We aimed to analyze the efficacy and safety of arketamine, the
R
(−)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD ...received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points CI 95% 13.6–27.0;
p
< 0.001; dissociation was nearly absent. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed.
Cells challenged by photosensitized oxidations face strong redox stresses and rely on autophagy to either survive or die. However, the use of macroautophagy/autophagy to improve the efficiency of ...photosensitizers, in terms of inducing cell death, remains unexplored. Here, we addressed the concept that a parallel damage in the membranes of mitochondria and lysosomes leads to a scenario of autophagy malfunction that can greatly improve the efficiency of the photosensitizer to cause cell death. Specific damage to these organelles was induced by irradiation of cells pretreated with 2 phenothiazinium salts, methylene blue (MB) and 1,9-dimethyl methylene blue (DMMB). At a low concentration level (10 nM), only DMMB could induce mitochondrial damage, leading to mitophagy activation, which did not progress to completion because of the parallel damage in lysosome, triggering cell death. MB-induced photodamage was perceived almost instantaneously after irradiation, in response to a massive and nonspecific oxidative stress at a higher concentration range (2 µM). We showed that the parallel damage in mitochondria and lysosomes activates and inhibits mitophagy, leading to a late and more efficient cell death, offering significant advantage (2 orders of magnitude) over photosensitizers that cause unspecific oxidative stress. We are confident that this concept can be used to develop better light-activated drugs.
Abbreviations: ΔΨm: mitochondrial transmembrane inner potential; AAU: autophagy arbitrary units; ATG5, autophagy related 5; ATG7: autophagy related 7; BAF: bafilomycin A
1
; BSA: bovine serum albumin; CASP3: caspase 3; CF: carboxyfluorescein; CTSB: cathepsin B; CVS: crystal violet staining; DCF: dichlorofluorescein; DCFH
2
: 2ʹ,7ʹ-dichlorodihydrofluorescein; DMMB: 1,9-dimethyl methylene blue; ER: endoplasmic reticulum; HaCaT: non-malignant immortal keratinocyte cell line from adult human skin; HP: hydrogen peroxide; LC3B-II: microtubule associated protein 1 light chain 3 beta-II; LMP: lysosomal membrane permeabilization; LTG: LysoTracker™ Green DND-26; LTR: LysoTracker™ Red DND-99; 3-MA: 3-methyladenine; MB: methylene blue; mtDNA: mitochondrial DNA; MitoSOX™: red mitochondrial superoxide probe; MTDR: MitoTracker™ Deep Red FM; MTO: MitoTracker™ Orange CMTMRos; MT-ND1: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1; MTT: methylthiazolyldiphenyl-tetrazolium bromide;
1
O
2
: singlet oxygen; OH
.
hydroxil radical; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PBS: phosphate-buffered saline; PI: propidium iodide; PDT: photodynamic therapy; PS: photosensitizer; QPCR: gene-specific quantitative PCR-based; Rh123: rhodamine 123; ROS: reactive oxygen species RTN: rotenone; SQSTM1/p62: sequestosome 1; SUVs: small unilamellar vesicles; TBS: Tris-buffered saline
Graphene-based materials present unique properties for electrochemical applications, and laser-induced conversion of polyimide to graphene is an emerging route to obtain a high-quality material for ...sensing. Herein we present compact and low-cost equipment constructed from an open-source 3D printer at which a 3.5-W visible (449 nm) laser was adapted to fabricate laser-induced graphene (LIG) electrodes from commercial polyimide, which resulted in electron transfer kinetic (
k
0
) of 5.6 × 10
−3
cm s
−1
and reproducibility calculated by relative standard deviation (RSD < 5%) from cyclic voltammograms of Fe(CN)
6
3−/4−
using 5 different electrodes. LIG electrodes enabled the simultaneous voltammetric determination of uric acid (+ 0.1 V vs. pseudo-reference) and nitrite (+ 0.4 V vs pseudo-reference), with limit of detection (LOD) values of 0.07 and 0.27 µmol L
−1
, respectively. Amperometric measurements for the detection of H
2
O
2
(applying + 0.0 V vs. Ag|AgCl|KCl
(sat.)
) after Prussian blue (PB) modification and ciprofloxacin (applying + 1.2 V vs. Ag|AgCl|KCl
(sat.)
) were performed under flow conditions, which confirmed the high stability of LIG and LIG-PB surfaces. The LOD values were 1.0 and 0.2 µmol L
−1
for H
2
O
2
and ciprofloxacin, respectively. The RSD values (< 12%) obtained for the analysis using three different electrodes attested the precision of LIG electrodes manufactured in two designs. No sample matrix effects on the determination of ciprofloxacin in milk samples were observed (recoveries between 84 and 96%). The equipment can be built with less than $300 and each LIG electrode costs less than $0.01.
