Early markers are needed for more effective prevention of Alzheimer's disease. We previously showed that individuals with Alzheimer's disease have decreased plasma DYRK1A levels compared to controls. ...We assessed DYRK1A in the plasma of cognitively healthy elderly volunteers, individuals with either Alzheimer's disease (AD), tauopathies or Down syndrome (DS), and in lymphoblastoids from individuals with DS. DYRK1A levels were inversely correlated with brain amyloid β burden in asymptomatic elderly individuals and AD patients. Low DYRK1A levels were also detected in patients with tauopathies. Individuals with DS had higher DYRK1A levels than controls, although levels were lower in individuals with DS and with dementia. These data suggest that plasma DYRK1A levels could be used for early detection of at risk individuals of AD and for early detection of AD. We hypothesize that lack of increase of DYRK1A at middle age (40-50 years) could be a warning before the cognitive decline, reflecting increased risk for AD.
Pulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation. Yet tools and techniques used for confirmation of PVI vary greatly, and it is unclear whether the use of any ...particular combination of tools and techniques provides greater sensitivity for identifying gaps periprocedurally. It has been suggested the use of a high-density mapping catheter, which enables simultaneous recording of adjacent bipolar EGMs in two directions, may provide improved sensitivity for gap identification. Anonymized, acute procedural data was prospectively collected in AF ablation cases utilizing various workflows for confirmation of PVI. Post-hoc analysis was performed to evaluate the incidence of gaps detected by different diagnostic catheter technologies, including a high-density mapping catheter and circular mapping catheters (CMCs), and common techniques such as pacing the ablation lines. A total of 139 cases were included across three subgroup analyses: 99 cases were included in an indirect comparison of three mapping catheter technologies, revealing gaps in 36.7%, 38.9%, and 81.8% of cases utilizing a 10-pole CMC, 20-pole CMC, and a high-density mapping catheter, respectively; a direct comparison of diagnostic catheter technologies in 18 cryoballoon ablation cases revealed residual gaps in 22.2% of patients identified by high-density mapping which were missed previously with the use of a 3.3F CMC; in 22 cases utilizing a technique of pacing the ablation lines, high-density mapping identified residual gaps in 68.2% of patients. This proof of concept analysis demonstrated that the use of a high-density catheter which records orthogonal bipoles simultaneously, appears to improve acute detection of gaps in PVI lines relative to other commonly utilized techniques and technologies. The long-term impact of ablating these concealed gaps remains unclear. Further study, including direct comparison of diagnostic catheter technologies in a randomized setting with long-term followup, is warranted.
Water-soluble metalla-cages were used to deliver hydrophobic porphin molecules to cancer cells. After internalization, the photosensitizer was photoactivated, significantly increasing the ...cytotoxicity in cells. During the transport, the photosensitizer remains nonreactive to light, offering a new strategy to tackle overall photosensitization, a limitation often encountered in photodynamic therapy.
CSF-1 and IL-34 share the CSF-1 receptor and no differences have been reported in the signaling pathways triggered by both ligands in human monocytes. IL-34 promotes the differentiation and survival ...of monocytes, macrophages and osteoclasts, as CSF-1 does. However, IL-34 binds other receptors, suggesting that differences exist in the effect of both cytokines. In the present study, we compared the differentiation and polarization abilities of human primary monocytes in response to CSF-1 or IL-34. CSF-1R engagement by one or the other ligands leads to AKT and caspase activation and autophagy induction through expression and activation of AMPK and ULK1. As no differences were detected on monocyte differentiation, we investigated the effect of CSF-1 and IL-34 on macrophage polarization into the M1 or M2 phenotype. We highlighted a striking increase in IL-10 and CCL17 secretion in M1 and M2 macrophages derived from IL-34 stimulated monocytes, respectively, compared to CSF-1 stimulated monocytes. Variations in the secretome induced by CSF-1 or IL-34 may account for their different ability to polarize naïve T cells into Th1 cells. In conclusion, our findings indicate that CSF-1 and IL-34 exhibit the same ability to induce human monocyte differentiation but may have a different ability to polarize macrophages.
Here were report on a laboratory study aiming to reproduce specificities of near-Earth Asteroid. We study how the elevated surface temperature, their surface roughness (rock or regolith), as well as ...observation geometry can affect the absorption features detected on asteroids. For that purpose, we selected a recent carbonaceous chondrite fall, the Mukundpura CM2 chondrite which fell in India in June 2017. Bidirectional reflectance spectroscopy was performed to analyze the effect of the geometrical configuration (incidence, emergence and azimuth angle) on the measurement. Our results show that reflectance spectra obtained under warm environment (NEA-like) tends to show shallower absorption bands compared to low-temperature conditions (MBA-like), but still detectable in our experiments under laboratory timescales. Irreversible alteration of the sample because of the warm environment (from room temperature to 250 °C) has been detected as an increase of the spectral slope and a decrease of the band depths (at 0.7 μm, 0.9 μm and 2.7 μm). Comparing the meteoritic chip and the powdered sample, we found that surface texture strongly affects the shape of the reflectance spectra of meteorites and thus of asteroids, where a dust-covered surface presents deeper absorption features. We found that all spectral parameters, such as the reflectance value, spectral slope and possible absorption bands are affected by the geometry of measurement. We observed the disappearance of the 0.7 μm absorption feature at phase angle larger than 120°, but the 3 μm band remains detectable on all measured spectra.
•Reflectance spectroscopy of surfaces strongly depends on the viewing geometry.•Slope, absorption bands and photometry are affected by the geometry.•Warm meteorites present shallower absorption bands than in cold environment.•Irreversible alteration of the spectra are met at high temperature.•Dust-covered samples present deeper absorption bands than raw surface.
