82 research outputs found
Generation of Silver Nanoparticle Pharmacokinetic Profiles in a Lung Model
Nanomaterial technologies are becoming increasingly prevalent in consumer and industrial applications, including drug delivery, energy harvesting, environmental applications, and medicine due to their unique physiochemical properties. As nanomaterial use increases, so too does human exposure. This has made it progressively more important to understand the toxicological effects of nanomaterials and their interactions with the human body. Silver nanoparticles (AgNPs) are one of the most commonly used nanomaterials due to their antibacterial properties. As inhalation is one of the most common exposure routes, understanding the toxicity of these AgNPs on lung tissue was studied. Using A549 cells for a lung tissue model, AgNPs of two sizes, 10 nm and 50 nm, and two different coatings, citrate and polyvinylpyrrolidone (PVP), were studied. Toxicity analysis was performed to determine the effects of dose on cell viability. Pharmacokinetic profiles in static conditions were developed using deposition analysis. Future work will include deposition analysis on dynamic conditions to replicate conditions within a body. This work is part of a larger project to develop an enhanced microcellular model (EMM) to bridge the in vitro - in vivo gap and characterize nanomaterials, evaluate biological responses, and develop pharmacokinetic profiles
Left ventricular function after takotsubo is not fully recovered in long-term follow-up: A speckle tracking echocardiography study
Background: Complete improvement of left ventricle (LV) systolic function is an essential feature of takotsubo cardiomyopathy (TTC). It is suggested that 2-dimensional speckle tracking echocardiography (2D STE) can evaluate LV dysfunction more accurately than conventional echocardiography. Thus, the purpose of this research was to assertain whether LV function recovery is complete after the acute phase of TTC using 2D STE commencing 6 to 9 months after discharge.
Methods: Thirty patients (29 females, 67 ± 11 years) with an apical ballooning TTC pattern 225.5 ± 27.4 days after their index event were enrolled. The control group consisted of 20 (19 females, 64 ± 9 years) age- and sex-matched volunteers without structural heart disease. Classic echocardiographic parameters, longitudinal strain and LV twist parameters were assessed and compared between the groups.
Results: There were no differences in traditional LV systolic, diastolic parameters and in global peak longitudinal strain. In comparison to controls, patients with TTC had lower mean apical rotation (14.4° ± 6.5° vs. 18.3° ± 6.7°; p = 0.048), slower mean peak early diastolic apical rotation rate (–85.1−°/s ± 40.9−°/s vs –119.4−°/s ± 41.9−°/s; p = 0.006) and higher pre-stretch index in the apex (2.16, IQR 0.33–5.50 vs. 0.00, IQR 0.00–2.95, p = 0.008).
Conclusions: The improvement of LV function in patients with TTC as assessed by 2D STE may not always be complete. Some residual abnormalities in LV apex function were observed in long-term recovery following TTC episodes.
Genome-wide inhibition of pro-atherogenic gene expression by multi-STAT targeting compounds as a novel treatment strategy of CVDs
Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)a and IFN? and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT3-specific. We hypothesized that multi-STAT-inhibitors that simultaneously block STAT1, STAT2, and STAT3 activity and pro-inflammatory target gene expression may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple STAT-SH2 models on multi-million compound libraries, we identified the novel multi-STAT inhibitor, C01L-F03. This compound targets the SH2 domain of STAT1, STAT2, and STAT3 with the same affinity and simultaneously blocks their activity and expression of multiple STAT-target genes in HMECs in response to IFNa. The same in silico and in vitro multi-STAT inhibiting capacity was shown for STATTIC and STX-0119. Moreover, C01L-F03, STATTIC and STX-0119 were also able to affect genome-wide interactions between IFN? and TLR4 by commonly inhibiting pro-inflammatory and pro-atherogenic gene expression directed by cooperative involvement of STATs with IRFs and/or NF-κB. Moreover, we observed that multi-STAT inhibitors could be used to inhibit IFN?+LPS-induced HMECs migration, leukocyte adhesion to ECs as well as impairment of mesenteric artery contractility. Together, this implicates that application of a multi-STAT inhibitory strategy could provide great promise for the treatment of CVDsThis publication was supported by grants UMO-2015/17/B/NZ2/00967 (HB) and UMO-2015/16/T/NZ2/00055 (MS) from National Science Centre Poland. This work was
supported by the KNOW RNA Research Centre in Poznan (No. 01/KNOW2/2014) and in part by PL-Grid Infrastructure (MS
Poly(vinylidene fluoride) derived fluorine-doped magnetic carbon nanoadsorbents for enhanced chromium removal
Newly designed fluorine-doped magnetic carbon (F-MC) was synthesized in situ though a facile one-step pyrolysis-carbonization method. Poly(vinylidene fluoride) (PVDF) served as the precursor for both carbon and fluorine. 2.5% F content with core-shell structure was obtained over F-MC, which was used as a adsorbent for the Cr(VI) removal. To our best knowledge, this is the first time to report that the fluorine doped material was applied for the Cr(VI) removal, demonstrating very high removal capacity (1423.4 mg g−1), higher than most reported adsorbents. The unexpected performance of F-MC can be attributed to the configuration of F dopants on the surface. The observed pseudo-second-order kinetic study indicated the dominance of chemical adsorption for this process. High stability of F-MC after 5 recycling test for the Cr(VI) removal was also observed, indicating that F-MC could be used as an excellent adsorbent for the toxic heavy metal removal from the wastewater
The influence of textile materials on flame resistance ratings of professional uniforms
This study compares the flame speed of different textile materials employed in professional uniforms. Five different garments
of aeronauts’ uniforms were analyzed (totaling 200 specimens submitted to flammability tests). Plain weaves and
twill weaves composed by 100% CO; 100% PES; 67% PES/33% CO; 50% PES/50% WO; and 55% PES/45%WO were analyzed
in the warp and filling directions. The flame speed of each material was determined, and differences in the flame propagation
