Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFbeta cell cycle arrest

TGFbeta is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFbeta in disease. We asked how Rb-deficiency would affect responses to TGFbeta-induced cell cycle arrest.Publisher PDFPeer reviewe

Metabotropic glutamate receptor 2/3 (mGluR2/3) activation suppresses TRPV1 sensitization in mouse, but not human sensory neurons

AbstractThe use of human tissue to validate putative analgesic targets identified in rodents is a promising strategy for improving the historically poor translational record of preclinical pain research. We recently demonstrated that in mouse and human sensory neurons, agonists for metabotropic glutamate receptors 2 and 3 (mGluR2/3) reduce membrane hyperexcitability produced by the inflammatory mediator prostaglandin E2(PGE2). Previous rodent studies indicate that mGluR2/3 can also reduce peripheral sensitization by suppressing inflammation-induced sensitization of TRPV1. Whether this observation similarly translates to human sensory neurons has not yet been tested. We found that activation of mGluR2/3 with the agonist APDC suppressed PGE2-induced sensitization of TRPV1 in mouse, but not human, sensory neurons. We also evaluated sensory neuron expression of the gene transcripts for mGluR2 (Grm2), mGluR3 (Grm3), and TRPV1 (Trpv1). The majority ofTrpv1+mouse and human sensory neurons expressedGrm2and/orGrm3, and in both mice and humans,Grm2was expressed in a greater percentage of sensory neurons thanGrm3. Although we demonstrated a functional difference in the modulation of TRPV1 sensitization by mGluR2/3 activation between mouse and human, there were no species differences in the gene transcript colocalization of mGluR2 or mGluR3 with TRPV1 that might explain this functional difference. Taken together with our previous work, these results suggest that mGluR2/3 activation suppresses only some aspects of human sensory neuron sensitization caused by PGE2. These differences have implications for potential healthy human voluntary studies or clinical trials evaluating the analgesic efficacy of mGluR2/3 agonists or positive allosteric modulators.</jats:p

Using early life stages of marine animals to screen the toxicity of priority hazardous and noxious substances

This study provides toxicity values for early life stages (ELS) of two phylogenetically distinct marine animal taxa, the sea urchin (Paracentrotus lividus), a deuterostome invertebrate, and the turbot (Scophthalmus maximus), a vertebrate (teleost), when challenged by six hazardous and noxious substances (HNS): aniline, butyl acrylate, m-cresol, cyclohexylbenzene, hexane and trichloroethylene. The aim of the study was to provide preliminary information on toxic effects of representative and relevant priority HNS to assess the risk posed by spills to marine habitats and therefore improve preparedness and the response at the operational level. Selection criteria to include each compound in the study were (1) inclusion in the HASREP (2005) list; (2) presence on the priority list established by Neuparth et al. (2011); (3) paucity of toxicological data (TOXnet and ECOTOX) for marine organisms; (4) behaviour in the water according to the categories defined by the European Behaviour classification system (GESAMP 2002), by selecting compounds with different behaviours in water; and (5) physicochemical and toxicological properties, where available, in order to anticipate the most toxic compounds. Aniline and m-cresol were the most toxic compounds with no observed apical effect concentration (NOAEC) values for sea urchin ranging between 0.01 and 0.1 mg/L, followed by butyl acrylate and cyclohexylbenzene with NOAECs ranging between 0.1 and 1.0 mg/L and trichloroethylene with NOAEC values that were in the range between 1 and 10 mg/L, reflecting their behaviour in water, mostly vapour pressure, but also solubility and log Kow. Hexane was toxic only for turbot embryos, due to its neurotoxic effects, and not for sea urchin larvae, at concentrations in the range between 1 and 10 mg/L. The concentrations tested were of the same order of magnitude for both species, and it was observed that sea urchin embryos (length of the longest arm) are more sensitive than turbot eggs larvae (hatching and cumulative mortality rates) to the HNS tested (except hexane). For this specific compound, concentrations up to 70 mg/L were tested in sea urchin larvae and no effects were observed on the length of the larvae. Both tests were found to be complementary depending on behaviour in water and toxicity target of the compounds analysed.info:eu-repo/semantics/publishedVersio

An improved experimental test set-up to study the performance of granular columns

