Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism ...underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine’s antidepressant actions – such as cortical excitation, synaptogenesis, and involved molecular determinants – are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.
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CUPID-Mo is a bolometric experiment to search for neutrinoless double-beta decay (
0
ν
β
β
) of
100
Mo
. In this article, we detail the CUPID-Mo detector concept, assembly and installation in the ...Modane underground laboratory, providing results from the first datasets. The CUPID-Mo detector consists of an array of 20
100
Mo
-enriched 0.2 kg
Li
2
MoO
4
crystals operated as scintillating bolometers at
∼
20
mK
. The
Li
2
MoO
4
crystals are complemented by 20 thin Ge optical bolometers to reject
α
events by the simultaneous detection of heat and scintillation light. We observe a good detector uniformity and an excellent energy resolution of 5.3 keV (6.5 keV) FWHM at 2615 keV, in calibration (physics) data. Light collection ensures the rejection of
α
particles at a level much higher than 99.9% – with equally high acceptance for
γ
/
β
events – in the region of interest for
100
Mo
0
ν
β
β
. We present limits on the crystals’ radiopurity:
≤
3
μ
Bq/kg
of
226
Ra
and
≤
2
μ
Bq/kg
of
232
Th
. We discuss the science reach of CUPID-Mo, which can set the most stringent half-life limit on the
100
Mo
0
ν
β
β
decay in half-a-year’s livetime. The achieved results show that CUPID-Mo is a successful demonstrator of the technology developed by the LUMINEU project and subsequently selected for the CUPID experiment, a proposed follow-up of CUORE, the currently running first tonne-scale bolometric
0
ν
β
β
experiment.
The development and creation of a new generation vaccines based on recombinant proteins that assemble into virus-like particles (VLPs), as well as recombinant proteins in the form of nanoparticles, ...are promising directions in modern biotechnology. Due to their large size (20–200 nm) and multiplicity of viral antigenic determinants on the surface, VLPs can stimulate strong humoral and cellular immune responses. The main types of VLPs, as well as the features and disadvantages of the main expression systems used for their biosynthesis, are considered in this review. The main focus was on plant expression systems that ensure the biosynthesis of a target recombinant protein from a DNA matrix integrated into the nuclear or chloroplast genomes of a plant (stable expression) or from a matrix for temporary production of the target product (transient expression). Various approaches for increasing the yield of VLP-forming recombinant proteins, including fusion with a transit peptide that directed the protein into the chloroplast, were discussed. The possibility of accumulation of recombinant proteins expressed in plants and intended for creation of VLP-vaccines in another type of nanoparticle, protein bodies, using specific signal sequences was also considered.
Most the pharmaceutical proteins are derived not from their natural sources, rather their recombinant analogs are synthesized in various expression systems. Plant expression systems, unlike mammalian ...cell cultures, combine simplicity and low cost of procaryotic systems and the ability for posttranslational modifications inherent in eucaryotes. More than 50% of all human proteins and more than 40% of the currently used pharmaceutical proteins are glycosylated, that is, they are glycoproteins, and their biological activity, pharmacodynamics, and immunogenicity depend on the correct glycosylation pattern. This review examines in detail the similarities and differences between N- and O–glycosylation in plant and mammalian cells, as well as the effect of plant glycans on the activity, pharmacokinetics, immunity, and intensity of biosynthesis of pharmaceutical proteins. The main current strategies of glycoengineering of plant expression systems aimed at obtaining fully humanized proteins for pharmaceutical application are summarized.
We report the measurement of the two-neutrino double-beta ($2\nu\beta\beta$) decay of $^{100}$Mo to the ground state of $^{100}$Ru using lithium molybdate (\crystal) scintillating bolometers. The ...detectors were developed for the CUPID-Mo program and operated at the EDELWEISS-III low background facility in the Modane underground laboratory. From a total exposure of $42.235$ kg$\times$d, the half-life of $^{100}$Mo is determined to be $T_{1/2}^{2\nu}=7.12^{+0.18}_{-0.14}\,\mathrm{(stat.)}\pm0.10\,\mathrm{(syst.)}\times10^{18}$ years. This is the most accurate determination of the $2\nu\beta\beta$ half-life of $^{100}$Mo to date. We also confirm, with the statistical significance of $>3\sigma$, that the single-state dominance model of the $2\nu\beta\beta$ decay of $^{100}$Mo is favored over the high-state dominance model.
Mesencephalic astrocyte derived neurotrophic factor (MANF) is recognized as a dopaminergic neurotrophic factor, which can protect dopaminergic neurons from neurotoxic damage. However, little is known ...about the function of MANF during the vertebrate development. Here, we report that MANF expression is widespread during embryonic development and in adult organs analyzed by qPCR and in situ hybridization in zebrafish. Knockdown of MANF expression with antisense splice-blocking morpholino oligonucleotides resulted in no apparent abnormal phenotype. Nevertheless, the dopamine level of MANF morphants was lower than that of the wild type larvae, the expression levels of the two tyrosine hydroxylase gene transcripts were decreased and a decrease in neuron number in certain groups of th1 and th2 cells in the diencephalon region in MANF morphants was observed. These defects were rescued by injection of exogenous manf mRNA. Strikingly, manf mRNA could partly restore the decrease of th1 positive cells in Nr4a2-deficient larvae. These results suggest that MANF is involved in the regulation of the development of dopaminergic system in zebrafish.
► We report the developmental expression of mesencephalic astrocyte derived neurotrophic factor (MANF) in zebrafish. ► Specific translation inhibition of MANF reduces expression of tyrosine hydroxylases and dopamine levels. ► Specific groups of dopaminergic neurons were affected, whereas non-dopaminergic ones were not. ► manf mRNA could restore the decrease of th1 positive cells in Nr4a2-deficient larvae.
Study of the dielectric parameters of different materials attracts great attention of researchers as these parameters allow knowing various characteristics of different materials and chemical ...substances. This article presents studies of dielectric loss tangent of albumin protein water solution. Measurements of the frequency dependence of dielectric loss tangent in the range 10-106 Hz were performed. The experimental results showed non-linear frequency dependences of the dielectric loss tangent.
To find a high purity flux for low background experiments is one of the most challenging problems. In this work, we report the production process of a highly purified ammonium acetate flux solution ...for low background experiments. A sub-distilled method has been used to purify initial precursors from contamination for the syntheses of final product. As a result, a high purity ammonium acetate solution was synthesized with a minimum content of elements which collectively represent the main source of background radiation (K < 2.3 × 10
–8
g/g, Th < 2.6 × 10
–11
g/g and U < 1 × 10
–11
g/g). An Estimation of the impurity content of the product has been performed with Instrumental neutron activation analysis, inductively coupled plasma atomic emission spectrometry and inductively coupled plasma mass spectrometry.
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