Sleep and Alzheimer’s Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects

Background: Alzheimer’s disease (AD) was associated with sleep-related phenotypes (SRPs). Whether they share common genetic etiology remains largely unknown. We explored the shared genetics and causality between AD and SRPs by using high-definition likelihood (HDL), cross phenotype association study (CPASSOC), transcriptome wide association study (TWAS), and bidirectional Mendelian randomization (MR) in summary-level data for AD (n = 79145) and summary-level data for seven SRPs (sample size ranges from 345552 to 386577). Results: AD shared strong genetic basis with insomnia (rg = 0.20; P = 9.70×10-5), snoring (rg = 0.13; P = 2.45×10-3), and sleep duration (rg = -0.11; P = 1.18×10-3). CPASSOC identifies 31 independent loci shared between AD and SRPs, including four novel shared loci. Functional analysis and TWAS showed shared genes were enriched in liver, brain, breast, and heart tissues, and highlighted the regulatory role of immunological disorders, very-low-density lipoprotein particle clearance, triglyceride-rich lipoprotein particle clearance, chylomicron remnant clearance and positive regulation of T cell mediated cytotoxicity pathways. Protein-protein interaction analysis provided three potential drug target genes (APOE, MARK4 and HLA-DRA) that interacted with known FDA-approved drug target genes. CPASSOC and TWAS demonstrated three regions 11p11.2, 6p22.3 and 16p11.2 may account for the shared basis between AD and sleep duration or snoring. MR showed AD had causal effect on sleep duration (βIVW = -0.056, PIVW = 1.03×10-3). Conclusion: Our findings provide strong evidence of shared genetics and causation between AD and sleep, and advance our understanding the genetic overlap between them. Identifying shared drug targets and molecular pathways can be beneficial to treat AD and sleep disorders more efficiently.

Study on the Enhancement of Immune Function of Astaxanthin from Haematococcus pluvialis

This study was aimed at investigating the effect of astaxanthin on the immune function and its safety in mice. It was administered once daily at low, medium and high doses (4.2, 8.35, 16.70 mg/kg BW) to mice for 30 days. Subsequently, the spleen and thymus index, spleen lymphocyte transformation activity, delayed allergy reaction, amounts of antibody-producing cells, half-hemolytic value HC50, carbon particle clearance rate, macrophage phagocytosis, and natural killer cell (NK) activity were determined. Acute oral toxicity and genotoxicity tests were conducted to evaluate the safety of astaxanthin. Compared with the control group, medium and high doses of astaxanthin significantly increased the proliferation and transformation activities of spleen lymphocytes, activities of antibody-producing cells, serum hemolysin levels, and carbon particle clearance rate in mice (phagocytic index). High doses significantly improved delayed allergy reaction and NK cell activity. Results of acute oral toxicity and genotoxicity tests were negative. Gross anatomical observations and histopathological examination showed no abnormal changes associated with the treatments. In the article, it is confirmed that astaxanthin treatments significantly improve immune functions and show no toxic effects in the experimental doses.

IMMUNOSTIMULATORY ACTIVITY OF AQUEOUS LEAVES EXTRACT OF CASSIA OCCIDENTALIS ON INNATE AND ADAPTIVE IMMUNE RESPONSE IN MICE

Different types of plants have been studied for their roles in immunostimulation and treatment of other diseases. The study aimed at evaluating the stimulatory activity of aqueous leaf extract of Cassia occidentalis on innate and adaptive immune responses in mice. Study mice were grouped into five and studied for 21 days; group I (control group) received normal saline. While the treatment groups: group II - V received aqueous leaf extract of C. occidentalis at different concentrations (250, 500, 1000, and 1500) mg/kg body weight (BW). The mice were sensitized and challenged with sheep red blood cells (SRBCs) on day 13th and 18th of the treatment, respectively. On the 19th, 20th, and 21st days, the animals’ delayed-type hypersensitivity (DTH) responses in each group were measured using a digital Vernier calliper, and humoral immune response was evaluated using the haemagglutination (HA) antibody technique. Blood samples were collected for Carbonic particle clearance index (K) and phagocytic index of Macrophage (α). Organ weight index (g/100g) was also recorded (α). The result showed a significant increase in the Carbonic particle clearance index (p=0.02) and phagocytic index of Macrophage (p<0.0001) in a dose-dependent manner. The study revealed a statistically significant difference in HA titres across the five groups, (p=0.02), also the DTH shows a statistically significant difference across the time (24 hours, 48 hours, 72 hours), Wilks’ Lambda = 0. 291, F = 15. 86, p = 0. 0001. The aqueous leaf extract of C. occidentalis has an immunostimulatory effect on innate and adaptive immunity.

