Bhlhe40 Regulates Proliferation and Angiogenesis in Mouse Embryoid Bodies under Hypoxia.

Knowledge of the molecular mechanisms that underlie the regulation of major adaptive responses to an unbalanced oxygen tension is central to understanding tissue homeostasis and disease. Hypoxia-inducible transcription factors (HIFs) coordinate changes in the transcriptome that control these adaptive responses. Here, we focused on the functional role of the transcriptional repressor basic-helix-loop-helix family member e40 (Bhlhe40), which we previously identified in a meta-analysis as one of the most consistently upregulated genes in response to hypoxia across various cell types. We investigated the role of Bhlhe40 in controlling proliferation and angiogenesis using a gene editing strategy in mouse embryonic stem cells (mESCs) that we differentiated in embryoid bodies (EBs). We observed that hypoxia-induced Bhlhe40 expression was compatible with the rapid proliferation of pluripotent mESCs under low oxygen tension. However, in EBs, hypoxia triggered a Bhlhe40-dependent cell cycle arrest in most progenitor cells and endothelial cells within vascular structures. Furthermore, Bhlhe40 knockout increased the basal vascularization of the EBs in normoxia and exacerbated the hypoxia-induced vascularization, supporting a novel role for Bhlhe40 as a negative regulator of blood vessel formation. Our findings implicate Bhlhe40 in mediating key functional adaptive responses to hypoxia, such as proliferation arrest and angiogenesis.

Autonomy-supportive parenting as a moderator of associations between ethnic and racial identity processes and psychological adjustment during college.

OBJECTIVES: The purpose of this study was to test the roles of ethnic and racial identity (ERI) processes and autonomy-supportive parenting on college students' psychological adjustment. METHOD: American college students of color (N = 505) completed questionnaires assessing ERI exploration and commitment, autonomy-supportive parenting, and psychological adjustment (self-esteem, depressive symptoms). Key variables were operationalized as latent constructs, and main and interaction effects were tested using the latent moderated structural equation modeling approach. RESULTS: Higher levels of ERI commitment (but not exploration) and parental autonomy support each uniquely predicted higher levels of self-esteem and lower levels of depressive symptoms. Parental autonomy support moderated associations between ERI processes and psychological adjustment, and the nature of moderation did not differ across Black and Latino/a/x students. CONCLUSIONS: Supporting the psychological adjustment of college students of color necessitates acknowledging the importance of both parental and institutional efforts to encourage students' autonomy strivings and ERI processes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Lance-Adams Syndrome in the Intensive Care Unit: A Case Report.

Lance-Adams syndrome (LAS), or chronic post-hypoxic myoclonus, is a myoclonic disorder following acute cerebral hypoxia after successful cardiopulmonary resuscitation (CPR). LAS is distinct from acute post-hypoxic myoclonus (acute PHM), presenting with myoclonic jerks and cerebellar ataxia after regaining consciousness. However, the overlap at the onset complicates differentiation and may lead to the withdrawal of life-sustaining measures, especially in sedated ICU patients. The presented case involves a 77-year-old male diagnosed with LAS post-CPR. Despite the presence of early myoclonic jerks EEG, laboratory testing, and neuroimaging showed no definitive proof of irreversible neurological damage. Once diagnosed, treatment involved sequential antiseizure medications and physical therapy when the patient achieved full consciousness. However, the patient ultimately faced severe disabilities and was unable to recover. This case report emphasizes the importance of limiting sedation, comprehensive clinical examination, and the use of complementary tests when no definitive proof of irreversible neurological damage is present after acute cerebral hypoxia. While LAS has a better vital prognosis than acute PHM, it is associated with poor neurofunctional recovery and chronic disability in most cases. Further research is essential for evidence-based management.

SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma.

The sterile alpha motif and histidine-aspartate (HD) domain containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara-C) resistance in several haematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara-C efficacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMG-box containing protein 11 (SOX11) as a novel direct binding partner and first known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Co-immunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identified SAMHD1 as the top SOX11 interaction partner which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar affinity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara-C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identified SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its first known endogenous inhibitor with potentially important implications for clinical therapy stratification.