of the fabrics were identified. The lowest flame speed occurred for the material 50% PES/50% WO plain weave and
weft direction (0.742 ± 0.140 m/s). The highest flame speed was 3.698 ± 1.806 cm/s for the material 67%PES/33%CO, plain
weave and filling direction. Future experiments for reducing the fabric flammability of the uniforms could be related to
more closed fabric constructions; mixtures with synthetic fibers to add functionality; changing the direction of the fabric;
and changing the weight and torsion of its constituent yarns.São Paulo Research Foundation—FAPESP (“Fundação de Amparo à Pesquisa do Estado de São Paulo”) Grant Number 2016/01331-
Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease
Interferon regulatory factors (IRFs) are a family of homologous proteins that regulate the transcription of interferons (IFNs) and IFN-induced gene expression. As such they are important modulating proteins in the Toll-like receptor (TLR) and IFN signaling pathways, which are vital elements of the innate immune system. IRFs have a multi-domain structure, with the N-terminal part acting as a DNA binding domain (DBD) that recognizes a DNA-binding motif similar to the IFN-stimulated response element (ISRE). The C-terminal part contains the IRF-association domain (IAD), with which they can self-associate, bind to IRF family members or interact with other transcription factors. This complex formation is crucial for DNA binding and the commencing of target-gene expression. IRFs bind DNA and exert their activating potential as homo or heterodimers with other IRFs. Moreover, they can form complexes (e.g., with Signal transducers and activators of transcription, STATs) and collaborate with other co-acting transcription factors such as Nuclear factor-κB (NF-κB) and PU.1. In time, more of these IRF co-activating mechanisms have been discovered, which may play a key role in the pathogenesis of many diseases, such as acute and chronic inflammation, autoimmune diseases, and cancer. Detailed knowledge of IRFs structure and activating mechanisms predisposes IRFs as potential targets for inhibition in therapeutic strategies connected to numerous immune system-originated diseases. Until now only indirect IRF modulation has been studied in terms of antiviral response regulation and cancer treatment, using mainly antisense oligonucleotides and siRNA knockdown strategies. However, none of these approaches so far entered clinical trials. Moreover, no direct IRF-inhibitory strategies have been reported. In this review, we summarize current knowledge of the different IRF-mediated transcriptional regulatory mechanisms and how they reflect the diverse functions of IRFs in homeostasis and in TLR and IFN signaling. Moreover, we present IRFs as promising inhibitory targets and propose a novel direct IRF-modulating strategy employing a pipeline approach that combines comparative in silico docking to the IRF-DBD with in vitro validation of IRF inhibition. We hypothesize that our methodology will enable the efficient identification of IRF-specific and pan-IRF inhibitors that can be used for the treatment of IRF-dependent disorders and malignancies
Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs
Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT3-specific. We hypothesized that multi-STAT-inhibitors that simultaneously block STAT1, STAT2, and STAT3 activity and pro-inflammatory target gene expression may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple STAT-SH2 models on multi-million compound libraries, we identified the novel multi-STAT inhibitor, C01L_F03. This compound targets the SH2 domain of STAT1, STAT2, and STAT3 with the same affinity and simultaneously blocks their activity and expression of multiple STAT-target genes in HMECs in response to IFNα. The same in silico and in vitro multi-STAT inhibiting capacity was shown for STATTIC and STX-0119. Moreover, C01L_F03, STATTIC and STX-0119 were also able to affect genome-wide interactions between IFNγ and TLR4 by commonly inhibiting pro-inflammatory and pro-atherogenic gene expression directed by cooperative involvement of STATs with IRFs and/or NF-κB. Moreover, we observed that multi-STAT inhibitors could be used to inhibit IFNγ+LPS-induced HMECs migration, leukocyte adhesion to ECs as well as impairment of mesenteric artery contractility. Together, this implicates that application of a multi-STAT inhibitory strategy could provide great promise for the treatment of CVDs
Distributional Patterns of Polychaetes Across the West Antarctic Based on DNA Barcoding and Particle Tracking Analyses
Recent genetic investigations have uncovered a high proportion of cryptic species
within Antarctic polychaetes. It is likely that these evolved in isolation during periods of
glaciation, and it is possible that cryptic populations would have remained geographically
restricted from one another occupying different regions of Antarctica. By analysing
the distributions of nine morphospecies, (six of which contained potential cryptic
species), we find evidence for widespread distributions within the West Antarctic. Around
60% of the cryptic species exhibited sympatric distributions, and at least one cryptic
clade was found to be widespread. Additional DNA barcodes from GenBank and
morphological records extended the observed range of three species studied here,
and indicate potential circum-Antarctic traits. Particle tracking analyses were used to
model theoretical dispersal ranges of pelagic larvae. Data from these models suggest
that the observed species distributions inferred from genetic similarity could have been
established and maintained through the regional oceanographic currents, including
the Antarctic Circumpolar Current (ACC) and its coastal counter current. Improved
understanding of the distribution of Antarctic fauna is essential for predicting the impacts
of environmental change and determining management strategies for the region.Copyright © 2017 Brasier, Harle, Wiklund, Jeffreys, Linse, Ruhl and Glover. This
is an open-access article distributed under the terms of the Creative Commons
Attribution License (CC BY). The use, distribution or reproduction in other forums
is permitted, provided the original author(s) or licensor are credited and that the
original publication in this journal is cited, in accordance with accepted academic
practice. No use, distribution or reproduction is permitted which does not comply
with these terms
International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.
Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist
- …