for 2 weeks showed benefits in blood lipid profile and energy consumption during exercise among recreational athletes. This suggests a potential role for PG in enhancing exercise performance and metabolic health in this population.

Structural basis of human Nav1.5 gating mechanisms.

Voltage-gated Nav1.5 channels are central to the generation and propagation of cardiac action potentials1. Aberrations in their function are associated with a wide spectrum of cardiac diseases including arrhythmias and heart failure2-5. Despite decades of progress in Nav1.5 biology6-8, the lack of structural insights into intracellular regions has hampered our understanding of its gating mechanisms. Here we present three cryo-EM structures of human Nav1.5 in previously unanticipated open states, revealing sequential conformational changes in gating charges of the voltage-sensing domains (VSDs) and several intracellular regions. Despite the channel being in the open state, these structures show the IFM motif repositioned in the receptor site but not dislodged. In particular, our structural findings highlight a dynamic C-terminal domain (CTD) and III-IV linker interaction, which regulates the conformation of VSDs and pore opening. Electrophysiological studies confirm that disrupting this interaction results in the fast inactivation of Nav1.5. Together, our structure-function studies establish a foundation for understanding the gating mechanisms of Nav1.5 and the mechanisms underlying CTD-related channelopathies.

Glycosaminoglycan-mediated lipoprotein uptake protects cancer cells from ferroptosis.

Lipids are essential for tumours because of their structural, energetic, and signaling roles. While many cancer cells upregulate lipid synthesis, growing evidence suggests that tumours simultaneously intensify the uptake of circulating lipids carried by lipoproteins. Which mechanisms promote the uptake of extracellular lipids, and how this pool of lipids contributes to cancer progression, are poorly understood. Here, using functional genetic screens, we find that lipoprotein uptake confers resistance to lipid peroxidation and ferroptotic cell death. Lipoprotein supplementation robustly inhibits ferroptosis across numerous cancer types. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Tumour GAGs are a major determinant of the uptake of both low and high density lipoproteins. Impairment of glycosaminoglycan synthesis or acute degradation of surface GAGs decreases the uptake of lipoproteins, sensitizes cells to ferroptosis and reduces tumour growth in mice. We also find that human clear cell renal cell carcinomas, a distinctively lipid-rich tumour type, display elevated levels of lipoprotein-derived antioxidants and the GAG chondroitin sulfate than non-malignant human kidney. Altogether, our work identifies lipoprotein uptake as an essential anti-ferroptotic mechanism for cancer cells to overcome lipid oxidative stress in vivo, and reveals GAG biosynthesis as an unexpected mediator of this process.

Stigma in Pediatric Cancer: An Exploratory Study of Osteosarcoma and Retinoblastoma in Guatemala, Jordan, and Zimbabwe.

PURPOSE: Stigma is an understudied barrier to health care acceptance in pediatric oncology. We sought to explore the stigma experience, including its impact on cancer treatment decision making, and identify strategies to mitigate stigma for patients with osteosarcoma and retinoblastoma in Guatemala, Jordan, and Zimbabwe. METHODS: Participants included caregivers, adolescent patients (age 12-19 years), and health care clinicians. A semistructured interview guide based on The Health Stigma and Discrimination Framework (HSDF) was adapted for use at each site. Interviews were conducted in English, Spanish, Arabic, or Shona, audio-recorded, translated, and transcribed. Thematic analysis focused on stigma practices, experiences, outcomes, drivers, mitigators, and interventions. RESULTS: We conducted 56 interviews (28 caregivers, 19 health care clinicians, nine patients; 20 in Guatemala, 21 in Jordan, 15 in Zimbabwe). Major themes were organized into categories used to adapt the HSDF to global pediatric cancer care. Themes were described similarly across all sites, ages, and diagnoses, with specific cultural nuances noted. Pediatric cancer stigma was depicted as an isolating and emotional experience beginning at diagnosis and including internalized and associative stigma. Stigma affected decision making and contributed to negative outcomes including delayed diagnosis, treatment abandonment, regret, and psychosocial fragility. Overcoming stigma led to positive outcomes including resilience, treatment adherence, pride, and advocacy. Identified stigma drivers and mitigators were linked to potential interventions. CONCLUSION: Participants describe a shared stigma experience that transcends geography, cultural context, age, and diagnosis. Stigma manifestations have the potential to impact medical decision making and affect long-term psychological outcomes. Stigma assessment tools and interventions aimed at stigma mitigation including educational initiatives and support groups specific to pediatric cancer should be the focus of future research.

