Cannabinoids induce cell death in leukaemic cells through Parthanatos and PARP-related metabolic disruptions.

BACKGROUND: Several studies have described a potential anti-tumour effect of cannabinoids (CNB). CNB receptor 2 (CB2) is mostly present in hematopoietic stem cells (HSC). The present study evaluates the anti-leukaemic effect of CNB. METHODS: Cell lines and primary cells from acute myeloid leukaemia (AML) patients were used and the effect of the CNB derivative WIN-55 was evaluated in vitro, ex vivo and in vivo. RESULTS: We demonstrate a potent antileukemic effect of WIN-55 which is abolished with CB antagonists. WIN-treated mice, xenografted with AML cells, had better survival as compared to vehicle or cytarabine. DNA damage-related genes were affected upon exposure to WIN. Co-incubation with the PARP inhibitor Olaparib prevented WIN-induced cell death, suggesting PARP-mediated apoptosis which was further confirmed with the translocation of AIF to the nucleus observed in WIN-treated cells. Nicotinamide prevented WIN-related apoptosis, indicating NAD+ depletion. Finally, WIN altered glycolytic enzymes levels as well as the activity of G6PDH. These effects are reversed through PARP1 inhibition. CONCLUSIONS: WIN-55 exerts an antileukemic effect through Parthanatos, leading to translocation of AIF to the nucleus and depletion of NAD+, which are reversed through PARP1 inhibition. It also induces metabolic disruptions. These effects are not observed in normal HSC.

Energy-Efficient Edge and Cloud Image Classification with Multi-Reservoir Echo State Network and Data Processing Units.

In an era dominated by Internet of Things (IoT) devices, software-as-a-service (SaaS) platforms, and rapid advances in cloud and edge computing, the demand for efficient and lightweight models suitable for resource-constrained devices such as data processing units (DPUs) has surged. Traditional deep learning models, such as convolutional neural networks (CNNs), pose significant computational and memory challenges, limiting their use in resource-constrained environments. Echo State Networks (ESNs), based on reservoir computing principles, offer a promising alternative with reduced computational complexity and shorter training times. This study explores the applicability of ESN-based architectures in image classification and weather forecasting tasks, using benchmarks such as the MNIST, FashionMnist, and CloudCast datasets. Through comprehensive evaluations, the Multi-Reservoir ESN (MRESN) architecture emerges as a standout performer, demonstrating its potential for deployment on DPUs or home stations. In exploiting the dynamic adaptability of MRESN to changing input signals, such as weather forecasts, continuous on-device training becomes feasible, eliminating the need for static pre-trained models. Our results highlight the importance of lightweight models such as MRESN in cloud and edge computing applications where efficiency and sustainability are paramount. This study contributes to the advancement of efficient computing practices by providing novel insights into the performance and versatility of MRESN architectures. By facilitating the adoption of lightweight models in resource-constrained environments, our research provides a viable alternative for improved efficiency and scalability in modern computing paradigms.

P1 of Sweet Potato Feathery Mottle Virus Shows Strong Adaptation Capacity, Replacing P1-HCPro in a Chimeric Plum Pox Virus.

Potyviridae is the largest family of plant RNA viruses. Their genomes are expressed through long polyproteins that are usually headed by the leader endopeptidase P1. This protein can be classified as type A or type B based on host proteolytic requirements and RNA silencing suppression (RSS) capacity. The main Potyviridae genus is Potyvirus, and a group of potyviruses infecting sweet potato presents an enlarged P1 protein with a polymerase slippage motif that produces an extra product termed P1N-PISPO. These two proteins display some RSS activity and are expressed followed by HCPro, which appears to be the main RNA silencing suppressor in these viruses. Here, we studied the behavior of the P1 protein of Sweet potato feathery mottle virus (SPFMV) using a viral system based on a canonical potyvirus, Plum pox virus (PPV), and discovered that this protein is able to replace both PPV P1 and HCPro. We also found that P1N-PISPO, produced after polymerase slippage, provides extra RNA silencing suppression capacity to SPFMV P1 in this viral context. In addition, the results showed that presence of two type A P1 proteins was detrimental for viral viability. The ample recombination spectrum that we found in the recovered viruses supports the strong adaptation capacity of P1 proteins and signals the N-terminal part of SPFMV P1 as essential for RSS activity. Further analyses provided data to add extra layers to the evolutionary history of sweet potato-infecting potyvirids. IMPORTANCE Plant viruses represent a major challenge for agriculture worldwide and Potyviridae, being the largest family of plant RNA viruses, is one of the primary players. P1, the leader endopeptidase, is a multifunctional protein that contributes to the successful spread of these viruses over a wide host range. Understanding how P1 proteins work, their dynamic interplay during viral infection, and their evolutionary path is critical for the development of strategic tools to fight the multiple diseases these viruses cause. We focused our efforts on the P1 protein of Sweet potato feathery mottle virus, which is coresponsible for the most devastating disease in sweet potato. The significance of our research is in understanding the capacity of this protein to perform several independent functions, using this knowledge to learn more about P1 proteins in general and the potyvirids infecting this host.

