The retinoid agonist Tazarotene promotes angiogenesis and wound healing

Therapeutic angiogenesis is a major goal ofregenerative medicine, but no clinically approved small molecule exists that enhancesnew blood vessel formation. Here we show, using a phenotype-driven high-content imaging screen of an annotated chemical library of 1280 bioactive small molecules, that the retinoid agonist Tazarotene, enhances in vitroangiogenesis, promoting branching morphogenesis, and tubule remodeling. The pro-angiogenic phenotype is mediated by Retinoic Acid Receptor (RAR) but not Retinoic X Receptor(RXR) activation, and is characterized by secretion of the pro-angiogenic factors Hepatocyte Growth Factor (HGF), Vascular Endothelial Growth Factor (VEGFA), Plasminogen Activator, Urokinase (PLAU) and Placental Growth Factor (PGF), and reduced secretion of the antiangiogenic factor Pentraxin-3 (PTX3) from adjacent fibroblasts. In vivo, Tazarotene enhanced the growth of mature and functional microvessels in Matrigel implants and wound healing models, and increased blood flow. Notably, in ear punch wound healing model, Tazarotene promoted tissue repair characterized by rapid ear punch closure with normal-appearing skin containing new hair follicles, and maturing collagen fibers. Our study suggests that Tazarotene, an FDA-approved small molecule, could be potentially exploited for therapeutic applications in neovascularization and wound healing

Potentially toxic contamination of sediments, water and two animal species in Lake Kalimanci, FYR Macedonia: Relevance to human health

The objectives of the research were: (1) to examine the concentrations of metals in Vimba melanops and Rana temporaria and (2) to evaluate the potential risks of the contaminated organisms to human health in Makedonska Kamenica region. Analyses identified high levels of Cr, Hg, Ni and Pb in studied animals, which also exceeded their permissible levels in food. In sediment and soil samples, levels of Cd, Cu, Cr, Pb, Zn and As were perceived, while Cd, Cu, Ni, Pb, Se and As were increased in water samples. Results of transfer factor revealed that the examined animals had higher bioaccumulation rate from surrounding waters than from sediments or soils. The accomplished Health Risk Index disclosed that studied animals can have considerably high health risks for inhabitants. Conclusively, they could be considered as highly contaminated with metals and can consequently harm human health, especially children in their early development stages

High Efficiency Colloidal Quantum Dot Infrared Light Emitting Diodes via Engineering at the Supra-Nanocrystalline Level

Colloidal quantum dot (CQD) light-emitting diodes (LEDs) deliver a compelling performance in the visible, yet infrared CQD LEDs underperform their visible-emitting counterparts, largely due to their low photoluminescence quantum efficiency. Here we employ a ternary blend of CQD thin film that comprises a binary host matrix that serves to electronically passivate as well as to cater for an efficient and balanced carrier supply to the emitting quantum dot species. In doing so, we report infrared PbS CQD LEDs with an external quantum efficiency of ~7.9% and a power conversion efficiency of ~9.3%, thanks to their very low density of trap states, on the order of 1014 cm−3, and very high photoluminescence quantum efficiency in electrically conductive quantum dot solids of more than 60%. When these blend devices operate as solar cells they deliver an open circuit voltage that approaches their radiative limit thanks to the synergistic effect of the reduced trap-state density and the density of state modification in the nanocomposite.Peer ReviewedPostprint (author's final draft

Epigenetic regulation by RARα maintains ligand-independent transcriptional activity

