NLRP1 inflammasome promotes senescence and senescence-associated secretory phenotype.

BACKGROUND: Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as senescence-associated secretory phenotype (SASP), some of which are produced by the NLRP3 inflammasome. Here, we present evidence that the NLRP1 inflammasome is a DNA damage sensor and a key mediator of senescence. METHODS: Senescence was induced in fibroblasts in vitro and in mice. Cellular senescence was assessed by Western blot analysis of several proteins, including p16, p21, p53, and SASP factors, released in the culture media or serum. Inflammasome components, including NLRP1, NLRP3 and GSDMD were knocked out or silenced using siRNAs. RESULTS: In vitro and in vivo results suggest that the NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP factors in a Gasdermin D (GSDMD)-dependent manner. Mechanistically, the NLRP1 inflammasome is activated in response to genomic damage detected by the cytosolic DNA sensor cGMP-AMP (cGAMP) synthase (cGAS). CONCLUSION: Our findings show that NLRP1 is a cGAS-dependent DNA damage sensor during senescence and a mediator of SASP release through GSDMD. This study advances the knowledge on the biology of the NLRP1 inflammasome and highlights this pathway as a potential pharmcological target to modulate senescence.

Prevalence and time trends of symptoms of allergic rhinitis and rhinoconjunctivitis in Spanish children: Global Asthma Network (GAN) study.

INTRODUCTION: The time trends of the prevalence of rhinitis, rhinoconjunctivitis and nasal allergy previously described in the ISAAC (International Study of Asthma and Allergies in Childhood) in 2002 are unknown; or if the geographical or age differences in Spain persist. OBJECTIVE: To describe the prevalence of rhinitis, rhinoconjunctivitis and nasal allergy in different Spanish geographical areas and compare them with those of the ISAAC. METHODS: Cross-sectional study of the prevalence of rhinitis, rhinoconjunctivitis and nasal allergy, carried out in 2016-2019 on 19943 adolescents aged 13-14 years and 17215 schoolchildren aged 6-7 years from six Spanish areas (Cartagena, Bilbao, Cantabria, La Coruña, Pamplona, and Salamanca), through a questionnaire based on the Global Asthma Network (GAN) protocol. RESULTS: The prevalences of recent rhinitis and rhinoconjunctivitis (last 12 months), and nasal allergy/hay fever were 35.1%, 17.6%, and 14.6% in the adolescents and 20%, 8.5%, and 8.9% in the schoolchildren, respectively, with rhinoconjunctivitis in adolescents varying from 20.9% in Bilbao to 13.4% in Cartagena; and in schoolchildren, from 9.8% in La Coruña to 6.4% in Pamplona. These prevalences of rhinoconjunctivitis and nasal allergy in adolescents were higher than those described in the ISAAC (16.3% and 13%) and similar in schoolchildren to the ISAAC (9% and 9.4%). CONCLUSIONS: There has been a stabilisation of rhinitis, rhinoconjunctivitis and nasal allergy in schoolchildren that slows the previous upward trend of ISAAC; and a slight non-significant increase in rhinoconjunctivitis and nasal allergy in adolescents. The variability found in adolescents would require local research to be better understood.

Mitochondrial electron transport chain defects modify Parkinson's disease phenotypes in a Drosophila model.