SOX11/PRDX2 axis modulates redox homeostasis and chemoresistance in aggressive mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B-cell neoplasm characterized by an aggressive behavior, short responses to conventional therapies and SOX11 overexpression, which is associated with aggressive disease features and inferior clinical outcome of patients. Oxidative stress is known to induce tumorigenesis and tumor progression, whereas high expression levels of antioxidant genes have been associated with chemoresistance in different cancers. However, the role of oxidative stress in MCL pathogenesis and the involvement of SOX11 regulating redox homeostasis in MCL cells are largely unknown. Here, by integrating gene set enrichment analysis of two independent series of MCL, we observed that SOX11+ MCL had higher reactive oxygen species (ROS) levels compared to SOX11- MCL primary tumors and increased expression of Peredoxine2 (PRDX2), which upregulation significantly correlated with SOX11 overexpression, higher ROS production and worse overall survival of patients. SOX11 knockout (SOX11KO) significantly reduced PRDX2 expression, and SOX11KO and PRDX2 knockdown (PRDX2KD) had increased ROS levels and ROS-mediated tumor cell death upon treatment with drugs, compared to control MCL cell lines. Our results suggest an aberrant redox homeostasis associated with chemoresistance in aggressive MCL through SOX11-mediated PRDX2 upregulation, highlighting PRDX2 as promising target for new therapeutic strategies to overcome chemoresistance in aggressive MCLs.

SOX11 expression is restricted to EBV-negative Burkitt lymphoma and is associated with molecular genetic features.

ABSTRACT: SRY-related HMG-box gene 11 (SOX11) is a transcription factor overexpressed in mantle cell lymphoma (MCL), a subset of Burkitt lymphomas (BL) and precursor lymphoid cell neoplasms but is absent in normal B cells and other B-cell lymphomas. SOX11 has an oncogenic role in MCL but its contribution to BL pathogenesis remains uncertain. Here, we observed that the presence of Epstein-Barr virus (EBV) and SOX11 expression were mutually exclusive in BL. SOX11 expression in EBV-negative (EVB-) BL was associated with an IG∷MYC translocation generated by aberrant class switch recombination, whereas in EBV-negative (EBV-)/SOX11-negative (SOX11-) tumors the IG∷MYC translocation was mediated by mistaken somatic hypermutations. Interestingly, EBV- SOX11-expressing BL showed higher frequency of SMARCA4 and ID3 mutations than EBV-/SOX11- cases. By RNA sequencing, we identified a SOX11-associated gene expression profile, with functional annotations showing partial overlap with the SOX11 transcriptional program of MCL. Contrary to MCL, no differences on cell migration or B-cell receptor signaling were found between SOX11- and SOX11-positive (SOX11+) BL cells. However, SOX11+ BL showed higher adhesion to vascular cell adhesion molecule 1 (VCAM-1) than SOX11- BL cell lines. Here, we demonstrate that EBV- BL comprises 2 subsets of cases based on SOX11 expression. The mutual exclusion of SOX11 and EBV, and the association of SOX11 with a specific genetic landscape suggest a role of SOX11 in the early pathogenesis of BL.

Inhibition of RhoA prevents Cryptococcus neoformans capsule glucuronoxylomannan-stimulated brain endothelial barrier disruption.

Cryptococcus neoformans (Cn) is an opportunistic fungus that causes severe central nervous system (CNS) disease in immunocompromised individuals. Brain parenchyma invasion requires fungal traversal of the blood-brain barrier. In this study, we describe that Cn alters the brain endothelium by activating small GTPase RhoA, causing reorganization of the actin cytoskeleton and tight junction modulation to regulate endothelial barrier permeability. We confirm that the main fungal capsule polysaccharide glucuronoxylomannan is responsible for these alterations. We reveal a therapeutic benefit of RhoA inhibition by CCG-1423 in vivo. RhoA inhibition prolonged survival and reduced fungal burden in a murine model of disseminated cryptococcosis, supporting the therapeutic potential targeting RhoA in the context of cryptococcal infection. We examine the complex virulence of Cn in establishing CNS disease, describing cellular components of the brain endothelium that may serve as molecular targets for future antifungal therapies to alleviate the burden of life-threatening cryptococcal CNS infection.

Clinicopathological and Genomic Identification of Breast Cancers with No Impact on Mortality.

