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

Организационные резервы повышения производительности труда на предприятиях нефтегазовой отрасли

Проблема повышения производительности труда в современной экономике России имеет значительную актуальность, поскольку повышение уровня производительности труда является важнейшим условием социально-экономического развития общества, устойчивого экономического роста и повышения конкурентоспособности национальной экономики. Актуальность представленного исследования определяется необходимостью повышения производительности труда на современных предприятиях России, что может быть достигнуто за счет реализации организационных резервов роста. Целью исследования является структурирование факторов, оказывающих влияние на уровень производительности труда, подтверждение значимости организационных резервов роста, апробация методики выявления организационных резервов повышения производительности труда. Методы исследования. В настоящей работе нашли применение методы сбора первичной экономической информации, включая анализ законодательных и нормативно-правовых актов РФ, официальных статистических данных, данных публичной отчетности отечественных предприятий, анализ прочих открытых источников информации, системный подход, методы статистического и сравнительного анализа. The country's labor productivity in modern Russia over recent years has acquired impressive relevance. Since it is a key indicator of overall economic efficiency, strong labor productivity growth has always been a sufficient condition for socio-economic development, economic stability and enhancing competitiveness of the national economy. The relevance of the study is determined by the urgency of the labor productivity growth at the modern Russian factories that can be achieved through realization of organizational reserves. The main aim of the study is identifying and structuring the factors that seem to affect labor productivity level. It is also pointed at corroborating the necessity of labor productivity growth and approbation of organizational reserves seeking method. Methods. In the present work different methods of information gathering and processing were used to obtain the economic data including the analysis of appropriate laws and regulations, official statistics, companies' public statements and reporting and other open available resources. Also system approach, comparative and statistical analysis were adopted in this research

Bending AdS Waves with New Massive Gravity

We study AdS-waves in the three-dimensional new theory of massive gravity recently proposed by Bergshoeff, Hohm, and Townsend. The general configuration of this type is derived and shown to exhibit different branches, with different asymptotic behaviors. In particular, for the special fine tuning $m^2=\pm1/(2l^2)$, solutions with logarithmic fall-off arise, while in the range $m^2>-1/(2l^2)$, spacetimes with Schrodinger isometry group are admitted as solutions. Solutions that are asymptotically AdS$_3$, both for Brown-Henneaux and for the weakened boundary conditions, are also identified. The metric function that characterizes the profile of the AdS-wave behaves as a massive excitation on the spacetime, with an effective mass given by $m_{eff}^2=m^2-1/(2l^2)$. For the critical value $m^2=-1/(2l^2)$, the value of the effective mass precisely saturates the Breitenlohner-Freedman bound for the AdS$_3$ space where the wave is propagating on. The analogies with the AdS-wave solutions of topologically massive gravity are also discussed. Besides, we consider the coupling of both massive deformations to Einstein gravity and find the exact configurations for the complete theory, discussing all the different branches exhaustively. One of the effects of introducing the Chern-Simons gravitational term is that of breaking the degeneracy in the effective mass of the generic modes of pure New Massive Gravity, producing a fine structure due to parity violation. Another effect is that the zoo of exact logarithmic specimens becomes considerably enlarged.Comment: 9 pages. Minor typos correcte

Structure of UBE2K-Ub/E3/polyUb reveals mechanisms of K48-linked Ub chain extension

Ubiquitin (Ub) chain types govern distinct biological processes. K48-linked polyUb chains target substrates for proteasomal degradation, but the mechanism of Ub chain synthesis remains elusive due to the transient nature of Ub-handover. Here, we present the structure of a chemically trapped complex of E2 UBE2K covalently linked to donor Ub and acceptor K48-linked di-Ub, primed for K48-linked Ub chain synthesis by a RING E3. The structure reveals the basis for acceptor Ub recognition by UBE2K active site residues and the C-terminal Ub-associated (UBA) domain to impart K48-linked Ub specificity and catalysis. Furthermore, the structure unveils multiple Ub binding surfaces on the UBA domain that allow distinct binding modes for K48-linked and K63-linked Ub chains. This multivalent Ub binding feature serves to recruit UBE2K to ubiquitinated substrates to overcome weak acceptor Ub affinity and thereby promote chain elongation. These findings elucidate the mechanism of processive K48-linked polyUb chain formation by UBE2K

Antimicrobial activity of alcoholic extracts of medicinal plants against Phytopathogenic fungi.

