Parkinson's disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly ...based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1
,2
,6
)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured näive dopamine neurons; (2) supported the survival of MPP
-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood-brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug.
Several anti-cytokine therapies were tested in the randomized trials in hospitalized patients with severe acute respiratory syndrome coronavirus 2 infection (COVID-19). Previously, dexamethasone ...demonstrated a reduction of case-fatality rate in hospitalized patients with respiratory failure. In this matched control study we compared dexamethasone to a Janus kinase inhibitor, ruxolitinib.
The matched cohort study included 146 hospitalized patients with COVID-19 and oxygen support requirement. The control group was selected 1:1 from 1355 dexamethasone-treated patients and was matched by main clinical and laboratory parameters predicting survival. Recruitment period was April 7, 2020 through September 9, 2020.
Ruxolitinib treatment in the general cohort of patients was associated with case-fatality rate similar to dexamethasone treatment: 9.6% (95% CI 4.6-14.6%) vs 13.0% (95% CI 7.5-18.5%) respectively (p = 0.35, OR = 0.71, 95% CI 0.31-1.57). Median time to discharge without oxygen support requirement was also not different between these groups: 13 vs. 11 days (p = 0.13). Subgroup analysis without adjustment for multiple comparisons demonstrated a reduced case-fatality rate in ruxolitnib-treated patients with a high fever (≥ 38.5 °C) (OR 0.33, 95% CI 0.11-1.00). Except higher incidence of grade 1 thrombocytopenia (37% vs 23%, p = 0.042), ruxolitinib therapy was associated with a better safety profile due to a reduced rate of severe cardiovascular adverse events (6.8% vs 15%, p = 0.025). For 32 patients from ruxolitinib group (21.9%) with ongoing progression of respiratory failure after 72 h of treatment, additional anti-cytokine therapy was prescribed (8-16 mg dexamethasone).
Ruxolitinib may be an alternative initial anti-cytokine therapy with comparable effectiveness in patients with potential risks of steroid administration. Patients with a high fever (≥ 38.5 °C) at admission may potentially benefit from ruxolitinib administration. Trial registration The Ruxolitinib Managed Access Program (MAP) for Patients Diagnosed With Severe/Very Severe COVID-19 Illness NCT04337359, CINC424A2001M, registered April, 7, 2020. First participant was recruited after registration date.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We studied the effect of reduced tryptophan hydroxylase (TPH) activity and short daylight exposure on the behavior and the 5-HT system of the brain in
D. rerio
. Male and female
D. rerio
were exposed ...for 30 days to standard (12:12 h light:dark) and short (4:20 h light:dark) photoperiods in the presence or absence of TPH inhibitor (
p
-chlorophenylalanine, pCPA, 5 mg/liter). On day 31, the fish behavior in the “novel tank diving” test, their sex and body weight were determined, and the levels of pCPA, 5-HT, and its metabolite 5-HIAA were measured by HPLC; the levels of the key genes encoding metabolism enzymes (
Tph1a
,
Tph1b
,
Tph2
, and
Mao
) and receptors of 5-HT (
Htr1aa
,
Htr2aa
) were assessed by real-time PCR with reverse transcription. The short daylight exposure caused masculinization of females, reduced body weight, and motor activity in the “novel tank diving” test, but did not affect the 5-HT system of the brain. Long-term pCPA treatment had no effect on sex and body weight, significantly reduced the 5-HIAA level, but increased
Tph1a
and
Tph2
gene expression in the brain. No effects of the interaction of short daylight and pCPA exposure on the sex, body weight, behavior, and 5-HT system of the brain were found. Thus, a moderate decrease in TPH activity cannot potentiate the negative effects of short daylight exposure on the sex, body weight, behavior, and 5-HT system of
D. rerio
.
•EthoStudio and 3-D sensor were applied for automated tracking of minpig behavior.•3-D sensor can trace white, black and agouti minipigs in the open field test.•Agouti minipigs explored arena more ...than white or black animals.•3-D imaging system can be used to study behavior of farm-bred animals.
The minipig is a promising model in neurobiology and psychopharmacology. However, automated tracking of minipig behavior is still unresolved problem.
