Ned-19 inhibition of parasite growth and multiplication suggests a role for NAADP mediated signalling in the asexual development of plasmodium falciparum

BACKGROUND: Although malaria is a preventable and curable human disease, millions of people risk to be infected by the Plasmodium parasites and to develop this illness. Therefore, there is an urgent need to identify new anti-malarial drugs. Ca2+ signalling regulates different processes in the life cycle of Plasmodium falciparum, representing a suitable target for the development of new drugs. RESULTS: This study investigated for the first time the effect of a highly specific inhibitor of nicotinic acid adenine dinucleotide phosphate (NAADP)-induced Ca2+ release (Ned-19) on P. falciparum, revealing the inhibitory effect of this compound on the blood stage development of this parasite. Ned-19 inhibits both the transition of the parasite from the early to the late trophozoite stage and the ability of the late trophozoite to develop to the multinucleated schizont stage. In addition, Ned-19 affects spontaneous intracellular Ca2+ oscillations in ring and trophozoite stage parasites, suggesting that the observed inhibitory effects may be associated to regulation of intracellular Ca2+ levels. CONCLUSIONS: This study highlights the inhibitory effect of Ned-19 on progression of the asexual life cycle of P. falciparum. The observation that Ned-19 inhibits spontaneous Ca2+ oscillations suggests a potential role of NAADP in regulating Ca2+ signalling of P. falciparum

Cadmium exposure and cardiovascular disease risk: A systematic review and dose-response meta-analysis

: Exposure to toxic metals is a global public health threat. Among other adverse effects, exposure to the heavy metal cadmium has been associated with greater risk of cardiovascular disease (CVD). Nonetheless, the shape of the association between cadmium exposure and CVD risk is not clear. This systematic review summarizes data on the association between cadmium exposure and risk of CVD using a dose-response approach. We carried out a literature search in PubMed, Web of Science, and Embase from inception to December 30, 2023. Inclusion criteria were: studies on adult populations, assessment of cadmium exposure, risk of overall CVD and main CVD subgroups as endpoints, and observational study design (cohort, cross-sectional, or case-control). We retrieved 26 eligible studies published during 2005-2023, measuring cadmium exposure mainly in urine and whole blood. In a dose-response meta-analysis using the one-stage method within a random-effects model, we observed a positive association between cadmium exposure and risk of overall CVD. When using whole blood cadmium as a biomarker, the association with overall CVD risk was linear, yielding a risk ratio (RR) of 2.58 (95 % confidence interval-CI 1.78-3.74) at 1 μg/L. When using urinary cadmium as a biomarker, the association was linear until 0.5 μg/g creatinine (RR = 2.79, 95 % CI 1.26-6.16), after which risk plateaued. We found similar patterns of association of cadmium exposure with overall CVD mortality and risks of heart failure, coronary heart disease, and overall stroke, whereas for ischemic stroke there was a positive association with mortality only. Overall, our results suggest that cadmium exposure, whether measured in urine or whole blood, is associated with increased CVD risk, further highlighting the importance of reducing environmental pollution from this heavy metal

Commitment of Autologous Human Multipotent Stem Cells on Biomimetic Poly-L-lactic Acid-Based Scaffolds Is Strongly Influenced by Structure and Concentration of Carbon Nanomaterial

Nanocomposite scaffolds combining carbon nanomaterials (CNMs) with a biocompatible matrix are able to favor the neuronal differentiation and growth of a number of cell types, because they mimic neural-tissue nanotopography and/or conductivity. We performed comparative analysis of biomimetic scaffolds with poly-L-lactic acid (PLLA) matrix and three different p-methoxyphenyl functionalized carbon nanofillers, namely, carbon nanotubes (CNTs), carbon nanohorns (CNHs), and reduced graphene oxide (RGO), dispersed at varying concentrations. qRT-PCR analysis of the modulation of neuronal markers in human circulating multipotent cells cultured on nanocomposite scaffolds showed high variability in their expression patterns depending on the scaffolds\u2019 inhomogeneities. Local stimuli variation could result in a multi- to oligopotency shift and commitment towards multiple cell lineages, which was assessed by the qRT-PCR profiling of markers for neural, adipogenic, and myogenic cell lineages. Less conductive scaffolds, i.e., bare poly-L-lactic acid (PLLA)-, CNH-, and RGO-based nanocomposites, appeared to boost the expression of myogenic-lineage marker genes. Moreover, scaffolds are much more effective on early commitment than in subsequent differentiation. This work suggests that biomimetic PLLA carbon-nanomaterial (PLLA-CNM) scaffolds combined with multipotent autologous cells can represent a powerful tool in the regenerative medicine of multiple tissue types, opening the route to next analyses with specific and standardized scaffold features

