Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could ...provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTauP301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTauP301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.
Detection technologies employing optically encoded particles have gained much interest toward clinical diagnostics and drug discovery, but the portfolio of available systems is still limited. The ...fabrication and characterization of highly stable surface‐enhanced resonance Raman scattering (SERRS)‐encoded colloids for the identification and imaging of proteins expressed in cells are reported. These plasmonic nanostructures are made of gold octahedra coated with poly(N‐isopropylacrylamide) microgels and can be readily encoded with Raman active dyes while retaining high colloidal stability in biofluids. A layer‐by‐layer polyelectrolyte coating is used to seal the outer surface of the encoded particles and to provide a reactive surface for covalent conjugation with antibodies. The targeted multiplexing capabilities of the SERRS tags are demonstrated by the simultaneous detection and imaging of three tumor‐associated surface biomarkers: epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), and homing cell adhesion molecule (CD44) by SERRS spectroscopy. The plasmonic microgels are able to discriminate tumor A431 (EGFR+/EpCAM+/CD44+) and nontumor 3T3 2.2 (EGFR−/EpCAM−/CD44+) cells while cocultured in vitro.
Surface‐enhanced resonance Raman scattering (SERRS) tags with a multiplex capability for targeted identification of cellular receptors are prepared by dye encoding poly(N‐isopropylacrylamide)‐encapsulated Au nanooctahedra. Upon irradiation with a single laser line, the plasmonic microgels are able to discriminate tumor and nontumor cells while co‐cultured in vitro. Hence, these SERRS labels may be applied to high‐throughput, multiplex assays for in vitro screening and diagnostics.
To develop and validate a calculator to predict the risk of in-hospital mortality in patients with active infective endocarditis (IE) undergoing cardiac surgery.
Thousand two hundred and ninety-nine ...consecutive patients with IE were prospectively recruited (1996-2014) and retrospectively analysed. Left-sided patients who underwent cardiac surgery (n=671) form our study population and were randomised into development (n=424) and validation (n=247) samples. Variables statistically significant to predict in-mortality were integrated in a multivariable prediction model, the Risk-Endocarditis Score (RISK-E). The predictive performance of the score and four existing surgical scores (European System for Cardiac Operative Risk Evaluation (EuroSCORE) I and II), Prosthesis, Age ≥70, Large Intracardiac Destruction,
, Urgent Surgery, Sex (Female) (PALSUSE), EuroSCORE ≥10) and Society of Thoracic Surgeons's Infective endocarditis score (STS-IE)) were assessed and compared in our cohort. Finally, an external validation of the RISK-E in a separate population was done.
Variables included in the final model were age, prosthetic infection, periannular complications,
or fungi infection, acute renal failure, septic shock, cardiogenic shock and thrombocytopaenia. Area under the receiver operating characteristic curve in the validation sample was 0.82 (95% CI 0.75 to 0.88). The accuracy of the other surgical scores when compared with the RISK-E was inferior (p=0.010). Our score also obtained a good predictive performance, area under the curve 0.76 (95% CI 0.64 to 0.88), in the external validation.
IE-specific factors (microorganisms, periannular complications and sepsis) beside classical variables in heart surgery (age, haemodynamic condition and renal failure) independently predicted perioperative mortality in IE. The RISK-E had better ability to predict surgical mortality in patients with IE when compared with other surgical scores.
The gold-standard diagnostic test for peroxisomal disorders (PDs) is plasma concentration analysis of very long-chain fatty acids (VLCFAs). However, this method’s time-consuming nature and ...limitations in cases which present normal VLCFA levels necessitates alternative approaches. The analysis of C26:0-lysophosphatydylcholine (C26:0-LPC) in dried blood spot samples by tandem-mass spectrometry (MS/MS) has successfully been implemented in certain newborn screening programs to diagnose X-linked adrenoleukodystrophy (ALD). However, the diagnostic potential of very long-chain LPCs concentrations in plasma remains poorly understood. This study sought to evaluate the diagnostic performance of C26:0-LPC and other very long-chain LPCs, comparing them to VLCFA analysis in plasma. The study, which included 330 individuals affected by a peroxisomal β-oxidation deficiency and 407 control individuals, revealed that C26:0- and C24:0-LPC concentrations demonstrated the highest diagnostic accuracy (98.8% and 98.4%, respectively), outperforming VLCFA when C26:0/C22:0 and C24:0/C22:0 ratios were combined (98.1%). Combining C24:0- and C26:0-LPC gave the highest sensitivity (99.7%), with ALD females exhibiting notably higher sensitivity compared with the VLCFA ratio combination (98.7% vs. 93.5%, respectively). In contrast, C22:0-LPC exhibited suboptimal performance, primarily due to its low sensitivity (75%), but we identified a potential use to help distinguish between ALD and Zellweger spectrum disorders. In summary, MS/MS analysis of plasma C24:0- and C26:0-LPC concentrations represents a rapid and straightforward approach to diagnose PDs, demonstrating superior diagnostic accuracy, particularly in ALD females, compared with conventional VLCFA biomarkers. We strongly recommend integrating very-long chain LPC plasma analysis in the diagnostic evaluation of individuals suspected of having a PD.