Retinoic acid receptors (RARs) α, β and γ are key regulators of embryonic development. Hematopoietic differentiation is regulated by RARα, and several types of leukemia show aberrant RARα activity. Through microarray expression analysis, we identified transcripts differentially expressed between F9 wild-type (Wt) and RARα knockout cells cultured in the absence or presence of the RAR-specific ligand all trans retinoic acid (RA). We validated the decreased Mest, Tex13, Gab1, Bcl11a, Tcfap2a and HMGcs1 transcript levels, and increased Slc38a4, Stmn2, RpL39l, Ref2L, Mobp and Rlf1 transcript levels in the RARa knockout cells. The decreased Mest and Tex13 transcript levels were associated with increased promoter CpG-island methylation and increased repressive histone modifications (H3K9me3) in RARα knockout cells. Increased Slc38a4 and Stmn2 transcript levels were associated with decreased promoter CpG-island methylation and increased permissive histone modifications (H3K9/K14ac, H3K4me3) in RARα knockout cells. We demonstrated specific association of RARα and RXRα with the Mest promoter. Importantly, stable expression of a dominant negative, oncogenic PML–RARα fusion protein in F9 Wt cells recapitulated the decreased Mest transcript levels observed in RARα knockout cells. We propose that RARα plays an important role in cellular memory and imprinting by regulating the CpG methylation status of specific promoter regions

The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis

BACKGROUND: MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). CONCLUSIONS/SIGNIFICANCE: This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future

Comparative analysis of co-processed starches prepared by three different methods

Co-processing is currently of interest in the generation of high-functionality excipients for tablet formulation. In the present study, comparative analysis of the powder and tableting properties of three co-processed starches prepared by three different methods was carried out. The co-processed excipients consisting of maize starch (90%), acacia gum (7.5%) and colloidal silicon dioxide (2.5%) were prepared by co-dispersion (SAS-CD), co-fusion (SAS-CF) and co-granulation (SAS-CG). Powder properties of each co-processed excipient were characterized by measuring particle size, flow indices, particle density, dilution potential and lubricant sensitivity ratio. Heckel and Walker models were used to evaluate the compaction behaviour of the three co-processed starches. Tablets were produced with paracetamol as the model drug by direct compression on an eccentric Tablet Press fitted with 12 mm flat-faced punches and compressed at 216 MPa. The tablets were stored at room temperature for 24 h prior to evaluation. The results revealed that co-granulated co-processed excipient (SAS-CG) gave relatively better properties in terms of flow, compressibility, dilution potential, deformation, disintegration, crushing strength and friability. This study has shown that the method of co-processing influences the powder and tableting properties of the co-processed excipient

Comparative analysis of co-processed starches prepared by three different methods

Co-processing is currently of interest in the generation of high-functionality excipients for tablet formulation. In the present study, comparative analysis of the powder and tableting properties of three co-processed starches prepared by three different methods was carried out. The co-processed excipients consisting of maize starch (90%), acacia gum (7.5%) and colloidal silicon dioxide (2.5%) were prepared by co-dispersion (SAS-CD), co-fusion (SAS-CF) and co-granulation (SAS-CG). Powder properties of each co-processed excipient were characterized by measuring particle size, flow indices, particle density, dilution potential and lubricant sensitivity ratio. Heckel and Walker models were used to evaluate the compaction behaviour of the three co-processed starches. Tablets were produced with paracetamol as the model drug by direct compression on an eccentric Tablet Press fitted with 12 mm flat-faced punches and compressed at 216 MPa. The tablets were stored at room temperature for 24 h prior to evaluation. The results revealed that co-granulated co-processed excipient (SAS-CG) gave relatively better properties in terms of flow, compressibility, dilution potential, deformation, disintegration, crushing strength and friability. This study has shown that the method of co-processing influences the powder and tableting properties of the co-processed excipient

Looking beyond the hype : applied AI and machine learning in translational medicine

Big data problems are becoming more prevalent for laboratory scientists who look to make clinical impact. A large part of this is due to increased computing power, in parallel with new technologies for high quality data generation. Both new and old techniques of artificial intelligence (AI) and machine learning (ML) can now help increase the success of translational studies in three areas: drug discovery, imaging, and genomic medicine. However, ML technologies do not come without their limitations and shortcomings. Current technical limitations and other limitations including governance, reproducibility, and interpretation will be discussed in this article. Overcoming these limitations will enable ML methods to be more powerful for discovery and reduce ambiguity within translational medicine, allowing data-informed decision-making to deliver the next generation of diagnostics and therapeutics to patients quicker, at lowered costs, and at scale