Immune Dysregulation and the Increased Risk of Complications and Mortality Following Respiratory Tract Infections in Adults With Down Syndrome.

The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.

Specific Susceptibility to COVID-19 in Adults with Down Syndrome.

The current SARS-CoV-2 outbreak, which causes COVID-19, is particularly devastating for individuals with chronic medical conditions, in particular those with Down Syndrome (DS) who often exhibit a higher prevalence of respiratory tract infections, immune dysregulation and potential complications. The incidence of Alzheimer's disease (AD) is much higher in DS than in the general population, possibly increasing further the risk of COVID-19 infection and its complications. Here we provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. We see an urgent need to protect people with DS, especially those with AD, from COVID-19 and future pandemics and focus on developing protective measures, which also include interventions by health systems worldwide for reducing the negative social effects of long-term isolation and increased periods of hospitalization.

Hydrological and biogeochemical controls governing the speciation and accumulation of selenium in a wetland influenced by mine drainage.

Controls governing the speciation and accumulation of Se in a 3.7-ha marsh influenced by mine drainage were assessed through examination of water balance, water quality, sediment, and plant tissue components. Over the 8-mo study period (April through November, 2009), mean monthly flows ranged from 1600 to 2300 m3 d-1 (hydraulic retention time of 1-3 d). Total Se concentrations in the marsh outflow were lower than the inflow by 0.4 to 6.2 µg L-1 (mean difference = 3.3 µg L-1 ), illustrating Se removal. The Se accumulation pathways are illustrated by elevated concentrations of Se in sediments (3-35 mg kg-1 dry wt) as well as in below-ground (2-41 mg kg-1 dry wt; mean = 10 mg kg-1 dry wt) and above-ground (0.8-6.3 mg kg-1 dry wt; mean = 2 mg kg-1 dry wt) emergent plant tissues. Redox stratification in the shallow water column had a marked effect on Se speciation and behavior, illustrating bottom water removal of dissolved selenate in suboxic horizons and increased mobility of dissolved organo-Se. Mass balance data yielded inflow and outflow loading rates for Se of 27 and 23 g d-1 , respectively (net accumulation rate of 4 g d-1 or 0.11 mg m2 d-1 ). The rate of accumulation as calculated from the mass balance agrees with independently measured rates of Se accumulation in sediments for the site (3.6-8.1 g d-1 or 0.10-0.22 mg m-2 d-1 ). Environ Toxicol Chem 2018;37:1824-1838. © 2018 SETAC.

Overexpression of the DYRK1A Gene (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) Induces Alterations of the Serotoninergic and Dopaminergic Processing in Murine Brain Tissues.

Trisomy 21 (T21) or Down syndrome (DS) is the most common genetic disorder associated with intellectual disability and affects around 5 million persons worldwide. Neuroanatomical phenotypes associated with T21 include slight reduction of brain size and weight, abnormalities in several brain areas including spines dysgenesis, dendritic morphogenesis, and early neuroanatomical characteristics of Alzheimer's disease. Monoamine neurotransmitters are involved in dendrites development, functioning of synapses, memory consolidation, and their levels measured in the cerebrospinal fluid, blood, or brain areas that are modified in individuals with T21. DYRK1A is one of the recognized key genes that could explain some of the deficits present in individuals with T21. We investigated by high-performance liquid chromatography with electrochemical detection the contents and processing of monoamines neurotransmitters in four brain areas of female and male transgenic mice for the Dyrk1a gene (mBactgDyrk1a). DYRK1A overexpression induced dramatic deficits in the serotonin contents of the four brain areas tested and major deficits in dopamine and adrenaline contents especially in the hypothalamus. These results suggest that DYRK1A overexpression might be associated with the modification of monoamines content found in individuals with T21 and reinforce the interest to target the level of DYRK1A expression as a therapeutic approach for persons with T21.

APP/SOD1 overexpressing mice present reduced neuropathic pain sensitivity.