The study was carried out on white, agouti and black (or spotted) minipiglets (n=108) bred in the Institute of Cytology and Genetics. New method of automated tracking of minipig behavior is based on Microsoft Kinect 3-D image sensor and the 3-D image reconstruction with EthoStudio software. The algorithms of distance run and time in the center evaluation were adapted for 3-D image data and new algorithm of vertical activity quantification was developed.
The 3-D imaging system successfully detects white, black, spotted and agouti pigs in the open field test (OFT). No effect of sex or color on horizontal (distance run), vertical activities and time in the center was shown. Agouti pigs explored the arena more intensive than white or black animals, respectively. The OFT behavioral traits were compared with the fear reaction to experimenter. Time in the center of the OFT was positively correlated with fear reaction rank (ρ=0.21, p<0.05). Black pigs were significantly more fearful compared with white or agouti animals.
The 3-D imaging system has three advantages over existing automated tracking systems: it avoids perspective distortion, distinguishes animals any color from any background and automatically evaluates vertical activity.
The 3-D imaging system can be successfully applied for automated measurement of minipig behavior in neurobiological and psychopharmacological experiments.
Mitophagy: Link to cancer development and therapy Kulikov, Andrey V.; Luchkina, Ekaterina A.; Gogvadze, Vladimir ...
Biochemical and biophysical research communications,
01/2017, Letnik:
482, Številka:
3
Journal Article
Recenzirano
Mitophagy, the selective degradation of mitochondria via the autophagic pathway, is a vital mechanism of mitochondrial quality control in cells. Mitophagy is responsible for the removal of ...malfunctioning or damaged mitochondria, which is essential for normal cellular physiology and tissue development. Pathways involved in the regulation of mitophagy, tumorigenesis, and cell death are overlapping in many cases and may be triggered by common upstream signals, which converge at the mitochondria. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses can either stimulate or suppress tumorigenesis. Thus, the analysis of crosstalk among the processes of mitophagy, cell death and tumorigenesis is important for the identification of targets responsible for the stimulation of cell death and selective elimination of cancer cells. In the present review, we analyze the mechanisms of mitophagy regulation, the pathways underlying the utilization of damaged mitochondria, and how intervention with mitophagy can affect tumor cell resistance to treatment.
•Mitophagy, the selective degradation of mitochondria via the autophagic pathway.•Intervention with mitophagy can affect tumor cell resistance to treatment.•A cross-talk between mitophagy, tumorigenesis and cell death exists.
A new algorithm for long-term continuous computer recording and analysis of motor activity of a group of zebrafish in the home tank has been developed. The movements of a group of
Danio rerio
during ...the entire light period and for several days are recorded at a frequency of 1 frame/sec in the form of short (15 min) files. Then these files are analyzed by the unique DanioStudo software, which, using a threshold algorithm and appropriate masks, calculates for each frame the sum of pixels associated with fish (the sum of fish silhouettes), and for two consecutive frames, the sum of altered pixels (the sum of altered fish silhouettes). The following indexes are calculated: the rate of sum of silhouettes alteration as the ratio of the sum of altered silhouettes to the sum of silhouettes (1) and the time spent in the selected area of the home tank as the ratio of the sum of silhouettes in this area to the sum of silhouettes in the entire tank (2). The mean rate of silhouette alteration correlates to the length of the path travelled by the fish and, therefore, serves as a correct measure of the motor activity of a group of fish. Using these algorithms, completely new data were obtained: it was shown that the motor activity of fish remains constant throughout the entire light period, but depends on the size of the home tank. The proposed approach, together with the DanioStudio software, can be effective in studying the dynamics of changes in the behavior of fish under long-term exposure to short daylight, drugs and toxic substances.
Herein, we present a systematic study of the photochemical behavior of a set of fullerene compounds bearing various organic addends attached to the fullerene cage. It has been shown that the yield of ...photodimerization products strongly depends on the structure and electronic properties of the material, primarily the electron affinity (acceptor strength) of the modified fullerene core. This finding being inconsistent with the conventional 2+2cycloaddition mechanism and pointed to an alternative pathway. This proposed pathway involves photoinduced charge separation followed by back charge transfer events leading to the efficient generation of triplet excitons, which are responsible for the formation of dimerized species. The light‐induced charge separation pathway was confirmed by electron spin resonance spectroscopy and was supported by theoretical calculations. The revealed mechanism allows one to control the photochemical behavior of the fullerene derivatives via rational structural engineering: some of the compounds were shown to be fully resistant to photodimerization, which makes them promising candidates in the development of stable organic photovoltaics. Furthermore, this approach could be used to suppress back charge transfer in donor‐acceptor blends and hinder the formation of triplet excitons which represents one a major energy loss channel in the current generation of organic solar cells.