INTRODUCTION: Mitochondrial defects have been implicated in Parkinson's disease (PD) since complex I poisons were found to cause accelerated parkinsonism in young people in the early 1980s. More evidence of mitochondrial involvement arose when many of the genes whose mutations caused inherited PD were discovered to be subcellularly localized to mitochondria or have mitochondrial functions. However, the details of how mitochondrial dysfunction might impact or cause PD remain unclear. The aim of our study was to better understand mitochondrial dysfunction in PD by evaluating mitochondrial respiratory complex mutations in a Drosophila melanogaster (fruit fly) model of PD. METHODS: We have conducted a targeted heterozygous enhancer/suppressor screen using Drosophila mutations within mitochondrial electron transport chain (ETC) genes against a null PD mutation in parkin. The interactions were assessed by climbing assays at 2-5 days as an indicator of motor function. A strong enhancer mutation in COX5A was examined further for L-dopa rescue, oxygen consumption, mitochondrial content, and reactive oxygen species. A later timepoint of 16-20 days was also investigated for both COX5A and a suppressor mutation in cyclope. Generalized Linear Models and similar statistical tests were used to verify significance of the findings. RESULTS: We have discovered that mutations in individual genes for subunits within the mitochondrial respiratory complexes have interactions with parkin, while others do not, irrespective of complex. One intriguing mutation in a complex IV subunit (cyclope) shows a suppressor rescue effect at early time points, improving the gross motor defects caused by the PD mutation, providing a strong candidate for drug discovery. Most mutations, however, show varying degrees of enhancement or slight suppression of the PD phenotypes. Thus, individual mitochondrial mutations within different oxidative phosphorylation complexes have different interactions with PD with regard to degree and direction. Upon further investigation of the strongest enhancer (COX5A), the mechanism by which these interactions occur initially does not appear to be based on defects in ATP production, but rather may be related to increased levels of reactive oxygen species. CONCLUSIONS: Our work highlights some key subunits potentially involved in mechanisms underlying PD pathogenesis, implicating ETC complexes other than complex I in PD.

Infection with SARS-CoV-2 among children with asthma: evidence from Global Asthma Network.

BACKGROUND: Clinical presentations of coronavirus disease 2019 (COVID-19) among children with asthma have rarely been investigated. This study aimed to assess clinical manifestations and outcome of COVID-19 among children with asthma, and whether the use of asthma medications was associated with outcomes of interest. METHODS: The Global Asthma Network (GAN) conducted a global survey among GAN centers. Data collection was between November 2020 and April 2021. RESULTS: Fourteen GAN centers from 10 countries provided data on 169 children with asthma infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 was asymptomatic in 58 (34.3%), mild in 93 (55.0%), moderate in 14 (8.3%), and severe/critical in 4 (2.4%). Thirty-eight (22.5%) patients had exacerbation of asthma and 21 (12.4%) were hospitalized for a median of 7 days (interquartile range 3-16). Those who had moderate or more severe COVID-19 were significantly more likely to have exacerbation of asthma as compared to those who were asymptomatic or had mild COVID-19 (adjusted odds ratio (adjOR) 3.97, 95% CI 1.23-12.84). Those who used inhaled bronchodilators were significantly more likely to have a change of asthma medications (adjOR 2.39, 95% CI 1.02-5.63) compared to those who did not. Children who used inhaled corticosteroids (ICS) did not differ from those who did not use ICS with regard to being symptomatic, severity of COVID-19, asthma exacerbation, and hospitalization. CONCLUSIONS: Over dependence on inhaled bronchodilator may be inappropriate. Use of ICS may be safe and should be continued in children with asthma during the pandemic of COVID-19.

Mitochondrial reactive oxygen species: Do they extend or shorten animal lifespan?

Testing the predictions of the Mitochondrial Free Radical Theory of Ageing (MFRTA) has provided a deep understanding of the role of reactive oxygen species (ROS) and mitochondria in the aging process. However those data, which support MFRTA are in the majority correlative (e.g. increasing oxidative damage with age). In contrast the majority of direct experimental data contradict MFRTA (e.g. changes in ROS levels do not alter longevity as expected). Unfortunately, in the past, ROS measurements have mainly been performed using isolated mitochondria, a method which is prone to experimental artifacts and does not reflect the complexity of the in vivo process. New technology to study different ROS (e.g. superoxide or hydrogen peroxide) in vivo is now available; these new methods combined with state-of-the-art genetic engineering technology will allow a deeper interrogation of, where, when and how free radicals affect aging and pathological processes. In fact data that combine these new approaches, indicate that boosting mitochondrial ROS in lower animals is a way to extend both healthy and maximum lifespan. In this review, I discuss the latest literature focused on the role of mitochondrial ROS in aging, and how these new discoveries are helping to better understand the role of mitochondria in health and disease. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Recent progress with next-generation biomarkers in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer is a heterogeneous disease with different clinical phenotypes. Histomorphological variants, variable mutation rates and aberrant protein expression, along with the recently identified molecular subtypes, have been linked to prognosis and response to therapy. Complete response to chemotherapy and outcome after radical cystectomy are difficult to predict. To date, no validated pathological or clinical test exists to predict response. Advances in high-throughput, next-generation, genomic techniques to study the molecular pathways that govern the disease have led to novel strategies for the identification of such biomarkers relevant to muscle-invasive bladder cancer. Progress has been made not only in tissue-based biomarkers, but also in the liquid biopsy field. Liquid biopsies represent an opportunity to obtain patient samples non-invasively at multiple time-points during their treatment course without the need for biopsy. Especially in the metastatic setting, this will allow monitoring of the molecular evolution of the tumor under treatment, which should inform subsequent therapeutic decisions.

