UrdA Controls Secondary Metabolite Production and the Balance between Asexual and Sexual Development in Aspergillus Nidulans

The genus Aspergillus includes important plant pathogens, opportunistic human pathogens and mycotoxigenic fungi. In these organisms, secondary metabolism and morphogenesis are subject to a complex genetic regulation. Here we functionally characterized urdA, a gene encoding a putative helix-loop-helix (HLH)-type regulator in the model fungus Aspergillus nidulans. urdA governs asexual and sexual development in strains with a wild-type veA background; absence of urdA resulted in severe morphological alterations, with a significant reduction of conidial production and an increase in cleistothecial formation, even in the presence of light, a repressor of sex. The positive effect of urdA on conidiation is mediated by the central developmental pathway (CDP). However, brlA overexpression was not sufficient to restore wild-type conidiation in the Delta urdA strain. Heterologous complementation of Delta urdA with the putative Aspergillus flavus urdA homolog also failed to rescue conidiation wild-type levels, indicating that both genes perform different functions, probably reflected by key sequence divergence. UrdA also represses sterigmatocystin (ST) toxin production in the presence of light by affecting the expression of aflR, the activator of the ST gene cluster. Furthermore, UrdA regulates the production of several unknown secondary metabolites, revealing a broader regulatory scope. Interestingly, UrdA affects the abundance and distribution of the VeA protein in hyphae, and our genetics studies indicated that veA appears epistatic to urdA regarding ST production. However, the distinct fluffy phenotype of the Delta urdA Delta veA double mutant suggests that both regulators conduct independent developmental roles. Overall, these results suggest that UrdA plays a pivotal role in the coordination of development and secondary metabolism in A. nidulans.This research and The APC was supported by the Department of Biological Sciences at Northern Illinois University. The research at CIB-CSIC was funded by MINECO/FEDER/EU (grant BFU2015-66806-R). The research at UPV/EHU was funded by grant EHUA15/08

Energetic substrate availability regulates synchronous activity in an excitatory neural network.

Neural networks are required to meet significant metabolic demands associated with performing sophisticated computational tasks in the brain. The necessity for efficient transmission of information imposes stringent constraints on the metabolic pathways that can be used for energy generation at the synapse, and thus low availability of energetic substrates can reduce the efficacy of synaptic function. Here we study the effects of energetic substrate availability on global neural network behavior and find that glucose alone can sustain excitatory neurotransmission required to generate high-frequency synchronous bursting that emerges in culture. In contrast, obligatory oxidative energetic substrates such as lactate and pyruvate are unable to substitute for glucose, indicating that processes involving glucose metabolism form the primary energy-generating pathways supporting coordinated network activity. Our experimental results are discussed in the context of the role that metabolism plays in supporting the performance of individual synapses, including the relative contributions from postsynaptic responses, astrocytes, and presynaptic vesicle cycling. We propose a simple computational model for our excitatory cultures that accurately captures the inability of metabolically compromised synapses to sustain synchronous bursting when extracellular glucose is depleted

Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8

Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8+ T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8+ T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8+ T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8+ tumour-infiltrating lymphocytes

Differentiation stage of myeloma plasma cells: biological and clinical significance

[EN] The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n = 20) that the CD19 − CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19 − CD81+ and CD19 − CD81 − BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19 − CD81 −) clones, 38% intermediate-differentiated (CD19 − CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P = 0.005) and overall survival (HR: 2.1; P = 0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n = 40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles

Use of non-steroidal anti-inflammatory drugs and risk of breast cancer: The Spanish Multi-Case-control (MCC) study

Background: The relationship between non-steroidal anti-inflammatory drug (NSAID) consumption and breast cancer has been repeatedly studied, although the results remain controversial. Most case-control studies reported that NSAID consumption protected against breast cancer, while most cohort studies did not find this effect. Most studies have dealt with NSAIDs as a whole group or with specific drugs, such aspirin, ibuprofen, or others, but not with NSAID subgroups according to the Anatomical Therapeutic Chemical Classification System; moreover, scarce attention has been paid to their effect on different tumor categories (i.e.: ductal/non-ductal, stage at diagnosis or presence of hormonal receptors). Methods: In this case-control study, we report the NSAID – breast cancer relationship in 1736 breast cancer cases and 1895 healthy controls; results are reported stratifying by the women’s characteristics (i.e.: menopausal status or body mass index category) and by tumor characteristics. Results: In our study, NSAID use was associated with a 24 % reduction in breast cancer risk (Odds ratio [OR] = 0.76; 95 % Confidence Interval [CI]: 0.64–0.89), and similar results were found for acetic acid derivatives, propionic acid derivatives and COXIBs, but not for aspirin. Similar results were found in postmenopausal and premenopausal women. NSAID consumption also protected against hormone + or HER2+ cancers, but not against triple negative breast cancers. The COX-2 selectivity showed an inverse association with breast cancer (i.e. OR < 1), except in advanced clinical stage and triple negative cancers. Conclusion: Most NSAIDs, but not aspirin, showed an inverse association against breast cancer; this effect seems to be restricted to hormone + or HER2+ cancers. Keywords: Breast cancer, Non-steroidal anti-inflammatory drug, Hormone receptor positive breast cancer, HER2 positive breast cancer, Triple negative breast cance

The influence of population size, noise strength and behavioral task on best-encoded stimulus for neurons with unimodal or monotonic tuning curves

Tuning curves and receptive fields are widely used to describe the selectivity of sensory neurons, but the relationship between firing rates and information is not always intuitive.Neither high firing rates nor high tuning curve gradients necessarily mean that stimuli at that part of the tuning curve are well represented by a neuron.Recent research has shown that trial-to-trial variability (noise) and population size can strongly affect which stimuli are most precisely represented by a neuron in the context of a population code (the best-encoded stimulus), and that different measures of information can give conflicting indications.Specifically, the Fisher information is greatest where the tuning curve gradient is greatest, such as on the flanks of peaked tuning curves, but the stimulus-specific information (SSI) is greatest at the tuning curve peak for small populations with high trial-to-trial variability.Previous research in this area has focussed upon unimodal (peaked) tuning curves, and in this article we extend these analyses to monotonic tuning curves.In addition, we examine how stimulus spacing in forced choice tasks affects the best-encoded stimulus.Our results show that, regardless of the tuning curve, Fisher information correctly predicts the best-encoded stimulus for large populations and where the stimuli are closely spaced in forced choice tasks.In smaller populations with high variability, or in forced choice tasks with widely-spaced choices, the best-encoded stimulus falls at the peak of unimodal tuning curves, but is more variable for monotonic tuning curves.Task, population size and variability all need to be considered when assessing which stimuli a neuron represents, but the best-encoded stimulus can be estimated on a case-by case basis using commonly available computing facilities

The Use of Antihypertensive Medication and the Risk of Breast Cancer in a Case-Control Study in a Spanish Population: The MCC-Spain Study

The evidence on the relationship between breast cancer and different types of antihypertensive drugs taken for at least 5 years is limited and inconsistent. Furthermore, the debate has recently been fueled again with new data reporting an increased risk of breast cancer among women with a long history of use of antihypertensive drugs compared with nonusers