Finneganvad0329

Osteoarthritis (OA) is a debilitating joint disorder affecting more than 240 million people. There is no disease modifying therapeutic, and drugs that are used to alleviate OA symptoms result in side effects. Recent research indicates that inhibition of peroxisome proliferator-activated receptor δ (PPARδ) in cartilage may attenuate the development or progression of OA. PPARδ antagonists such as GSK3787 exist, but would benefit from delivery to joints to avoid side effects. Described here is the loading of GSK3787 into poly(ester amide) (PEA) particles. The particles contained 8 wt.% drug and had mean diameters of about 600 nm. Differential scanning calorimetry indicated the drug was in crystalline domains in the particles. Atomic force microscopy was used to measure the Young's moduli of individual particles as 2.8 MPa. In vitro drug release studies showed 11% GSK3787 was released over 30 days. Studies in immature murine articular cartilage (IMAC) cells indicated low toxicity from the drug, empty particles, and drug-loaded particles and that the particles were not taken up by the cells. Ex vivo studies on murine joints showed that the particles could be injected into the joint space and resided there for at least 7 days. Overall, these results indicate that GSK3787-loaded PEA particles warrant further investigation as a delivery system for potential OA therapy.Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in lower grade gliomas. The neomorphic enzyme activity of IDH mutants leads to tumor formation through epigenetic alteration, dysfunction of dioxygenases, and metabolic reprogramming. However, it remains elusive as to how IDH mutants regulate the pathways associated with oncogenic transformation and aggressiveness. In the present study, by using unbiased transcriptomic profiling, we showed that IDH1 mutations result in substantial changes in the gene sets that govern cellular motility, chemotaxis, and invasion. Mechanistically, rapamycin-insensitive companion of mammalian target of rapamycin (Rictor)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling plays an essential role in the motility and proliferation of IDH1-mutated cells by prompting cytoskeleton reorganization, lamellipodia formation, and enhanced endocytosis. Targeting the Rictor/Rac1 pathway suppresses IDH1-mutated cells by limiting endocytosis and cell proliferation. Overall, our findings indicate a novel metabolic reprogramming mechanism of IDH1-mutated cells by exploiting metabolites from the extracellular milieu. Targeting the Rictor/Rac1 pathway could be an alternative therapeutic strategy for IDH1-mutated malignancies.Anterior segment dysgenesis (ASD) comprises a wide spectrum of developmental conditions affecting the cornea, iris, and lens, which may be associated with abnormalities of other organs. To identify disease-causing variants, we performed exome sequencing in 24 South Florida families with ASD. We identified 12 likely causative variants in 10 families (42%), including single nucleotide or small insertion-deletion variants in B3GLCT, BMP4, CYP1B1, FOXC1, FOXE3, GJA1, PXDN, and TP63, and a large copy number variant involving PAX6. Four variants were novel. Each variant was detected only in one family. Likely causative variants were detected in 1 out of 7 black and 9 out of 17 white families. In conclusion, exome sequencing for ASD allows us to identify a wide spectrum of rare DNA variants in South Florida. Further studies will explore missing variants, especially in the black communities.Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyzed and validated the cytogenetic alterations that arise after treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines by 1-million microarray-based comparative genomic hybridization (array-CGH) and qRT-PCR methodologies. RNA-sequencing, functional transfection assays, and gene-pathway activity analysis were used to identify genes with a potential role in the development of this malignancy. The results were further explored in 55 lung and ovarian primary tumors and control samples, and in two extensive in silico databases. Long-term cell exposure to platinum induces the frequent deletion of ITF2 gene. Its expression re-sensitized tumor cells to platinum and recovered the levels of Wnt/β-catenin transcriptional activity. ITF2 expression was also frequently downregulated in epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation between ITF2 and HOXD9 expression, revealing that Non-small cell lung cancer (NSCLC) patients with lower expression of HOXD9 had a better overall survival rate. We defined the implication of ITF2 as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. This data highlights the possible role of ITF2 and HOXD9 as novel therapeutic targets for platinum resistant tumors.Background/Objective Findings from the 2009 and 2014 National Pharmacist Workforce Surveys showed that approximately 40% of U.S. pharmacists devoted their time primarily to medication providing, 40% contributed a significant portion of their time to patient care service provision, and the remaining 20% contributed most of their time to other health-system improvement activities. The objective of this study was to characterize the U.S. pharmacist workforce into segments based on the proportion of time they spend in medication providing and patient care services and compare changes in these segments between 2009, 2014, and 2019. Methods Data from 2009, 2014, and 2019 National Pharmacist Workforce Surveys were analyzed. Responses from 1200 pharmacists in 2009, 1382 in 2014, and 4766 in 2019 were used for analysis. Respondents working in the pharmacy or pharmacy-related fields reported both their percent time devoted to medication providing and to patient care services. Medication providing included preparing, di that recent growth in the pharmacist workforce has been in the patient care services, with more being provided through remote means in organizations that are not licensed as