Graphical abstract
ABSTRACT
The Southern Photometric Local Universe Survey (S-PLUS) is imaging ∼9300 deg2 of the celestial sphere in 12 optical bands using a dedicated 0.8 m robotic telescope, the T80-South, at the ...Cerro Tololo Inter-american Observatory, Chile. The telescope is equipped with a 9.2k × 9.2k e2v detector with 10 $\rm {\mu m}$ pixels, resulting in a field of view of 2 deg2 with a plate scale of 0.55 arcsec pixel−1. The survey consists of four main subfields, which include two non-contiguous fields at high Galactic latitudes (|b| > 30°, 8000 deg2) and two areas of the Galactic Disc and Bulge (for an additional 1300 deg2). S-PLUS uses the Javalambre 12-band magnitude system, which includes the 5 ugriz broad-band filters and 7 narrow-band filters centred on prominent stellar spectral features: the Balmer jump/OII, Ca H + K, H δ, G band, Mg b triplet, H α, and the Ca triplet. S-PLUS delivers accurate photometric redshifts (δz/(1 + z) = 0.02 or better) for galaxies with r < 19.7 AB mag and z < 0.4, thus producing a 3D map of the local Universe over a volume of more than $1\, (\mathrm{Gpc}/h)^3$. The final S-PLUS catalogue will also enable the study of star formation and stellar populations in and around the Milky Way and nearby galaxies, as well as searches for quasars, variable sources, and low-metallicity stars. In this paper we introduce the main characteristics of the survey, illustrated with science verification data highlighting the unique capabilities of S-PLUS. We also present the first public data release of ∼336 deg2 of the Stripe 82 area, in 12 bands, to a limiting magnitude of r = 21, available at datalab.noao.edu/splus.
ABSTRACT
The structure of the Small Magellanic Cloud (SMC) is very complex, in particular in the periphery that suffers more from the interactions with the Large Magellanic Cloud (LMC). A wealth of ...observational evidence has been accumulated revealing tidal tails and bridges made up of gas, stars, and star clusters. Nevertheless, a full picture of the SMC outskirts is only recently starting to emerge with a 6D phase-space map plus age and metallicity using star clusters as tracers. In this work, we continue our analysis of another outer region of the SMC, the so-called West Halo, and combined it with the previously analysed Northern Bridge. We use both structures to define the Bridge and Counter-bridge trailing and leading tidal tails. These two structures are moving away from each other, roughly in the SMC–LMC direction. The West Halo form a ring around the SMC inner regions that goes up to the background of the Northern Bridge shaping an extended layer of the Counter-bridge. Four old Bridge clusters were identified at distances larger than 8 kpc from the SMC centre moving towards the LMC, which is consistent with the SMC–LMC closest distance of 7.5 kpc when the Magellanic Bridge was formed about 150Myr ago; this shows that the Magellanic Bridge was not formed only by pulled gas, but it also removed older stars from the SMC during its formation. We also found age and metallicity radial gradients using projected distances on sky, which are vanished when we use the real 3D distances.
This study presents the first molecular epidemiological data for Plasmodium malariae and Plasmodium brasilianum from Brazil obtained from different hosts and uses them to explore the genetic ...diversity in relation to geographical origin and hosts. Display omitted
► Plasmodium malariae is a protozoan parasite that causes malaria in humans. ► Plasmodium brasilianum is a parasite that infects New World monkeys. ► Until now these parasites are considered genetically indistinguishable. ► By using microsatellite genotyping, we found a restricted polymorphism of P. malariae. ► P. brasilianum from simian samples presented a greater diversity. ► Our data support the origin of P. malariae from P. brasilianum.
Plasmodium malariae is a protozoan parasite that causes malaria in humans and is genetically indistinguishable from Plasmodium brasilianum, a parasite infecting New World monkeys in Central and South America. P. malariae has a wide and patchy global distribution in tropical and subtropical regions, being found in South America, Asia, and Africa. However, little is known regarding the genetics of these parasites and the similarity between them could be because until now there are only a very few genomic sequences available from simian Plasmodium species. This study presents the first molecular epidemiological data for P. malariae and P. brasilianum from Brazil obtained from different hosts and uses them to explore the genetic diversity in relation to geographical origin and hosts. By using microsatellite genotyping, we discovered that of the 14 human samples obtained from areas of the Atlantic forest, 5 different multilocus genotypes were recorded, while in a sample from an infected mosquito from the same region a different haplotype was found. We also analyzed the longitudinal change of circulating plasmodial genetic profile in two untreated non-symptomatic patients during a 12-months interval. The circulating genotypes in the two samples from the same patient presented nearly identical multilocus haplotypes (differing by a single locus). The more frequent haplotype persisted for almost 3 years in the human population. The allele Pm09-299 described previously as a genetic marker for South American P. malariae was not found in our samples. Of the 3 non-human primate samples from the Amazon Region, 3 different multilocus genotypes were recorded indicating a greater diversity among isolates of P. brasilianum compared to P. malariae and thus, P. malariae might in fact derive from P. brasilianum as has been proposed in recent studies. Taken together, our data show that based on the microsatellite data there is a relatively restricted polymorphism of P. malariae parasites as opposed to other geographic locations.
