The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1.

Proapoptotic Bcl-2 family members, such as Bax, promote release of cytochrome c from mitochondria, leading to caspase activation and cell death. It was previously reported that modulator of apoptosis protein 1 (MOAP-1), an enhancer of Bax activation induced by DNA damage, is stabilized by Trim39, a protein of unknown function. In this paper, we show that MOAP-1 is a novel substrate of the anaphase-promoting complex (APC/C(Cdh1)) ubiquitin ligase. The influence of Trim39 on MOAP-1 levels stems from the ability of Trim39 (a RING domain E3 ligase) to directly inhibit APC/C(Cdh1)-mediated protein ubiquitylation. Accordingly, small interfering ribonucleic acid-mediated knockdown of Cdh1 stabilized MOAP-1, thereby enhancing etoposide-induced Bax activation and apoptosis. These data identify Trim39 as a novel APC/C regulator and provide an unexpected link between the APC/C and apoptotic regulation via MOAP-1.

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.

PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.

The numerical simulation of noncharring thermal degradation and its application to the prediction of compartment fire development

In this paper we present some work concerned with the development and testing of a simple solid fuel combustion model incorporated within a Computational Fluid Dynamics (CFD) framework. The model is intended for use in engineering applications of fire field modeling and represents an extension of this technique to situations involving the combustion of solid fuels. The CFD model is coupled with a simple thermal pyrolysis model for combustible solid noncharring fuels, a six-flux radiation model and an eddy-dissipation model for gaseous combustion. The model is then used to simulate a series of small-scale room fire experiments in which the target solid fuel is polymethylmethacrylate. The numerical predictions produced by this coupled model are found to be in very good agreement with experimental data. Furthermore, numerical predictions of the relationship between the air entrained into the fire compartment and the ventilation factor produce a characteristic linear correlation with constant of proportionality 0.38 kg/sm5/12. The simulation results also suggest that the model is capable of predicting the onset of "flashover" type behavior within the fire compartment.

Computational modelling of particle degradation in dilute phase pneumatic conveyors

The aim of this paper is to develop a mathematical model with the ability to predict particle degradation during dilute phase pneumatic conveying. A numerical procedure, based on a matrix representation of degradation processes, is presented to determine the particle impact degradation propensity from a small number of particle single impact tests carried out in a new designed laboratory scale degradation tester. A complete model of particle degradation during dilute phase pneumatic conveying is then described, where the calculation of degradation propensity is coupled with a flow model of the solids and gas phases in the pipeline. Numerical results are presented for degradation of granulated sugar in an industrial scale pneumatic conveyor.

Numerical predictions of particle degradation in industrial-scale pneumatic conveyors

This paper presents an Eulerian-based numerical model of particle degradation in dilute-phase pneumatic conveying systems including bends of different angles. The model shows reasonable agreement with detailed measurements from a pilot-sized pneumatic conveying system and a much larger scale pneumatic conveyor. The potential of the model to predict degradation in a large-scale conveying system from an industrial plant is demonstrated. The importance of the effect of the bend angle on the damage imparted to the particles is discussed.

Computational model for prediction of particle degradation during dilute phase pneumatic conveying: the use of a laboratory scale degradation tester for the determination of degradation propensity

The overall objective of this work is to develop a computational model of particle degradation during dilute-phasepneumatic conveying. A key feature of such a model is the prediction of particle breakage due to particle–wall collisions in pipeline bends. This paper presents a method for calculating particle impact degradation propensity under a range of particle velocities and particle sizes. It is based on interpolation on impact data obtained in a new laboratory-scale degradation tester. The method is tested and validated against experimental results for degradation at 90± impact angle of a full-size distribution sample of granulated sugar. In a subsequent work, the calculation of degradation propensity is coupled with a ow model of the solids and gas phases in the pipeline.