The contractile properties of adult myofibers are shaped by their Myosin heavy chain isoform content. Here, we identify by snATAC-seq a 42 kb super-enhancer at the locus regrouping the fast Myosin ...genes. By 4C-seq we show that active fast Myosin promoters interact with this super-enhancer by DNA looping, leading to the activation of a single promoter per nucleus. A rainbow mouse transgenic model of the locus including the super-enhancer recapitulates the endogenous spatio-temporal expression of adult fast Myosin genes. In situ deletion of the super-enhancer by CRISPR/Cas9 editing demonstrates its major role in the control of associated fast Myosin genes, and deletion of two fast Myosin genes at the locus reveals an active competition of the promoters for the shared super-enhancer. Last, by disrupting the organization of fast Myosin, we uncover positional heterogeneity within limb skeletal muscles that may underlie selective muscle susceptibility to damage in certain myopathies.
The introduction of neonicotinoids for managing insecticide resistance in mosquitoes is of high interest as they interact with a biochemical target not previously used in public health. In this ...concern, Bayer developed a combination of the neonicotinoid clothianidin and the pyrethroid deltamethrin (brand name Fludora Fusion) as a new vector control tool. Although this combination proved to be efficient against pyrethroid-resistant mosquitoes, its ability to prevent the selection of pyrethroid and neonicotinoid resistance alleles was not investigated. In this context, the objective of this work was to study the dynamics and the molecular mechanisms of resistance of An. gambiae to the separated or combined components of this combination. A field-derived An. gambiae line carrying resistance alleles to multiple insecticides at low frequencies was used as a starting for 33 successive generations of controlled selection. Resistance levels to each insecticide and target site mutation frequencies were monitored throughout the selection process. Cross resistance to other public health insecticides were also investigated. RNA-seq was used to compare gene transcription variations and polymorphisms across all lines. This study confirmed the potential of this insecticide combination to impair the selection of resistance as compared to its two separated components. Deltamethrin selection led to the rapid enrichment of the kdr L1014F target-site mutation. Clothianidin selection led to the over-transcription of multiple cytochrome P450s including some showing high homology with those conferring neonicotinoid resistance in other insects. A strong selection signature associated with clothianidin selection was also observed on a P450 gene cluster previously associated with resistance. Within this cluster, the gene CYP6M1 showed the highest selection signature together with a transcription profile supporting a role in clothianidin resistance. Modelling the impact of point mutations selected by clothianidin on CYP6M1 protein structure showed that selection retained a protein variant with a modified active site potentially enhancing clothianidin metabolism. In the context of the recent deployment of neonicotinoids for mosquito control and their frequent usage in agriculture, the present study highlights the benefit of combining them with other insecticides for preventing the selection of resistance and sustaining vector control activities.
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Local ocular delivery of cyclosporine A (CsA) is the preferred method for CsA delivery as a treatment for ocular inflammatory diseases such as uveitis, corneal healing, vernal ...keratoconjunctivitis and dry eye disease. However, due to the large molecular weight and hydrophobic nature of CsA and the natural protective mechanisms of the eye, achieving therapeutic levels of CsA in ocular tissues can be difficult. This review gives a comprehensive overview of the current products available to clinicians as well as emerging drug delivery solutions that have been developed at both the academic and industry levels.
Global climate change (GCC) increasingly threatens biodiversity through the loss of species, and the transformation of entire ecosystems. Many species are challenged by the pace of GCC because they ...might not be able to respond fast enough to changing biotic and abiotic conditions. Species can respond either by shifting their range, or by persisting in their local habitat. If populations persist, they can tolerate climatic changes through phenotypic plasticity, or genetically adapt to changing conditions depending on their genetic variability and census population size to allow for de novo mutations. Otherwise, populations will experience demographic collapses and species may go extinct. Current approaches to predicting species responses to GCC begin to combine ecological and evolutionary information for species distribution modelling. Including an evolutionary dimension will substantially improve species distribution projections which have not accounted for key processes such as dispersal, adaptive genetic change, demography, or species interactions. However, eco‐evolutionary models require new data and methods for the estimation of a species' adaptive potential, which have so far only been available for a small number of model species. To represent global biodiversity, we need to devise large‐scale data collection strategies to define the ecology and evolutionary potential of a broad range of species, especially of keystone species of ecosystems. We also need standardized and replicable modelling approaches that integrate these new data to account for eco‐evolutionary processes when predicting the impact of GCC on species' survival. Here, we discuss different genomic approaches that can be used to investigate and predict species responses to GCC. This can serve as guidance for researchers looking for the appropriate experimental setup for their particular system. We furthermore highlight future directions for moving forward in the field and allocating available resources more effectively, to implement mitigation measures before species go extinct and ecosystems lose important functions.
Most radiative transfer models developed for the analysis of urban configurations consider a transparent urban atmosphere and gray sky conditions. The aim of the present work is to investigate these ...assumptions, focusing on the longwave domain. For this purpose, reference Line-by-Line Monte-Carlo calculations are first performed. A more efficient radiative transfer model based on the Finite Volume Method and SLW modeling is also developed to treat several street canyon configurations. The aspect ratio of the street canyon, a parameter frequently encountered in urban scenarios, is considered for the analysis. It is shown that, in most cases, real urban problems need to take into account a non-gray participating atmosphere within the streets, together with its spectral coupling with the non-gray sky downward radiation, to provide accurate net fluxes on urban surfaces and volumetric radiative powers in the urban atmosphere.
•The interaction between radiation and the atmosphere is studied in a street canyon.•The strong spectral coupling between sky emission and air absorption is analyzed.•An efficient model (FVM-SLW) is proposed to accurately simulate these interactions.•A parametric study of wall fluxes with respect to street aspect ratio is carried out.
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