There are controversies regarding pain expression in mentally disabled people, including Down syndrome patients. The aim of this study was to examine neuropathic pain-related behavior and peripheral nerve regeneration in mouse model of Down syndrome. Sciatic nerves of double transgenic mice, overexpressing both amyloid precursor protein (APP) and Cu/Zn superoxide dismutase (SOD1) genes, and FVB/N wild type mice were transected and immediately resutured. Evaluation of autotomy and functional recovery was carried out during 4-week follow-up. We found markedly less severe autotomy in transgenic animals, although the onset of autotomy was significantly delayed in control mice. Interestingly, neuroma formation at the injury site was significantly more prominent in transgenic animals. Sciatic function index outcome was better in transgenic mice than in wild-type group. Histological evaluation revealed no statistically significant differences in the number of GAP-43-positive growth cones and macrophages in the distal stump of the transected nerve between groups. However, in transgenic animals, the regenerating axons were arranged more chaotically. The number of Schwann cells in the distal stump of the transected nerves was significantly lower in transgenic mice. The number of surviving motoneurons was markedly decreased in transgenic group. We measured also the atrophy of denervated muscles and found it decreased in APP/SOD1 overexpressing mice. Taken together, in this model of Down syndrome, we observed increased neuroma formation and decreased autotomy after peripheral nerve injury. Our findings suggest that APP/SOD1 overexpressing mice are less sensitive for neuropathic pain associated with neuroma.

Biogeochemical mechanisms of selenium exchange between water and sediments in two contrasting lentic environments.

The biogeochemical mechanisms of Se exchange between water and sediments in two contrasting lentic environments were assessed through examination of Se speciation in the water column, porewater, and sediment. High-resolution (7 mm) vertical profiles of <0.45 µm Se species across the sediment-water interface demonstrate that the behavior of dissolved Se(VI), Se(IV), and organo-Se are closely linked to redox conditions as revealed by porewater profiles of redox-sensitive species (dissolved O2, NO3-, Fe, Mn, SO4(2-), and ΣH2S). At both sites Se(VI) is removed from solution in suboxic near-surface porewaters demonstrating that the sediments are serving as diffusive sinks for Se. X-ray absorption near edge spectroscopy (XANES) of sediments suggests that elemental Se and organo-Se represent the dominant sedimentary sinks for dissolved Se. Dissolved Se(IV) and organo-Se are released to porewaters in the near-surface sediments resulting in the diffusive transport of these species into the water column, where between-site differences in the depths of release can be linked to differences in redox zonation. The presence or absence of emergent vegetation is proposed to present a dominant control on sedimentary redox conditions as well as on the recycling and persistence of reduced Se species in bottom waters.

APP overexpression prevents neuropathic pain and motoneuron death after peripheral nerve injury in mice.

Despite general capacity of peripheral nervous system to regenerate, peripheral nerve injury is often followed by incomplete recovery of function and sometimes burdened by neuropathic pain. Amyloid precursor protein (APP) was suggested to play a role in neuronal growth, however, its role in peripheral nerve repair was not studied. The aim of this study was to examine the role of APP overexpression in peripheral nerve regeneration and neuropathic pain-related behavior in mice. Sciatic nerves of APP overexpressing and FVB/N wild-type mice were transected and immediately resutured. Evaluation of motor and sensory function and autotomy was carried out during 4-week follow up. We found no autotomy behavior as well as less significant atrophy of denervated muscles in APP overexpressing animals when compared to wild-type ones. Sciatic nerve function index outcome did not differ between groups. Histological evaluation revealed that the intensity of regeneration features, including GAP-43-positive growth cones and Schwann cells number in the distal stump of the transected nerve, was also similar in both groups. However, the regenerating fibers were organized more chaotically in wild-type mice and neuromas were much more often seen in this group. The number of macrophages infiltrating the injury site was significantly higher in control group. The number of surviving motoneurons was higher in transgenic mice than in control animals. Taken together, our findings suggest that APP overexpression is beneficial for nerve regeneration processes due to better organization of regenerating fibers, increased survival of motoneurons after autotomy and prevention of neuropathic pain.

Increased heart rate variability in mice overexpressing the Cu/Zn superoxide dismutase.

Cu/Zn superoxide dismutase (SOD1) is implicated in various pathological conditions including Down's syndrome, neurodegenerative diseases, and afflictions of the autonomic nervous system (ANS). To assess the SOD1 contribution to ANS dysfunction, especially its influence on cardiac regulation, we studied the heart rate variability (HRV) and cardiac arrhythmias in conscious 12-month-old male and female transgenic mice for the human SOD1 gene (TghSOD1). TghSOD1 mice presented heart rate reduction as compared with control FVB/N individuals. All HRV parameters reflecting parasympathetic activity were increased in TghSOD1. Pharmacological studies confirmed that the parasympathetic tone was exacerbated and the sympathetic pathway was functional in TghSOD1 mice. A high frequency of atrioventricular block and premature ventricular contractions was observed in TghSOD1. By biochemical assays we found that SOD1 activities were multiplied by 9 and 4 respectively in the heart and brainstem of transgenic mice. A twofold decrease in cholinesterase activity was observed in the heart but not in the brainstem. We demonstrate that SOD1 overexpression induces an ANS dysfunction by an exacerbated vagal tone that may be related to impaired cardiac activity of the cholinesterases and may explain the high occurrence of arrhythmias.