This paper describes an innovative design of a newly developed large test setup for testing the performance of footings supported on soft clay reinforced with granular columns. This advanced testing method is used to examine the settlement of footings supported on granular columns. Two important features of the equipment are (a) the axial loading system which allows samples to be consolidated under Ko condition while the load is applied onto a small foundation area of the sample, and (b) a relatively large sample size of 300-mm diameter and 400-mm high. The system is also equipped with pressure cells located beneath the footing and top cap to measure the pressure distribution with respect to foundation displacement and a lateral strain gage to monitor boundary effects. This paper reports on some of the early findings from the preliminary tests carried out using this equipment. Samples for testing were prepared by consolidating kaolin slurry in a large one-dimensional consolidation chamber. The granular columns were installed using the replacement method by compacting crushed basalt (uniformly graded with 90 % between 1.5–2-mm particle sizes) into a preformed hole. The preliminary tests have yielded promising results, validating the functionality of the equipment and support the prospect of increasing the knowledge with respect to settlement response and design of a footing supported on granular columns

Teaching across disciplines: a case study of a project-based short course to teach holistic coastal adaptation design

Climate change has led to the need for innovation in resilient infrastructure and the social policies which will support those. This requires greater interdisciplinary interactions and knowledge building among emerging professionals. This paper presents a case study of a pilot short course intended to immerse graduate students in the design of resilient infrastructure using place-based and interdisciplinary active team learning. This course helps graduate students bridge the gap between research and practice on the social science and engineering of resilient infrastructure for coastal adaptation. The intellectual framework for the course (the Adaptive Gradients Framework) provides a holistic evaluation of adaptation design proposals and was used to recognize the complexity of social, ecological and engineering aspects and varied social benefits. The course provides a model to move outside rigid boundaries of institutions and disciplines to begin to build, in both students and instructors, the ability to work more effectively on complex social-ecological-engineering problems. Finally, this paper presents a summary of lessons learned from this pilot short course

Final Report

Forest products provide essential resources for human civilization, including energy and materials. In processing forest products, however, unwanted byproducts, such as volatile organic compounds (VOCs) and hazardous air pollutants (HAPs) are generated. The goal of this study was to develop a cost effective and reliable air pollution control system to reduce VOC and HAP emissions from pulp, paper and paperboard mills and solid wood product facilities. Specifically, this work focused on the removal of VOCs and HAPs from high volume low concentration (HVLC) gases, particularly methanol since it is the largest HAP constituent in these gases. Three technologies were developed and tested at the bench-scale: (1) A novel composite material of activated carbon coated with a photocatalyst titanium dioxide (TiO{sub 2}) (referred to as TiO{sub 2}-coated activated carbon or TiO{sub 2}/AC), (2) a novel silica gel impregnated with nanosized TiO{sub 2} (referred to as silica-titania composites or STC), and (3) biofiltration. A pilot-scale reactor was also fabricated and tested for methanol removal using the TiO{sub 2}/AC and STC. The technical feasibility of removing methanol with TiO{sub 2}/AC was studied using a composite synthesized via a spay desiccation method. The removal of methanol consists of two consecutive operation steps: removal of methanol using fixed-bed activated carbon adsorption and regeneration of spent activated carbon using in-situ photocatalytic oxidation. Regeneration using photocatalytic oxidation employed irradiation of the TiO{sub 2} catalyst with low-energy ultraviolet (UV) light. Results of this technical feasibility study showed that photocatalytic oxidation can be used to regenerate a spent TiO{sub 2}/AC adsorbent. A TiO{sub 2}/AC adsorbent was then developed using a dry impregnation method, which performed better than the TiO{sub 2}/AC synthesized using the spray desiccation method. The enhanced performance was likely a result of the better distribution of TiO2 particles on the activated carbon surface. A method for pore volume impregnation using microwave irradiation was also developed. A commercial microwave oven (800 W) was used as the microwave source. Under 2450 MHz microwave irradiation, TTIP was quickly hydrolyzed and anatase TiO2 was formed in a short time (&lt; 20 minutes). Due to the volumetric heating and selective heating of microwave, the solvent and by-products were quickly removed which reduced energy consumption and processing time. Activated carbon and TiO{sub 2}/AC were also tested for the removal of hydrogen sulfide, which was chosen as the representative total reduced sulfur (TRS) species. The BioNuchar AC support itself was a good H{sub 2}S remover. After coating TiO{sub 2} by dry impregnation, H{sub 2}S removal efficiency of TiO{sub 2}/AC decreased compared with the virgin AC due to the change of surface pH. Under UV light irradiation, H{sub 2}S removal efficiency of TiO{sub 2}/AC composite doubled, and its sulfate conversion efficiency was higher than that of AC. The formation of sulfate is preferred since the sulfate can be removed from the composite by rising with water. A pilot-scale fluidized bed reactor was designed to test the efficiency of methanol oxidation with TiO{sub 2}/AC in the presence of UV light. TiO{sub 2}/AC was prepared using the spray desiccation method. The TiO{sub 2}/AC was pre-loaded with (1) methanol (equivalent to about 2%wt) and (2) methanol and water. When the TiO{sub 2}/AC loaded with methanol only was exposed to UV light for one hour in the reactor, most of the methanol remained in the carbon pores and, thus, was not oxidized. The TiO{sub 2}/AC loaded with methanol and water desorbed about 2/3 of the methanol from its pores during fluidization, however, only a small portion of this desorbed methanol was oxidized. A biofilter system employing biological activated carbon was developed for methanol removal. The biofilter contained a mixed packing with Westvaco BioNuchar granular activated carbon, perlite, Osmocote slow release ammonium nitrate pellets, and Agrasoke water crystals in a 4:2:1:1 ratio by volume. The biofilter was inoculated with a bacterial culture collected from a Florida pulp and paperboard plant. A non-inoculated biofilter column was also tested. Use of a biological inoculum enriched from biofilm in the pulp and paper process has the potential to enhance the performance of a GAC biofilter. During testing, packing material was removed from the inlet and oulet of the biofilters and analyzed for genetic diversity using molecular techniques. The biofilter inoculated with specifically-enhanced inoculum showed higher bacterial diversity for methylotrophs and all bacteria, as compared to a non-inoculated biofilter. Mixed methylotrophic cultures, selected as potential biofilter inocula, showed increased methanol removal with highest concentrations of nitrogen provided as nitrate

