Early Events in the Endoplasmic Reticulum Unfolded Protein Response.

The physiological consequences of the unfolded protein response (UPR) are mediated by changes in gene expression. Underlying them are rapid processes involving preexisting components. We review recent insights gained into the regulation of the endoplasmic reticulum (ER) Hsp70 chaperone BiP, whose incorporation into inactive oligomers and reversible AMPylation and de-AMPylation present a first line of response to fluctuating levels of unfolded proteins. BiP activity is tied to the regulation of the UPR transducers by a recently discovered cycle of ER-localized, J protein-mediated formation of a repressive IRE1-BiP complex, whose working we contrast to an alternative model for UPR regulation that relies on direct recognition of unfolded proteins. We conclude with a discussion of mechanisms that repress messenger RNA (mRNA) translation to limit the flux of newly synthesized proteins into the ER, a rapid adaptation that does not rely on new macromolecule biosynthesis.Wellcome Trus

National Councils for Sustainable Development – an appropriate tool of common use?

W kontekście bieżących kwestii dotyczących zrównoważonego rozwoju, Unia Europejska (UE) podkreśla ostatnio znaczenie Narodowych Rad ds. Zrównoważonego Rozwoju (NRZR; ang.: National Councils for Sustainable Development – NCSD) jako skutecznego i efektywnegoinstrumentu służącego wdrażaniu zrównoważonego rozwoju (ZR). Odkąd mogą one udzielać niezależnych porad i sprzyjać dialogowi pomiędzy społeczeństwem a interesariuszami na temat ZR, NRZR zdają się jawić jako właściwe narzędzie na szczeblu rządowym. Mimo to przegląd ich działalności w krajach Europy Środkowo-Wschodniej daje różnorodny obraz. NRZR znacząco różnią się między sobą pod kątem definicji, składu, stopnia niezależności oraz dostępnych zasobów, jak też efektów działania. Biorąc od uwagę pozytywne doświadczenia związane ze skutecznymi NRZR w niektórych państwach członkowskich, można postawić następujące pytanie: Jakie cechy powinny posiadać NRZR? Czy NRZR są powszechnie wykorzystywane w Europie Środkowo-Wschodniej? W tym celu w poniższym artykule przeanalizowano NRZR w kilku państwach Europy Środkowo-Wschodniej poprzez wskazanie podobieństw oraz różnic pomiędzy poszczególnymi NRZR, włączając w to ich zasięg oraz podejście, aby wyjaśnić rozbieżności w ich osiągnięciach w skali krajowej. UE rekomenduje zestaw cech i właściwości, którymi powinny charakteryzować się NRZR w celu funkcjonowania jako efektywne narzędzie rządowe podczas dążenia do osiągnięcia zrównoważonego rozwoju

An XML-Based Streaming Concept for Business Process Execution

Service-oriented environments are central backbone of todays enterprise workflows. These workflow includes traditional process types like travel booking or order processing as well as data-intensive integration processes like operational business intelligence and data analytics. For the latter process types, current execution semantics and concepts do not scale very well in terms of performance and resource consumption. In this paper, we present a concept for data streaming in business processes that is inspired by the typical execution semantics in data management environments. Therefore, we present a conceptual process and execution model that leverages the idea of stream-based service invocation for a scalable and efficient process execution. In selected results of the evaluation we show, that it outperforms the execution model of current process engines

EU Communication on Corporate Social Responsibility and the effects on national and corporate sustainability agendas

Niedawne komunikaty Unii Europejskiej dotyczące celów zrównoważonego rozwoju zawierały wytyczne, jak korporacje powinny reagować na społeczne i polityczne potrzeby poprzez społecznie odpowiedzialne działania gospodarcze. Biznes społecznie odpowiedzialny (ang.:corporate social responsibility – CSR) staje się coraz powszechniej wykorzystywanym i spornym terminem, mającym obejmować zaangażowanie świata biznesu w działania ukierunkowane na zaspokajanie społecznych i środowiskowych wymagań. Niniejszy artykuł omawia, w jaki sposób komunikat Unii Europejskiej wpływa na politykę CSR korporacji pod kątem zrównoważonego rozwoju. Wskazano na najświeższe kroki Komisji Europejskiej dotyczące CSR i przedstawiono ich odzwierciedlenie w polityce szczebla narodowego i europejskiego. Poniżej skoncentrowano się na przedsiębiorstwach z trzech europejskich państw, a mianowicie z Węgier, Niemiec i Wielkiej Brytanii. Ponadto z każdego kraju wybrano po jednej firmie reprezentującej sektory paliwowy i / lub energetyczny, aby zaobserwować sposób implementacji określonej polityki, a także jej wpływ na zachowanie korporacji (przejawiające się w raportach finansowych i  raportach CSR). Polityka CSR przedsiębiorstw będzie oceniana według 20 elementów CSR wskazanych przez Welforda (2005), bazujących na podobnych przesłaniach międzynarodowych  kodeksów i konwencji, takich jak konwencja ILO czy program Global Compact, które zaadoptowała Komisja Europejska