Synthesis and characterization ofα-Fe2O3nanoparticles showing potential applications for sensing quaternary ammonium vapor at room temperature.

P-type and n-type metal oxide semiconductors are widely used in the manufacture of gas sensing materials, due to their excellent electronic, electrical and electrocatalytic properties. Hematite (α-Fe2O3) compound has been reported as a promising material for sensing broad types of gases, due to its affordability, good stability and semiconducting properties. In the present work, the efficient and easy-to-implement sol-gel method has been used to synthesizeα-Fe2O3nanoparticles (NPs). The TGA-DSC characterizations of the precursor gel provided information about the phase transformation temperature and the mass percentage of the hematite NPs. X-ray diffraction, transmission electron microscopy and x-ray photoelectron spectroscopy data analyses indicated the formation of two iron oxide phases (hematite and magnetite) when the NPs are subjected to thermal treatment at 400 °C. Meanwhile, only the hematite phase was determined for thermal annealing above 500 °C up to 800 °C. Besides, the crystallite size shows an increasing trend with the thermal annealing and no defined morphology. A clear reduction of surface defects, associated with oxygen vacancies was also evidenced when the annealing temperature was increased, resulting in changes on the electrical properties of hematite NPs. Resistive gas-sensing tests were carried out using hematite NPs + glycerin paste, to detect quaternary ammonium compounds. Room-temperature high sensitivity values (Sr âˆ¼ 4) have been obtained during the detection of ∼1 mM quaternary ammonium compounds vapor. The dependence of the sensitivity on the particle size, the mass ratio of NPs with respect to the organic ligand, changes in the dielectric properties, and the electrical conduction mechanism of gas sensing was discussed.

A state level analyses of suicide and the COVID-19 pandemic in Mexico.

BACKGROUND: While suicide rates in high- and middle-income countries appeared stable in the early stages of the pandemic, we know little about within-country variations. We sought to investigate the impact of COVID-19 on suicide in Mexico's 32 states and to identify factors that may have contributed to observed variations between states. METHODS: Interrupted time-series analysis to model the trend in monthly suicides before COVID-19 (from Jan 1, 2010, to March 31, 2020), comparing the expected number of suicides derived from the model with the observed number for the remainder of the year (April 1 to December 31, 2020) for each of Mexico's 32 states. Next, we modeled state-level trends using linear regression to study likely contributing factors at ecological level. RESULTS: Suicide increased slightly across Mexico during the first nine months of the pandemic (RR 1.03; 95%CI 1.01-1.05). Suicides remained stable in 19 states, increase in seven states (RR range: 1.12-2.04) and a decrease in six states (RR range: 0.46-0.88). Suicide RR at the state level was positively associated with population density in 2020 and state level suicide death rate in 2019. CONCLUSIONS: The COVID-19 pandemic had a differential effect on suicide death within the 32 states of Mexico. Higher population density and higher suicide rates in 2019 were associated with increased suicide. As the country struggles to cope with the ongoing pandemic, efforts to improve access to primary care and mental health care services (including suicide crisis intervention services) in these settings should be given priority.

Polymorphisms in eicosanoid-related biosynthesis enzymes associated with acute urticaria/angioedema induced by nonsteroidal anti-inflammatory drug hypersensitivity.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity, with NSAID-induced acute urticaria/angioedema (NIUA) the most frequent phenotype. NSAID hypersensitivity is caused by cyclooxygenase 1 inhibition, which leads to an imbalance in prostaglandin (PG) and cysteinyl leukotriene (CysLT) synthesis. As only susceptible individuals develop NSAID hypersensitivity, genetic factors are believed to be involved; however, no study has assessed the overall genetic variability of key enzymes in PG and CysLT synthesis in NSAID hypersensitivity. OBJECTIVES: To evaluate simultaneously variants in the main genes involved in PG and CysLT biosynthesis in NIUA. METHODS: Two independent cohorts of patients were recruited in Spain, alongside NSAID-tolerant controls. The discovery cohort included only patients with NIUA; the replication cohort included patients with NSAID-exacerbated respiratory disease (NERD). A set of tagging single-nucleotide polymorphisms (tagSNPs) in PTGS1, PTGS2, ALOX5 and LTC4S was genotyped using mass spectrometry coupled with endpoint polymerase chain reaction. RESULTS: The study included 1272 individuals. Thirty-five tagSNPs were successfully genotyped in the discovery cohort, with three being significantly associated after Bonferroni correction (rs10306194 and rs1330344 in PTGS1; rs28395868 in ALOX5). These polymorphisms were genotyped in the replication cohort: rs10306194 and rs28395868 remained associated with NIUA, and rs28395868 was marginally associated with NERD. Odds ratios (ORs) in the combined analysis (discovery and replication NIUA populations) were 1·7 for rs10306194 [95% confidence interval (CI) 1·34-2·14; Pcorrected = 2·83 × 10-4 ) and 2·19 for rs28395868 (95% CI 1·43-3·36; Pcorrected = 0·002). CONCLUSIONS: Variants of PTGS1 and ALOX5 may play a role in NIUA and NERD, supporting the proposed mechanisms of NSAID-hypersensitivity and shedding light on their genetic basis.

