Chronic ethanol-mediated hepatocyte apoptosis links to decreased TET1 and 5-hydroxymethylcytosine formation.

The 5-hydroxymethylcytosine (5hmc) is a newly identified epigenetic modification thought to be regulated by the TET family of proteins. Little information is available about how ethanol consumption may modulate 5hmC formation and alcoholic liver disease (ALD) progression. A rat ALD model was used to study 5hmC in relationship to hepatocyte apoptosis. Human ALD liver samples were also used to validate these findings. It was found that chronic ethanol feeding significantly reduced 5hmC formation in a rat ALD model. There were no significant changes in TET2 and TET3 between the control- and ethanol-fed animals. In contrast, methylcytosine dioxygenase TET1 (TET1) expression was substantially reduced in the ethanol-fed rats and was accompanied by increased hepatocyte apoptosis. Similarly, knockdown of TET1 in human hepatocyte-like cells also significantly promoted apoptosis. Down-regulation of TET1 resulted in elevated expression of the DNA damage marker, suggesting a role for 5hmc in hepatocyte DNA damage as well. Mechanistic studies revealed that inhibition of TET1 promoted apoptotic gene expression. Similarly, targeting TET1 activity by removing cosubstrate promoted apoptosis and DNA damage. Furthermore, treatment with 5-azacitidine significantly mimics these effects, suggesting that chronic ethanol consumption promotes hepatocyte apoptosis and DNA damage by diminishing TET1-mediated 5hmC formation and DNA methylation. In summary, the current study provides a novel molecular insight that TET1-mediated 5hmC is involved in hepatocyte apoptosis in ALD progression.-Ji, C., Nagaoka, K., Zou, J., Casulli, S., Lu, S., Cao, K. Y., Zhang, H., Iwagami, Y., Carlson, R. I., Brooks, K., Lawrence, J., Mueller, W., Wands, J. R., Huang, C.-K. Chronic ethanol-mediated hepatocyte apoptosis links to decreased TET1 and 5-hydroxymethylcytosine formation.

On the Droplet Size and Application of Wettability Analysis for the Development of Ink and Printing Substrates.

For the printing industry to grow and for companies in the field to remain competitive, there is a drive toward enhancing research and development so that costs of inks and substrates can be minimized. This paper details one of the first studies into the importance of liquid droplet size for applying wettability science to the development of inks and substrates using a newly developed picoliter droplet dispensing system (PDDS). Differences between using microliter, µL (0.2-5 µL), and picoliter, pL (15-380 pL), droplets for wettability analysis is considered, showing the importance of using pL droplets within the development of inks and substrates for printing applications. This is due to differences in contact angle being up to 40° when comparing results from pL- and µL-sized water-based droplets. Wetting, absorption, and evaporation behavior of different droplet sizes are also discussed with specific consideration to the use of wettability science for ink development and the development of inkjet printing substrates. A newly developed commercially available water-based blue ink and a commercially available water-based black ink are studied using pL experimentation to show how pL-sized droplets for inkjet wettability analysis is the optimum volume range to ensure optimized inkjet printing analysis and development.

Structure-based discovery of LpxC inhibitors.

The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria. Our efforts toward the discovery of novel LpxC inhibitors are presented herein.

Engineering of nickel, cobalt oxides and nickel/cobalt binary oxides by electrodeposition and application as binder free electrodes in supercapacitors.

Cobalt oxide, nickel oxide and cobalt/nickel binary oxides were synthesised by electrodeposition. To fine tune composition of CoNi alloys, growth parameters including voltage, electrolyte pH/concentration and deposition time were varied. These produced nanomaterials were used as binder free electrodes in supercapacitor cells and tested using three electrode setup in 2 MKOH aqueous electrolyte. Cyclic voltammetry and galvanostatic charge/discharge were used at different scan rates (5-100 mV/s) and current densities (1-10 A/g) respectively to investigate the capacitive behaviour and measure the capacitance of active material. Electrochemical impedance spectroscopy was used to analyse the resistive/conductive behaviours of these electrodes in frequency range of 100 kHz to 0.01 Hz at applied voltage of 10 mV. Binary oxide electrode displayed superior electrochemical performance with the specific capacitance of 176 F/g at current density of 1 A/g. This hybrid electrode also displayed capacitance retention of over 83% after 5000 charge/discharge cycles. Cell displayed low solution resistance of 0.35 Ω along with good conductivity. The proposed facile approach to synthesise binder free blended metal electrodes can result in enhanced redox activity of pseudocapacitive materials. Consequently, fine tuning of these materials by controlling the cobalt and nickel contents can assist in broadening their applications in electrochemical energy storage in general and in supercapacitors in particular.

