Alginate Formulations: Current Developments in the Race for Hydrogel-Based Cardiac Regeneration

Cardiovascular diseases, including myocardial infarction (MI), represent the main worldwide cause of mortality and morbidity. In this scenario, to contrast the irreversible damages following MI, cardiac regeneration has emerged as a novel and promising solution for in situ cellular regeneration, preserving cell behavior and tissue cytoarchitecture. Among the huge variety of natural, synthetic, and hybrid compounds used for tissue regeneration, alginate emerged as a good candidate for cellular preservation and delivery, becoming one of the first biomaterial tested in pre-clinical research and clinical trials concerning cardiovascular diseases. Although promising results have been obtained, recellularization and revascularization of the infarcted area present still major limitations. Therefore, the demand is rising for alginate functionalization and its combination with molecules, factors, and drugs capable to boost the regenerative potential of the cardiac tissue. The focus of this review is to elucidate the promising properties of alginate and to highlight its benefits in clinical trials in relation to cardiac regeneration. The definition of hydrogels, the alginate characteristics, and recent biomedical applications are herewith described. Afterward, the review examines in depth the ongoing developments to refine the material relevance in cardiac recovery and regeneration after MI and presents current clinical trials based on alginate

Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions

The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because of its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown that the LC has heterogeneous connections and cellular features, no studies have yet assessed its functional topography in vivo, how this heterogeneity changes over aging, and whether it is associated with cognition and mood. Here, we employ a gradient-based approach to characterize the functional heterogeneity in the organization of the LC over aging using 3T resting-state fMRI in a population-based cohort aged from 18 to 88 years of age (Cambridge Centre for Ageing and Neuroscience cohort, n=618). We show that the LC exhibits a rostro-caudal functional gradient along its longitudinal axis, which was replicated in an independent dataset (Human Connectome Project [HCP] 7T dataset, n=184). Although the main rostrocaudal direction of this gradient was consistent across age groups, its spatial features varied with increasing age, emotional memory, and emotion regulation. More specifically, a loss of rostral-like connectivity, more clustered functional topography, and greater asymmetry between right and left LC gradients was associated with higher age and worse behavioral performance. Furthermore, participants with higher-than-normal Hospital Anxiety and Depression Scale (HADS) ratings exhibited alterations in the gradient as well, which manifested in greater asymmetry. These results provide an in vivo account of how the functional topography of the LC changes over aging, and imply that spatial features of this organization are relevant markers of LC-related behavioral measures and psychopathology. © Veréb et al

Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions

The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because of its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown that the LC has heterogeneous connections and cellular features, no studies have yet assessed its functional topography in vivo, how this heterogeneity changes over aging, and whether it is associated with cognition and mood. Here, we employ a gradient-based approach to characterize the functional heterogeneity in the organization of the LC over aging using 3T resting-state fMRI in a population-based cohort aged from 18 to 88 years of age (Cambridge Centre for Ageing and Neuroscience cohort, n=618). We show that the LC exhibits a rostro-caudal functional gradient along its longitudinal axis, which was replicated in an independent dataset (Human Connectome Project [HCP] 7T dataset, n=184). Although the main rostro-caudal direction of this gradient was consistent across age groups, its spatial features varied with increasing age, emotional memory, and emotion regulation. More specifically, a loss of rostral-like connectivity, more clustered functional topography, and greater asymmetry between right and left LC gradients was associated with higher age and worse behavioral performance. Furthermore, participants with higher-than-normal Hospital Anxiety and Depression Scale (HADS) ratings exhibited alterations in the gradient as well, which manifested in greater asymmetry. These results provide an in vivo account of how the functional topography of the LC changes over aging, and imply that spatial features of this organization are relevant markers of LC-related behavioral measures and psychopathology

Frequent polymorphic changes but not mutations of TRAIL receptors DR4 and DR5 in mantle cell lymphoma and other B-cell lymphoid neoplasms

Background and objectives: tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5 have been mapped to chromosome 8p21-22, a region frequently deleted in different lymphoid neoplasms. Design and methods: to investigate the potential alterations of these genes in lymphoid neoplasms, we examined the presence of gene mutations in exons 3, 4, and 9 in 69 cases with mantle cell lymphoma (MCL), 16 with chronic lymphocytic leukemia (CLL), 12 with follicular lymphomas (FL) and 17 with large B-cell-lymphomas (DLBCL), as well as in 4 lymphoid cell lines carrying the t(11;14) translocation, and 91 healthy blood donors. Results: three CLL and three MCL cases had 8p deletions. Two nucleotide changes in or near the intron 3 splice consensus sequence and a silent change were found. These rare changes were also present in the germ-line of the patients. The DR4 death domain A1322G polymorphism was significantly more frequent in MCL [odds ratio (OR) = 5.9; 95% confidence interval (CI), 1.92-18.1] and CLL (OR = 4.5; CI, 1.18-17) patients than in a sex and age-adjusted healthy population. In contrast, the DR4 exon 4 C626G polymorphism was associated with a significant overall decreased risk for MCL (OR = 0.3; CI, 0.12-0.8). No mutations or cancer-associated polymorphic changes were found in DR5 domains. Interpretation and conclusions: these findings indicate that mutations of DR4 and DR5 are uncommon in lymphoid neoplasms but DR4 polymorphic alleles may contribute to the pathogenesis of these malignancies

Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors

Intercomparison Exercise for Heavy Metals in PM10

The Joint Research Centre (JRC) has carried out an Intercomparison Exercise (IE) for the determination of heavy metals in particulate matter (PM10). The IE focussed on Lead (Pb), Arsenic (As), Nickel (Ni) and Cadmium (Cd), the heavy metals regulated by the 1st and 4th Daughter Directives for Air Pollution. Copper (Cu), Chromium (Cr) and Zinc (Zn), the elements included in the EMEP programme together with Aluminium (Al), Cobalt (Co), Iron (Fe), Manganese (Mn) and Vanadium (V) were also tested. Fourteen Laboratories, generally members of the Network of Air Quality Reference Laboratories (AQUILA), participated in the IE. The participants mainly used microwave digestion with nitric acid and hydrogen peroxide and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) or Graphite Furnace Atomic Absorption Spectrometry (GF-AAS) for analysis as recommended in the reference method (EN 14902). However, a few participants used other methods: Energy Dispersive X-ray Fluorescence (EDXRF), Atomic Emission Spectrometry (ICP-AES) and Voltammetry for analysis and vaporisation on hot plate before microwave digestion, Soxhlet extraction, high pressure or cold Hydrogen Fluoride methods for digestion. Each participant received 5 samples to be analysed: a liquid sample prepared by dilution of a Certified Reference Material (CRM), a solution of a dust CRM sample digested by the JRC13F, a sub-sample of a dust CRM that each participating laboratory had to digest and analyse, a solution prepared by JRC after digestion of an exposed filter and a pair of filters (one blank filter and one exposed filter) to be digested and analysed by each participant. For 89 % of all types of samples, the DQOs of the 1st and 4th European Directives (uncertainty of 25 % for Pb and 40 % for As, Cd and Ni) were met. All together, this is a very good score. The best results were obtained for the liquid CRM, dust CRM digested by JRC, dust CRM and filter digested by JRC with 92, 90, 96 and 93 % of DQOs being met, respectively. It was found that the DQOs were not met if the difference of acidity between test samples and participant calibration standards was high. Conversely, only 76 % of DQOs were met for the filter to be digested by each participant with (about 85 % for Cd and Ni, 73/64 % for Pb and As, the most difficult element to determine). The worst results were associated with special events: explosion in microwave oven during digestion for two participants, a wrong dilution factor used by one participant and a huge contamination in the blank filter for another participant. Among the two explosions, one of them was probably the effect of a lack of temperature control in the digestion vessel. For the other explosion, the microwave digestion and the digestion program advised by EN 14902 is to be questioned. Moreover, satisfactory results were obtained using Soxhlet extraction, high pressure method and cold Hydrogen Fluoride digestion methods which are not presented in EN 14902. The DQOs of As and Cd could not be met with EDXRF whose limit of detection was too high for these two elements and for Cd using Voltammetry which suffered a strong interference for this element. Regarding the methods of analysis, apart the points mentioned just before about EDXRF and Voltammetry, good results were observed using ICP-OES for Cd, Ni and Pb. A few discrepancies were also registered for GF-AAS and ICP-MS but they were created by the special events or acidity problem mentioned before. This shows that even though GF-AAS and ICP-MS are found suitable, the implementation by each participant may be responsible for important mistakes.JRC.H.4-Transport and air qualit

Deliberating performance targets workshop: Potential paths for emerging PM2.5 and O3 air sensor progress

The United States Environmental Protection Agency held an international two-day workshop in June 2018 to deliberate possible performance targets for non-regulatory fine particulate matter (PM2.5) and ozone (O3) air sensors. The need for a workshop arose from the lack of any market-wide manufacturer requirement for documented sensor performance evaluations, the lack of any independent third party or government-based sensor performance certification program, and uncertainty among all users as to the general usability of air sensor data. A multi-sector subject matter expert panel was assembled to facilitate an open discussion on these issues with multiple stakeholders. This summary provides an overview of the workshop purpose, key findings from the deliberations, and considerations for future actions specific to sensors. Important findings concerning PM2.5 and O3 sensors included the lack of consistent performance indicators and statistical metrics as well as highly variable data quality requirements depending on the intended use. While the workshop did not attempt to yield consensus on any topic, a key message was that a number of possible future actions would be beneficial to all stakeholders regarding sensor technologies. These included documentation of best practices, sharing quality assurance results along with sensor data, and the development of a common performance target lexicon, performance targets, and test protocols. Keywords: Low-cost air quality sensors, Performance targets, PM2.5, Ozon

On the Regression and Assimilation for Air Quality Mapping Using Dense Low-Cost WSN

International audienceThe use of low-cost Wireless Sensor Networks (WSNs) for air quality monitoring has recently attracted a great deal of interest. Indeed, the cost-effectiveness of emerging sensors and their small size allow for dense deployments and hence improve the spatial granularity. However, these sensors offer a low accuracy and their measurement errors may be significant due to the underlying sensing technologies. The main aim of this work is to reconsider and compare some regression approaches to assimilation ones while taking into account the intrinsic characteristics of dense deployment of low cost WSN for air quality monitoring (high density, numerical model errors and sensing errors). For that, we propose a general framework that allows the comparison of different strategies based on numerical simulations and an adequate estimation of the simulation error covariances as well as the sensing errors covariances. While considering the case of Lyon city and a widely used numerical model, we characterize the simulation errors, conduct extensive simulations and compare several regression and assimilation approaches. The results show that from a given sensing error threshold, regression methods present an optimal sensor density from which the mapping quality decreases. Results also show that the Random Forest method is often the best regression approach but still less efficient than the BLUE assimilation approach when using adequate correction parameters

Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high-B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT