Postnatal Maturation of the Blood-Brain Barrier in Senescence-Accelerated OXYS Rats, Which Are Prone to an Alzheimer's Disease-like Pathology.

Alzheimer's disease (AD) is an old-age neurodegenerative disorder; however, AD predisposition may arise early in life. Vascular dysfunction makes a big contribution to AD development. Nonetheless, the possible role of early-life vascular dysfunction in AD development is still poorly investigated. Here, using OXYS rats as a suitable model of the most common (sporadic) type of AD, we investigated maturation of the blood-brain barrier (BBB) in the hippocampus and frontal cortex in the first 3 weeks of life. Using RNA-Seq data, we found an altered expression of BBB-associated genes in the middle of the first and second weeks of life in OXYS rats compared to control rats (Wistar strain). Moreover, by immunohistochemistry and electronic microscopy, we revealed a delay of vascularization and of subsequent pericyte coating of blood vessels in OXYS rats. These specific features were accompanied by an accelerated decrease in BBB permeability estimated using Evans blue dye. Notably, almost all of the observed differences from Wistar rats disappeared on postnatal day 20. Nonetheless, the observed features, which are characteristic of the postnatal period, may have long-term consequences and contribute to neurovascular dysfunction observed in OXYS rats late in life, thereby promoting early development of AD signs.

Effect of Abscisic Acid on Growth, Fatty Acid Profile, and Pigment Composition of the Chlorophyte Chlorella (Chromochloris) zofingiensis and Its Co-Culture Microbiome.

Microalga Chlorella (Chromochloris) zofingiensis has been gaining increasing attention of investigators as a potential competitor to Haematococcus pluvialis for astaxanthin and other xanthophylls production. Phytohormones, including abscisic acid (ABA), at concentrations relevant to that in hydroponic wastewater, have proven themselves as strong inductors of microalgae biomass productivity and biosynthesis of valuable molecules. The main goal of this research was to evaluate the influence of phytohormone ABA on the physiology of C. zofingiensis in a non-aseptic batch experiment. Exogenous ABA stimulated C. zofingiensis cell division, biomass production, as well as chlorophyll, carotenoid, and lipid biosynthesis. The relationship between exogenous ABA concentration and the magnitude of the observed effects was non-linear, with the exception of cell growth and biomass production. Fatty acid accumulation and composition depended on the concentration of ABA tested. Exogenous ABA induced spectacular changes in the major components of the culture microbiome of C. zofingiensis. Thus, the abundance of the representatives of the genus Rhodococcus increased drastically with an increase in ABA concentration, whereas the abundance of the representatives of Reyranella and Bradyrhizobium genera declined. The possibilities of exogenous ABA applications for the enhancing of the biomass, carotenoid, and fatty acid productivity of the C. zofingiensis cultures are discussed.

Delayed Formation of Neonatal Reflexes and of Locomotor Skills Is Associated with Poor Maternal Behavior in OXYS Rats Prone to Alzheimer's Disease-like Pathology.

Postnatal brain development is characterized by high plasticity with critical windows of opportunity where any intervention may positively or adversely influence postnatal growth and lead to long-lasting consequences later in life. Poor maternal care is among these interventions. Here, we found that senescence-accelerated OXYS rats prone to an Alzheimer's disease-like pathology are characterized by more passive maternal behavior and insufficient care for pups as compared to control (Wistar) rats. OXYS pups demonstrated a delay in physical development (of auricle detachment, of emergence of pelage and incisors, of eye opening, and of vaginal opening in females) and late manifestation of reflexes and locomotor skills. All observed behavioral abnormalities are connected either with poor coordination of limbs' movements or with a decrease in motivation and development of depression-like behavior. It is possible that their manifestations can be promoted by the features of maternal behavior of OXYS rats. Overall, these early-life events may have long-lasting consequences and contribute to neurodegeneration and development of the Alzheimer's disease-like pathology later in life.

Effect of 17ß-Estradiol on Growth and Biosynthesis of Microalgae Scenedesmus quadricauda (CPCC-158) and Duckweed Lemna minor (CPCC-490) Grown in Three Different Media.