Aims: This work aimed to evaluate the antimicrobial effects of 14 alcoholic extracts of medicinal plants on the mycelial growth of Colletotrichum gloeosporioides, Fusarium oxysporum f. sp. passiflorae, Fusarium solani and Rhizoctonia solani. Those are fungi that cause diseases in Passiflora edulis. Study Design: With the obtained data the mycelial growth rate index (MGRI) was calculated, afterwards the analysis of variance was performed and the means were compared by the Scott-Knott test at 5% probability. Place and Duration of Study: Plant Pathology Laboratory, Embrapa Eastern Amazon, Belém, Pará, Brazil, between May 2014 and April 2015. Methodology: The extracts were prepared with 1.0 g of powdered plant material and 10 mL of commercial ethyl alcohol 92.8º (0.1 g mL-1) under constant agitation in an orbital shaker at 200 rpm for 20 minutes. They were then kept in the refrigerator for 24 hours at rest. The extracts were centrifuged and filtered on Millipore membranes with 0.22 µm porosity. The tests with the phytopathogenic fungi were carried out in vitro with the alcoholic extracts at 1% concentration. The experimental design was completely randomized with 15 treatments and 5 replicates. Results: All the extracts reduced the growth of the fungi C. gloeosporioides. The extracts the Eucalyptus angulosa, Lippia alba, Zingiber officinale, Cymbopagon citratus, Azadirachta indica, Plectranthus barbathus, Hibiscus sabdariffa, Aloe vera, Pedilanthus tithymaloides, Mansoa alliacea and Chenopodium ambrosioides reduced the mycelial growth of F. oxysporum f. sp. passiflorae. Only the extract of E. angulosa presented reduction in the growth of F. solani. Meanwhile the extracts of E. angulosa, Z. officinale, L. alba, M. alliacea and P. barbathus reduced the mycelial growth of R. solani. Conclusion: All extracts presented antimicrobial potential, being that the extract of E. angulosa reduced the mycelial growth of all the evaluated fungi

Discussing Quantum Aspects of Higher-Derivative 3D-Gravity in the First-Order Formalism

In this paper, we reassess the issue of deriving the propagators and identifying the spectrum of excitations associated to the vielbein and spin connection of (1+2)-D gravity in the presence of dynamical torsion, while working in the first-order formulation. A number of peculiarities is pointed out whenever the Chern-Simons term is taken into account along with a combination of bilinear terms in the torsion tensor. We present a procedure to derive the full set of propagators, based on an algebra of enlarged spin-type operators, and we discuss under which conditions the poles of the tree-level 2-point functions correspond to physical excitations that do not conflict with causality and unitarity

Three-dimensional black holes, gravitational solitons, kinks and wormholes for BHT massive gravity

The theory of massive gravity in three dimensions recently proposed by Bergshoeff, Hohm and Townsend (BHT) is considered. At the special case when the theory admits a unique maximally symmetric solution, a conformally flat space that contains black holes and gravitational solitons for any value of the cosmological constant is found. For negative cosmological constant, the black hole is characterized in terms of the mass and the "gravitational hair" parameter, providing a lower bound for the mass. For negative mass parameter, the black hole acquires an inner horizon, and the entropy vanishes at the extremal case. Gravitational solitons and kinks, being regular everywhere, are obtained from a double Wick rotation of the black hole. A wormhole solution in vacuum that interpolates between two static universes of negative spatial curvature is obtained as a limiting case of the gravitational soliton with a suitable identification. The black hole and the gravitational soliton fit within a set of relaxed asymptotically AdS conditions as compared with the ones of Brown and Henneaux. In the case of positive cosmological constant the black hole possesses an event and a cosmological horizon, whose mass is bounded from above. Remarkably, the temperatures of the event and the cosmological horizons coincide, and at the extremal case one obtains the analogue of the Nariai solution, $dS_{2}\times S^{1}$. A gravitational soliton is also obtained through a double Wick rotation of the black hole. The Euclidean continuation of these solutions describes instantons with vanishing Euclidean action. For vanishing cosmological constant the black hole and the gravitational soliton are asymptotically locally flat spacetimes. The rotating solutions can be obtained by boosting the previous ones in the $t-\phi$ plane.Comment: Talk given at the "Workshop on Gravity in Three Dimensions," 14-24 April 2009, ESI, Vienna. 30 pages, 6 figures. V2: minor changes and section 6 slightly improved. Last version for JHE

Extra gauge symmetries in BHT gravity

We study the canonical structure of the Bergshoeff-Hohm-Townsend massive gravity, linearized around a maximally symmetric background. At the critical point in the space of parameters, defined by $\Lambda_0/m^2=-1$, we discover an extra gauge symmetry, which reflects the existence of the partially massless mode. The number of the Lagrangian degrees of freedom is found to be 1. We show that the canonical structure of the theory at the critical point is unstable under linearization.Comment: LATEX, 12 page

Harnessing the immune system in the battle against breast cancer

Breast cancer is the most prevalent malignancy in women and the second most common cause of cancer-related death worldwide. Despite major innovations in early detection and advanced therapeutics, up to 30% of women with nodenegative breast cancer and 70% of women with node-positive breast cancer will develop recurrence. The recognition that breast tumors are infiltrated by a complex array of immune cells that influence their development, progression, and metastasis, as well as their responsiveness to systemic therapies has sparked major interest in the development of immunotherapies. In fact, not only the native host immune system can be altered to promote potent antitumor response, but also its components can be manipulated to generate effective therapeutic strategies. We present here a review of the major approaches to immunotherapy in breast cancers, both successes and failures, as well as new therapies on the horizon