Histopathologic evaluation of patent ductus arteriosus stents after hybrid stage I palliation.

The aim of this study was to determine the histopathology of patent ductus arteriosus (PDA) in-stent stenosis after hybrid stage I palliation. The hybrid approach to palliation of hypoplastic left heart syndrome can be complicated by the development of in-stent stenosis of the PDA. This may obstruct retrograde aortic arch flow, decrease systemic circulation, and lead to interstage interventional procedures. Stented PDA samples removed from eight patients undergoing comprehensive stage II repair were examined by way of radiography and histochemistry (hematoxylin and eosin, Movat pentachrome, α-smooth muscle actin, and proliferating cell nuclear antigen). A retrospective chart review of the patients was also performed. PDA stents were in place in the PDA for a mean period of 169 ± 28 days in patients who had a mean age of 176 ± 30 days at the time of stent removal. Stent deployment caused chronic inflammation, caused fibrin deposition, and induced vascular smooth muscle-cell (VSMC) proliferation in the area immediately surrounding the stent struts. The neointimal region was composed largely of smooth muscle cells that appeared to be fully differentiated by the lack of PCNA staining. Neointimal thickening occurs in the PDA after stent placement for hybrid palliation of HLHS and is the result of inflammation, extracellular matrix deposition, and smooth muscle-cell proliferation in the peristrut region. This finding suggests that proliferating VSMCs in the peristrut region may provide the impetus for inward neointimal formation and therefore the manifestation of in-stent stenosis.

Large-scale preparation of key building blocks for the manufacture of fully synthetic macrolide antibiotics.

Key building blocks for the production of fully synthetic macrolides have been scaled-up in first time pilot plant and kilo-lab campaigns. These building blocks have supported the discovery of new macrolide antibiotics as well as ongoing preclinical studies.

Variability in vehicle and dummy responses in rear-end collisions.

OBJECTIVE: The objective of this study was to quantify the occupant response variability due to differences in vehicle and seat design in low-speed rear-end collisions. METHODS: Occupant response variability was quantified using a BioRID dummy exposed to rear-end collisions in 20 different vehicles. Vehicles were rolled rearward into a rigid barrier at 8 km/h and the dynamic responses of the vehicle and dummy were measured with the head restraint adjusted to the up most position. In vehicles not damaged by this collision, additional tests were conducted with the head restraint down and at different impact speeds. RESULTS: Despite a coefficient of variation (COV) of less than 2% for the impact speed of the initial 8 km/h tests, the vehicle response parameters (speed change, acceleration, restitution, bumper force) had COVs of 7 to 23% and the dummy response parameters (head and T1 kinematics, neck loads, NIC, N(ij) and N(km)) had COVs of 14 to 52%. In five vehicles tested multiple times, a head restraint in the down position significantly increased the peak magnitude of many dummy kinematic and kinetic response parameters. Peak head kinematics and neck kinetics generally varied linearly with head restraint back set and height, although the neck reaction moment reversed and increased considerably if the dummy's head wrapped onto the top of the head restraint. CONCLUSIONS: The results of this study support the proposition that the vehicle, seat, and head restraint are a safety system and that the design of vehicle bumpers and seats/head restraint should be considered together to maximize the potential reduction in whiplash injuries.

Collagenase-aided insertion of intracortical microelectrode arrays: evaluation of insertion force and chronic recording performance.

Typically intracortical electrodes are required to puncture the intact pia mater during insertion which in the process can lead to brain dimpling and trauma. Furthermore, there is interest in the development of more flexible substrates to reduce relative micromotion after implantation, but such device have difficulty penetrating the pia without buckling. In this paper a strategy for reducing the mechanical integrity of the pia's collagen network by treatment with collagenase is evaluated experimentally. Measurements of the insertion force were carried out with a load cell during computer controlled slow (10 microm/sec) electrode insertion into the cortex of rats. It is shown that controlled application of collagenase reduces the peak insertion force experienced by the microwire arrays around 30% on average. In addition, chronic neural recordings (up to 1 month) suggest that there is no appreciable difference in the signal quality as recorded from the collagenase treated and the control sites. The results suggest the technique is useful for reducing insertion forces without compromising neural recording capabilities.