Reduced complement of dopaminergic neurons in the substantia nigra pars compacta of mice with a constitutive “low footprint” genetic knockout of alpha-synuclein

Previous studies of the alpha-synuclein null mutant mice on the C57Bl6 genetic background have revealed reduced number of dopaminergic neurons in their substantia nigra pars compacta (SNpc). However, the presence in genomes of the studied mouse lines of additional genetic modifications that affect expression of genes located in a close proximity to the alpha-synuclein-encoding Snca gene makes these data open to various interpretations. To unambiguously demonstrate that the absence of alpha-synuclein is the primary cause of the observed deficit of dopaminergic neurons, we employed a recently produced constituent alpha-synuclein knockout mouse line B6(Cg)-Sncatm1.2Vlb/J. The only modification introduced to the genome of these mice is a substitution of the first coding exon and adjusted short intronic fragments of the Snca gene by a single loxP site. We compared the number of dopaminergic neurons in the SNpc of this line, previously studied B6(Cg)-Sncatm1Rosl/J line and wild type littermate mice. A similar decrease was observed in both knockout lines when compared with wild type mice. In a recently published study we revealed no loss of dopaminergic neurons following conditional inactivation of the Snca gene in neurons of adult mice. Taken together, these results strongly suggest that alpha-synuclein is required for efficient survival or maturation of dopaminergic neurons in the developing SNpc but is dispensable for survival of mature SNpc dopaminergic neurons

Alterations in the nigrostriatal system following conditional inactivation of α-synuclein in neurons of adult and aging mice

The aetiology and pathogenesis of Parkinson’s disease (PD) are tightly linked to he gain-offunction of α-synuclein. However, gradual accumulation of α-synuclein aggregates in dopaminergic neurons of substantia nigra pars compacta (SNpc) leads to the depletion of the functional pool of soluble α-synuclein and therefore, creates a loss-of-function conditions, particularly in presynaptic terminals of these neurons. Studies of if and how this late-onset depletion of a protein involved in many important steps of neurotransmission contributes to PD progression and particularly, to worsening the nigrostriatal pathology at late stages of the disease are limited and obtained data are controversial. Recently we produced a mouse line for conditional knockout of the gene encoding α-synuclein and here we used its tamoxifen-inducible pan-neuronal inactivation to study consequences of the adult-onset (from the age of 6 months) and late-onset (from the age of 12 months) α-synuclein depletion to the nigrostriatal system. No significant changes of animal balance/coordination, the number of dopaminergic neurons in the SNpc and the content of dopamine and its metabolites in the striatum were observed after adult-onset α synuclein depletion but in ageing (18-month old) late-onset depleted mice we found significant reduction of major dopamine metabolites without changes to the content of dopamine itself. Our data suggest that this might be caused, at least partially, by reduced expression of aldehyde dehydrogenase ALDH1a1 and could lead to accumulation of toxic intermediates of dopamine catabolism. By extrapolating our findings to a potential clinical situation, we suggest that therapeutic downregulation of α-synuclein expression in PD patients is a generally safe option as it should not cause adverse side effects on the functionality of their nigrostriatal system. However, if started in aged patients, this type of therapy might trigger slight functional changes of the nigrostriatal system with potentially unwanted additive effect to already existing pathology

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration.

Multiple clinical and experimental evidence suggest that ALS and FTLD are members of a disease continuum. Pathological FUS inclusions have been observed in subsets of patients with these diseases but their anatomical distribution is different for two diseases. These structures are present in motor neurons in ALS cases but in cortical neurons in FTLD cases. Expression of a C‐terminally truncated form of human FUS causes an early onset and progressive motor neuron pathology in transgenic mice but only when these neurons express a certain level of this protein. Severe motor dysfunction and early lethality of mice with expression above this level prevent their use for studies of FTLD‐related pathology caused by expression of this form of FUS. In the present study we used another line of mice expressing the same protein but not developing any signs of motor system dysfunction due to substantially lower level of transgene expression in motor neurons. In a set of tests 5‐month old mice displayed certain behavioural abnormalities, including increased impulsivity, decreased anxiety and compromised social interaction, that recapitulate behaviour characteristics typically seen in FTLD patients

Interaction of two rivulets on the bottom side of an inclined plate

The flow of rivulets and droplets over the bottom side of inclined hydrophobic surface was studied in this work. Interacting of two nearby draining rivulets is investigated. Distilled water was used as the working liquid. The experiments were carried out on the bottom side of a smooth plate with the width of 440 mm and length of 1400 mm. The angle of plate surface deviation from the vertical was 14°. The switching centre consisted of two nozzles with diameter of 0.8 mm. Tubes placed perpendicularly plate surfaces on distance of 10 mm from each other. The experiments were carried out at the flow rates from 0.1 to 1.0 ml/s, and flow rate supported constant. The flow patterns were recorded video with the speed of 1200 fps. It was shown at a constant liquid flow rate at the nozzle exit the direction of and shape of the rivulet depend on maldistribution of the liquid flow rate along the rivulet. It is shown, that the regime of flow rivulet can be changed by interacting with another rivulet. Change regime of flow of rivulet occurs according to the laws defining character of a current of a liquid in rivulet

Steadiness of a “water bell” surface to a destruction at a flow around of the thin rods assembly