BACKGROUND: Implementing mammogram screening means that clinicians are seeing many breast cancers that will never develop metastases. The purpose of this study was to identify subgroups of breast cancer patients who did not present events related to long-term breast cancer mortality, taking into account diagnosis at breast screening, absence of palpability and axillary involvement, and genomic analysis with PAM50. PATIENTS AND METHODS: To identify them, a retrospective observational study was carried out selecting patients without any palpable tumor and without axillary involvement, and a genomic analysis was performed with PAM50. RESULTS: The probability of distant metastasis-free interval (DMFI) of 337 patients was 0.92 (95% CI, 0.90-0.93) at 20 years and 0.96 (95% CI, 0.92-1.00) in 95 patients (28%) with available PAM50 tests. In 22 (23.15%) luminal A tumors and in 9 (9.47%) luminal B tumors smaller than 1 cm, and in HER2 and basal type tumors, there were no metastatic events (20-year DMFI of 1.00). CONCLUSION: Patients with nonpalpable breast cancer found at screening with negative nodes are at very low risk. It is possible to identify subgroups without metastatic events by determining the intrinsic subtype and tumor size less than 1 cm. Therefore, de-escalation of treatment should be considered.

SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma.

ABSTRACT: Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara-C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara-C efficacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMG-box containing protein 11 (SOX11) as a novel direct binding partner and first known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identified SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar affinity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara-C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identified SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its first known endogenous inhibitor with potentially important implications for clinical therapy stratification.

Predicting survival in patients with 'non-high-risk' acute variceal bleeding receiving ß-blockers+ligation to prevent re-bleeding.

BACKGROUND & AIMS: Pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice for high-risk acute variceal bleeding (AVB; i.e., Child-Turcotte-Pugh [CTP] B8-9+active bleeding/C10-13). Nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation for secondary prophylaxis. We investigated prognostic factors for re-bleeding and mortality in 'non-high-risk' AVB to identify subgroups who may benefit from more potent treatments (i.e., TIPS) to prevent further decompensation and mortality. METHODS: A total of 2,225 adults with cirrhosis and variceal bleeding were prospectively recruited at 34 centres between 2011-2015; for the purpose of this study, case definitions and information on prognostic indicators at index AVB and on day 5 were further refined in low-risk patients, of whom 581 (without failure to control bleeding or contraindications to TIPS) who were managed by non-selective beta-blockers/endoscopic variceal ligation, were finally included. Patients were followed for 1 year. RESULTS: Overall, 90 patients (15%) re-bled and 70 (12%) patients died during follow-up. Using clinical routine data, no meaningful predictors of re-bleeding were identified. However, re-bleeding (included as a time-dependent co-variable) increased mortality, even after accounting for differences in patient characteristics (adjusted cause-specific hazard ratio: 2.57; 95% CI 1.43-4.62; p = 0.002). A nomogram including CTP, creatinine, and sodium measured at baseline accurately (concordance: 0.752) stratified the risk of death. CONCLUSION: The majority of 'non-high-risk' patients with AVB have an excellent prognosis, if treated according to current recommendations. However, about one-fifth of patients, i.e. those with CTP ≥8 and/or high creatinine levels or hyponatremia, have a considerable risk of death within 1 year of the index bleed. Future clinical trials should investigate whether elective TIPS placement reduces mortality in these patients. IMPACT AND IMPLICATIONS: Pre-emptive transjugular intrahepatic portosystemic shunt placement improves outcomes in high-risk acute variceal bleeding; nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation. This is the first large-scale study investigating prognostic factors for re-bleeding and mortality in 'non-high-risk' acute variceal bleeding. While no clinically meaningful predictors were identified for re-bleeding, we developed a nomogram integrating baseline Child-Turcotte-Pugh score, creatinine, and sodium to stratify mortality risk. Our study paves the way for future clinical trials evaluating whether elective transjugular intrahepatic portosystemic shunt placement improves outcomes in presumably 'non-high-risk' patients who are identified as being at increased risk of death.

[Association between reproductive history, breast cancer subtype, and survival in premenopausal women]. / Asociación entre la historia reproductiva, el subtipo de cáncer de mama y la supervivencia de mujeres premenopáusicas.