An Information Model For Exchanging Hydrological Rating Tables

Many hydrological data systems provide Internet access to observational and processed data in various forms, from websites to web services. This data is generally described with basic metadata, such as units, names of measured variables, spatial coordinates, and so on. This metadata is largely suitable for further analysis or ingestion into hydrological models. However, when the data has been processed through many – potentially complex – steps, more information is required to give users details of implicit assumptions, inaccuracies, or uncertainties that may have been introduced. A common example of this within hydrology is the use of ratings tables to derive variables such as river discharge. Rating tables are generally developed through field observations using a wide range of methods and are subject to constant revision to adapt to changes in the physical world. Extracting details of rating conversions used in any of the hydrological data repositories found on the Internet is currently either not possible or quite difficult. A contributing factor to this is the lack of standard representations for rating tables and their related concepts. This paper describes work by members of the joint World Meteorology Organisation/Open Geospatial Consortium’s Hydrology Domain Working Group on development of an internationally harmonized information model to describe rating tables, called WaterML2.0 part 2. The paper covers the core aspects of the information model, its implementation within web services, and a visualization client for web-based analysis of rating tables. An international data exchange experiment has been setup to further test the information model in a number of exchange scenarios. The results will be used to refine and progress WaterML2.0 part 2 towards an open standard for data exchange. The standard will lead to increased transparency for data derived using ratings, resulting in improved integration with models and other analytical processes

Actin filament dynamics are dominated by rapid growth and severing activity in the Arabidopsis cortical array

Metazoan cells harness the power of actin dynamics to create cytoskeletal arrays that stimulate protrusions and drive intracellular organelle movements. In plant cells, the actin cytoskeleton is understood to participate in cell elongation; however, a detailed description and molecular mechanism(s) underpinning filament nucleation, growth, and turnover are lacking. Here, we use variable-angle epifluorescence microscopy (VAEM) to examine the organization and dynamics of the cortical cytoskeleton in growing and nongrowing epidermal cells. One population of filaments in the cortical array, which most likely represent single actin filaments, is randomly oriented and highly dynamic. These filaments grow at rates of 1.7 µm/s, but are generally short-lived. Instead of depolymerization at their ends, actin filaments are disassembled by severing activity. Remodeling of the cortical actin array also features filament buckling and straightening events. These observations indicate a mechanism inconsistent with treadmilling. Instead, cortical actin filament dynamics resemble the stochastic dynamics of an in vitro biomimetic system for actin assembly

Relevance of shrinkage versus fragmented response patterns in rectal cancer

AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome.METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P &lt; 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS.CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.</p

Relevance of shrinkage versus fragmented response patterns in rectal cancer

AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome.METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P &lt; 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS.CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.</p