The experimental research of hydrodynamic stability of a dome-shaped film liquid at a flow around a thin plate has been carried out. Experiments were carry out with a film in shape a «water bell». The film was formed by a leak-in jet of water width 10 mm on a hard disk with diameter 14.5 mm. The width of a plate ζ changed from 0.05 to 3.5 mm. The plate placed along or across relative to the vector of velocity of a liquid in a film. Experiments have shown, that stability of a film of liquid at a flow around the plate is defined by velocity of water and a thickness of a film δ in front of the rod. It is shown, that for the appointed value of Reynolds number Reδ probably continuous flow at a flow around the plate, if Weber number Weζ less than threshold value. The criterion of steadiness a film of the «water bell» by a surface destruction at a flow around the rod is determined on the transverse size of the rod relative to the vector of velocity of a liquid

Steadiness of a “water bell” surface to a destruction at a flow around of the thin rods assembly

The experimental research of hydrodynamic stability of a dome-shaped film liquid at a flow around a thin plate has been carried out. Experiments were carry out with a film in shape a «water bell». The film was formed by a leak-in jet of water width 10 mm on a hard disk with diameter 14.5 mm. The width of a plate ζ changed from 0.05 to 3.5 mm. The plate placed along or across relative to the vector of velocity of a liquid in a film. Experiments have shown, that stability of a film of liquid at a flow around the plate is defined by velocity of water and a thickness of a film δ in front of the rod. It is shown, that for the appointed value of Reynolds number Reδ probably continuous flow at a flow around the plate, if Weber number Weζ less than threshold value. The criterion of steadiness a film of the «water bell» by a surface destruction at a flow around the rod is determined on the transverse size of the rod relative to the vector of velocity of a liquid

Dynamics of the vapor cavity in the vertical tube of a small diameter after boiling-up in aqueous lithium bromide solutions

Dynamics of a single vapor cavity, moving under gravity in a vertical tube of a small diameter, has been studied. The experiment was carried out in water and aqueous LiBr solution in a tube with the length of 400 mm and diameter of 16 mm. Experiments have shown that dynamics of the rising vapor cavity after-the-fact boiling-up of aqueous LiBr solution in a vertical tube of a small diameter for some initial conditions differs qualitatively from dynamics of a gas bubble rising in a pool. Dynamics of the vapor cavity in aqueous LiBr solution and in water demonstrates quantitative but not qualitative differences. During bubble rising in a small diameter tube to time dependence for volume and mass of the vapor bubble, the regimes with pulsations were detected

Dynamics of the vapor cavity in the vertical tube of a small diameter after boiling-up in aqueous lithium bromide solutions

Dynamics of a single vapor cavity, moving under gravity in a vertical tube of a small diameter, has been studied. The experiment was carried out in water and aqueous LiBr solution in a tube with the length of 400 mm and diameter of 16 mm. Experiments have shown that dynamics of the rising vapor cavity after-the-fact boiling-up of aqueous LiBr solution in a vertical tube of a small diameter for some initial conditions differs qualitatively from dynamics of a gas bubble rising in a pool. Dynamics of the vapor cavity in aqueous LiBr solution and in water demonstrates quantitative but not qualitative differences. During bubble rising in a small diameter tube to time dependence for volume and mass of the vapor bubble, the regimes with pulsations were detected

Interaction of two rivulets on the bottom side of an inclined plate

The flow of rivulets and droplets over the bottom side of inclined hydrophobic surface was studied in this work. Interacting of two nearby draining rivulets is investigated. Distilled water was used as the working liquid. The experiments were carried out on the bottom side of a smooth plate with the width of 440 mm and length of 1400 mm. The angle of plate surface deviation from the vertical was 14°. The switching centre consisted of two nozzles with diameter of 0.8 mm. Tubes placed perpendicularly plate surfaces on distance of 10 mm from each other. The experiments were carried out at the flow rates from 0.1 to 1.0 ml/s, and flow rate supported constant. The flow patterns were recorded video with the speed of 1200 fps. It was shown at a constant liquid flow rate at the nozzle exit the direction of and shape of the rivulet depend on maldistribution of the liquid flow rate along the rivulet. It is shown, that the regime of flow rivulet can be changed by interacting with another rivulet. Change regime of flow of rivulet occurs according to the laws defining character of a current of a liquid in rivulet

Transitional regimes of rivulet gravity flow on the bottom side of an inclined plate

The relevance of the discussed issue is caused by the need to use liquid films in heat exchangers (steam generators of coal-fired power station, compressors of drilling device, absorbers, distillation columns, heat pumps etc.). Along with searches and development of traditional sources (gas, oil) the promising trend is the use of energy stored in the reservoirs, ground, geothermal sources, industrial emissions (air, water, drains, etc.) and its transformation to heat by means of thermal pumps. Now thermal pumps are energetically effective heating equipment. The main aim of the research is to substantiate the selection of design models and programs for distributing devices of supplying absorbent solution based on the experimental data on rivulet flow on a hydrophobic surface at various orientation of a plate normal in relation to a gravity vector; to define the conditions under which the rivulet form and liquid stream direction change; to test the distributing devices, which are capable of stabilizing flow for non-stationary meandering rivulet. The methods used in the study. The visualization of flow regimes by a high-speed video for rivulet on an inclined surface is used. Using the methods of digital processing of video frame, the parameters (size, velocity, acceleration) of various flow patterns for form deviation along rivulet are defined. The results. The authors have obtained the experimental data of the rivulet flow regime on the bottom side of the inclined plate and determined the conditions for meandering rivulet. The data obtained allow testing the computing programs on adequacy of calculation results. The method of liquid flow stabilization at meandering rivulet is tested using the dripping device