BACKGROUND AND OBJECTIVE: Reproductive history influences breast cancer risk. We analysed its association with tumour subtype and survival in premenopausal women. PATIENTS AND METHODS: Retrospective, observational study of premenopausal women with stage I-III breast carcinoma in the last 20 years. Review of reproductive history, clinical data, and treatments in health records. RESULTS: In 661 premenopausal women (32.40% of 1377 total cases), median age was 47 years (19-53), menarche 12 (7-17), first delivery 28 (16-41) and number of deliveries 2 (0-9). One hundred and eleven (18.20%) were nulliparous. Three hundred and fifty-nine (58.80%) used natural lactation, with a median duration of 6 months. Anovulatory drugs were used by 271 (44.40%), with a median duration of 36 months. Associations were found between menarche <10 years and lower risk of luminal subtype (OR: 0.52, 95% CI: 0.28-0.94; P=.03), between menarche >11 years and lower risk of HER2 subtype (OR: 0.50, 95% CI: 0.26-0.97; P=.04) and between first birth >30 years and lower risk of triple negative subtype (OR: 0.40, 95% CI: 0.17-0.93; P=.03). The 20-year overall and disease-free survival probabilities were 0.80 (95% CI: 0.71-0.90) and 0.72 (95% CI: 0.64-0.79) respectively. Patients with ≥1 delivery had better overall survival than nulliparous patients (HR: 0.51, 95% CI: 0.27-0.96, P=.04). CONCLUSIONS: The findings suggest an association between age at menarche and age at first delivery and breast cancer subtype. Nulliparity is associated with worse survival.

PDZome-wide and structural characterization of the PDZ-binding motif of VANGL2.

VANGL2 is a core component of the non-canonical Wnt/Planar Cell Polarity signaling pathway that uses its highly conserved carboxy-terminal type 1 PDZ-binding motif (PBM) to bind a variety of PDZ proteins. In this study, we characterize and quantitatively assess the largest VANGL2 PDZome-binding profile documented so far, using orthogonal methods. The results of our holdup approach support VANGL2 interactions with a large panel of both long-recognized and unprecedented PDZ domains. Truncation and point mutation analyses of the VANGL2 PBM establish that, beyond the strict requirement of the P-0 / V521 and P-2 / T519 amino acids, upstream residues, including E518, Q516 and R514 at, respectively, P-3, P-5 and P-7 further contribute to the robustness of VANGL2 interactions with two distinct PDZ domains, SNX27 and SCRIBBLE-PDZ3. In agreement with these data, incremental amino-terminal deletions of the VANGL2 PBM causes its overall affinity to progressively decline. Moreover, the holdup data establish that the PDZome binding repertoire of VANGL2 starts to diverge significantly with the truncation of E518. A structural analysis of the SYNJ2BP-PDZ/VANGL2 interaction with truncated PBMs identifies a major conformational change in the binding direction of the PBM peptide after the P-2 position. Finally, we report that the PDZome binding profile of VANGL2 is dramatically rearranged upon phosphorylation of S517, T519 and S520. Our crystallographic approach illustrates how SYNJ2BP accommodates a S520-phosphorylated PBM peptide through the ideal positioning of two basic residues, K48 and R86. Altogether our data provides a comprehensive view of the VANGL2 PDZ network and how this network specifically responds to the post-translation modification of distinct PBM residues. These findings should prove useful in guiding future functional and molecular studies of the key PCP component VANGL2.

Upregulation in Inflammation and Collagen Expression in Perirenal but Not in Mesenteric Adipose Tissue from Diabetic Munich Wistar Frömter Rats.