Determination of methylated arsenic-sulfur compounds in groundwater.

Arsenic speciation was determined by anion-exchange chromatography-inductively coupled plasma-mass spectrometry (AEC-ICP-MS) in groundwater samples collected from an aquifer impacted by methylated As pesticides. Besides the four expected arsenic species AsO3(3-), As4(3-), (CH3)AsO3(2-) and (CH3)2AsO2-, up to nine other arsenic species were encountered, which constituted a major fraction of the total arsenic concentration in most samples. We then synthesized the thio-derivatives of (CH3)AsO3(2-) and (CH3)2AsO2-, and characterized the formed products by electrospray-tandem mass spectrometry (ES-MS-MS). The presence of (CH3)AsO2S2-, (CH3)AsOS2(2-), (CH3)2AsOS- and (CH3)2AsS2-, was confirmed in the groundwater by retention time matching plus ES-MS-MS in collected AEC fraction, and the presence of the trivalent methylated arsenic species (CH3)AsO2(2-) was suggested based on retention time matching only. These arsenic species have not been observed in ambient waters before, and are likely to occur in many environments containing methylated arsenic species and reduced sulfur compounds. They can persist in some of these particular samples for periods of up to six months without preservation, but tend to convert into the corresponding pentavalent oxy-species. Acidification with HCI shifted speciation equilibria rapidly, and is thus unsuitable for stabilizing samples containing these novel arsenic species; cryofreezing or no sample preservation avoided this artifact.

Thioarsenates in geothermal waters of Yellowstone National Park: determination, preservation, and geochemical importance.

Mono-, di-, tri-, and tetrathioarsenate, as well as methylated arsenic oxy- and thioanions, were determined besides arsenite and arsenate in geothermal waters of Yellowstone National Park using anion-exchange chromatography inductively coupled plasma mass spectrometry. Retention time match with synthetic standards, measured S:As ratios, and molecular electrospray mass spectra support the identification. Acidification was unsuitable for arsenic species preservation in sulfidic waters, with HCI addition causing loss of total dissolved arsenic, presumably by precipitation of arsenic-sulfides. Flash-freezing is preferred for the preservation of arsenic species for several weeks. After thawing, samples must be analyzed immediately. Thioarsenates occurred over a pH range of 2.1 to 9.3 in the geothermal waters. They clearly predominated under alkaline conditions (up to 83% of total arsenic), but monothioarsenate also was detected in acidic waters (up to 34%). Kinetic studies along a drainage channel showed the importance of thioarsenates for the fate of arsenic discharged from the sulfidic hot spring. The observed arsenic speciation changes suggest three separate reactions: the transformation of trithioarsenate to arsenite (major initial reaction), the stepwise ligand exchange from tri- via di- and monothioarsenate to arsenate (minor reaction), and the oxidation of arsenite to arsenate, which only becomes quantitatively important after thioarsenates have disappeared.

Analysis of the TCR alpha-chain rearrangement profile in human T lymphocytes.

The size of the available human alphabeta T cell repertoire is difficult to determine and is open to debate. Empirical analysis of TCR beta-chain diversity reveals approximately 10(6) different beta chains in peripheral blood. Due in part to locus complexity, comparable information for TCR alpha is lacking. Rather, current estimates for human TCR alpha diversity, and hence, total repertoire diversity, are based on theoretical analyses that assume equal probabilities of rearrangement between any V alpha gene and J alpha gene. Here, we report on a systematic locus-wide rearrangement analysis of the TCR alpha-chain in human T cells. We first demonstrate that the V-J alpha recombination in the thymus is not random but depends on the reciprocal V alpha and J alpha position within the locus. Characterization of the frequency of gene usage combined with identification of five previously unrecognized pseudogenes enables us to empirically estimate the human TCR alpha combinatorial repertoire. The number of V-J alpha combinations achieved is approximately 44-56% of the total combinatorial possibilities, significantly lower than theoretical estimates. We also demonstrate that TCR alpha-chain diversity in peripheral T lymphocytes mimics the same general patterns of rearrangement as observed in the thymus, and these patterns appear conserved among different individuals. This unexpected observation indicates that, unlike the TCR beta locus, the human TCR alpha-chain repertoire is primarily predetermined by genetic recombination and its size is restricted by limits on the combinatorial repertoire rather than post-thymic selection.

Overexpression of copper/zinc-superoxide dismutase in transgenic mice markedly impairs regeneration and increases development of neuropathic pain after sciatic nerve injury.

