Current pharmacological treatments for Parkinson’s disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible ...dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
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•Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD•Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits•Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation
Heo et al. report that astrocytic GABA-mediated aberrant tonic inhibition of DA neurons leads to a reduction in TH expression and dopamine production, causing dormant DA neurons and motor deficits. Blocking astrocytic GABA synthesis by MAO-B inhibition or optogenetic activation of dormant DA neurons reverses PD pathology.
FeCrV alloy (high-wear-resistance steel or HWS) has been extensively used in additive manufacturing for hardfacing and repairing owing to its excellent hardness, superior weldability, and wear ...resistance. This alloy must possess superior mechanical property under harsh environments, such as friction and wear, to facilitate its application in repairing gears and strengthening the surface of a die locally. HWS deposited by directed energy deposition was subjected to heat treatment by quenching and tempering (QT) to improve the mechanical property and investigate the influence of martensitic transformation. During the solidification of the molten pool, the as-deposited HWS exhibited compressive residual stress (−102 (±72) MPa) on the surface, resulting from martensitic transformation. In contrast, the surface of the heat-treated HWS (HT-HWS) had tensile residual stress (150 (±34) MPa), which was induced by released carbon from the matrix and decarburization at the surface. QT heat treatment precipitated spherical chromium carbide (W0·07Mo0·07Cr1·31V0·31Fe1·38C) and rod-like vanadium carbide (W0·07Mo0·08Cr0·48V0·56Fe1·08C) on the grain boundaries and nanosized-vanadium carbide on the martensite lath boundaries. During heat treatment, the austenite of the as-deposited HWS transformed into martensite, and only 4.80% of the austenite remained. Despite heat treatment, the dislocation density did not decrease because the martensitic transformation caused plastic deformation of the adjacent grains. In addition, the precipitation of fine carbide inhibited grain growth during the heat treatment. For these reasons, the hardness of the as-deposited HWS increased by 17% (i.e., from 659 (±18.7) HV to 773 (±3.33) HV), corresponding to the hardness of carburized SCM420 (774 (±4.31) HV). The tensile strength of the as-deposited HWS increased from 570.6 (±21.5) MPa to 848.1 (±47.7) MPa by removing the melt pool boundary and needle-shaped austenite which are the crack propagation paths of the QT-heat-treated alloy. The carbide that precipitated during heat treatment changed the fracture mechanism from intergranular with dimples to cleavage.
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•This study examined the microstructural evolution of additive-manufactured FeCrV alloys according to heat treatment.•Compressive residual stresses formed on the surface transformed into a tensile residual stress during heat treatment.•The martensitic transformation and precipitation composed chromium and vanadium-rich carbides improve mechanical properties.•Microstructure evolution changed the fracture mechanism from intergranular into cleavage.
The current study aimed to characterize cellular uptake and bioconversion of retinol in fully differentiated human immortalized keratinocytes cells (HaCaT) and artificial skin by measuring the cell ...integrity of skin barriers, time‐dependent transport of retinol, and bioconversion to its metabolites. The expression of epidermal differentiation related genes including Keratin 1 (KRT1), Keratin 10 (KRT10), and Involucrin (IVL) significantly increased in differentiated HaCaT. TEER of HaCaT did not decrease after incubating retinol compared to control (p > 0.05), indicating that retinol tends to maintain strength and integrity of epidermal barrier. TEER of artificial skin decreased treatment of retinol for 2 h, but it was recovered after 4 h. During retinol transport, metabolite was eluted at 13.37 and 13.82 min of basal medium of both keratinocytes and artificial skin, which was identified as retinoic acid by product ion of m/z 283.47. Retinol appeared to be accumulated in keratinocytes, but its uptake tends to be reduced in a time‐dependent manner. Retinoic acid converted from retinol in keratinocytes was time dependently transported. In case of artificial skin, retinol was mostly found in apical at initial incubation time, but it was reduced during incubation for 24 h. Retinoic acid was time‐dependently found in a basal, which was converted via epidermis–dermis. Results from the current study suggest that topical application of retinol to human skin optimal concentration and time exposure could maintain epidermal barrier function and promote skin function due to its remarkable bioconversion to retinoic acid in the epidermis–dermis.
In the world wide, food poisoning accidents related to Vibrio spp. are on the rise, even numbers of food poisoning by other foodborne pathogens are decreasing. Therefore, the requirement of the ...rapid, sensitive and convenient detection method for V. parahaemolyticus has been grown. The objective of this study is to develop a colorimetric loop-mediated isothermal amplification (LAMP) assay using a molecular beacon (HRPzyme connected with complementary oligonucleotides at the 5′ and 3′ ends) for the rapid, sensitive, and convenient detection of V. parahaemolyticus. The colorimetric LAMP assay optimized at 58.8°C showed a detection limit of 1 × 100 CFU/mL and was confirmed to be specific to V. parahaemolyticus. The colorimetric LAMP assay can be finished within 1 h including DNA extraction step. The method was successfully applied to flatfish samples artificially inoculated with known amount of V. parahaemolyticus, and its cut-off value for the flatfish samples was 1 × 101 CFU/g. In addition, the colorimetric LAMP assay developed in the study was found to be able to correct false-positive results, which are known to be a disadvantage of conventional LAMP assays. Therefore, these results indicated that the colorimetric LAMP method is a useful tool for the rapid, sensitive and convenient detection of V. parahaemolyticus in fishes and can also be used as a point-of-care molecular diagnostic technique since it does not require any expensive equipment such as a thermocycler and detectors.
