NADPH Oxidases in Neurodegenerative Disorders: Mechanisms and Therapeutic Opportunities.

Significance: The nicotinamide adenine dinucleotide phosphate oxidase (NOX) enzyme family, located in the central nervous system, is recognized as a source of reactive oxygen species (ROS) in the brain. Despite its importance in cellular processes, excessive ROS generation leads to cell death and is involved in the pathogenesis of neurodegenerative disorders. Recent advances: NOX enzymes contribute to the development of neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke, highlighting their potential as targets for future therapeutic development. This review will discuss NOX's contribution and therapeutic targeting potential in neurodegenerative diseases, focusing on PD, AD, ALS, and stroke. Critical issues: Homeostatic and physiological levels of ROS are crucial for regulating several processes, such as development, memory, neuronal signaling, and vascular homeostasis. However, NOX-mediated excessive ROS generation is deeply involved in the damage of DNA, proteins, and lipids, leading to cell death in the pathogenesis of a wide range of diseases, namely neurodegenerative diseases. Future directions: It is essential to understand the role of NOX homologs in neurodegenerative disorders and the pathological mechanisms undergoing neurodegeneration mediated by increased levels of ROS. This further knowledge will allow the development of new specific NOX inhibitors and their application for neurodegenerative disease therapeutics.

Severe Influenza Virus and Respiratory Syncytial Virus Infections in Intensive Care Over the Last 15 Years.

INTRODUCTION: Influenza virus is a common agent of pediatric infections. Most cases are mild, but severe illness and death can occur. We aimed to analyze severe cases associated the influenza virus and compare it with respiratory syncytial virus (RSV). METHODS: This is a retrospective study of 0-17-year-old patients admitted to the intensive care unit (ICU) of Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra (Pediatric Hospital, Coimbra Hospital and University Center), a tertiary pediatric hospital in Coimbra, Portugal, over the last 15 years (2008-2022) due to influenza virus infection. Clinical presentation, severity, and evolution were analyzed. A comparison of children with RSV infection admitted in the same period was performed. RESULTS: We identified 47 cases of influenza virus infection (34% coinfection with other viruses), median age of 2.3 years (interquartile range (IQR) 6.1), and 38% had comorbidities. The median admissions were three/year (maximum 11 in 2019). Influenza A was identified in 96%. Ninety-six percent had respiratory symptoms, 38% had neurologic symptoms, and 28% had sepsis. The main reason for admission was respiratory failure (68%). The mean pediatric index of mortality 2 (PIM2) at admission was 9±15.9%. Ventilatory support was necessary in 66%, vasoactive support in 19%, and blood products in 17%. The median length of stay was four days (IQR 5). There were four (8.5%) deaths. During the same study period, there were 171 RSV-related admissions. When comparing influenza (group A, without RSV coinfection) and RSV (group B), the first had a higher PIM2 on admission, greater need of ventilatory support, more complications, and higher mortality (p=0.001). CONCLUSIONS: The number of influenza virus infections admitted to ICU was much lower than RSV. However, influenza was more severe and associated with all deaths registered.

Spatial orientation: A relationship with inferential memory.

Two branches of the scientific literature have dominated our understanding of hippocampal function. One focuses on the support this structure offers to declarative memory, while the other views the hippocampus as a part of a system dedicated to spatial navigation. These two different visions can be reconciled in relational theory, which suggests that the hippocampus processes all kinds of associations and sequences of events. According to this, processing would be similar to a route calculation based on associations of spatial information acquired during navigation and the associative relationship established between memories without spatial content. In this paper, we present a behavioral study of healthy individuals to explore the performance of inferential memory tasks and spatial orientation tasks in a virtual environment. Inferential memory and spatial orientation task performances were positively correlated. However, after controlling for a non-inferential memory task, only the correlation between allocentric spatial orientation and inferential memory remained significant. These results provide support for the similarity between the two cognitive functions, lending credence to the relational theory of the hippocampus. Additionally, our behavioral findings are in line with the cognitive map theory, which suggests a potential association between the hippocampus and allocentric spatial representations.

Age related variation of health markers in Asian elephants.