A systematic study of a series of differently functionalized fullerene derivatives reveals that its light‐induced dimerization involves charge separation between the organic addend and carbon cage coupled with a back charge transfer (BCT) yielding reactive triplet states. This pathway appears to be general and provides a new tool to control the photostability organic semiconductors used as materials in solar cells.
A novel neutral tetranitrosyl iron complex {Fe(H
2
O)
4
2+
FeR
2
(NO)
2
2
2−
}·4H
2
O (
1
) with R = 5-(3-pyridyl)-4
H
-1,2,4-triazole-3-thiolyls (C
7
H
5
N
4
S), which is a supramolecular ...ensemble, has been synthesized and studied. As follows from X-ray diffraction analysis, this is an octahedral Fe
2+
complex (Lewis acid) with two monoanionic dinitrosyl groups FeR
2
(NO)
2
−
(Lewis base) and 4 water molecules as the ligands. As follows from Mössbauer spectra, the coordinating Fe
2+
ion is in a low-spin state
S
= 0, and the dinitrosyl Fe
+
ion is in a low-spin state
S
= 1/2. According to the data of EPR spectroscopy, mass-spectrometry and amperometry, complex
1
in solution forms dinitrosyl particles of Fe(C
7
H
6
N
4
S-H)
2
(NO)
2
−
composition, which are responsible for NO generation. In addition, complex
1
was shown to be a 5-6 times more efficient phosphodiesterase (PDE) inhibitor at 5 × 10
−5
M and 10
−4
M concentrations than its thioligand. Probable binding sites of the FeR
2
(NO)
2
−
ligand for the bovine PDE1B model have been determined by molecular docking and quantum-chemical calculations.
A novel neutral tetranitrosyl iron complex {Fe(H
2
O)
4
2+
FeR
2
(NO)
2
2
2−
}·4H
2
O (
1
) with R = 5-(3-pyridyl)-4
H
-1,2,4-triazole-3-thiolyls (C
7
H
5
N
4
S), which is a supramolecular ensemble, has been synthesized and studied.
The lion's share of bacteria in various environments cannot be cloned in the laboratory and thus cannot be sequenced using existing technologies. A major goal of single-cell genomics is to complement ...gene-centric metagenomic data with whole-genome assemblies of uncultivated organisms. Assembly of single-cell data is challenging because of highly non-uniform read coverage as well as elevated levels of sequencing errors and chimeric reads. We describe SPAdes, a new assembler for both single-cell and standard (multicell) assembly, and demonstrate that it improves on the recently released E+V-SC assembler (specialized for single-cell data) and on popular assemblers Velvet and SoapDeNovo (for multicell data). SPAdes generates single-cell assemblies, providing information about genomes of uncultivatable bacteria that vastly exceeds what may be obtained via traditional metagenomics studies. SPAdes is available online ( http://bioinf.spbau.ru/spades ). It is distributed as open source software.
•Rh/Ce0.75Zr0.25O2/Al2O3/FeCrAl wire mesh composite catalyst after 250 h on stream.•Autothermal reforming (ATR) of diesel, gasoline, iso-octane and n-hexadecane.•Catalyst coking by fibrous carbon ...growth under diesel ATR conditions.•Coking was attributed to contamination by iron.•No morphology and microstructure degradation of catalytic coating was identified.
Front and end zones of Rh/Ce0.75Zr0.25O2−δ-ƞ-Al2O3/FeCrAl wire mesh catalytic module were studied by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) techniques after more than 250 h on stream under hydrocarbon fuels steam (SR) and autothermal reforming (ATR) conditions. Catalyst coking by fibrous carbon growth under diesel ATR conditions was confirmed. This process was mainly located on the surface of the catalytic coating and did not induce exfoliation and damage of coating. Coking was attributed to contamination by iron, which was confirmed by TEM and energy-dispersive X-ray spectroscopy (EDX). Despite catalyst carbonization, the composite catalyst was shown to be stable and regeneratable under hydrocarbon ATR and SR conditions, no morphology and microstructure degradation was identified in both front and end zones of the monolith.
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