Computational model for prediction of particle degradation during dilute-phase pneumatic conveying: modeling of dilute-phase pneumatic conveying

A complete model of particle impact degradation during dilute-phase pneumatic conveying is developed, which combines a degradation model, based on the experimental determination of breakage matrices, and a physical model of solids and gas flow in the pipeline. The solids flow in a straight pipe element is represented by a model consisting of two zones: a strand-type flow zone immediately downstream of a bend, followed by a fully suspended flow region after dispersion of the strand. The breakage matrices constructed from data on 90° angle single-impact tests are shown to give a good representation of the degradation occurring in a pipe bend of 90° angle. Numerical results are presented for degradation of granulated sugar in a large scale pneumatic conveyor.

HPLC-ESI-MS method development for the elucidation of nicardipine degradation products

Purpose: Nicardipine is a member of a family of calcium channel blockers named dihydropiridines that are known to be photolabile and may cause phototoxicity. It is therefore vital to develop analytical method which can study the photodegradation of nicardipine. Method: Forced acid degradation of nicardipine was conducted by heating 12 ml of 1 mg/ml nicardipine with 3 ml of 2.5 M HCl for two hours. A gradient HPLC medthod was developed using Agilent Technologies 1200 series quaternary system. Separation was achieved with a Hichrome (250 x 4.6 mm) 5 μm C18 reversed phase column and mobile phase composition of 70% A(100%v/v water) and 30% B(99%v/v acetonitrile + 1%v/v formic acid) at time zero, composition of A and B was then charged to 60%v/v A;40%v/v B at 10minutes, 50%v/v A; 50%v/v B at 30minutes and 70%v/v A; 30%v/v B at 35minutes. 20μl of 0.8mg/ml of nicardipine degradation was injected at room temperature (25oC). The gradient method was transferred onto a HPLC-ESI-MS system (HP 1050 series - AQUAMAX mass detector) and analysis conducted with an acid degradation concentration of 0.25mg/ml and 20μl injection volume. ESI spectra were acquired in positive ionisation mode with MRM 0-600 m/z. Results: Eleven nicardipine degradation products were detected in the HPLC analysis and the resolution (RS) between the respective degradants where 1.0, 1.2, 6.0, 0.4, 1.7, 3.7, 1.8, 1.0, and 1.7 respectively. Nine degradation products were identified in the ESI spectra with the respective m/z ratio; 171.0, 166.1, 441.2, 423.2, 455.2, 455.2, 331.1, 273.1, and 290.1. The possible molecular formulae for each degradants were ambiguously determined. Conclusion: A sensitive and specific method was developed for the analysis of nicardipine degradants. Method enables detection and quantification of nicardipine degradation products that can be used for the study of the kinetics of nicardipine degradation processes.

Assessment of the degradation of Aspirin by Differential Scanning Calorimetry (DSC)

Purpose. To study thermal stability of Aspirin and define thermal events that are associated with the thermal degradation of aspirin. Methods. Experiments were performed using a DSC 823e (Mettler Toledo, Swiss). Aspirin is prone to thermal degradation upon exposure to high temperatures. The melting point of aspirin is 140.1±0.4ºC (DSC). Aspirin has been examined by heating samples to 120ºC, 155ºC and 185ºC with subsequent cooling to -55ºC and a final heating to 155ºC. Although different heating and cooling ranges have been used, only results obtained at a rate of 10ºC/min will be presented. All runs where conducted in hermetically sealed pans. Results. Upon heating the sample to 120ºC no significant thermal event can be detected. After cooling the sample and reheating a glass transition can be observed at ~-8ºC, followed by the melting of aspirin at ~139ºC. By heating the sample to 155ºC melting of aspirin has been detected at ~139ºC. On cooling and subsequent heating a glass transition occurs at ~-32ºC, together with a broad crystallisation (onset at ~38ºC and peak maximum at ~57ºC) followed by a broad melting with an onset at 94ºC and peak maximum at ~112ºC. Finally, by heating the sample to 185ºC melting at ~ 139ºC was observed, and upon cooling and reheating a glass transition was detected at ~-26ºC and no further events could be recorded. Conclusions. This research demonstrates that the degradation steps of Aspirin depend on the thermal treatment. The main degradation products of different thermal treatments are currently unknown it is clear that acetic acid, which is one of the degradation products, acts as an antiplasticiser by lowering the glass transition temperature. In addition, due to the presence of the degradation products in liquid form (observed by hot stage microscopy), Aspirin is still present in the sample and recrystallises during the second heating step and melts at much lower temperatures.