Although senescence is often observed in the wild, its underlying mechanistic causes can rarely be studied alongside its consequences, because data on health, molecular and physiological measures of senescence are rare. Documenting how different age-related changes in health accelerate ageing at a mechanistic level is key if we are to better understand the ageing process. Nevertheless, very few studies, particularly on natural populations of long-lived animals, have investigated age-related variation in biological markers of health and sex differences therein. Using blood samples collected from semi-captive Asian elephants, we show that pronounced differences in haematology, blood chemistry, immune, and liver functions among age classes are also evident under natural conditions in this extremely long-lived mammal. We provide strong support that overall health declined with age, with progressive declines in immune and liver functions similarly in both males and females. These changes parallel those mainly observed to-date in humans and laboratory mammals, and suggest a certain ubiquity in the ageing patterns.

Impacts of sheep versus cattle livestock systems on birds of Mediterranean grasslands.

Mediterranean pastures are experiencing strong changes in management, involving shifts from sheep to cattle-based livestock systems. The impacts of such shifts on biodiversity are still poorly understood. Here, we sought to contrast the grazing regime, vegetation structure, bird species richness and abundance, between sheep and cattle grazed parcels, to understand the mechanisms through which management decisions impact farmland birds. During spring 2019, we characterized livestock management, bird populations and sward structure in 23 cattle and 27 sheep grazed parcels. We used a Structural Equation Model to infer the direct and indirect effects of sheep and cattle grazing on birds. Although no effects were found on overall species richness, there were species-specific responses to sheep and cattle grazed systems. Grazing pressure (variable integrating stocking rate and the number of days in the parcel) had negative impacts on the prevalence/abundance of Zitting Cisticola, Corn Bunting and Little Bustard, either directly or indirectly, through the effects of grazing pressure on vegetation height. Animal density and vegetation cover had direct positive effects in Galerida spp. and Common Quail, respectively. Zitting Cisticola and Little Bustard also showed a direct response to livestock type. Our study emphasizes the importance of grazing pressure as a driver of negative impacts for bird populations in Mediterranean grasslands. Since the ongoing transition from sheep to cattle-based systems involves increases in stocking rate, and therefore potentially higher grazing pressure, we propose a policy change to cap the maximum allowed grazing pressure. At the landscape scale, a mix of sheep and cattle grazed fields would be beneficial for maintaining bird diversity.

Support for the evolutionary speed hypothesis from intraspecific population genetic data in the non-biting midge Chironomus riparius.

The evolutionary speed hypothesis (ESH) proposes a causal mechanism for the latitudinal diversity gradient. The central idea of the ESH is that warmer temperatures lead to shorter generation times and increased mutation rates. On an absolute time scale, both should lead to an acceleration of selection and drift. Based on the ESH, we developed predictions regarding the distribution of intraspecific genetic diversity: populations of ectothermic species with more generations per year owing to warmer ambient temperatures should be more differentiated from each other, accumulate more mutations and show evidence for increased mutation rates compared with populations in colder regions. We used the multivoltine insect species Chironomus riparius to test these predictions with cytochrome oxidase I (COI) sequence data and found that populations from warmer regions are indeed significantly more differentiated and have significantly more derived haplotypes than populations from colder regions. We also found a significant correlation of the annual mean temperature with the population mutation parameter θ that serves as a proxy for the per generation mutation rate under certain assumptions. This pattern could be corroborated with two nuclear loci. Overall, our results support the ESH and indicate that the thermal regime experienced may be crucially driving the evolution of ectotherms and may thus ultimately govern their speciation rate.

Simulated climate change conditions unveil the toxic potential of the fungicide pyrimethanil on the midge Chironomus riparius: a multigeneration experiment.

Although it has been suggested that temperature increase may alter the toxic potential of environmental pollutants, few studies have investigated the potential risk of chemical stressors for wildlife under Global Climate Change (GCC) impact. We applied a bifactorial multigeneration study in order to test if GCC conditions alter the effects of low pesticide concentrations on life history and genetic diversity of the aquatic model organism Chironomus riparius. Experimental populations of the species were chronically exposed to a low concentration of the fungicide pyrimethanil (half of the no-observed-adverse-effect concentration: NOAEC/2) under two dynamic present-day temperature simulations (11.0-22.7°C; 14.0-25.2°C) and one future scenario (16.5-28.1°C). During the 140-day multigeneration study, survival, emergence, reproduction, population growth, and genetic diversity of C. riparius were analyzed. Our results reveal that high temperature and pyrimethanil act synergistically on the midge C. riparius. In simulated present-day scenarios, a NOAEC/2 of pyrimethanil as derived from a life-cycle toxicity test provoked only slight-to-moderate beneficial or adverse effects on C. riparius. In contrast, exposure to a NOAEC/2 concentration of pyrimethanil at a thermal situation likely for a summer under GCC conditions uncovered adverse effects on mortality and population growth rate. In addition, genetic diversity was considerably reduced by pyrimethanil in the future scenario, but only slightly under current climatic conditions. Our multigeneration study under near-natural (climatic) conditions indicates that not only the impact of climate change, but also low concentrations of pesticides may pose a reasonable risk for aquatic insects in future.