Heme oxygenase-1 (HO-1) is an inducible enzyme known for its anti-inflammatory, antioxidant and neuroprotective effects. However, increased expression of HO-1 during aging and age-related ...neurodegenerative diseases have been associated to neurotoxic ferric iron deposits. Being microglia responsible for the brain's innate immune response, the aim of this study was to understand the role of microglial HO-1 under inflammatory conditions in aged mice. For this purpose, aged wild type (WT) and LysMCreHmox1△△ (HMOX1M-KO) mice that lack HO-1 in microglial cells, were used. Aged WT mice showed higher basal expression levels of microglial HO-1 in the brain than adult mice. This increase was even higher when exposed to an inflammatory stimulus (LPS via i.p.) and was accompanied by alterations in different iron-related metabolism proteins, resulting in an increase of iron deposits, oxidative stress, ferroptosis and cognitive decline. Furthermore, microglia exhibited a primed phenotype and increased levels of inflammatory markers such as iNOS, p65, IL-1β, TNF-α, Caspase-1 and NLRP3. Interestingly, all these alterations were prevented in aged HMOX1M-KO and WT mice treated with the HO-1 inhibitor ZnPPIX. In order to determine the effects of microglial HO-1-dependent iron overload, aged WT mice were treated with the iron chelator deferoxamine (DFX). DFX caused major improvements in iron, inflammatory and behavioral alterations found in aged mice exposed to LPS. In conclusion, this study highlights how microglial HO-1 overexpression contributes to neurotoxic iron accumulation providing deleterious effects in aged mice exposed to an inflammatory insult.
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•Microglial HO-1 increases with aging and under an acute inflammatory stimulus.•LPS-dependent microglial HO-1 upregulation during aging leads to iron overload.•Microglial HO-1-dependent iron accumulation leads to ferroptosis.•HO-1-dependent iron alterations lead to neuroinflammation.•HO-1 inhibitors/iron chelators reduce iron accumulation and neuroinflammation.
Thiol-modified poly(ethylene glycol) (mPEG-SH) has been used to replace standard capping agents from the surfaces of gold nanoparticles with different sizes and shapes. Upon PEG stabilization, the ...nanoparticles can be transferred into ethanol, where silica can be directly grown on the particle surfaces through the standard Stöber process. The obtained silica shells are uniform and homogeneous, and the method allows a high degree of control over shell thickness for any particle size and shape. Additionally, Raman-active molecules can be readily incorporated within the composite nanoparticles during silica growth so that SERS/SERRS-encoded nanoparticles can be fabricated containing a variety of tags, thereby envisaging multiplexing capability.
Shape-controlled synthesis of uniform noble metal nanoparticles (NPs) is crucial for the development of future plasmonic devices. The use of nanocrystals with well-defined morphologies and ...crystallinity as seed particles is expected to provide excellent shape control and monodispersity. We report the aqueous-based seed-mediated growth of monodisperse gold octahedra with wide range of sizes (50–150 nm in side length) by reducing different amounts of HAuCl4 on preformed single crystalline gold nanorods using butenoic acid as reducing agent. Butenoic acid plays a key role as a mild reducing agent as well as favoring the thermodynamic control of the reaction. The uniformity of the as-prepared Au octahedra combined with the use of a microfluidic technique based on microevaporation will allow the self-assembly of octahedra into uniform 3D supercrystals. Additionally, these plasmonic substrates exhibit high and uniform SERS signals over extended areas with intensities increasing with the Au nanoparticle size.
Key PointsBabies tend to show lesions earlier than adults. Therefore, the absence of other affected people in the infant's close environment should not lead to the exclusion of scabies of the ...differential diagnosis.Babies have special forms of presentation of scabies, with cephalic, hand and foot involvement, localised or unilateral distributions, as well as more frequent nodular lesions, particularly in axilla. J-shaped burrows are also characteristic in this age group.Direct visualisation of mites, ova or faeces by microscopy, high-power image or dermoscopy is required to confirm the diagnosis. However, the sensitivity of these techniques is highly operator-dependent, and the equipment is not always available. Thus, knowing the different patterns of scabies according to age is essential for early clinical diagnosis and treatment.
In this Article, we report on the assembly of hybrid Au@PNIPAM core–shell particles at the air/water interface, their transfer onto solid substrates, and the controlled combustion of the organic ...material to produce arrays of gold nanoparticles. A detailed investigation on the assembly behavior of such soft hybrid colloids at the air/water interface was performed by correlating the surface pressure–area isotherms with SEM and AFM images from samples transferred at different surface pressures. The hybrid particles display a complex behavior at the interface, and we could distinguish three distinct phases with varying interparticle spacings at different compression. The transfer process presented enables the decoration of topologically structured substrates with gold nanoparticle arrays, and the order of the initial monolayers is retained in the arrays of inorganic gold nanoparticles. The change in monolayer morphology upon compression can therefore be used to tailor the interparticle distance between approximately 650 and 300 nm without exchanging the colloids. More sophisticated gold nanostructures can be patterned into symmetric arrays using a similar protocol, which we demonstrate for nanostars and nanorods.
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