Altered urothelial ATP signaling in a major subset of human overactive bladder patients with pyuria.

Overactive Bladder (OAB) is an idiopathic condition, characterized by urgency, urinary frequency, and urgency incontinence, in the absence of routinely traceable urinary infection. We have described microscopic pyuria (≥10 wbc/µl) in patients suffering from the worst symptoms. It is established that inflammation is associated with increased ATP release from epithelial cells, and extracellular ATP originating from the urothelium following increased hydrostatic pressure is a mediator of bladder sensation. Here, using bladder biopsy samples, we have investigated urothelial ATP signaling in OAB patients with microscopic pyuria. Basal, but not stretch-evoked, release of ATP was significantly greater from the urothelium of OAB patients with pyuria than from non-OAB patients or OAB patients without pyuria (<10 wbc/µl). Basal ATP release from the urothelium of OAB patients with pyuria was inhibited by the P2 receptor antagonist suramin and abolished by the hemichannel blocker carbenoxolone, which differed from stretch-activated ATP release. Altered P2 receptor expression was evident in the urothelium from pyuric OAB patients. Furthermore, intracellular bacteria were visualized in shed urothelial cells from ∼80% of OAB patients with pyuria. These data suggest that increased ATP release from the urothelium, involving bacterial colonization, may play a role in the heightened symptoms associated with pyuric OAB patients.

Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency.

Mitochondrial dysfunction is a significant factor in human disease, ranging from systemic disorders of childhood to cardiomyopathy, ischaemia and neurodegeneration. Cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, is a frequent target. Lower eukaryotes possess alternative respiratory-chain enzymes that provide non-proton-translocating bypasses for respiratory complexes I (single-subunit reduced nicotinamide adenine dinucleotide dehydrogenases, e.g. Ndi1 from yeast) or III + IV [alternative oxidase (AOX)], under conditions of respiratory stress or overload. In previous studies, it was shown that transfer of yeast Ndi1 or Ciona intestinalis AOX to Drosophila was able to overcome the lethality produced by toxins or partial knockdown of complex I or IV. Here, we show that AOX can provide a complete or substantial rescue of a range of phenotypes induced by global or tissue-specific knockdown of different cIV subunits, including integral subunits required for catalysis, as well as peripheral subunits required for multimerization and assembly. AOX was also able to overcome the pupal lethality produced by muscle-specific knockdown of subunit CoVb, although the rescued flies were short lived and had a motility defect. cIV knockdown in neurons was not lethal during development but produced a rapidly progressing locomotor and seizure-sensitivity phenotype, which was substantially alleviated by AOX. Expression of Ndi1 exacerbated the neuronal phenotype produced by cIV knockdown. Ndi1 expressed in place of essential cI subunits produced a distinct residual phenotype of delayed development, bang sensitivity and male sterility. These findings confirm the potential utility of alternative respiratory chain enzymes as tools to combat mitochondrial disease, while indicating important limitations thereof.

ß carbonic anhydrase is required for female fertility in Drosophila melanogaster.