Nanoarchitecture of CaV2.1 channels and GABAB receptors in the mouse hippocampus: Impact of APP/PS1 pathology.

Voltage-gated CaV2.1 (P/Q-type) Ca2+ channels play a crucial role in regulating neurotransmitter release, thus contributing to synaptic plasticity and to processes such as learning and memory. Despite their recognized importance in neural function, there is limited information on their potential involvement in neurodegenerative conditions such as Alzheimer's disease (AD). Here, we aimed to explore the impact of AD pathology on the density and nanoscale compartmentalization of CaV2.1 channels in the hippocampus in association with GABAB receptors. Histoblotting experiments showed that the density of CaV2.1 channel was significantly reduced in the hippocampus of APP/PS1 mice in a laminar-dependent manner. CaV2.1 channel was enriched in the active zone of the axon terminals and was present at a very low density over the surface of dendritic tree of the CA1 pyramidal cells, as shown by quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL). In APP/PS1 mice, the density of CaV2.1 channel in the active zone was significantly reduced in the strata radiatum and lacunosum-moleculare, while it remained unaltered in the stratum oriens. The decline in Cav2.1 channel density was found to be associated with a corresponding impairment in the GABAergic synaptic function, as evidenced by electrophysiological experiments carried out in the hippocampus of APP/PS1 mice. Remarkably, double SDS-FRL showed a co-clustering of CaV2.1 channel and GABAB1 receptor in nanodomains (~40-50 nm) in wild type mice, while in APP/PS1 mice this nanoarchitecture was absent. Together, these findings suggest that the AD pathology-induced reduction in CaV2.1 channel density and CaV2.1-GABAB1 de-clustering may play a role in the synaptic transmission alterations shown in the AD hippocampus. Therefore, uncovering these layer-dependent changes in P/Q calcium currents associated with AD pathology can benefit the development of future strategies for AD management.

Changes in the Liver Transplant Waiting List after Expanding to the 'Up-to-Seven' Criteria for Hepatocellular Carcinoma.

We aimed to assess changes in the composition of the waiting list for liver transplantation (LT) after expanding from Milan to "up-to-seven" criteria in patients with hepatocellular carcinoma (HCC). A consecutive cohort of 255 LT candidates was stratified in a pre-expansion era (2016-2018; n = 149) and a post-expansion era (2019-2021; n = 106). The most frequent indication for LT was HCC in both groups (47.7% vs. 43.4%; p = 0.5). The proportion of patients exceeding the Milan criteria in the explanted liver was nearly doubled after expansion (12.5% vs. 21.1%; p = 0.25). Expanding criteria had no effect in drop-out (12.3% vs. 20.4%; p = 0.23) or microvascular invasion rates (37.8% vs. 38.7%; p = 0.93). The length on the waiting list did not increase after the expansion (172 days [IQR 74-282] vs. 118 days [IQR 67-251]; p = 0.135) and was even shortened in the post-expansion HCC subcohort (181 days [IQR 125-232] vs. 116 days [IQR 74-224]; p = 0.04). Tumor recurrence rates were reduced in the post-expansion cohort (15.4% vs. 0%; p = 0.012). In conclusion, expanding from Milan to up-to-seven criteria for LT in patients with HCC had no meaningful impact on the waiting list length and composition, thus offering the opportunity for the adoption of more liberal policies in the future.