As fish farm wastewaters have detectable levels of fish hormones, such as 17ß-estradiol (E2), an understanding of the influence of fish steroids on algal (Scenedesmus quadricauda) and duckweed (Lemna minor) physiology is relevant to the potential use of fishery wastewaters for microalgae and plant biomass production. The study was conducted using three types of media: Bold Basal Medium (BBM), natural fishery wastewater (FWW), and reconstituted fishery wastewater (RFWW) with the nutrient composition adjusted to mimic FWW. During the experiment, the media were aerated and changes in the pH and conductivity of the water were closely monitored. E2 promoted the growth of S. quadricauda and L. minor, with significant accumulation of high-value biomolecules at very low steroid concentrations. However, clear differences in growth performance were observed in both test cultures, S. quadricauda and L. minor, grown in different media, and the most effective hormone concentrations were evidently different for the algae and the plant.

Changes in Glial Support of the Hippocampus during the Development of an Alzheimer's Disease-like Pathology and Their Correction by Mitochondria-Targeted Antioxidant SkQ1.

Astrocytes and microglia are the first cells to react to neurodegeneration, e.g., in Alzheimer's disease (AD); however, the data on changes in glial support during the most common (sporadic) type of the disease are sparse. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, and Wistar rats (parental normal strain, control), we investigated hippocampal neurogenesis and glial changes during AD-like pathology. Using immunohistochemistry, we showed that the early stage of the pathology is accompanied by a lower intensity of neurogenesis and decreased astrocyte density in the dentate gyrus. The progressive stage is concurrent with reactive astrogliosis and microglia activation, as confirmed by increased cell densities and by the acquisition of cell-specific gene expression profiles, according to transcriptome sequencing data. Besides, here, we continued to analyze the anti-AD effects of prolonged supplementation with mitochondria-targeted antioxidant SkQ1. The antioxidant did not affect neurogenesis, partly normalized the gene expression profile of astrocytes and microglia, and shifted the resting/activated microglia ratio toward a decrease in the activated-cell density. In summary, both astrocytes and microglia are more vulnerable to AD-associated neurodegeneration in the CA3 area than in other hippocampal areas; SkQ1 had an anti-inflammatory effect and is a promising modality for AD prevention and treatment.

Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer's Disease.

Sporadic Alzheimer's disease (AD) is a severe disorder of unknown etiology with no definite time frame of onset. Recent studies suggest that middle age is a critical period for the relevant pathological processes of AD. Nonetheless, sufficient data have accumulated supporting the hypothesis of "neurodevelopmental origin of neurodegenerative disorders": prerequisites for neurodegeneration may occur during early brain development. Therefore, we investigated the development of the most AD-affected brain structures (hippocampus and prefrontal cortex) using an immunohistochemical approach in senescence-accelerated OXYS rats, which are considered a suitable model of the most common-sporadic-type of AD. We noticed an additional peak of neurogenesis, which coincides in time with the peak of apoptosis in the hippocampus of OXYS rats on postnatal day three. Besides, we showed signs of delayed migration of neurons to the prefrontal cortex as well as disturbances in astrocytic and microglial support of the hippocampus and prefrontal cortex during the first postnatal week. Altogether, our results point to dysmaturation during early development of the brain-especially insufficient glial support-as a possible "first hit" leading to neurodegenerative processes and AD pathology manifestation later in life.

Cognitive Training as a Potential Activator of Hippocampal Neurogenesis in the Rat Model of Sporadic Alzheimer's Disease.

There is a growing body of evidence that interventions like cognitive training or exercises prior to the manifestation of Alzheimer's disease (AD) symptoms may decelerate cognitive decline. Nonetheless, evidence of prevention or a delay of dementia is still insufficient. Using OXYS rats as a suitable model of sporadic AD and Wistar rats as a control, we examined effects of cognitive training in the Morris water maze on neurogenesis in the dentate gyrus in presymptomatic (young rats) and symptomatic (adult rats) periods of development of AD signs. Four weeks after the cognitive training, we immunohistochemically estimated densities of quiescent and amplifying neuronal progenitors, neuronal-lineage cells (neuroblasts and immature and mature neurons), and astrocytes in young and adult rats, and the amyloid precursor protein and amyloid-ß in adult rats. Reference memory was defective in OXYS rats. The cognitive training did not affect neuronal-lineage cells' density in either rat strain either at the young or adult age, but activated neuronal progenitors in young rats and increased astrocyte density and downregulated amyloid-ß in adult OXYS rats. Thus, to activate adult neurogenesis, cognitive training should be started before first neurodegenerative changes, whereas cognitive training accompanying amyloid-ß accumulation affects only astrocytic support.