BACKGROUND: Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous enzymes that catalyze the reversible hydration reaction of carbon dioxide. CAs are present as six structurally divergent enzyme families: α, ß, γ, δ, ζ and η. ß-CAs have a wide distribution across different species including invertebrates. Previously, we showed that Drosophila melanogaster ß-CA is a highly active mitochondrial enzyme. In this study, we investigated the function of Drosophila ß-CA by silencing the expression of the ß-CA gene using UAS/GAL4-based RNA interference (RNAi) in Drosophila in vivo. RESULTS: Crossing ß-CA RNAi lines over ubiquitous Actin driver flies did not produce any viable progeny, indicating that ß-CA expression is required for fly development. RNAi silencing of ß-CA ubiquitously in adult flies did not affect their survival rate or function of mitochondrial electron transport chain. Importantly, ß-CA RNAi led to impaired reproduction. All ß-CA knockdown females were sterile, and produced few or no eggs. Whole ovaries of knockdown females looked normal but upon cadherin staining, there was an apparent functional defect in migration of border cells, which are considered essential for normal fertilization. CONCLUSIONS: These results indicate that although Drosophila ß-CA is dispensable for survival of adult flies, it is essential for female fertility.

High consumption of fructose rather than glucose promotes a diet-induced obese phenotype in Drosophila melanogaster.

During the last 20 years, there has been a considerable scientific debate about the possible mechanisms of induction of metabolic disorders by reducing monosaccharides such as glucose or fructose. In this study, we report the metabolic rearrangement in response to consumption of these monosaccharides at concentrations ranging from 0.25% to 20% in a Drosophila model. Flies raised on high-glucose diet displayed delay in pupation and increased developmental mortality compared with fructose consumers. Both monosaccharides at high concentrations promoted an obese-like phenotype indicated by increased fly body mass, levels of uric acid, and circulating and stored carbohydrates and lipids; and decreased percentage of water in the body. However, flies raised on fructose showed lower levels of circulating glucose and higher concentrations of stored carbohydrates, lipids, and uric acid. The preferential induction of obesity caused by fructose in Drosophila was associated with increased food consumption and reduced mRNA levels of DILP2 and DILP5 in the brain of adult flies. Our data show that glucose and fructose differently affect carbohydrate and lipid metabolism in Drosophila in part by modulation of insulin/insulin-like growth factor signaling. Some reported similarities with effects observed in mammals make Drosophila as a useful model to study carbohydrate influence on metabolism and development of metabolic disorders.

Restriction of glucose and fructose causes mild oxidative stress independently of mitochondrial activity and reactive oxygen species in Drosophila melanogaster.

Our recent study showed different effects of glucose and fructose overconsumption on the development of obese phenotypes in Drosophila. Glucose induced glucose toxicity due to the increase in circulating glucose, whereas fructose was more prone to induce obesity promoting accumulation of reserve lipids and carbohydrates (Rovenko et al., Comp. Biochem. Physiol. A Mol. Integr. Physiol. 2015, 180, 75-85). Searching for mechanisms responsible for these phenotypes in this study, we analyzed mitochondrial activity, mitochondrial density, mtROS production, oxidative stress markers and antioxidant defense in fruit flies fed 0.25%, 4% and 10% glucose or fructose. It is shown that there is a complex interaction between dietary monosaccharide concentrations, mitochondrial activity and oxidative modifications to proteins and lipids. Glucose at high concentration (10%) reduced mitochondrial protein density and consequently respiration in flies, while fructose did not affect these parameters. The production of ROS by mitochondria did not reflect activities of mitochondrial complexes. Moreover, there was no clear connection between mtROS production and antioxidant defense or between antioxidant defense and developmental survival, shown in our previous study (Rovenko et al., Comp. Biochem. Physiol. A Mol. Integr. Physiol. 2015, 180, 75-85). Instead, mtROS and antioxidant machinery cooperated to maintain a redox state that determined survival rates, and paradoxically, pro-oxidant conditions facilitated larva survival independently of the type of carbohydrate. It seems that in this complex system glucose controls the amount of oxidative modification regulating mitochondrial activity, while fructose regulates steady-state mRNA levels of antioxidant enzymes.

Association between quality of life in parents and components of asthma control in children.