Urban green spaces and childhood leukemia incidence: A population-based case-control study in Madrid.

BACKGROUND: Childhood leukemia is the most common childhood cancer. To date, few risk factors related to predisposition have been identified; therefore, new hypotheses should be considered. OBJECTIVE: To explore the possible relationship of residential proximity to urban green spaces on childhood leukemia. METHODS: We conducted a population-based case control study in the metropolitan area of Madrid from 2000 to 2015. It included 383 incident cases and 1935 controls, individually matched by birth year, sex and area of residence. Using the geographical coordinates of the participants' home residences, we built a proxy for exposure with four distances (250 m, 500 m, 750 m and 1 km) to urban parks (UPs) and urban wooded areas (UWAs). We employed logistic regression models to determinate the effect of them on childhood leukemia adjusting for environmental and socio-demographic covariates. RESULTS: we found a reduction in childhood leukemia incidence at a distance of 250 m from UPs (OR = 0.78; 95%CI = 0.62-0.98), as well as a reduction of the incidence in the Q3 and Q4 quintiles for exposure to UWAs, in the 250 m and 500 m buffers respectively (Q3 (250 m): OR = 0.69; 95%CI = 0.48-1.00; and, Q4 (500 m): OR = 0.69; 95%CI = 0.48-0.99). CONCLUSIONS: Our results suggest a possible association between lower incidence of childhood leukemia and proximity to different forms of urban green space. This study is a first approach to the possible urban green space effects on childhood leukemia so is necessary to continue studying this spaces taking into account more individual data and other environmental risk factors.

Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure.

BACKGROUND: Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11ß-hydroxysteroid dehydrogenase-2 (11ß-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences. PATIENTS AND METHODS: Human kidney tissues were stained for AR and 11ß-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median. RESULTS: Concurrent AR and 11ß-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. CONCLUSION: Enzalutamide and apalutamide treatment toggles renal 11ß-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

Promoter Genotyping and mRNA Expression - Based Analysis of the PTGDR Gene in Allergy.

BACKGROUND AND OBJECTIVE: Prostaglandin D2 receptors are acquiring a relevant role as potential therapeutic targets in allergy. PTGDR has been described as a candidate gene in allergic disease, although functional studies on this gene are lacking. Objective: The objective of this case-control study was to investigate the potential role of PTGDR in allergy. METHODS: The study population comprised 195 allergic patients and 112 healthy controls. The PTGDR promoter polymorphisms -1289G>A, -1122T>C, -881C>T, -834C>T, -613C>T, -549T>C, -441C>T, -197T>C, and -95G>T were amplified by polymerase chain reaction (PCR) and sequenced. PTGDR expression levels were analyzed using quantitative PCR and normalized to GAPDH and TBP mRNA levels. All procedures were performed following the Minimum Information for Publication of Quantitative Real-Time PCR Experiment guidelines. RESULTS: PTGDR expression levels were significantly higher in allergic patients than in controls (P<.001). Receiver operating characteristic analysis for expression of PTGDR showed a sensitivity of 81.4% compared with 67% for IgE levels. In addition, differences in the genotypic distribution of the polymorphisms -1289G>A and -1122T>C were found in allergic patients (P=.009). CONCLUSIONS: The results indicate that PTGDR overexpression is associated with allergy. The polymorphisms -1289G>A and -1122T>C partly explain the variation in expression we observed. PTGDR expression could have a potential role as a biomarker and pharmacogenetic factor in allergy.

Oral lesions in patients with primary Sjögren's syndrome. A case-control cross-sectional study.

BACKGROUND: To evaluate the presence of oral lesions in a group of patients with primary Sjögren's syndrome (pSS) and compare these results with a matched control group (CG). MATERIAL AND METHODS: An observational cross-sectional study was conducted. 61 pSS patients (60 women, 1 man, mean age 57.64±13.52) diagnosed according to the American European Criteria (2002), and 122 matched control patients (120 women, 2 men, mean age 60.02±13.13) were included. Demographic and medical data, oral lesions and salivary flow rate were collected. RESULTS: Compared with the controls, pSS patients were 3.95 more likely to have oral lesions (OR 3.95; 95% CI 2.06-7.58; p=0.0001). 57.4% pSS patients presented oral lesions compared to 25.4% in CG. The most common were candidiasis (13.1% vs 2.5%), traumatic lesions (13.1% vs 4.1%), apthae (8.2% vs 0), and fissuration of the tongue (8.2% vs 0.8%). pSS patients with oral lesions had lower salivary flow levels (stimulated and unstimulated), although these differences were not significant. Significant associations were found between the presence of oral lesions and systemic manifestations and history of parotid gland enlargement in pSS patients. CONCLUSION: pSS patients suffer more oral lesions than general population and these lesions may aggravate the pSS disease.