Effects of cadmium on life-cycle parameters in a multi-generation study with Chironomus riparius following a pre-exposure of populations to two different tributyltin concentrations for several generations.

So far only a few studies have been performed to assess the effects of dynamic pollutant exposure on life-history parameters of invertebrates. In a previous multi-generation approach with the midge Chironomus riparius we tested if a chronic tributyltin pre-exposure alters the ability of a population to cope with subsequent cadmium stress. In the experiment two separate chironomid populations were exposed via sediments to different TBT-concentrations (4.46 and 8.93 µg Sn/kg dw) for several generations, followed by subsequent cadmium exposure (1.2 mg Cd/kg dw) for three generations. While the TBT-exposure to 4.46 µg Sn/kg dw had only small effects on the development and reproduction of C. riparius the higher TBT-concentration of 8.93 µg Sn/kg dw led to negative effects on life-history traits. Therefore, a higher adverse effect of the higher TBT-concentration and thus a higher susceptibility to other stressors could be assumed. Within, this paper only the results of the second stressor experiment were presented; clear effects of Cd on development and reproduction of C. riparius were determined independent of the pre-exposure scenario. While no differences in Cd-sensitivity were found between the population without pre-exposure to TBT and the population pre-exposed to the low TBT-concentration (4.46 µg Sn/kg dw), the pre-exposure of midges to the higher TBT-concentration (8.93 µg Sn/kg dw) resulted in a significantly higher susceptibility to subsequent Cd-stress. These results document that the exposure history may influence the reaction to altered chemical stress. Our findings are relevant to understand and predict the evolutionary fate of populations in rapidly changing, human-impacted environments. However, the fact that chemical-induced reduced genetic diversity, which is not necessarily linked to genetic adaptation, leads to a reduced fitness under altered stress conditions, is to our knowledge a novel finding.

Genetic impoverishment in laboratory cultures of the test organism Chironomus riparius.

Genetic diversity among laboratory and field populations of Chironomus riparius was investigated using microsatellite DNA analysis. Individuals of midge cultures reared in 10 different laboratories showed a clear reduction in the number of alleles per locus and in the level of heterozygosity compared to two natural populations sampled in southern Germany. To reconstruct the rate of genetic impoverishment under laboratory conditions, genetic diversity was monitored in a C. riparius laboratory population for 23 generations. Additionally, 11 populations originating from different laboratories were crossed, and genetic diversity was compared among pure, crossed, and natural populations. The results demonstrate that C. riparius strains used in standard toxicity tests exhibit low levels of genetic variability. In addition, our experiments show that refreshment of stocks with individuals from other laboratories is not sufficient to restore genetic variation. Potential consequences of genetic impoverishment and improvements for toxicological bioassays are discussed.

Multi-generation studies with Chironomus riparius--effects of low tributyltin concentrations on life history parameters and genetic diversity.

While toxicological data are available for numerous chemicals from standard tests, little is known on effects of pollutants over several generations or regarding chronic effects of chemicals on genetic diversity. Within the experiments, effects of the model pollutant tributyltin (TBT) were investigated over eleven generations at a sublethal TBT concentration of 4.46 microg as Sn kg-1 sediment dw on life-cycle parameters and genetic variability of Chironomus riparius. Moreover, the adaptation potential towards TBT was determined. This experimental design enables the identification of TBT effects on life-cycle parameters and the determination of a potential extinction risk caused by chronic exposure. Furthermore, effects on the genetic structure can be determined, which are not predictable based solely on knowledge of the toxic mode of action of the chemical. Genetic variety was determined via microsatellite analysis, measuring individual length differences of highly variable satellite DNA fragments. For the identification of changes in tolerances towards the stressor, acute and chronic toxicity experiments were conducted. During the multi-generation study, significant effects on development and reproduction were determined. For some generations, the emergence was significantly (p<0.05) delayed under TBT exposure. Reproduction seems to be a sensitive parameter as well, whereby females laid significantly larger egg masses (p<0.05) in the latter generations. TBT did not affect the population growth rate nor the genetic variability, while clear deviations from the Hardy-Weinberg equilibrium appeared. The study also provides strong evidence for the acquirement of a higher tolerance towards the stressor in the TBT-exposed group.