Features of Postnatal Hippocampal Development in a Rat Model of Sporadic Alzheimer's Disease.

Aging is the major risk factor of the most common (∼95% of cases) sporadic Alzheimer's disease (AD). Accumulating data indicate middle age as a critical period for the relevant pathological processes, however, the question of when AD starts to develop remains open. It has been reported only recently that in the early postnatal period-when brain development is completing-preconditions for a decrease in cognitive abilities and for accelerated aging can form. Here, we hypothesized that specific features of early postnatal brain development may be considered some of the prerequisites of AD development at an advanced age. To test this hypothesis, we used OXYS rats, which are a suitable model of sporadic AD. The duration of gestation, litter size, and weight at birth were lower in OXYS rats compared to control Wistar rats. The shortened duration of gestation may result in developmental retardation. Indeed, we noted decreased locomotor activity and increased anxiety in OXYS rats already at a young age: possible signs of altered brain development. We demonstrated retardation of the peak of postnatal neurogenesis in the hippocampal dentate gyrus of OXYS rats. Delayed neuronal maturation led to alterations of mossy-fiber formation: a shortened suprapyramidal bundle and longer infrapyramidal bundle, less pronounced fasciculation of granule cells' axons, and smaller size and irregular shape of nuclei in the CA3 pyramidal layer. These changes were accompanied by altered astrocytic migration. The observed features of early development may be considered some of the risk factors of the AD-like pathology that manifests itself in OXYS rats late in life.

Alterations of hippocampal neurogenesis during development of Alzheimer's disease-like pathology in OXYS rats.

Neurogenesis is the key mechanism of neuronal plasticity in the adult mammalian brain. Alterations of neurogenesis happen concurrently with (and contribute to) development and progression of numerous neuropathological conditions including Alzheimer's disease (AD). Being the most common type of dementia, AD is studied extensively; however, the data concerning changes in neurogenesis in the pathogenesis of this disease are inconsistent. Here, using OXYS rats as a suitable model of the most common (sporadic) form of AD, we examined neurogenesis in the hippocampal dentate gyrus in early ontogenesis prior to appearance of any signs of neurodegeneration and during development and progression of AD-like pathology. We demonstrated retardation of hippocampal development in OXYS rats at an early age; this problem may contribute to the emergence of AD signs late in life. Manifestation and progression of AD-like pathology are accompanied by transcriptome changes affecting genes involved in neurogenesis in the hippocampus. These genes are associated with the extracellular matrix and angiogenesis; this observation points to alteration of a cellular microenvironment. This change along with an increased TrkA/p75NTR ratio of nerve growth factor receptors in the hippocampus may contribute to increased density of immature neurons that we observed at the progressive stage of AD-like pathology in OXYS rats. These changes may be considered a compensatory reaction intended to slow down AD-associated neurodegeneration at the progressive stage of the disease. Collectively, these data suggest that alterations of neurogenesis may not only accompany the course of Alzheimer's disease but also play a causative role in this disorder.

In situ visualisation of electromigration in Pt nanobridges at elevated temperatures.

We used a combination of in situ TEM, a MEMS-based heater as a substrate and a dedicated biasing sample holder to study the temperature dependence of electromigration in Pt nanobridges (500 nm wide, 15 nm high and 1000 nm long). We visualised changes in the nanobridges under both dynamic conditions, i.e. heating (substrate temperatures up to 660 K) and current passage. Our electromigration experiments at various substrate temperatures (100, 300, 420 and 660 K) show the same tendency: material transport occurs from the cathode to the anode side, which can be explained by the electron-wind force. In all cases the bridge breaks due to the formation of a neck closer to the cathode side. At 300, 420 and 660 K, voids and the neck form at the cathode contact pad simultaneously. The higher the temperature, the bigger the voids size. As expected, at higher temperatures a lower power is needed to break the nanobridge.