OBJECTIVE: Describe the association between parents' quality of life and the two components of asthma control in children: impairment and risk. METHODS: Cross-sectional study with children between 4 and 14 years of age with active asthma recruited at primary care centers in Spain. Asthma control was assessed according to the Third National Asthma Expert Panel Report, classifying "impairment" in three levels (well-controlled asthma, partially controlled, and poorly controlled), and "risk" as high or low. The parents' quality of life was evaluated using the specific Family Impact of Childhood Bronchial Asthma Questionnaire instrument (IFABI-R). The association between asthma control and the parents' quality of life was analyzed using multivariate regression models adjusted for other social and family variables. RESULTS: Data from 408 children were analyzed. The parents' quality of life was affected in the partially controlled asthma group when compared with well-controlled asthma, as showed by an increase in IFABI-R scores in all dimensions: functional 17.2% (p < 0.001), emotional 10.4% (p = 0.021), and socio-occupational 6.8% (p = 0.056). The differences were higher in poorly controlled asthma compared with well-controlled asthma: functional 24.3% (p = 0.001), emotional 18.9% (p = 0.008), and socio-occupational 11.5% (p = 0.036). The "risk" component was independently associated with the parents' quality of life. Of all the elements used to assess the control, the only one independently associated with the parents' quality of life was recurrent asthma crisis. CONCLUSIONS: In asthma control, both "impairment" and "risk" in children are gradually associated with the parents' quality of life. The global assessment of the control surpasses the importance of each individual element used in this assessment.

First case of evolved herbicide resistance in the holoparasite sunflower broomrape, Orobanche cumana Wallr.

The development and commercialisation of sunflower varieties tolerant to acetolactate synthase (ALS)-inhibiting herbicides some 20 years ago provided farmers with an alternative method for the cost-effective control of Orobanche cumana. In 2020, however, two independent sunflower broomrape populations from Drama (GR-DRA) and Orestiada (GR-ORE), Greece, were reported to be heavily infested with O. cumana after application of the ALS-inhibiting herbicide imazamox. Here we have investigated the race of GR-DRA and GR-ORE and determined the basis of resistance to imazamox in the two Greek O. cumana samples. Using a set of five diagnostic sunflower varieties characterised by different resistant genes with respect to O. cumana infestation, we have clearly established that the GR-ORE and GR-DRA populations belong to the invasive broomrape races G and G+, respectively. Live underground tubercles and emerged shoots were identified at the recommended field rate of imazamox for GR-DRA and GR-ORE but not for two other standard sensitive populations in a whole plant dose response test using two different herbicide-tolerant sunflower hybrids as hosts. Sequencing of the ALS gene identified an alanine 205 to aspartate mutation in all GR-ORE samples. Most GR-DRA tubercles were characterised by a second serine 653 to asparagine ALS mutation whilst a few GR-DRA individuals contained the A205D mutation. Mutations at ALS codons 205 and 653 are known to impact on the binding and efficacy of imazamox and other imidazolinone herbicides. The knowledge generated here will be important for tracking and managing broomrape resistance to ALS-inhibiting herbicides in sunflower growing regions.

A systematic review of nanocarriers for treatment of urologic cancers.

Nanocarriers (NCs) are a form of nanotechnology widely investigated in cancer treatment to improve the safety and efficacy of systemic therapies by increasing tumor specificity. Numerous clinical trials have explored the use of NCs in urologic cancers since the approval of the first NCs for cancer treatment over 20 years ago. The objective of this systematic review is to examine the effectiveness and safety of NCs in treating urological cancers. This paper summarizes the state of the field by investigating peer-reviewed, published results from 43 clinical trials involving the use of NCs in bladder, prostate, and kidney cancer patients with a focus on safety and efficacy data. Among the 43 trials, 16 were phase I, 20 phase II, and 4 phase I/II. No phase III trials have been reported. While both novel and classic NCs have been explored in urologic cancers, NCs already approved for the treatment of other cancers were more widely represented. Trials in prostate cancer and mixed trials involving both urologic and non-urologic cancer patients were the most commonly reported trials. Although NCs have demonstrable efficacy with adequate safety in non-urologic cancer patient populations, current clinical stage NC options appear to be less beneficial in the urologic cancer setting. For example, nab-paclitaxel and liposomal doxorubicin have proven ineffective in the treatment of urologic cancers despite successes in other cancers. However, several ongoing pre-clinical studies using targeted and locally applied improved NCs may eventually improve their utility.

