Morpholino-functionalized phosphorus dendrimers for precision regenerative medicine: osteogenic differentiation of mesenchymal stem cells

A novel bioactive macromolecule based on morpholino-functiona lized phosphorus dendrimers (generation 2, G2-Mor+ ) was devel oped for osteogenic differentiation of mesenchymal stem cells (MSCs). Interestingly, through in vitro tests, it was shown that G2- Mor+ dendrimer can strongly promote the transformation of MSCs into osteoblasts, which implies the potential application of phos phorus de medicine.info:eu-repo/semantics/publishedVersio

DNA methylation landscape of ocular tissue relative to matched peripheral blood

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Epigenetic variation is implicated in a range of non-communicable diseases, including those of the eye. However, investigating the role of epigenetic variation in central tissues, such as eye or brain, remains problematic and peripheral tissues are often used as surrogates. In this study, matched human blood and eye tissue (n = 8) were obtained post-mortem and DNA methylation profiling performed on blood, neurosensory retina, retinal pigment epithelium (RPE)/choroid and optic nerve tissue using the Illumina Infinium HumanMethylation450 platform. Unsupervised clustering and principal components analysis revealed tissue of origin as the main driver of methylation variation. Despite this, there was a strong correlation of methylation profiles between tissues with >255,000 CpG sites found to have similar methylation levels. An additional ~16,000 show similarity across ocular tissues only. A small proportion of probes showing inter-individual variation in blood co-varied with eye tissues within individuals, however much of this variation may be genetically driven. An improved understanding of the epigenetic landscape of the eye will have important implications for understanding eye disease. Despite a generally high correlation irrespective of origin, tissue type is the major driver of methylation variation, with only limited covariation between blood and any specific ocular tissue

The relationship of history of psychiatric and substance use disorders on risk of dementia among racial and ethnic groups in the United States

IntroductionDementia is characterized by significant declines in cognitive, physical, social, and behavioral functioning, and includes multiple subtypes that differ in etiology. There is limited evidence of the influence of psychiatric and substance use history on the risk of dementia subtypes among older underrepresented racial/ethnic minorities in the United States. Our study explored the role of psychiatric and substance use history on the risk of etiology-specific dementias: Alzheimer’s disease (AD) and vascular dementia (VaD), in the context of a racially and ethnically diverse sample based on national data.MethodsWe conducted secondary data analyses based on the National Alzheimer’s Coordinating Center Uniform Data Set (N = 17,592) which is comprised a large, racially, and ethnically diverse cohort of adult research participants in the network of US Alzheimer Disease Research Centers (ADRCs). From 2005 to 2019, participants were assessed for history of five psychiatric and substance use disorders (depression, traumatic brain injury, other psychiatric disorders, alcohol use, and other substance use). Cox proportional hazard models were used to examine the influence of psychiatric and substance use history on the risk of AD and VaD subtypes, and the interactions between psychiatric and substance use history and race/ethnicity with adjustment for demographic and health-related factors.ResultsIn addition to other substance use, having any one type of psychiatric and substance use history increased the risk of developing AD by 22–51% and VaD by 22–53%. The risk of other psychiatric disorders on AD and VaD risk varied by race/ethnicity. For non-Hispanic White people, history of other psychiatric disorders increased AD risk by 27%, and VaD risk by 116%. For African Americans, AD risk increased by 28% and VaD risk increased by 108% when other psychiatric disorder history was present.ConclusionThe findings indicate that having psychiatric and substance use history increases the risk of developing AD and VaD in later life. Preventing the onset and recurrence of such disorders may prevent or delay the onset of AD and VaD dementia subtypes. Prevention efforts should pay particular attention to non-Hispanic White and African American older adults who have history of other psychiatric disorders.Future research should address diagnostic shortcomings in the measurement of such disorders in ADRCs, especially with regard to diverse racial and ethnic groups

Metabolomics reveals metabolic alterations by intrauterine growth restriction in the fetal rabbit brain

Background: Intrauterine Growth Restriction (IUGR) due to placental insufficiency occurs in 5-10% of pregnancies and is a major risk factor for abnormal neurodevelopment. The perinatal diagnosis of IUGR related abnormal neurodevelopment represents a major challenge in fetal medicine. The development of clinical biomarkers is considered a promising approach, but requires the identification of biochemical/molecular alterations by IUGR in the fetal brain. This targeted metabolomics study in a rabbit IUGR model aimed to obtain mechanistic insight into the effects of IUGR on the fetal brain and identify metabolite candidates for biomarker development. Methodology/Principal Findings: At gestation day 25, IUGR was induced in two New Zealand rabbits by 40-50% uteroplacental vessel ligation in one horn and the contralateral horn was used as control. At day 30, fetuses were delivered by Cesarian section, weighed and brains collected for metabolomics analysis. Results showed that IUGR fetuses had a significantly lower birth and brain weight compared to controls. Metabolomics analysis using liquid chromatographyquadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and database matching identified 78 metabolites. Comparison of metabolite intensities using a t-test demonstrated that 18 metabolites were significantly different between control and IUGR brain tissue, including neurotransmitters/peptides, amino acids, fatty acids, energy metabolism intermediates and oxidative stress metabolites. Principle component and hierarchical cluster analysis showed cluster formations that clearly separated control from IUGR brain tissue samples, revealing the potential to develop predictive biomarkers. Moreover birth weight and metabolite intensity correlations indicated that the extent of alterations was dependent on the severity of IUGR. Conclusions: IUGR leads to metabolic alterations in the fetal rabbit brain, involving neuronal viability, energy metabolism, amino acid levels, fatty acid profiles and oxidative stress mechanisms. Overall findings identified aspargine, ornithine, Nacetylaspartylglutamic acid, N-acetylaspartate and palmitoleic acid as potential metabolite candidates to develop clinical biomarkers for the perinatal diagnosis of IUGR related abnormal neurodevelopment