Perirenal adipose tissue (PRAT) surrounding the kidney is emerging as a player and novel independent risk factor in diabetic kidney disease (DKD); DKD is a complication of diabetes and is a major cause of increased cardiovascular (CV) risk and CV mortality in affected patients. We determined the effect of diabetes induction on (i) kidney and CV damage and (ii) on the expression of proinflammatory and profibrotic factors in both the PRAT and the mesenteric adipose tissue (MAT) of Munich Wistar Frömter (MWF) rats. The 16-week-old male MWF rats (n = 10 rats/group) were fed standard chow (MWF-C) or a high-fat/high-sucrose diet for 6 weeks together with low-dose streptozotocin (15 mg/kg i.p.) at the start of dietary exposure (MWF-D). Phenotyping was performed at the end of treatment through determining water intake, urine excretion, and oral glucose tolerance; use of the homeostatic model assessment-insulin resistance index (HOMA-IR) evidenced the development of overt diabetes manifestation in MWF-D rats. The kidney damage markers Kim-1 and Ngal were significantly higher in MWF-D rats, as were the amounts of PRAT and MAT. A diabetes-induced upregulation in IL-1, IL-6, Tnf-α, and Tgf-ß was observed in both the PRAT and the MAT. Col1A1 was increased in the PRAT but not in the MAT of MWF-D, whereas IL-10 was lower and higher in the PRAT and the MAT, respectively. Urinary albumin excretion and blood pressure were not further increased by diabetes induction, while heart weight was higher in the MWF-D. In conclusion, our results show a proinflammatory and profibrotic in vivo environment in PRAT induced by diabetes which might be associated with kidney damage progression in the MWF strain.

Innovative and potential treatments for fungal central nervous system infections.

Fungal infections of the central nervous system (FI-CNS) are a problematic and important medical challenge considering that those most affected are immunocompromised. Individuals with systemic cryptococcosis (67-84%), candidiasis (3-64%), blastomycosis (40%), coccidioidomycosis (25%), histoplasmosis (5-20%), mucormycosis (12%), and aspergillosis (4-6%) are highly susceptible to develop CNS involvement, which often results in high mortality (15-100%) depending on the mycosis and the affected immunosuppressed population. Current antifungal drugs are limited, prone to resistance, present host toxicity, and show reduced brain penetration, making FI-CNS very difficult to treat. Given these limitations and the rise in FI-CNS, there is a need for innovative strategies for therapeutic development and treatments to manage FI-CNS in at-risk populations. Here, we discuss standards of care, antifungal drug candidates, and novel molecular targets in the blood-brain barrier, which is a protective structure that regulates movement of particles in and out of the brain, to prevent and combat FI-CNS.

Dietary proteins modulate high-density lipoprotein characteristics in a sex-specific way in Apoe-deficient mice.

OBJECTIVES: The type and amount of dietary protein have become a topic of renewed interest, considering their involvement in several diseases. However, little attention has been devoted to the effect of avian proteins despite their wide human consumption. In a previous study, we saw that compared with soybean protein, the consumption of avian proteins, depending on sex, resulted in similar or lower atherosclerosis with a higher paraoxonase 1 activity, an antioxidant enzyme carried by high-density lipoproteins (HDL). This suggests that under these conditions, the HDL lipoproteins may undergo important changes. The aim of this research was to study the influence of soybean, chicken, and turkey proteins on the characteristics of HDL. METHODS: Male and female Apoe-deficient mice were fed purified Western diets based on the AIN-93 diet, differing only in the protein source, for 12 wk. After this period, blood and liver samples were taken for analysis of HDL composition and hepatic expression of genes related to HDL metabolism (Abca1, Lcat, Pltp, Pon1, and Scarb1). Depending on sex, these genes define a different network of interactions. Females consuming the turkey protein-containing diet showed decreased atherosclerotic foci, which can be due to larger very-low-density lipoproteins (VLDLs) calculated by molar ratio triacylglycerols/VLDL cholesterol and higher expression of Lcat. In contrast, in males, a higher ratio of paraoxonase1 to apolipoprotein A1 decreased the oxidative status of the different lipoproteins, and augmented Abca1 expression was observed. CONCLUSIONS: The source of protein has an effect on the development of atherosclerosis depending on sex by modifying HDL characteristics and the expression of genes involved in their properties.

Frequency of symptoms and the associated factors of eating disorders in a group of dental students in Medellín, Colombia.

