A novel, pan-PDE inhibitor exerts anti-fibrotic effects in human lung fibroblasts via inhibition of TGF-β\beta signaling and activation of cAMP/PKA signaling

Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832-a pan-PDE inhibitor, 869-a TRPA1 modulator, and 145-a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type β1 (TGF-β1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-β pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research

Enzymatic Activities of Isolated Cytochrome bc1-like Complexes Containing Fused Cytochrome b Subunits with Asymmetrically Inactivated Segments of Electron Transfer Chains

Homodimeric structure of cytochrome bc_1, a common component of biological energy conversion systems, builds in four catalytic quinone oxidation/reduction sites and four chains of cofactors (branches) that, connected by a centrally located bridge, form a symmetric H-shaped electron transfer system. The mechanism of operation of this complex system is under constant debate. Here, we report on isolation and enzymatic examination of cytochrome bc1-like complexes containing fused cytochrome b subunits in which asymmetrically introduced mutations inactivated individual branches in various combinations. The structural asymmetry of those forms was confirmed spectroscopically. All the asymmetric forms corresponding to cytochrome bc_1 with partial or full inactivation of one monomer retain high enzymatic activity but at the same time show a decrease in the maximum turnover rate by a factor close to 2. This strongly supports the model assuming independent operation of monomers. The cross-inactivated form corresponding to cytochrome bc_1 with disabled complementary parts of each monomer retains the enzymatic activity at the level that, for the first time on isolated from membranes and purified to homogeneity preparations, demonstrates that intermonomer electron transfer through the bridge effectively sustains the enzymatic turnover. The results fully support the concept that electrons freely distribute between the four catalytic sites of a dimer and that any path connecting the catalytic sites on the opposite sides of the membrane is enzymatically competent. The possibility to examine enzymatic properties of isolated forms of asymmetric complexes constructed using the cytochrome b fusion system extends the array of tools available for investigating the engineering of dimeric cytochrome bc1 from the mechanistic and physiological perspectives

Cryo-EM structure of the spinach cytochrome b6 f complex at 3.6 Å resolution.

The cytochrome b6 f (cytb6 f ) complex has a central role in oxygenic photosynthesis, linking electron transfer between photosystems I and II and converting solar energy into a transmembrane proton gradient for ATP synthesis1-3. Electron transfer within cytb6 f occurs via the quinol (Q) cycle, which catalyses the oxidation of plastoquinol (PQH2) and the reduction of both plastocyanin (PC) and plastoquinone (PQ) at two separate sites via electron bifurcation2. In higher plants, cytb6 f also acts as a redox-sensing hub, pivotal to the regulation of light harvesting and cyclic electron transfer that protect against metabolic and environmental stresses3. Here we present a 3.6 Å resolution cryo-electron microscopy (cryo-EM) structure of the dimeric cytb6 f complex from spinach, which reveals the structural basis for operation of the Q cycle and its redox-sensing function. The complex contains up to three natively bound PQ molecules. The first, PQ1, is located in one cytb6 f monomer near the PQ oxidation site (Qp) adjacent to haem bp and chlorophyll a. Two conformations of the chlorophyll a phytyl tail were resolved, one that prevents access to the Qp site and another that permits it, supporting a gating function for the chlorophyll a involved in redox sensing. PQ2 straddles the intermonomer cavity, partially obstructing the PQ reduction site (Qn) on the PQ1 side and committing the electron transfer network to turnover at the occupied Qn site in the neighbouring monomer. A conformational switch involving the haem cn propionate promotes two-electron, two-proton reduction at the Qn site and avoids formation of the reactive intermediate semiquinone. The location of a tentatively assigned third PQ molecule is consistent with a transition between the Qp and Qn sites in opposite monomers during the Q cycle. The spinach cytb6 f structure therefore provides new insights into how the complex fulfils its catalytic and regulatory roles in photosynthesis

Integration of energy and electron transfer processes in the photosynthetic membrane of Rhodobacter sphaeroides

Photosynthesis converts absorbed solar energy to a protonmotive force, which drives ATP synthesis. The membrane network of chlorophyll–protein complexes responsible for light absorption, photochemistry and quinol (QH2) production has been mapped in the purple phototrophic bacterium Rhodobacter (Rba.) sphaeroides using atomic force microscopy (AFM), but the membrane location of the cytochrome bc1 (cytbc1) complexes that oxidise QH2 to quinone (Q) to generate a protonmotive force is unknown. We labelled cytbc1 complexes with gold nanobeads, each attached by a Histidine10 (His10)-tag to the C-terminus of cytc1. Electron microscopy (EM) of negatively stained chromatophore vesicles showed that the majority of the cytbc1 complexes occur as dimers in the membrane. The cytbc1 complexes appeared to be adjacent to reaction centre light-harvesting 1-PufX (RC–LH1–PufX) complexes, consistent with AFM topographs of a gold-labelled membrane. His-tagged cytbc1 complexes were retrieved from chromatophores partially solubilised by detergent; RC–LH1–PufX complexes tended to co-purify with cytbc1 whereas LH2 complexes became detached, consistent with clusters of cytbc1 complexes close to RC–LH1–PufX arrays, but not with a fixed, stoichiometric cytbc1–RC–LH1–PufX supercomplex. This information was combined with a quantitative mass spectrometry (MS) analysis of the RC, cytbc1, ATP synthase, cytaa3 and cytcbb3 membrane protein complexes, to construct an atomic-level model of a chromatophore vesicle comprising 67 LH2 complexes, 11 LH1–RC–PufX dimers & 2 RC–LH1–PufX monomers, 4 cytbc1 dimers and 2 ATP synthases. Simulation of the interconnected energy, electron and proton transfer processes showed a half-maximal ATP turnover rate for a light intensity equivalent to only 1% of bright sunlight. Thus, the photosystem architecture of the chromatophore is optimised for growth at low light intensities

