Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen. N^2,N^4-dibenzylquinazoline-2,4-diamine (DBeQ) was identified as a selective, potent, reversible, and ATP-competitive p97 inhibitor. DBeQ blocks multiple processes that have been shown by RNAi to depend on p97, including degradation of ubiquitin fusion degradation and endoplasmic reticulum-associated degradation pathway reporters, as well as autophagosome maturation. DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy

Regulation of immune cell function and differentiation by the NKG2D receptor

NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties, expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage. Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation

Evolution of the deaminase fold and multiple origins of eukaryotic editing and mutagenic nucleic acid deaminases from bacterial toxin systems

The deaminase-like fold includes, in addition to nucleic acid/nucleotide deaminases, several catalytic domains such as the JAB domain, and others involved in nucleotide and ADP-ribose metabolism. Using sensitive sequence and structural comparison methods, we develop a comprehensive natural classification of the deaminase-like fold and show that its ancestral version was likely to operate on nucleotides or nucleic acids. Consequently, we present evidence that a specific group of JAB domains are likely to possess a DNA repair function, distinct from the previously known deubiquitinating peptidase activity. We also identified numerous previously unknown clades of nucleic acid deaminases. Using inference based on contextual information, we suggest that most of these clades are toxin domains of two distinct classes of bacterial toxin systems, namely polymorphic toxins implicated in bacterial interstrain competition and those that target distantly related cells. Genome context information suggests that these toxins might be delivered via diverse secretory systems, such as Type V, Type VI, PVC and a novel PrsW-like intramembrane peptidase-dependent mechanism. We propose that certain deaminase toxins might be deployed by diverse extracellular and intracellular pathogens as also endosymbionts as effectors targeting nucleic acids of host cells. Our analysis suggests that these toxin deaminases have been acquired by eukaryotes on several independent occasions and recruited as organellar or nucleo-cytoplasmic RNA modifiers, operating on tRNAs, mRNAs and short non-coding RNAs, and also as mutators of hyper-variable genes, viruses and selfish elements. This scenario potentially explains the origin of mutagenic AID/APOBEC-like deaminases, including novel versions from Caenorhabditis, Nematostella and diverse algae and a large class of fast-evolving fungal deaminases. These observations greatly expand the distribution of possible unidentified mutagenic processes catalyzed by nucleic acid deaminases

Use of statistical and non-statistical (Big Data) sources of information for determining the directions of urban development as illustrated by Rzeszow

Podejmując problematykę przestrzennego rozwoju miast powinniśmy uwzględnić wszystkie procesy społeczne i gospodarcze, które dotyczą danego obszaru. W praktyce występuje bardzo duże rozproszenie źródeł informacji, których gestorami jest wiele instytucji sektora prywatnego i publicznego. Celem artykułu jest próba integracji statystycznych i pozastatystycznych danych, które mogą być wykorzystane do wyznaczania kierunku rozwoju miast. Oprócz danych dotyczących procesów demograficznych, przedsiębiorczości czy inwestycji na szczególną uwagę zasługują informacje o miejscu pracy i zamieszkania pochodzące z administracji skarbowej oraz pomiary z czujników ruchu drogowego będące w dyspozycji Generalnej Dyrekcji Dróg Krajowych i Autostrad. W pracy wykorzystano metodę ekonometrii entropii nieekstensywnej do połączenia różnego rodzaju źródeł danych. W opracowaniu dokonano porównania Rzeszowskiego Obszaru Funkcjonalnego z Szerszą Strefą Miejską (LUZ – Larger Urban Zone). W artykule uwzględniono dojazdy do pracy, nasycenie przedsiębiorczością w podziale na: mikro, małe, średnie i duże przedsiębiorstwa oraz według wybranych sekcji Polskiej Klasyfikacji Działalności (przemysł, budownictwo, handel), a także nakłady inwestycyjne w układzie dwuwymiarowym: inwestycje pochodzące z sektora prywatnego oraz z sektora publicznego. Zastosowanie analizy dwuwymiarowej ujawniło cztery typy zachowań strategicznych w zakresie inwestycji: synergia inwestycji, budowanie potencjału inwestycyjnego, regres inwestycyjny oraz zbudowany potencjał inwestycyjny.In addressing the problems of spatial development of cities we should take into account all the social and economic processes that affect a given area. In practice there is a very large spread of information sources, whose holders are many private and public sector institutions. The purpose of this article is to attempt to integrate statistical and non-statistical data that can be used to determine directions of urban development. In addition to data on demographic processes, entrepreneurship and investment, special attention is paid to information on place of work and residence that are taken from the tax administration and measurements from traffic sensors that are at the disposal of the General Directorate for National Roads and Motorways. The paper uses the econometric method of non-extensive entropy to combine different types of data sources. The study compares Rzeszów Functional Area with the Larger Urban Zone (LUZ). The overview include commuting to work, entrepreneurship saturation which is broken down into micro, small, medium and large enterprises and by selected sections of the Polish Classification of Activities (industry, construction and trade) as well as two-dimensional investment expenditure: private and public sector investments, which we can treated as elements of a further and closer environment of city leaders. The use of two-dimensional analysis revealed four types of strategic investment behaviour: investment synergy, investment capacity building, investment recession and built investment potential