Despite the general capacity of peripheral nervous system to regenerate, peripheral nerve injury is often followed by incomplete recovery of function, sometimes with the burden of neuropathic pain. The mechanisms of both regeneration and nociception have not been clarified, but it is known that inflammatory reactions are involved. Cu/Zn-superoxide dismutase (SOD1) is an important scavenger protein that acts against oxidative stress. It has been shown to play an important role in apoptosis and inflammation. The aim of this study was to examine the role of SOD1 overexpression in peripheral nerve regeneration and neuropathic pain-related behavior in mice. Sciatic nerves of SOD1-overexpressing and FVB/N wild type-mice were transected and immediately resutured. Evaluation of motor and sensory function and autotomy was carried out during 4 weeks of followup. We found markedly worse sciatic function index outcome as well as more significant atrophy of denervated muscles in SOD1-overexpressing animals compared with wild type. Autotomy was markedly worse in SOD1 transgenic mice than in wild-type animals. Histological evaluation revealed that the intensity of regeneration features, including numbers of GAP-43-positive growth cones, Schwann cells, and macrophages in the distal stump of the transected nerve, was also decreased in transgenic mice. Neuroma formation at the injury site was significantly more prominent in this group. Taken together, our findings suggest that SOD1 overexpression is deleterious for nerve regeneration processes and aggravates neuropathic pain-like state in mice. This can be at least partially ascribed to disturbed inflammatory reactions at the injury site.

Early thymic T cell development in young transgenic mice overexpressing human Cu/Zn superoxide dismutase, a model of Down syndrome.

Previous studies have shown that transgenic mice overexpressing Cu/Zn superoxide dismutase, a model of Down syndrome, exhibit premature thymic involution. We have performed a flow cytometry analysis of the developing thymus in these homozygous transgenic mice (hSOD1/hSOD1: Tg-SOD). Longitudinal follow-up analysis from day 3 to day 280 showed an early thymic development in Tg-SOD mice compared with controls. This early thymic development was associated with an increased migration of mature T cells to peripheral lymphoid organs. BrdU labeling showed no difference between Tg-SOD and control mice, confirming that the greater number of peripheral T cells in Tg-SOD mice was not due to extensive proliferation of these cells but rather to a greater pool of emigrant T cells in Tg-SOD.

Oxidized SOD1 alters proteasome activities in vitro and in the cortex of SOD1 overexpressing mice.

Premature ageing, one of the characteristics of Down syndrome (DS), may involve oxidative stress and impairment of proteasome activity. Transgenic mice overexpressing the human copper/zinc superoxide dismutase (SOD1) gene are one of the first murine models for DS and it has been shown that SOD1 overexpression might be either deleterious or beneficial. Here, we show a reduction in proteasome activities in the cortex of SOD1 transgenic mice and an associated increase in the content of oxidized SOD1 protein. As we demonstrate that in vitro oxidized SOD can inhibit purified proteasome peptidase activities, modified SOD1 might be partially responsible for proteasome inhibition shown in SOD1 transgenic mice.

Proteome analysis in hippocampus of mice overexpressing human Cu/Zn-superoxide dismutase 1.

Cu/Zn-superoxide dismutase 1 (SOD1), encoded on chromosome 21, is a key enzyme in metabolism of oxygen free radicals and oxidative stress. Transgenic mice overexpressing human SOD1 (Tg-hSOD1) are useful model for Down syndrome (trisomy 21) and familial amyotrophic lateral sclerosis (ALS). It was shown recently that Tg-hSOD1 mice develop a characteristic set of neurodegenerative changes in hippocampus and we therefore decided to study differential protein expression patterns, constructing a mouse hippocampal proteome map using two-dimensional electrophoresis (2-DE) with in-gel digestion of spots followed by matrix-assisted laser desorption/ionisation-time of flight (MALDI-TOF) identification and quantitatively compared protein profiles between non-transgenic mice, hemizygous and homozygous Tg-hSOD1 mice. In total 1056 spots were analysed, resulting in the identification of 445 polypeptides that were the products of 157 different genes. Among these a series of proteins involved in scaffolding, metabolism, signaling and other functions were deranged. Our findings suggest that overexpressed SOD1 directly or by generating reactive oxygen species may lead to aberrant protein expressional patterns that in turn may lead to or reflect neurodegeneration observed in this animal model.

Aberrant neuronal and mitochondrial proteins in hippocampus of transgenic mice overexpressing human Cu/Zn superoxide dismutase 1.