pharmacies. The findings have implications for pharmacist training, continuing education, labor monitoring, regulations, work systems, and process designs. These changes will create new roles and tasks for pharmacy organizations and personnel that will be needed to support emerging patient care services provided by pharmacists.Star-shaped cyclophosphazene (ACP) was employed as covalent crosslinker to form a rigid segment in polyurethanes network, to enhance the mechanical performance and to add extra flame retardant property. The effects of different ACP contents on the shape memory ability and fire resistance performance of polyurethane (PU) were studied. Tensile tests suggested high flexibility of the PUs with the maximum elongation-at-break of 161.59%. Dynamic mechanical analysis (DMA) indicated good shape recovery ratio of 72.58% after more than three repeated cycles. Under thermal treatment, the temporary shape could recover to its original state in 10 s. The peak heat release rate (pHRR), total heat released (THR) and temperature at pHRR (Tp) of flame-retardant shape memory polyurethane (FSPU) by micro-combustion calorimeter (MCC) was as low as 183.2 W/g, 21.4 KJ/g, 330.8 °C respectively, suggesting good inherent fire-resistant performance. As amine-containing crosslinkers are one of the most common building units in thermosetting polymers, we anticipate that our finding will have significant benefits beyond shape memory and fire-resistance.The methods to enhance contrast ratios (CRs) in scattering-type transflective liquid crystal displays (ST-TRLCDs) based on polymer-network liquid crystal (PNLC) cells are investigated. Two configurations of ST-TRLCDs are studied and are compared with the common ST-TRLCDs. According to the comparisons, CRs are effectively enhanced by assembling a linear polarizer at the suitable position to achieve better dark states in the transmissive and reflective modes of the reported ST-TRLCDs with the optimized configuration, and its main trade-off is the loss of brightness in the reflective modes. The PNLC cell, which works as an electrically switchable polarizer herein, can be a PN-90° twisted nematic LC (PN-90° TNLC) cell or a homogeneous PNLC (H-PNLC) cell. The optoelectric properties of PN-90° TNLC and those of H-PNLC cells are compared in detail, and the results determine that the ST-TRLCD with the optimized configuration using an H-PNLC cell can achieve the highest CR. Moreover, no quarter-wave plate is used in the ST-TRLCD with the optimized configuration, so a parallax problem caused by QWPs can be solved. Other methods for enhancing the CRs of the ST-TRLCDs are also discussed.Developing polyols derived from natural sources and recycling materials attracts great interest for use in replacing petroleum-based polyols in polyurethane production. In this study, rigid polyurethane (PUR) foams with various isocyanate indices were obtained from polyols based on rapeseed oil and polyethylene terephthalate (RO/PET). The various properties of the prepared PUR foams were investigated, and the effect of the isocyanate index was evaluated. The closed-cell content and water absorption were not impacted by the change of the isocyanate index. The most significant effect of increasing the isocyanate index was on the dimensional stability of the resulting foams. This is due to the increased crosslink density, as evidenced by the increased formation of isocyanurate and increase of the glass transition temperature. Additionally, the influence on compression strength, modulus, and long-term thermal conductivity were evaluated and compared with reference PUR foams from commercially available polyols. Rigid PUR foams from RO/PET polyol were found to be competitive with reference materials and could be used as thermal insulation material.Perovskite solar cells (PSCs) have attracted tremendous research attention due to their potential as a next-generation photovoltaic cell. Transition metal oxides in N-I-P structures have been widely used as electron-transporting materials but the need for a high-temperature sintering step is incompatible with flexible substrate materials and perovskite materials which cannot withstand elevated temperatures. In this work, novel metal oxides prepared by sputtering deposition were investigated as electron-transport layers in planar PSCs with the N-I-P structure. The incorporation of tungsten in the oxide layer led to a power conversion efficiency (PCE) increase from 8.23% to 16.05% due to the enhanced electron transfer and reduced back-recombination. Scanning electron microscope (SEM) images reveal that relatively large grain sizes in the perovskite phase with small grain boundaries were formed when the perovskite was deposited on tungsten-doped films. This study demonstrates that novel metal oxides can be used as in perovskite devices as electron transfer layers to improve the efficiency.Tospoviruses cause significant losses to a wide range of agronomic and horticultural crops worldwide. GSK583 research buy The type member, Tomato spotted wilt tospovirus (TSWV), causes systemic infection in susceptible tomato cultivars, whereas its infection is localized in cultivars carrying the Sw-5 resistance gene. The response to TSWV infection in tomato cultivars with or without Sw-5 was determined at the virus small RNA level in the locally infected leaf. Predicted reads were aligned to TSWV reference sequences. The TSWV genome was found to be differentially processed among each of the three-viral genomic RNAs-Large (L), Medium (M) and Small (S)-in the Sw-5(+) compared to Sw-5(-) genotypes. In the Sw-5(+) cultivar, the L RNA had the highest number of viral small-interfering RNAs (vsiRNAs), whereas in the Sw-5(-) cultivar the number was higher in the S RNA. Among the three-viral genomic RNAs, the distribution of hotspots showed a higher number of reads per million reads of vsiRNAs of 21 and 22 nt class at the 5' and 3' ends of the L and the S RNAs, with less coverage in the M RNA.