Influence of dietary patterns on urinary excretion of cadmium in an Italian population: A cross-sectional study

Introduction: Cadmium is a toxic heavy metal with detrimental effects on human health. Apart from smoking and occupational factors, diet is the main source of cadmium. However, the relation between adherence to so-called "healthy" dietary patterns and cadmium exposure has not been investigated in detail. In this study, we aimed at assessing such association in a Northern Italian population. Methods: Using a cross-sectional study design, we investigated a population of non-smokers aged 30-60 years in the period 2017-2019. Each subject completed a validated food frequency questionnaire (FFQ) in order to estimate adherence to four dietary patterns, namely the Dietary Approach to Stopping Hypertension-DASH diet, Greek Mediterranean Index-GMI, the Italian Mediterranean Index-IMI, and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. We collected a fasting morning urinary sample to measure urinary levels of cadmium and cotinine. The association between increasing adherence to dietary patterns and cadmium exposure was evaluated using a cubic spline regression non-linear model and adjusting for relevant confounders (age, sex, body mass index, urinary cotinine levels, intake of fiber, and alcohol). Results: We recruited 137 participants (males/females: 62/75) with median (interquartile range-IQR) age of 47 (IQR: 43-53) years. Median scores for the investigated dietary patterns were 24 (IQR: 21-28), 4 (IQR: 3-6), 4 (IQR: 3-5), and 7.5 (IQR: 6.5-8.5) for DASH, GMI, IMI and MIND diets, respectively. The median urinary cadmium level was 0.21 μg/L (IQR: 0.11-0.34 μg/L). Spline regression analysis showed an inverse linear association between increasing adherence to the DASH and MIND diets and urinary cadmium levels, reaching a plateau at high adherence scores, approximately > 25 and > 9 for DASH and MIND diets, respectively. An increase of cadmium exposure with increasing MIND score also emerged. Conversely, the association was almost null for IMI, and slightly positive for GMI. Conclusions: The present findings suggest that increasing adherence to the DASH and MIND diets are associated with decreased cadmium levels only at moderate level. Overall, these results indicate that public health strategies, including the decrease of cadmium contamination in healthy foods should be implemented

Immunoevolution of mouse pancreatic organoid isografts from preinvasive to metastatic disease

Pancreatic ductal adenocarcinoma (PDA) has a highly immunosuppressive microenvironment, which is contributed by the complex interaction between cancer cells and a heterogeneous population of stromal cells. Therefore, facile and trackable models are needed for integrative and dynamic interrogation of cancer-stroma interaction. Here, we tracked the immunoevolution of PDA in a genetically-defined transplantable model of mouse pancreatic tumour organoids that recapitulates the progression of the disease from early preinvasive lesions to metastatic carcinomas. We demonstrated that organoid-derived isografts (ODI) can be used as a biological source of biomarkers (NT5E, TGFB1, FN1, and ITGA5) of aggressive molecular subtypes of human PDA. In ODI, infiltration from leukocytes is an early event during progression of the disease as observed for autochthonous models. Neoplastic progression was associated to accumulation of Maf+ macrophages, which inversely correlated with CD8+ T cells infiltration. Consistently, levels of MAF were enriched in human PDA subtypes characterized by abundance of macrophage-related transcripts and indicated poor patients' survival. Density of MAF+ macrophages was higher in human PDA tissues compared to preinvasive lesions. Our results suggest that ODIs represent a suitable system for genotypic-immunophenotypic studies and support the hypothesis of MAF+ macrophages as a prominent immunosuppressive population in PDA

Environmental and Occupational Risk Factors of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study

Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with still unknown etiology. We aimed at investigating the association between environmental and occupational factors with ALS risk. Methods: We performed a population-based case-control study in four Italian provinces (Catania, Modena, Novara, and Reggio Emilia) by administration of tailored questionnaires to ALS cases (n = 95) and randomly selected population referents (n = 135). We estimated ALS risk by calculating the odds ratio (OR) with its 95% confidence interval (CI) using an unconditional logistic regression model. Results: We found a positive association with disease risk for history of occupation in the agricultural sector (OR = 2.09, 95% CI 0.79-7.54), especially for longer than 10 years (OR = 2.72, 95% 1.02-7.20). Overall occupational exposure to solvents also suggested a positive association, especially for thinners (OR = 2.27, 95% CI 1.14-4.54) and paint removers (OR = 2.01, 95% CI 0.90-4.48). Both occupational and environmental exposure to electromagnetic fields show a slightly increased risk with OR = 1.69 (95% CI 0.70-4.09) and 2.41 (95% CI 1.13-5.12), respectively. Occupational but not environmental exposure to pesticides (OR = 1.22, 95% CI 0.63-2.37), particularly fungicides, and exposure to metals (OR = 4.20, 95% CI 1.88-9.38), particularly lead, mercury, and selenium, showed an imprecise but positive association. Finally, there was an indication of increased risk for living in proximity to water bodies. Conclusions: Despite the caution that needs to be used due to some study limitations, such as the low number of exposed subjects and the possibility of recall bias, these results suggest the potential role of some environmental and occupational factors in ALS etiology

Clinical and Lifestyle Factors and Risk of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study

Background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease of the motor neurons. The etiology of ALS remains largely unknown, particularly with reference to the potential environmental determinants. Methods: We performed a population-based case-control study in four provinces from both Northern and Southern Italy in order to assess non-genetic ALS risk factors by collecting through tailored questionnaires information about clinical and lifestyle factors. We estimated ALS risk by calculating odds ratio (OR) with its 95% confidence interval (CI) using unconditional logistic regression models adjusted for sex, age and educational attainment. Results: We recruited 230 participants (95 cases and 135 controls). We found a possible positive association of ALS risk with trauma, particularly head trauma (OR = 2.61, 95% CI 1.19-5.72), electric shock (OR = 2.09, 95% CI 0.62-7.06), and some sports, although at a competitive level only. In addition, our results suggest an increased risk for subjects reporting use of private wells for drinking water (OR = 1.38, 95% CI 0.73-2.27) and for use of herbicides during gardening (OR = 1.95, 95% CI 0.88-2.27). Conversely, there was a suggestion of an inverse association with overall fish consumption (OR = 0.27, 95% CI 0.12-0.60), but with no dose-response relation. Consumption of some dietary supplements, namely those containing amino acids and, in the Southern Italy population, vitamins and minerals such as selenium, seemed associated with a statistically imprecise increased risk. Conclusions: Our results suggest a potential etiologic role a number of clinical and lifestyle factors with ALS risk. However, caution is needed due to some study limitations. These include the small sample size and the low number of exposed subjects, which affect statistical precision of risk estimates, the potential for exposure misclassification, and the uncertainties about mechanisms underpinning the possible association between these factors and disease risk

Optical and Electronic NOx Sensors for Applications in Mechatronics

Current production and emerging NOx sensors based on optical and nanomaterials technologies are reviewed. In view of their potential applications in mechatronics, we compared the performance of: i) Quantum cascade lasers (QCL) based photoacoustic (PA) systems; ii) gold nanoparticles as catalytically active materials in field-effect transistor (FET) sensors, and iii) functionalized III-V semiconductor based devices. QCL-based PA sensors for NOx show a detection limit in the sub part-per-million range and are characterized by high selectivity and compact set-up. Electrochemically synthesized gold-nanoparticle FET sensors are able to monitor NOx in a concentration range from 50 to 200 parts per million and are suitable for miniaturization. Porphyrin-functionalized III-V semiconductor materials can be used for the fabrication of a reliable NOx sensor platform characterized by high conductivity, corrosion resistance, and strong surface state coupling

Variation in dopamine D2 and serotonin 5-HT2A receptor genes is associated with working memory processing and response to treatment with antipsychotics

Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with secondgeneration antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n¼63 and n¼54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype–phenotype relationships