Mutations of Cu/Zn superoxide dismutase 1 (SOD1), a metalloenzyme catalyzing the conversion of superoxide anion to hydrogen peroxide (H(2)O(2)), are linked to motor neuron degeneration. Transgenic mouse strains overexpressing wild-type human SOD1 (Tg-SOD1) were shown to have mitochondrial swelling, vacuolization, or learning and memory deficits and are widely used for biochemical, genetic, and cognitive studies; this, along with the advent of advanced proteomic methods, made us investigate protein expression in hippocampus. Hippocampal tissues of wild-type, hemizygous, and homozygous Tg-SOD1 mice were isolated and used for two-dimensional gel electrophoresis with subsequent matrix-assisted laser desorption/ionization-time of flight identification. We identified several synaptosomal, neuronal, antioxidant, and mitochondrial proteins in hippocampus, and expression levels of syntaxin-binding protein 1, N-ethylmaleimide-sensitive factor, synaptosomal-associated protein 25, dynamin-1, neurofilament triplet L protein, neurofilament triplet M protein, neuronal tropomodulin, and neuronal protein 25 were significantly decreased in Tg-SOD1. None of the antioxidant proteins were altered except mouse SOD1. Mitochondrial ATP synthase alpha/beta chain and elongation factor Tu were aberrant in Tg-SOD1. We conclude that derangement of neuronal and mitochondrial proteins may indicate synaptosomal and neuronal loss in Tg-SOD1 hippocampus, already reported in morphological terms. This observation is of relevance to understanding brain deficits in Down syndrome, as SOD1 is encoded on chromosome 21.

Altered expression of hypothetical proteins in hippocampus of transgenic mice overexpressing human Cu/Zn-superoxide dismutase 1.

BACKGROUND: Cu/Zn-superoxide dismutase 1 (SOD1), encoded on chromosome 21, is a key enzyme in the metabolism of reactive oxygen species (ROS) and pathogenetically relevant for several disease states including Down syndrome (DS; trisomy 21). Systematically studying protein expression in human brain and animal models of DS we decided to carry out "protein hunting" for hypothetical proteins, i.e. proteins that have been predicted based upon nucleic sequences only, in a transgenic mouse model overexpressing human SOD1. RESULTS: We applied a proteomics approach using two-dimensional electrophoresis (2-DE) with in-gel digestion of spots followed by mass spectrometric (matrix-assisted laser desorption/ionization-time of flight) identification and quantification of hypothetical proteins using specific software. Hippocampi of wild type, hemizygous and homozygous SOD1 transgenic mice (SOD1-TGs) were analysed.We identified fourteen hypothetical proteins in mouse hippocampus. Of these, expression levels of 2610008O03Rik protein (Q9D0K2) and 4632432E04Rik protein (Q9D358) were significantly decreased (P < 0.05 and 0.001) and hypothetical protein (Q99KP6) was significantly increased (P < 0.05) in hippocampus of SOD1-TGs as compared with non-transgenic mice. CONCLUSIONS: The biological meaning of aberrant expression of these proteins may be impairment of metabolism, signaling and transcription machinery in SOD1-TGs brain that in turn may help to explain deterioration of these systems in DS brain.

Sleep-wake architecture in mouse models for Down syndrome.

Sleep-wake homeostasis is crucial for behavioral performances and memory both in the general population and in patients with learning disability, among whom were Down syndrome (DS) patients. We investigated, in mouse models of DS, cortical EEG and sleep-wake architecture under baseline conditions and after a 4-h sleep deprivation (SD). Young hemizygous mice (hSODwt/+) transgenic for the human CuZn superoxide dismutase (hSOD1) or for the human amyloid precursor protein (HuAPP(695); hAPPwt/+) were obtained on the same FVB/N inbred background. Baseline records for slow wave sleep (SWS) and wake (W) parameters were unchanged, whereas paradoxical sleep (PS) episode numbers were decreased and PS latency increased after lights off in hSODwt/+ mice versus controls. hSODwt/+ mice did not experience SWS or PS rebounds after SD but EEG activity in the delta-SWS activity (SWA) was enhanced. hAPPwt/+ mice exhibited no change in PS but an increase in W and a decrease in SWS before light transition as well as an increase in theta-power in PS and W. After SD, hAPPwt/+ mice exhibited SWS and PS rebounds as well as enhancement of SWA. We investigated also the nitrite/nitrate levels in all mice and found an increase in the brainstem of hSODwt/+ mice only versus control ones. These preliminary data provide useful results to investigate other genetically manipulated mice and to better understand the biochemical basis of sleep disorders in DS patients.