A general strategy for discovery of inhibitors and activators of RING and U-box E3 ligases with ubiquitin variants

RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: monomeric UBE4B, phosphorylated active CBL, or dimeric XIAP. Structural and biochemical analyses revealed that UbVs specifically inhibited the activity of UBE4B or phosphorylated CBL by blocking the E2∼Ub binding site. Surprisingly, the UbV selective for dimeric XIAP formed a dimer to stimulate E3 activity by stabilizing the closed E2∼Ub conformation. We further verified the inhibitory and stimulatory functions of UbVs in cells. Our work provides a general strategy to inhibit or activate RING/U-box E3 ligases and provides a resource for the research community to modulate these enzymes

The thermal ignition problem in a cube

Steady state solutions for spontaneous thermal ignition in a unit cube are considered. For the unit sphere there are numerous solutions possible: these appear as ``wiggles'' in the bifurcation diagram. For the unit sphere this has been shown analytically. In contrast, for the unit cube analytic solutions are not possible and hence we must resort to numerical methods to determine the corresponding bifurcation diagram. Comparisons between the cube and the sphere are made

Role of contrast-enhanced ultrasound (CEUS) in paediatric practice: an EFSUMB position statement

The use of contrast-enhanced ultrasound (CEUS) in adults is well established in many different areas, with a number of current applications deemed off-label, but the use supported by clinical experience and evidence. Paediatric CEUS is also an off-label application until recently with approval specifically for assessment of focal liver lesions. Nevertheless there is mounting evidence of the usefulness of CEUS in children in many areas, primarily as an imaging technique that reduces exposure to radiation, iodinated contrast medium and the patient-friendly circumstances of ultrasonography. This position statement of the European Federation of Societies in Ultrasound and Medicine (EFSUMB) assesses the current status of CEUS applications in children and makes suggestions for further development of this technique

Combustion waves in a model with chain branching reaction and their stability

In this paper the travelling wave solutions in the adiabatic model with two-step chain branching reaction mechanism are investigated both numerically and analytically in the limit of equal diffusivity of reactant, radicals and heat. The properties of these solutions and their stability are investigated in detail. The behaviour of combustion waves are demonstrated to have similarities with the properties of nonadiabatic one-step combustion waves in that there is a residual amount of fuel left behind the travelling waves and the solutions can exhibit extinction. The difference between the nonadiabatic one-step and adiabatic two-step models is found in the behaviour of the combustion waves near the extinction condition. It is shown that the flame velocity drops down to zero and a standing combustion wave is formed as the extinction condition is reached. Prospects of further work are also discussed.Comment: pages 32, figures 2

A rule-based method for predicting the electrical activation of the heart with cardiac resynchronization therapy from non-invasive clinical data

Item does not contain fulltex

Gene delivery to in situ veins: Differential effects of adenovirus and adeno-associated viral vectors

AbstractPurpose: Gene transfer offers the potential to modify vein graft biology at the time of surgical implantation. Efficiency of gene delivery, stability of expression, and host responses are critical parameters for candidate vectors. We compared the effects of intraluminal exposure with adenovirus (AD) and adeno-associated virus (AAV) vectors on transgene expression and monocyte adhesion (MA) in treated vein segments. Methods: Adult New Zealand white rabbits (N = 51) were anesthetized, and the jugular veins were cannulated bilaterally. Veins were gently distended with either vector (2·108 to 1·1010 infective particles/mL) or vehicle (control) for 30 minutes, after which venous flow was restored. AD and AAV vectors encoding for the marker genes β-galactosidase (LacZ) and green fluorescent protein (GFP) were used. Vessels were explanted 2 to 40 days postinfection for analysis of gene expression (X-gal staining, reverse transcriptase-polymerase chain reaction), MA, and immunohistochemistry. Ex vivo adhesion assays used 51Cr-labeled THP-1 cells. Statistical significance was tested by using analysis of variance with a P value less than.05. Results: All animals survived, and all treated veins were patent at sacrifice. Intraluminal exposure to AD at a titer of 1·109 resulted in near complete transduction of the endothelium at 2 days, with no detectable expression by day 14. At an equal titer of infectious particles, transgene expression was markedly less for AAV at 2 to 7 days, but improved at 2 weeks and persisted to 40 days. MA was significantly increased 2 days after AD exposure (2.7-fold vs control, *P <.002); AAV treatment had no discernible effect on MA. Conclusion: AD-mediated gene transfer to vein segments resulted in robust, transient gene expression that disappeared after 2 weeks. In comparison, AAV-mediated gene delivery was less efficient, but resulted in delayed onset, persistent expression beyond 30 days. AD exposure induced an early increase in MA to the vein surface that was not seen with AAV treatment. Current generations of both AD and AAV vectors have significant, albeit different, limitations for vascular gene therapy. (J Vasc Surg 2000;31:1149-59.