Spin switching in electronic devices based on 2D assemblies of spin-crossover nanoparticles.

Two-dimensional assemblies of triazole-based spin-crossover nanoparticles (SCO NPs) presenting different morphologies are prepared and electrically characterized. The thermal hysteresis loop in the electrical conductance near room temperature correlates with the NP morphologies and their 2D organization. The unprecedentedly large difference - up to two orders of magnitude - in the electrical conductance of the two spin states is of interest for applications.

Role of ischemic preconditioning in hepatic ischemia-reperfusion injury.

BACKGROUND: Investigation into less traumatic method of vascular occlusion during liver resection is the actual problem in hepatic surgery because of high level of complications such as liver failure. In this connection, the goal of our study was to determine the optimal model of vascular clamping. The research showed that vascular occlusion with ischemic preconditioning in the mode 5/10/15 the most delicate technique. METHODS: Forty white giant rabbits were divided randomly into four groups (n=10 in each group). In group I we used continuous Pringle maneuver by 30 min. In group II we used intermittent Pringle maneuver: 15 min of clamping/5 min of unclamping (reperfusion)/15 min of clamping. In group III we used intermittent Pringle maneuver with ischemic precondition: 5 min of ischemia/5 min of reperfusion, 10 min of ischemia/5 min of reperfusion/15 min of ischemia. Group IV (control group) is without hepatic ischemia. All animals were performed a liver biopsy at the end of the surgery. Five rabbits from each group underwent re-laparotomy on day 3 after surgery with biopsy samples being taken for studying reparative processes in liver parenchyma. RESULTS: Results of morphometric analysis were the best to illustrate different level of liver injury in the groups. Thus, there were 95.5% damaged hepatocytes after vascular occlusion in hepatic preparations in group I, 70.3% damaged hepatocytes in group II, and 42.3% damaged hepatocytes in group III. There were 5.3% damaged hepatocytes in the control group. CONCLUSIONS: Vascular occlusion with ischemic preconditioning in the mode 5/10/15 the most delicate technique that does not involve major structural injuries and functional disorders in the remnant liver. Thus, it is amenable to translation into clinical practice and may improve outcomes in liver resection with inflow vascular occlusion.

Macrophytes may not contribute significantly to removal of nutrients, pharmaceuticals, and antibiotic resistance in model surface constructed wetlands.

Outdoor shallow wetland mesocosms, designed to simulate surface constructed wetlands to improve lagoon wastewater treatment, were used to assess the role of macrophytes in the dissipation of wastewater nutrients, selected pharmaceuticals, and antibiotic resistance genes (ARGs). Specifically, mesocosms were established with or without populations of Typha spp. (cattails), Myriophyllum sibiricum (northern water milfoil), and Utricularia vulgaris (bladderwort). Following macrophyte establishment, mesocosms were seeded with ARG-bearing organisms from a local wastewater lagoon, and treated with a single pulse of artificial municipal wastewater with or without carbamazepine, clofibric acid, fluoxetine, and naproxen (each at 7.6µg/L), as well as sulfamethoxazole and sulfapyridine (each at 150µg/L). Rates of pharmaceutical dissipation over 28d ranged from 0.073 to 3.0d(-1), corresponding to half-lives of 0.23 to 9.4d. Based on calculated rate constants, observed dissipation rates were consistent with photodegradation driving clofibric acid, naproxen, sulfamethoxazole, and sulfapyridine removal, and with sorption also contributing to carbamazepine and fluoxetine loss. Of the seven gene determinants assayed, only two genes for both beta-lactam resistance (blaCTX and blaTEM) and sulfonamide resistance (sulI and sulII) were found in sufficient quantity for monitoring. Genes disappeared relatively rapidly from the water column, with half-lives ranging from 2.1 to 99d. In contrast, detected gene levels did not change in the sediment, with the exception of sulI, which increased after 28d in pharmaceutical-treated systems. These shallow wetland mesocosms were able to dissipate wastewater contaminants rapidly. However, no significant enhancement in removal of nutrients or pharmaceuticals was observed in mesocosms with extensive aquatic plant communities. This was likely due to three factors: first, use of naïve systems with an unchallenged capacity for nutrient assimilation and contaminant removal; second, nutrient sequestration by ubiquitous filamentous algae; and third, dominance of photolytic processes in the removal of pharmaceuticals, which overshadowed putative plant-related processes.