Effect of species diversity on particle clearance and productivity in farmed bivalves

Most bivalve farms are designed as monocultures, yet diverse communities often outperform monocultures in various metrics of ecosystem functioning, including particle clearance and productivity. This study tested the feasibility of bivalve polyculture by examining particle clearance, growth, and survival of 4 species that are economically important to the northeastern USA. Three particle depletion experiments were conducted to determine if more diverse bivalve assemblages had greater clearance rates than those which were less diverse. Different assemblages of Crassostrea virginica, Spisula solidissima, Mercenaria mercenaria, and Mya arenaria were supplied with a single cultured algal species, a mix of 2 cultured algal species, or natural seston. To determine how species richness affects bivalve productivity, growth and survival were monitored in a flow-through mesocosm experiment, which simulated farm conditions. In the cultured algae experiments, more diverse assemblages did not exhibit significantly greater clearance rates than those that were less diverse. Instead, the clearance rates of each species were additive across assemblages. Surprisingly, most assemblages did not display a significant preference for the larger microalgae species, Pavlova lutheri (4.0-6.0 µm), over Nannochloropsis oculata (1.90-3.75 µm). Most notably, when supplied with natural seston, the 4-species polyculture demonstrated a significantly greater tank-level clearance rate for particles <25 µm compared to most monocultures. However, nearly all productivity metrics were not significantly affected by species richness. This work suggests that some degree of complementarity exists among these bivalves, and that in non-food limited systems, these bivalves could be co-cultured without outcompeting one another.

Commentary: the chronic inhalation study in rats for assessing lung cancer risk may be better than its reputation

Recently, Borm and Driscoll published a commentary discussing grouping of Poorly Soluble particles of Low Toxicity (PSLTs) and the use of rats as an animal model for human hazard assessment of PSLTs (Particle and Fibre Toxicology (2019) 16(1):11). The commentary was based on the scientific opinion of several international experts on these topics. The general conclusion from the authors was a cautious approach towards using chronic inhalation studies in rats for human hazard assessment of PSLTs. This was based on evidence of inhibition of particle clearance leading to overload in the rats after high dose exposure, and a suggested over reactivity of rat lung cancer responses compared to human risk.As a response to the commentary, we here discuss evidence from the scientific literature showing that a) diesel exhaust particles, carbon black nanoparticles and TiO2 nanoparticles have similar carcinogenic potential in rats, and induce lung cancer at air concentrations below the air concentrations that inhibit particle clearance in rats, and b) chronic inhalation studies of diesel exhaust particles are less sensitive than epidemiological studies, leading to higher risk estimates for lung cancer. Thus, evidence suggests that the chronic inhalation study in rats can be used for assessing lung cancer risk insoluble nanomaterials.

Multi-scale spatial heterogeneity enhances particle clearance in airway ciliary arrays

Mucus clearance constitutes the primary defence of the respiratory system against viruses, bacteria and environmental insults [1]. This transport across the entire airway emerges from the integrated activity of thousands of multiciliated cells, each containing hundreds of cilia, which together must coordinate their spatial arrangement, alignment and motility [2, 3]. The mechanisms of fluid transport have been studied extensively at the level of an individual cilium [4, 5], collectively moving metachronal waves [6–10], and more generally the hydrodynamics of active matter [11, 12]. However, the connection between local cilia architecture and the topology of the flows they generate remains largely unexplored. Here, we image the mouse airway from the sub-cellular (nm) to the organ scales (mm), characterising quantitatively its ciliary arrangement and the generated flows. Locally we measure heterogeneity in both cilia organisation and flow structure, but across the trachea fluid transport is coherent. To examine this result, a hydrodynamic model was developed for a systematic exploration of different tissue architectures. Surprisingly, we find that disorder enhances particle clearance, whether it originates from fluctuations, heterogeneity in multiciliated cell arrangement or ciliary misalignment. This resembles elements of ‘stochastic resonance’ [13–15] in a self-assembled biological system. Taken together, our results shed light on how the microstructure of an active carpet [16, 17] determines its emergent dynamics. Furthermore, this work is also directly applicable to human airway pathologies [1], which are the third leading cause of deaths worldwide [18].