STING Millennium Suite: integrated software for extensive analyses of 3d structures of proteins and their complexes

BACKGROUND: The integration of many aspects of protein/DNA structure analysis is an important requirement for software products in general area of structural bioinformatics. In fact, there are too few software packages on the internet which can be described as successful in this respect. We might say that what is still missing is publicly available, web based software for interactive analysis of the sequence/structure/function of proteins and their complexes with DNA and ligands. Some of existing software packages do have certain level of integration and do offer analysis of several structure related parameters, however not to the extent generally demanded by a user. RESULTS: We are reporting here about new Sting Millennium Suite (SMS) version which is fully accessible (including for local files at client end), web based software for molecular structure and sequence/structure/function analysis. The new SMS client version is now operational also on Linux boxes and it works with non-public pdb formatted files (structures not deposited at the RCSB/PDB), eliminating earlier requirement for the registration if SMS components were to be used with user's local files. At the same time the new SMS offers some important additions and improvements such as link to ProTherm as well as significant re-engineering of SMS component ConSSeq. Also, we have added 3 new SMS mirror sites to existing network of global SMS servers: Argentina, Japan and Spain. CONCLUSION: SMS is already established software package and many key data base and software servers worldwide, do offer either a link to, or host the SMS. SMS (Sting Millennium Suite) is web-based publicly available software developed to aid researches in their quest for translating information about the structures of macromolecules into knowledge. SMS allows to a user to interactively analyze molecular structures, cross-referencing visualized information with a correlated one, available across the internet. SMS is already used as a didactic tool by some universities. SMS analysis is now possible on Linux OS boxes and with no requirement for registration when using local files

A Tale of Two Current Sheets

I outline a new model of particle acceleration in the current sheet separating the closed from the open field lines in the force-free model of pulsar magnetospheres, based on reconnection at the light cylinder and "auroral" acceleration occurring in the return current channel that connects the light cylinder to the neutron star surface. I discuss recent studies of Pulsar Wind Nebulae, which find that pair outflow rates in excess of those predicted by existing theories of pair creation occur, and use those results to point out that dissipation of the magnetic field in a pulsar's wind upstream of the termination shock is restored to life as a viable model for the solution of the "$\sigma$" problem as a consequence of the lower wind 4-velocity implied by the larger mass loading.Comment: 17 pages, 6 figures, Invited Review, Proceedings of the "ICREA Workshop on The High-Energy Emission from Pulsars and their Systems", Sant Cugat, Spain, April 12-16, 201

MHD models of Pulsar Wind Nebulae

Pulsar Wind Nebulae (PWNe) are bubbles or relativistic plasma that form when the pulsar wind is confined by the SNR or the ISM. Recent observations have shown a richness of emission features that has driven a renewed interest in the theoretical modeling of these objects. In recent years a MHD paradigm has been developed, capable of reproducing almost all of the observed properties of PWNe, shedding new light on many old issues. Given that PWNe are perhaps the nearest systems where processes related to relativistic dynamics can be investigated with high accuracy, a reliable model of their behavior is paramount for a correct understanding of high energy astrophysics in general. I will review the present status of MHD models: what are the key ingredients, their successes, and open questions that still need further investigation.Comment: 18 pages, 5 figures, Invited Review, Proceedings of the "ICREA Workshop on The High-Energy Emission from Pulsars and their Systems", Sant Cugat, Spain, April 12-16, 201

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma

Proteasome inhibitors have provided a significant advance in the treatment of multiple myeloma (MM). Consequently, there is increasing interest in developing strategies to target E3 ligases, de-ubiquitinases, and/or ubiquitin receptors within the ubiquitin proteasome pathway, with an aim to achieve more specificity and reduced side-effects. Previous studies have shown a role for the E3 ligase HUWE1 in modulating c-MYC, an oncogene frequently dysregulated in MM. Here we investigated HUWE1 in MM. We identified elevated expression of HUWE1 in MM compared with normal cells. Small molecule-mediated inhibition of HUWE1 resulted in growth arrest of MM cell lines without significantly effecting the growth of normal bone marrow cells, suggesting a favorable therapeutic index. Studies using a HUWE1 knockdown model showed similar growth inhibition. HUWE1 expression positively correlated with MYC expression in MM bone marrow cells and correspondingly, genetic knockdown and biochemical inhibition of HUWE1 reduced MYC expression in MM cell lines. Proteomic identification of HUWE1 substrates revealed a strong association of HUWE1 with metabolic processes in MM cells. Intracellular glutamine levels are decreased in the absence of HUWE1 and may contribute to MYC degradation. Finally, HUWE1 depletion in combination with lenalidomide resulted in synergistic anti-MM activity in both in vitro and in vivo models. Taken together, our data demonstrate an important role of HUWE1 in MM cell growth and provides preclinical rationale for therapeutic strategies targeting HUWE1 in MM

MadGraph 5 : Going Beyond

MadGraph 5 is the new version of the MadGraph matrix element generator, written in the Python programming language. It implements a number of new, efficient algorithms that provide improved performance and functionality in all aspects of the program. It features a new user interface, several new output formats including C++ process libraries for Pythia 8, and full compatibility with FeynRules for new physics models implementation, allowing for event generation for any model that can be written in the form of a Lagrangian. MadGraph 5 builds on the same philosophy as the previous versions, and its design allows it to be used as a collaborative platform where theoretical, phenomenological and simulation projects can be developed and then distributed to the high-energy community. We describe the ideas and the most important developments of the code and illustrate its capabilities through a few simple phenomenological examples.Comment: 37 pages, 5 figures, 7 table

Attentional Performance, Age and Scholastic Achievement in Healthy Children

Attentional processes in children play a critical role in daily school demands and accomplishments. Studies on the association of attentional processes with school achievement and age in healthy school children are scarce. The aim of the present study was to identify correlations between dimensions of attentional performance, scholastic achievement and age.An extensive testing battery was used to assess a wide range of attentional dimensions. A principal component analysis revealed three factors that are related to attentional performance (distractibility, lapses of attention, cognitive speed). Age was negatively associated with distractibility, lapses of attention and cognitive speed, indicating that distractibility and lapses of attention decreased with age in healthy children and resulted in lower cognitive speed.Attentional processes in healthy children should be measured in relation to distractibility, lapses of attention and cognitive speed

Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans

Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life

Expression of angiotensin II type 1 receptor in rat bladder smooth muscle cells in response to a streptzotocin induced diabetes mellitus model

Introduction: The aim of this study was to investigate angiotensin II type 1 (AT1) receptors in rat bladder smooth muscle cells and alterations of AT1 receptors by diabetes mellitus and diuretic states. Materials and Methods: Diabetes and diuresis were induced in adult female rats by a single intraperitoneal injection of streptozotocin and feeding 5% sucrose in water. Cystometry was performed on control, diuretic, and diabetic rats at 2 and 8 weeks after treatment. Immunohistochemical staining was used to detect expression of AT1 receptors in the bladder smooth muscle cell membrane. Results and Conclusions: In diabetic rats, expression of AT1 receptors in the bladder smooth muscle cell membrane increased at 2 weeks and further increased at 8 weeks. The local renin-angiotensin system in the rat bladder might be activated by the continuous hyperglycemia caused by intraperitoneal injection of streptozotocin administration