In situ TEM and STEM studies of reversible electromigration in thin palladium-platinum bridges.

We investigated the reversible electromigration in Pd-Pt nanobridges by means of in situ electron microscopy. Real-time nanometer-scale imaging with scanning transmission electron microscopy was used to determine the material transport. For high current densities (3-5 × 10(7) A cm(-2)), material transport occurs from the cathode towards the anode side, indicating a negative effective charge. The electromigration is dominated by atom diffusion at grain boundaries on the free surface. The reversal of material transport upon a change of the electric field direction could be the basis of a memristor.

The use of STEM imaging to analyze thickness variations due to electromigration-induced mass transport in thin polycrystalline nanobridges.

Scanning transmission electron microscopy (STEM) imaging is applied to analyze the electromigration-induced thickness variations of thin polycrystalline films. It is shown that a high angle annular dark field (HAADF) detector is required to minimize the effect of diffraction contact. A further reduction of the diffraction contrast can be obtained using a tilt series. A correlation between the intensity of the STEM signal obtained with the HAADF detector and the real thickness value was found by comparing corresponding STEM and AFM images. STEM in combination with a tilt series can determine the material distribution in polycrystalline films and can accurately analyze 1-3 nm gaps of nanoelectrodes formed by electromigration.

Gas jet transection of liver parenchima: experimental research.

BACKGROUND: There exists a great variety of liver parenchyma transection techniques. The objective of this research is to develop a new method of liver transection, and to compare it with the traditional ones. METHODS: An original gas jet transection method of biological tissues and the apparatus "Pneumojet" to make the method practicable were developed in our institute. Comparison between the efficiency of gas jet, water jet, ultrasonic methods of liver transection and clamp crushing technique were carried out on 24 mini-pigs. Pringle maneuver was not included. RESULTS: The mean blood loss was the smallest in the group of animals that had a gas jet transection (3.5±0.15 mL/cm(2)) but the highest in the clamp crushing technique group (5.5±0.46 mL/cm(2)). Indicators significantly showed the statistical difference (P<0.001). The transection speed was the highest in the Clamp crushing technique group (2.9±0.25 cm(2)/min) and was credibly higher than in the gas jet (2.4±0.16 cm(2)/min), ultrasonic (2.4±0.13 cm(2)/min) and water jet (2.5±0.14 cm(2)/min) transection groups. Compared with the water jet and ultrasonic methods of liver transection, the original method does not have statistically significant distinctions on the basic indexes of work. CONCLUSIONS: The research conducted proves high efficiency and safety of the gas jet transection method. The gas jet transection, therefore, could be recommended for further improvement and clinical application.

Postoperative aqueous outflow in the human eye after glaucoma filtration surgery: biofluidmechanical considerations.

To evaluate the possible postoperative outflow from the anterior chamber of the eye after filtration surgery, a mathematical model based on fluid mechanical principles and clinical data is proposed. Two ophthalmic surgical procedures, non-penetrating deep sclerectomy and trabeculectomy, were analyzed. Based on mathematical modeling, the amount of postoperative outflow through the fistula (after trabeculectomy) or membrane (after non-penetrating surgery) as well as the outflow through residual natural drainage pathways were calculated and compared. From our model, the following results were obtained: 1) if trabeculectomy is carried out in an eye with preoperative intraocular pressure (IOP) of 30 mm Hg and postoperative IOP=10 mm Hg, only 10% of aqueous utilizes the natural outflow pathway via the trabecular meshwork, whereas if non-penetrating surgery is carried out in the same eye with postoperative IOP=16 mm Hg, the outflow through the trabecular meshwork amounts to 35%. Thus, non-penetrating surgery provides more aqueous outflow along the natural outflow pathways than trabeculectomy. 2) Generally, the higher the postoperative IOP and/or the lower the preoperative IOP, the higher the amount of aqueous, which will utilize the natural outflow pathways postoperatively. 3) The reestablishment of aqueous production postoperatively in addition to other factors, such as wound healing, may be a reason for IOP increase during the postoperative period.