•A colorimetric LAMP based on a molecular beacon that can intercalate to LAMP amplicon has not reported in any field.•Limits of detection of the colorimetric LAMP were 1x100 CFU/mL in buffer and 1x101 CFU/g in fish sample.•The molecular beacon-based colorimetric LAMP can correct the false-positives caused by the LAMP method.
The current study investigated that the vitamin C absorption in plasma depends on the individual muscle mass and the formulation including drinks (Vita 500), capsules, and tablets by using a ...randomized and double‐blind clinical study. The volunteers were divided into two groups that depended on their muscle mass, including those whose muscle mass was greater than 40% (≥$ \ge $40%) and less than 40% muscle mass (<40%). Levels of vitamin C in blood plasma was analyzed by high‐performance liquid chromatography by ultraviolet detection (HPLC‐UV). The existing HPLC method was modified according to lab conditions but maintained a constantly low pH sample reduction procedure. The analytical method validated stability, linearity, recovery, reliability, and accuracy. The vitamin C absorption was the highest at 120 min after ingesting Vita 500 (21.47 ± 15.99 µmol/L). It was higher in the group that has more than 40% muscle mass compared to other formulations, such as tablets and capsules. The results from the current study indicate that vitamin C formulations differently affect the vitamin C absorption, and its effect depends on the muscle mass. As the results, liquid type vitamin C formulations could enhance vitamin C absorption, which resulted in an improvement of vitamin C absorption according to muscle mass.
Practical Application
The results of this study may recommend using vitamin C supplementation as liquid type. It may also provide evidence that people with higher muscle mass can absorb vitamin C more efficiently.
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•Buckwheat-extracted thermal-stable soluble protein (TSSP) was used as an immunogen.•Three monoclonal antibodies (MAbs) were produced.•Cocktail MAbs enhanced the detection efficiency ...of buckwheat in processed food.•The TSSPs could act as a biomarker to detect buckwheat in processed foods.
Buckwheat is considered a severe food allergen, and its adulteration and mislabeling cause serious health risks. For protecting consumers suffering from buckwheat allergy, a high-sensitivity detection method is necessary to accurately identify intentional or unintentional adulteration of buckwheat in processed foods. The study revealed that buckwheat contains a significant amount of thermally stable-soluble proteins (TSSPs), which keep antigenicity even after heat treatment. Therefore, we used TSSPs to produce three monoclonal antibodies (MAbs) specific to buckwheat. A MAbs cocktail solution was subjected to enhance the sensitivity of an indirect enzyme-linked immunosorbent assay (iELISA), and the LOD was 1 ng/mL. The MAbs cocktail solution based-iELISA can successfully detect buckwheat adulterated in processed foods. The results suggested that the TSSPs in buckwheat can be used as suitable immunogens, and MAbs produced can be used as bioreceptor to develop immunoassays and biosensors for detecting buckwheat in food facilities and processed foods.
Since 2010, the Stewardship Code (SC) or similar regulations have been introduced in many countries in order to enhance the quality of institutional investors' engagement and to improve long-term ...firm value. Although the effectiveness of the SC has been the subject of ongoing controversy in prior anecdotal or legal studies, there has been little empirical evidence regarding the effects of these policies due to the relatively recent adoption of such codes worldwide. Accordingly, the purpose of this article is to investigate how capital market participants perceive and evaluate the implementation of the SC. Specifically, we examine how SC implementation affects nonprofessional investors' judgment and decision-making on an investee firm. Based on the results of an experiment with nonprofessional investors, we show that the implementation of the SC may negatively impact nonprofessional investors' assessments of the firm, contrary to the intended purpose of SC adoption. This study provides timely implications for the future operation and development of the stewardship policies recently adopted in many countries.
Emodin, an active constituent of oriental herbs, is widely used to treat allergy, inflammation, and other symptoms. This study provides the scientific basis for the anti-inflammasome effects of ...emodin on both in vitro and in vivo experimental models. Bone marrow-derived macrophages were used to study the effects of emodin on inflammasome activation by using inflammasome inducers such as ATP, nigericin, and silica crystals. The lipopolysaccharide (LPS)-induced endotoxin shock model was employed to study the effect of emodin on in vivo efficacy. Emodin treatment attenuated interleukin (IL)-1β secretion via the inhibition of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation induced by ATP, nigericin, and silica crystals. Further, emodin ameliorated the severity of NLRP3 inflammasome-mediated symptoms in LPS-induced endotoxin mouse models. This study is the first to reveal mechanism-based evidence, especially with respect to regulation of inflammasome activation, substantiating traditional claims of emodin in the treatment of inflammation-related disorders.
Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, ...including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future.
Contamination by
Escherichia coli
O157:H7 is considered a threat in the livestock and food industries. Therefore, it is necessary to develop methods for the convenient and rapid detection of ...Shiga-toxin-producing
E. coli
O157:H7. This study aimed to develop a colorimetric loop-mediated isothermal amplification (cLAMP) assay using a molecular beacon to rapidly detect
E. coli
O157:H7. Primers and a molecular beacon were designed for targeting the Shiga-toxin-producing virulence genes (
stx
1
and
stx
2
) as molecular markers. Additionally,
Bst
polymerase concentration and amplification conditions for bacterial detection were optimized. The sensitivity and specificity of the assay were also investigated and validated on artificially tainted (10
0
–10
4
CFU/g) Korean beef samples. The cLAMP assay could detect 1 × 10
1
CFU/g at 65 °C for both genes, and the assay was confirmed to be specific for
E. coli
O157:H7. The cLAMP takes about an hour and does not require expensive devices (e.g., thermal cycler and detector). Hence, the cLAMP assay proposed herein can be used in the meat industry as a fast and simple way to detect
E. coli
O157:H7.
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