A new fluorinated chalcone (
E
)-3-(2,6-difluorophenyl)-1-(4-fluorophenyl)prop-2-en-1-one was synthesized in 90% yield and crystallized by a slow evaporation technique. Its full structural ...characterization and purity were determined by scanning electron microscopy, infrared spectroscopy, gas chromatography-mass spectrometry,
1
H,
13
C and
19
F nuclear magnetic resonance, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), Raman microspectroscopy, UV-Vis absorption spectroscopy, single crystal X-ray diffraction (XRD) and Hirshfeld surface (HS) analysis. The fluorinated chalcone crystallized in centrosymmetric space group
P
2
1
/
c
stabilized by the C-H O and C-H F interactions and the π π contact. The crystalline environment was simulated through the supermolecule approach where a bulk with 378 000 atoms was built. The electric parameters were calculated at the DFT/CAM-B3LYP/6-311++G(d,p) level as function of the electric field frequency. The macroscopic parameters such as linear refractive index and third-order nonlinear susceptibility (
χ
(3)
) were calculated, and the results were compared with experimental data obtained from the literature. The
χ
(3)
-value for the chalcone crystal is 369.294 × 10
−22
m
2
V
−2
, higher than those obtained from a few similar types of molecule, showing that the chalcone crystal can be considered as a nonlinear optical material. Also, molecular theoretical calculations such as infrared spectrum assignments, frontier molecular orbital analysis and MEP were implemented, revealing that the most positive region is around the hydrogen atoms of the aromatic rings, and electrophilic attack occurs on the carbonyl group.
A new fluorinated chalcone (
E
)-3-(2,6-difluorophenyl)-1-(4-fluorophenyl)prop-2-en-1-one was synthesized in 90% yield and crystallized by a slow evaporation technique.
There have been significant advances in the biological use of hypervalent selenium and tellurium compounds as cysteine protease inhibitors. However, the full understanding of their reaction ...mechanisms for and cysteine proteases inhibition is still elusive. Kinetic studies suggest an irreversible inhibition mechanism, which was explained by forming a covalent bond between the enzyme sulfhydryl group and the chalcogen atom at its hypervalent state (+4). In this work, we performed a theoretical investigation using density functional theory to propose the active inhibitor form in an aqueous solution. To this end, we investigated chloride ligand exchange reactions by oxygen and sulfur nucleophiles on hypervalent selenium and tellurium compounds. All tetra‐ and tri‐coordinated chalcogen compounds and distinct protonation states of the nucleophiles were considered, totaling 34 unique species, 7 nucleophiles, and 155 free energies reactions. We discovered that chloride is easily replaced by a nonprotonated nucleophile (SH− or OH−) in R2SeCl2. We also found that tri‐coordinate species are more stable than their tetra‐coordinate counterparts, with selenoxide (R2SeO) protonation being strongly exergonic in acid pH. The thermodynamic and kinetic results suggest that the protonated selenoxide (R2SeOH+) is the most probable active chemical species in biological media. The computed energetic profiles paint a possible picture for selenuranes activity, with successive exergonic steps leading to a covalent inhibition of thiol‐dependent enzymes, like cysteine proteases. A second pathway has also been uncovered, with a direct reaction to chalcogenonium cation (R2SeCl+) as the inhibition step. Tellurium compounds showed similar trends but formed telluroxide in a pH‐independent fashion.
Selenium and Tellurium hypervalent organic derivatives are potent cysteine protease inhibitors with activity in several disease models. In this work, the reactions pathways leading to probable active species, chalcogenoxides, are enlightened by thermodynamic and kinetics theoretical calculations.
ABSTRACT
The morphological diversity of galaxies is a relevant probe of galaxy evolution and cosmological structure formation. However, in large sky surveys, even the morphological classification of ...galaxies into two classes, like late-type (LT) and early-type (ET), still represents a significant challenge. In this work, we present a Deep Learning (DL) based morphological catalogue built from images obtained by the Southern Photometric Local Universe Survey (S-PLUS) Data Release 3 (DR3). Our DL method achieves a purity rate of 98.5 per cent in accurately distinguishing between spiral, as part of the larger category of LT galaxies, and elliptical, belonging to ET galaxies. Additionally, we have implemented a secondary classifier that evaluates the quality of each galaxy stamp, which allows to select only high-quality images when studying properties of galaxies on the basis of their DL morphology. From our LT/ET catalogue of galaxies, we recover the expected colour–magnitude diagram in which LT galaxies display bluer colours than ET ones. Furthermore, we also investigate the clustering of galaxies based on their morphology, along with their relationship to the surrounding environment. As a result, we deliver a full morphological catalogue with 164 314 objects complete up to rpetro < 18, covering ∼1800 deg2, from which ∼55 000 are classified as high reliability, including a significant area of the Southern hemisphere that was not covered by previous morphology catalogues.
PDF