Impact of treatment adherence and inhalation technique on asthma outcomes of pediatric patients: a longitudinal study.

Introduction: We aimed to evaluate the longitudinal relationships, both at between- and within-person levels, that adherence to inhaled corticosteroid-based maintenance treatment and inhalation technique present with symptom control, exacerbations, and health-related quality of life (HRQoL) in children and adolescents with asthma. Methods: Participants (6-14 years old) from the ARCA (Asthma Research in Children and Adolescents) cohort-a prospective, multicenter, observational study (NCT04480242)-were followed for a period from 6 months to 5 years via computer-assisted telephone interviews and a smartphone application. The Medication Intake Survey-Asthma (MIS-A) was administered to assess the implementation stage of adherence, and the Inhalation Technique Questionnaire (InTeQ) was used to assess the five key steps when using an inhaler. Symptom control was measured with the Asthma Control Questionnaire (ACQ), and HRQL was measured with the EQ-5D and the Patient-Reported Outcomes Measurement Information System-Pediatric Asthma Impact Scale (PROMIS-PAIS). Multilevel longitudinal mixed models were constructed separately with symptom control, exacerbation occurrence, EQ-5D, and PROMIS-PAIS as the dependent variables. Results: Of the 360 participants enrolled, 303 (1,203 interviews) were included in the symptom control and exacerbation analyses, 265 (732) in the EQ-5D, and 215 (617) in the PROMIS-PAIS. Around 60% of participants were male subjects, and most of them underwent maintenance treatment with inhaled corticosteroids plus long-acting ß-agonists in a fixed dose (73.3%). Within-person variability was 83.6% for asthma control, 98.6% for exacerbations, 36.4% for EQ-5D, and 49.1% for PROMIS-PAIS. At the within-person level, patients with higher adherence had better symptom control (p = 0.002) and HRQoL over time (p = 0.016). Patients with a better inhalation technique reported worse HRQoL simultaneously (p = 0.012), but they showed better HRQoL in future assessments (p = 0.012). The frequency of reliever use was associated with symptom control (p < 0.001), exacerbation occurrence (p < 0.001), and HRQoL (p = 0.042); and boys were more likely to present better symptom control and HRQoL than girls. Conclusion: Our results confirm longitudinal associations at the within-person level of the two indicators of quality use of inhalers: for adherence to maintenance treatment with symptom control and HRQoL, and for the inhalation technique with HRQoL. Although treatment adherence was shown to be excellent, a third of the participants reported a suboptimal inhalation technique, highlighting the need for actions for improving asthma management of the pediatric population.

Strains of Pseudomonas syringae pv. syringae from pea are phylogenetically and pathogenically diverse.

Pseudomonas syringae pv. syringae causes extensive yield losses in the pea crop worldwide, although there is little information on its host specialization and its interactions with pea. A collection of 88 putative P. syringae pv. syringae strains (including 39 strains isolated from pea) was characterized by repetitive polymerase chain reaction (rep-PCR), multilocus sequence typing (MLST), and syrB amplification and evaluated for pathogenicity and virulence. rep-PCR data grouped the strains from pea into two groups (1B and 1C) together with strains from other hosts; a third group (1A) was formed exclusively with strains isolated from non-legume species. MLST data included all strains from pea in the genomospecies 1 of P. syringae pathovars defined in previous studies; they were distributed in the same three groups defined by rep-PCR. The inoculations performed in two pea cultivars showed that P. syringae pv. syringae strains from groups 1A and 1C were less virulent than strains from group 1B, suggesting a possible pathogenic specialization in this group. This study shows the existence of genetically and pathogenically distinct P. syringae pv. syringae strain groups from pea, which will be useful for the diagnostic and epidemiology of this pathogen and for disease resistance breeding.

Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction.

Mutations in mitochondrial oxidative phosphorylation complex I are associated with multiple pathologies, and complex I has been proposed as a crucial regulator of animal longevity. In yeast, the single-subunit NADH dehydrogenase Ndi1 serves as a non-proton-translocating alternative enzyme that replaces complex I, bringing about the reoxidation of intramitochondrial NADH. We have created transgenic strains of Drosophila that express yeast NDI1 ubiquitously. Mitochondrial extracts from NDI1-expressing flies displayed a rotenone-insensitive NADH dehydrogenase activity, and functionality of the enzyme in vivo was confirmed by the rescue of lethality resulting from RNAi knockdown of complex I. NDI1 expression increased median, mean, and maximum lifespan independently of dietary restriction, and with no change in sirtuin activity. NDI1 expression mitigated the aging associated decline in respiratory capacity and the accompanying increase in mitochondrial reactive oxygen species production, and resulted in decreased accumulation of markers of oxidative damage in aged flies. Our results support a central role of mitochondrial oxidative phosphorylation complex I in influencing longevity via oxidative stress, independently of pathways connected to nutrition and growth signaling.

Prevalence of asthma symptoms in schoolchildren, and climate in west European countries: an ecologic study.

The aim of the present study was to estimate the associations between the prevalence of asthma symptoms in schoolchildren and meteorological variables in west European countries that participated in the International Study of Asthma and Allergies in Children (ISAAC), Phase III 1997-2003. An ecologic study was carried out. The prevalence of asthma was obtained from this study from 48 centers in 14 countries, and meteorological variables from those stations closest to ISAAC centers, together with other socioeconomic and health care variables. Multilevel mixed-effects linear regression models were used. For schoolchildren aged 6-7 years, the prevalence rate of asthma decreased with an increase in mean annual sunshine hours, showed a positive association with rainy weather, and warm temperature, and a negative one with relative humidity and physician density (PD). Current wheeze prevalence was stronger in autumn/winter seasons and decreased with increasing PD. Severe current wheeze decreased with PD. For schoolchildren aged 13-14 years, the prevalence rates of asthma and current wheeze increased with rainy weather, and these rates decreased with increased PD. Current wheeze, as measured by a video questionnaire, was inversely associated with sunny weather, and nurse density. Severe current wheeze prevalence was stronger during autumn/winter seasons, decreased with PD, and indoor chlorinated public swimming pool density, and increased with rainy weather. Meteorological factors, including sunny and rainy weather, and PD may have some effect on the prevalence rates of asthma symptoms in children from west European countries.

How the Disruption of Mitochondrial Redox Signalling Contributes to Ageing.

In the past, mitochondrial reactive oxygen species (mtROS) were considered a byproduct of cellular metabolism. Due to the capacity of mtROS to cause oxidative damage, they were proposed as the main drivers of ageing and age-related diseases. Today, we know that mtROS are cellular messengers instrumental in maintaining cellular homeostasis. As cellular messengers, they are produced in specific places at specific times, and the intensity and duration of the ROS signal determine the downstream effects of mitochondrial redox signalling. We do not know yet all the processes for which mtROS are important, but we have learnt that they are essential in decisions that affect cellular differentiation, proliferation and survival. On top of causing damage due to their capacity to oxidize cellular components, mtROS contribute to the onset of degenerative diseases when redox signalling becomes dysregulated. Here, we review the best-characterized signalling pathways in which mtROS participate and those pathological processes in which they are involved. We focus on how mtROS signalling is altered during ageing and discuss whether the accumulation of damaged mitochondria without signalling capacity is a cause or a consequence of ageing.

Biological Stratification of Invasive and Advanced Urothelial Carcinoma.

Muscle-invasive urothelial carcinoma (UC) of the bladder remains a highly lethal malignancy. In this review the authors explore the underlying biology associated with the evolution from non-muscle-invasive UC to muscle-invasive and metastatic UC, with a special focus on the molecular stratification of UC and the potential of this stratification to be used for treatment selection.