Directed PCR-free engineering of highly repetitive DNA sequences

Background: Highly repetitive nucleotide sequences are commonly found in nature e.g. in telomeres, microsatellite DNA, polyadenine (poly(A)) tails of eukaryotic messenger RNA as well as in several inherited human disorders linked to trinucleotide repeat expansions in the genome. Therefore, studying repetitive sequences is of biological, biotechnological and medical relevance. However, cloning of such repetitive DNA sequences is challenging because specific PCR-based amplification is hampered by the lack of unique primer binding sites resulting in unspecific products.Results: For the PCR-free generation of repetitive DNA sequences we used antiparallel oligonucleotides flanked byrestriction sites of Type IIS endonucleases. The arrangement of recognition sites allowed for stepwise and seamless elongation of repetitive sequences. This facilitated the assembly of repetitive DNA segments and open reading frames encoding polypeptides with periodic amino acid sequences of any desired length. By this strategy wecloned a series of polyglutamine encoding sequences as well as highly repetitive polyadenine tracts. Such repetitive sequences can be used for diverse biotechnological applications. As an example, the polyglutamine sequences were expressed as His6-SUMO fusion proteins in Escherichia coli cells to study their aggregation behavior in vitro. The His6-SUMO moiety enabled affinity purification of the polyglutamine proteins, increased their solubility, and allowed controlled induction of the aggregation process. We successfully purified the fusions proteins and provide an example for their applicability in filter retardation assays.Conclusion: Our seamless cloning strategy is PCR-free and allows the directed and efficient generation of highlyrepetitive DNA sequences of defined lengths by simple standard cloning procedures

Cost-Based Vectorization of Instance-Based Integration Processes

The inefficiency of integration processes - as an abstraction of workflow-based integration tasks - is often reasoned by low resource utilization and significant waiting times for external systems. With the aim to overcome these problems, we proposed the concept of process vectorization. There, instance-based integration processes are transparently executed with the pipes-and-filters execution model. Here, the term vectorization is used in the sense of processing a sequence (vector) of messages by one standing process. Although it has been shown that process vectorization achieves a significant throughput improvement, this concept has two major drawbacks. First, the theoretical performance of a vectorized integration process mainly depends on the performance of the most cost-intensive operator. Second, the practical performance strongly depends on the number of available threads. In this paper, we present an advanced optimization approach that addresses the mentioned problems. Therefore, we generalize the vectorization problem and explain how to vectorize process plans in a cost-based manner. Due to the exponential complexity, we provide a heuristic computation approach and formally analyze its optimality. In conclusion of our evaluation, the message throughput can be significantly increased compared to both the instance-based execution as well as the rule-based process vectorization

Vectorizing Instance-Based Integration Processes

The inefficiency of integration processes as an abstraction of workflow-based integration tasks is often reasoned by low resource utilization and significant waiting times for external systems. Due to the increasing use of integration processes within IT infrastructures, the throughput optimization has high influence on the overall performance of such an infrastructure. In the area of computational engineering, low resource utilization is addressed with vectorization techniques. In this paper, we introduce the concept of vectorization in the context of integration processes in order to achieve a higher degree of parallelism. Here, transactional behavior and serialized execution must be ensured.In conclusion of our evaluation, the message throughput can be significantly increased

Structures of a deAMPylation complex rationalise the switch between antagonistic catalytic activities of FICD.

The endoplasmic reticulum (ER) Hsp70 chaperone BiP is regulated by AMPylation, a reversible inactivating post-translational modification. Both BiP AMPylation and deAMPylation are catalysed by a single ER-localised enzyme, FICD. Here we present crystallographic and solution structures of a deAMPylation Michaelis complex formed between mammalian AMPylated BiP and FICD. The latter, via its tetratricopeptide repeat domain, binds a surface that is specific to ATP-state Hsp70 chaperones, explaining the exquisite selectivity of FICD for BiP's ATP-bound conformation both when AMPylating and deAMPylating Thr518. The eukaryotic deAMPylation mechanism thus revealed, rationalises the role of the conserved Fic domain Glu234 as a gatekeeper residue that both inhibits AMPylation and facilitates hydrolytic deAMPylation catalysed by dimeric FICD. These findings point to a monomerisation-induced increase in Glu234 flexibility as the basis of an oligomeric state-dependent switch between FICD's antagonistic activities, despite a similar mode of engagement of its two substrates - unmodified and AMPylated BiP

MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP

Despite its known role as a secreted neuroprotectant, much of the mesencephalic astrocyte-derived neurotrophic factor (MANF) is retained in the endoplasmic reticulum (ER) of producer cells. There, by unknown mechanisms, MANF plays a role in protein folding homeostasis in complex with the ER-localized Hsp70 chaperone BiP. Here we report that the SAF-A/B, Acinus, and PIAS (SAP) domain of MANF selectively associates with the nucleotide binding domain (NBD) of ADP-bound BiP. In crystal structures the SAP domain engages the cleft between NBD subdomains Ia and IIa, stabilizing the ADP-bound conformation and clashing with the interdomain linker that occupies this site in ATP-bound BiP. MANF inhibits both ADP release from BiP and ATP rebinding to BiP, and thereby client release. Cells lacking MANF have fewer ER stress-induced BiP-containing high molecular weight complexes. These findings suggest that MANF contributes to protein folding homeostasis as a nucleotide exchange inhibitor that stabilizes certain BiP-client complexes.Wellcome Trust 200848/Z/16/