Evaluation of particle degradation due to high-speed impacts in a pneumatic handling system

Particle degradation can be a significant issue in particulate solids handling and processing, particularly in pneumatic conveying systems, in which high-speed impact is usually the main contributory factor leading to changes in particle size distribution (comparing the material to its virgin state). However, other factors may strongly influence particles breakage as well, such as particle concentrations, bend geometry,and hardness of pipe material. Because of such complex influences, it is often very difficult to predict particle degradation accurately and rapidly for industrial processes. In this article, a general method for evaluating particle degradation due to high-speed impacts is described, in which the breakage properties of particles are quantified using what are known as "breakage matrices". Rather than a pilot-size test facility, a bench-scale degradation tester has been used. Some advantages of using the bench-scale tester are briefly explored. Experimental determination of adipic acid has been carried out for a range of impact velocities in four particle size categories. Subsequently, particle breakage matrices of adipic acid have been established for these impact velocities. The experimental results show that the "breakage matrices" of particles is an effective and easy method for evaluation of particle degradation due to high-speed impacts. The possibility of the "breakage matrices" approach being applied to a pneumatic conveying system is also explored by a simulation example.

Aquatic Distribution And Heterotrophic Degradation Of Polycyclic Aromatic-Hydrocarbons (PAH) In The Tamar Estuary

Variations in the concentrations and microheterotrophic degradation rates of selected Polycyclic Aromatic Hydrocarbons (PAH) in the water column of the Tamar Estuary were investigated in relation to the major environmental variables. Concentrations of individual PAH varied typically between i and 50 ng l−1 Based on their observed environmental behaviour the PAH appeared divisible into two groupings: (1) low molecular weight PAH incorporating naphthalene, phenanthrene and anthracence and (a) the larger molecular weight homologues (fluoranthene, pyrene, chrysene, benz(a)anthracene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(a)-pyrene). Group 1 PAH showed a complex distribution throughout the estuary with no significant correlations with either salinity or suspended particulates. Based on their relatively low particle affinity and high water solubilities and vapour pressures, volatilization is proposed as an important process in determining their fate. Microheterotrophic turnover times of naphthalene varied between x and 30 days, and were independent of suspended solids with maximum degradation rates located in the central and urban regions of the Estuary. When compared with the flushing times for the Tamar (3–5 days), it is probable that heterotrophic activity is important in the removal of naphthalene (and possibly the other Group 1 PAH) from the estuarine environment. In contrast Group 2 PAH concentrations exhibited highly significant correlations with suspended particulates. Highest concentrations occurred at the turbidity maximum, with a secondary concentration maximum localized to the industrialized portion of the estuary and associated with anthropogenic inputs. Laboratory degradation studies of benzo(a)pyrene in water samples taken from the estuary showed turnover times for the compound of between 2000 and 9000 days. Degradation rates correlated positively with suspended solids. The high particulate affinity and microbial refractivity of Group 2 PAH indicate sediment burial as the principal tate of these PAH in the Tamar Estuary. Estuarine sediments contained typically 50–1500 ng g−1 dry weight of individual PAH which were comparable to the levels of Group 2 PAH associated with the suspended particulates. Highest concentrations occurred at the riverine end of the estuary resulting from unresolved inputs in the catchment. Subsequent dilution by less polluted marine sediments together with slow degradation results in a seaward trend of decreasing concentrations. However, there is a secondary maximum of PAH superimposed on this trend which is associated with urban Plymouth.