BACKGROUND: Eating disorders (EDs) are considered a public health problem. Scientific research has focused on teenagers due to their higher prevalence in this population. However, other groups, such as university students, may be exposed to suffering from EDs due to their academic, social and personal characteristics. Identifying the magnitude of EDs and the associated characteristics may impact the generation of prevention strategies. OBJECTIVES: The aim of the present study was to establish the prevalence of the risk of EDs (anorexia nervosa (AN) and bulimia nervosa (BN)) and the associated factors in dental students at the University of Antioquia, Medellín, Colombia.. MATERIAL AND METHODS: A cross-sectional study was conducted on 278 students (76 males, 202 females) with the use of a Google-Forms survey. The validated Spanish version of the Eating Attitudes Test-26 (EAT-26) and the Sick, Control, One Stone, Fat, Food (SCOFF) questionnaire were used. Other recorded variables included sociodemographic data, coronavirus disease 2019 (COVID-19)-related factors, health, and social support (the Duke-11 profile). The bivariate analysis of the risk of EDs was conducted according to different variables (95% confidence interval (CI)), followed by the logistic regression models adjusting for different variables (adjusted prevalence ratio (aPR) and 95% CI). RESULTS: According to EAT-26, the risk of EDs was 27.6% (18.8-38.6) for males and 28.7% (22.9-35.3) for females. However, differences between males and females were higher when the SCOFF questionnaire was applied (males: 6.6% (2.8-14.5); females: 22.3% (17.1-28.5); p < 0.01). According to the SCOFF instrument, after adjusting for sociodemographic and health variables, women were more likely to report the symptoms of EDs (aPR: 2.20; 95% CI: 1.06-4.57). Women receiving information from social networks were more likely to report the symptoms of EDs (aPR: 1.85; 95% CI: 1.19-2.88). Multivariate models showed that women reporting poor self-rated health and some symptoms during the mandatory confinement caused by the COVID-19 pandemic were more likely to report the symptoms of EDs. CONCLUSIONS: A higher risk of EDs was found in dental students. Healthcare, psychological and/or psychiatric interviews, and educational/early prevention strategies are required.

Palmitoylethanolamide shows limited efficacy in controlling cerebral cryptococcosis in vivo.

Cryptococcus neoformans (Cn) is an encapsulated neurotropic fungal pathogen and the causative agent of cryptococcal meningoencephalitis (CME) in humans. Recommended treatment for CME is Amphotericin B (AmpB) and 5-fluorocytosine (5-FC). Though effective, AmpB has displayed numerous adverse side effects due to its potency and nephrotoxicity, prompting investigation into alternative treatments. Palmitoylethanolamide (PEA) is an immunomodulatory compound capable of promoting neuroprotection and reducing inflammation. To investigate the efficacy of PEA as a therapeutic alternative for CME, we intracerebrally infected mice with Cn and treated them with PEA or AmpB alone or in combination. Our results demonstrate that PEA alone does not significantly prolong survival nor reduce fungal burden, but when combined with AmpB, PEA exerts an additive effect and promotes both survivability and fungal clearance. However, we compared this combination to traditional AmpB and 5-FC treatment in a survivability study and observed lower efficacy. Overall, our study revealed that PEA alone is not effective as an antifungal agent in the treatment of CME. Importantly, we describe the therapeutic capability of PEA in the context of Cn infection and show that its immunomodulatory properties may confer limited protection when combined with an effective fungicidal agent.

Short-term dietary intervention improves endothelial dysfunction induced by high-fat feeding in mice through upregulation of the AMPK-CREB signaling pathway.

AIM: In addition to functioning as an energy sensor switch, AMPK plays a key role in the maintenance of cardiovascular homeostasis. However, obesity disrupts AMPK signaling, contributing to endothelial dysfunction and cardiovascular disease. This study aimed to elucidate if a short-term dietary intervention consisting in replacing the high-fat diet with a standard diet for 2 weeks could reverse obesity-induced endothelial dysfunction via AMPK-CREB activation. METHODS: For this, 5-week-old male C57BL6J mice were fed a standard (Chow) or a high-fat (HF) diet for 8 weeks. The HF diet was replaced by the chow diet for the last 2 weeks in half of HF mice, generating 3 groups: Chow, HF and HF-Chow. Vascular reactivity and western-blot assays were performed in the thoracic aorta. RESULTS: Returning to a chow diet significantly reduced body weight and glucose intolerance. Relaxant responses to acetylcholine and the AMPK activator (AICAR) were significantly impaired in HF mice but improved in HF-Chow mice. The protein levels of AMPKα, p-CREB and antioxidant systems (heme oxygenase-1 (HO-1) and catalase) were significantly reduced in HF but normalized in HF-Chow mice. CONCLUSION: Improving dietary intake by replacing a HF diet with a standard diet improves AMPK-mediated responses due to the upregulation of the AMPK/CREB/HO-1 signaling pathway.