A comparative analysis of high-throughput platforms for validation of a circulating microRNA signature in diabetic retinopathy

MicroRNAs are now increasingly recognized as biomarkers of disease progression. Several quantitative real-time PCR (qPCR) platforms have been developed to determine the relative levels of microRNAs in biological fluids. We systematically compared the detection of cellular and circulating microRNA using a standard 96-well platform, a high-content microfluidics platform and two ultrahigh content platforms. We used extensive analytical tools to compute inter- and intra-run variability and concordance measured using fidelity scoring, coefficient of variation and cluster analysis. We carried out unprejudiced next generation sequencing to identify a microRNA signature for Diabetic Retinopathy (DR) and systematically assessed the validation of this signature on clinical samples using each of the above four qPCR platforms. The results indicate that sensitivity to measure low copy number microRNAs is inversely related to qPCR reaction volume and that the choice of platform for microRNA biomarker validation should be made based on the abundance of miRNAs of interest

Robustness, Security and Privacy in Location-Based Services for Future IoT : A Survey

Internet of Things (IoT) connects sensing devices to the Internet for the purpose of exchanging information. Location information is one of the most crucial pieces of information required to achieve intelligent and context-aware IoT systems. Recently, positioning and localization functions have been realized in a large amount of IoT systems. However, security and privacy threats related to positioning in IoT have not been sufficiently addressed so far. In this paper, we survey solutions for improving the robustness, security, and privacy of location-based services in IoT systems. First, we provide an in-depth evaluation of the threats and solutions related to both global navigation satellite system (GNSS) and non-GNSS-based solutions. Second, we describe certain cryptographic solutions for security and privacy of positioning and location-based services in IoT. Finally, we discuss the state-of-the-art of policy regulations regarding security of positioning solutions and legal instruments to location data privacy in detail. This survey paper addresses a broad range of security and privacy aspects in IoT-based positioning and localization from both technical and legal points of view and aims to give insight and recommendations for future IoT systems providing more robust, secure, and privacy-preserving location-based services.Peer reviewe

Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

Is Sensory Loss an Understudied Risk Factor for Frailty? A Systematic Review and Meta-analysis

[Abstract] Background. Age-related sensory loss and frailty are common conditions among older adults, but epidemiologic research on their possible links has been inconclusive. Clarifying this relationship is important because sensory loss may be a clinically relevant risk factor for frailty. Methods. In this systematic review and meta-analysis, we searched 3 databases for observational studies investigating 4 sensory impairments—vision (VI), hearing (HI), smell (SI), and taste (TI)—and their relationships with frailty. We meta-analyzed the cross-sectional associations of VI/HI each with pre-frailty and frailty, investigated sources of heterogeneity using meta-regression and subgroup analyses, and assessed publication bias using Egger’s test. Results. We included 17 cross-sectional and 7 longitudinal studies in our review (N = 34,085) from 766 records. Our cross-sectional meta-analyses found that HI and VI were, respectively, associated with 1.5- to 2-fold greater odds of pre-frailty and 2.5- to 3-fold greater odds of frailty. Our results remained largely unchanged after subgroup analyses and meta-regression, though the association between HI and pre-frailty was no longer significant in 2 subgroups which lacked sufficient studies. We did not detect publication bias. Longitudinal studies largely found positive associations between VI/HI and frailty progression from baseline robustness, though they were inconclusive about frailty progression from baseline pre-frailty. Sparse literature and heterogenous methods precluded meta-analyses and conclusions on the SI/TI–frailty relationships. Conclusions. Our meta-analyses demonstrate significant cross-sectional associations between VI/HI with pre-frailty and frailty. Our review also highlights knowledge gaps on the directionality and modifiability of these relationships and the impact of SI/TI and multiple sensory impairments on frailty

c-Jun N-Terminal Phosphorylation: Biomarker for Cellular Stress Rather than Cell Death in the Injured Cochlea.

Peer reviewe

Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles

Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.International Society for Advancement of Cytometry Marylou Ingram Scholar 2019-2023H2020 EXPERTSwedish foundation of Strategic Research (SSF-IRC; FormulaEx)ERC CoG (DELIVER)Swedish Medical Research CouncilAccepte