Composting Rice Straw in Semi-Arid Conditions

Five experiments were conducted, three with 10-kg lots (in cement cylinders/digesters) and two in heaps with 500-kg lots of rice straw. Results from three—one with cement cylinders and two with heaps—are reported here. All were conducted at Patancheru from 1998 to 2000 in the hot summer period (April–May). The use of 0.76% N (as urea) with or without added micro-organisms more quickly decomposed the rice straw (by a subjective visual rating scale and C:N ratio) by about 1 week than otherwise. Also, the compost of N-applied treatments had at least 40% more N than that from the non-applied control. But N loss, indicated by the odour of ammonia, was noticed only from the N-applied treatments. All the treatments, except the control, received 25% rock phosphate (RP), when composting was done in cement digesters. For heap composting, RP was reduced to 6% so that its concentration would not be excessive when the compost is applied to crops at high rates. Composting was accomplished within 45 days whether in the digesters or in heaps, even with a reduced use of N (0.36% in 1999 and 0.1% in the year 2000). Treatment effects due to N that were apparent in the final product, disappeared when N-application was reduced to 0.3% or 0.1%. It was only through the visual rating that amendment with N and micro-organisms was perceived to shorting composting time. The resultant compost, however, did not indicate differences in chemical characteristics (N, P, K, OC%) across treatments in heap composting. One apparent biological difference across treatments was the presence of fruiting bodies of Sclerotium rolfsii (causes root rots in many crops) in control treatments. This fungus was not seen in treatments receiving microbial inoculation. In the experiment in 1999, we composted over 6 t of rice straw in a single session, in multiple heaps of 500 kg. The composting protocol is proposed for a small-scale village-level enterprise and is not intended for individual farmer

Sustainability implications of burning rice- and wheat-straw in Punjab

It is noted that yields from rice-wheat cropping systems in the Indo-Gangetic plain are declining despite the increasing use of chemical fertilizers. Crop residues are important components of soil fertility management, but are burnt in some areas, such as Punjab, India. Not only does this mean a loss of nutrients but also causes environmental pollution (and the associated health effects): the production of substantial quantities of carbon dioxide. Limited published data suggest that rice-straw can be converted to high value manure of a better quality than that of farmyard manure. Its use, along with chemical fertilizers should not only sustain present levels of crop yields, but may also increase them. Data are presented from 237 farmers surveyed during September-October 199

A new index to assess soil quality and sustainability of wheat-based cropping systems

Sustainability index was calculated to assess soil quality under the influence of different fertilizer management practices. It is based on the area of the triangle in which nutrient index, microbial index and crop index of soil represented the three vertices of a triangle. Nutrient index reflected the nutrient status of soil and was calculated from the measurements of various soil chemical parameters. Microbial index was calculated by determining various soil microbial and biochemical activities and crop index by measuring of crop yield parameters. Eighteen soil indicators were determined to assess nutrient index, microbial index and crop index in order to compare the effect of different sources of nutrients such as green manure, farmyard manure and chemical fertilizer in a rice/corn-wheat rotation. The indices were applied to assess the sustainability of five field experiments with respect to the different fertilizer treatments. The long-term application of organic manures in rice/corn-wheat cropping system increased the index value because it increased the nutrient index, microbial index and crop index of soils. The use of only chemical fertilizers in the rice-wheat cropping system resulted in poor soil microbial index and crop index. In corn-wheat system, additional application of FYM at 10 t ha-1 before sowing corn made the system more sustainable than application of 100% NPK; the sustainability index values were 2.43 (the highest for this system) and 0.93, respectivel