Drosophila DHR38 nuclear receptor is required for adult cuticle integrity at eclosion.

DHR38 is the only Drosophila member of the NR4A subclass of vertebrate nuclear receptors, which have been implicated in multiple biological pathways, including neuronal function, apoptosis, and metabolism. Although an earlier study identified three point mutations in DHR38, none of these were shown to be a null allele for the locus, leaving it unclear whether a complete loss of DHR38 function might uncover novel roles for the receptor. Here we show that a specific DHR38 null allele, DHR38(Y214), leads to fully penetrant pharate adult lethality, similar to the most severe phenotype associated with the EMS-induced mutations. DHR38(Y214) mutants display minor effects on ecdysone-regulated transcription at the onset of metamorphosis. In contrast, cuticle gene expression is significantly reduced in DHR38(Y214) mutant pupae. These studies define the essential functions of DHR38 and provide a genetic context for further characterization of its roles during development.

The effect of water chemistry on the acute toxicity of nickel to the cladoceran Daphnia pulex and the development of a biotic ligand model.

The goal of this study was to evaluate the influence of water chemistry parameters on the acute toxicity of waterborne Ni to Daphnia pulex in soft waters and using this information to develop a biotic ligand model. The effects of Ca, Mg, Na, K, Cl, pH (two differently buffered sets) and natural organic matter (NOM) from two sources were evaluated in standardized 48h acute toxicity tests. Increases in Ca2+ had a protective effect on Ni toxicity, suggesting that this ion competes with Ni at the site of biological uptake. Increased waterborne Mg2+ also reduced Ni toxicity, but to a lesser degree compared with Ca2+. EC50 values increased at higher pH when the organic buffer 3-morpholinepropanesulfonic acid was used to adjust test pH, however in tests series where pH was varied using HCO(3)(-) the results were equivocal. Other testing showed that Na, K and Cl did not influence the toxicity response of D. pulex to Ni. Complexation of Ni by NOM reduced toxicity but Nordic Reservoir NOM was much more protective compared to Suwannee River NOM. Geochemical modeling of organic matter complexation of Ni was done using the HydroQual Biotic Ligand Model (BLM ver. 2.3.3; research mode) and the Windermere Humic Aqueous Model (WHAM ver 6.0). Results showed dramatic differences between the two models in dissolved organic matter complexation. Modelling of Ni geochemistry for test solutions other than those containing NOM showed consistent and minor differences between the WHAM and the BLM. The latter model was used to develop a comprehensive prediction model of Ni toxicity. logK values developed for competitive cationic effects showed that Ca and Mg have a much higher protective effect in soft water compared to models developed for Daphnia magna in hard water. The BLM developed for this species in soft water provided good predictions of toxicity across a wide range of Ni concentrations but also highlighted the need for an improved understanding of the effects of NOM and pH on Ni toxicity in soft waters.

Essential roles for the Dhr78 orphan nuclear receptor during molting of the Drosophila tracheal system.

The Drosophila Dhr78 orphan nuclear receptor has been proposed to play a role in molting of the tracheal cuticle and regulate gene expression during the third larval instar, possibly in response to a novel systemic hormonal signal. Here, we show that there are no essential maternal functions for Dhr78 during development, and that mutants missing both maternal and zygotic Dhr78 function die primarily during second and third instar larval development. We show that defects in the tracheal system can be observed as early as the first instar, manifested as regions of fluid in the dorsal tracheal trunks. In addition, Dhr78 mutant tracheae show a highly penetrant defect in gas filling at the first-to-second instar larval molt. Dhr78 expression in only the tracheal system is sufficient to rescue the lethality of Dhr78 mutants, and selective inactivation of Dhr78 function in the tracheae by targeted RNAi is sufficient to result in tracheal defects. Finally, we see no evidence for widespread activation of the Dhr78 ligand binding domain in third instar larvae using the GAL4-LBD system, arguing against a systemic hormone for the receptor at this stage in development. Taken together, our results indicate that Dhr78 exerts its essential functions during molting of the tracheal cuticle in Drosophila.