Koncepcja zarządzania procesami logistycznymi w przedsiębiorstwie

Istotą współczesnej logistyki jest przepływ materiałów i towarzyszący mu przepływ informacji. Stwierdzić zatem należy, że spójna i uporządkowana koncepcja zarządzania przepływem materiałowym (procesami logistycznymi) w sposób istotny przyczynia się do zrozumienia istoty samej logistyki. W niniejszym artykule przedstawiono klasyfi kację procesów logistycznych w przedsiębiorstwie, ze szczególnym uwzględnieniem podejścia systemowego oraz zaprezentowano istotę i cele zarządzania procesami logistycznymi. W dalszej części artykułu omówiono strategiczny i operacyjny charakter zarządzania procesami logistycznymi oraz wskazano na rolę i znaczenie zarządzania przepływem materiałowym (procesami logistycznymi) w kompleksowej koncepcji zarządzania logistycznego.The essence of contemporary logistics are material and information fl ows. Thus, presenting the coherent and ordered concept of material fl ow management (management of logistical activities) will contribute to understanding the essence of logistics. The article depicts the classifi cation of logistics activities in company taking into consideration system approach. It also presents the essence and goals of management of logistical activities. In next section of the article strategic and operational nature of management of logistical activities is discussed. Next, the article indicates the role and meaning of material fl ow management in the holistic concept of logistics management

Czynniki kształtowania elastycznych łańcuchów dostaw w Polsce

Łańcuch dostaw to jedna z najbardziej dynamicznie rozwijających się koncepcji, która w przeciągu ostatnich lat jest przedmiotem intensywnych badań na gruncie zarówno teorii, jak i praktyki działalności gospodarczej. Jej powstanie związane było z rozpoczynającymi się pod koniec lat osiemdziesiątych zmianami w otoczeniu gospodarczym i technologicznym przedsiębiorstw – tworzeniem się rynku globalnego, potrzebą sprostania wzrostowi nacisku ze strony konkurencji, dynamicznym rozwojem technologii informatycznych, wzrostem presji klientów związanym z odkrywaniem przez nich coraz to nowych, bardziej wyrafinowanych potrzeb, itp. Niniejszy artykuł przedstawia rezultaty pionierskich badań dotyczących czynników kształtowania jednego z typów łańcucha dostaw - elastycznego łańcucha dostaw. Analiza literatury przedmiotu wskazuje jednoznacznie na braki w zakresie teoretycznego ujęcia koncepcji oraz w metodyce badań zagadnień związanych z kształtowaniem elastycznego łańcucha dostaw. Celem podjęcia badań była zatem próba identyfikacji i analizy czynników, które umożliwiają powstanie i funkcjonowanie elastycznego łańcucha dostaw na polskim rynku. Prezentowane wyniki badań mogą z jednej strony choć częściowo wypełnić lukę w teorii elastycznych łańcuchów dostaw, stanowiąc jednocześnie naukowy fundament do dalszych prac nad tą koncepcją w Polsce.The supply chain, which in the last few years has been a subject of intense research both in theoretical and practical frameworks, is currently one of the most dynamically developing concepts. Its emergence was concerned with changes occurring in the late eighties of the last century in economical and technological environment: the creation of global market and worldwide economy, a necessity to gain control over new markets with the purpose of having better effect on customers as well as a need to challenge growing pressure from competition, the dynamic development of information technologies, the increasing pressure from customers connected with their newly discovered, more refined needs, etc. The article illustrates the results of pioneer research on logistical success factors for a type of supply chain - the agile supply chain. The analysis of literature indicates the deficiency in the theory of concept and research methodology associated with agile supply chains. The main goal of research was to identify and analyze the factors which enable to form and operate of agile supply chains on Polish market. The results of research enable to decrease deficiency in the theory of agile supply chains and to introduce a scientific foundation for further research on these issues in Poland

The normative-behavioral approach in supply chain management

Celem artykułu jest prezentacja koncepcji zarządzania łańcuchem dostaw w świetle założeń podejścia normatywnego i behawioralnego. W pierwszej części przedstawiono istotę i możliwości aplikacji podejścia normatywnego i behawioralnego na gruncie zarządzania łańcuchem dostaw. W drugiej części artykułu podjęto próbę integracji obu podejść, która następnie posłużyła sformułowaniu koncepcji zarządzania łańcuchem dostaw w świetle zintegrowanego podejścia normatywno-behawioralnego.The paper seeks to explore the concept of supply chain management in the light of the tenets of normative and behavioral approaches. First, the essence and conditions of using the normative and behavioral approaches in the field of supply chain management have been depicted. Then, an attempt of integration of these two approaches has been undertaken, followed by the formulation of the concept of supply chain management in the light of integrated normative-behavioral approach

Cross-sectoral comparison of the effect of sales planning practices on manufacturing strategy in supply chains

The goal of the paper is to make a cross-industrial comparison of the effect of sales planning practices on different types of manufacturing strategies applied in 343 producing companies operating in European, Asian and African supply chains. In order to achieve an empirical aim a necessary methodology and statistical analyses have been employed. In the result of the analysis multiple regression models have been developed for specific manufacturing strategies in supply chains operating in different industries worldwide. It enabled to make cross-sectoral comparisons of the contribution to variance in manufacturing strategy

The prevailing role of market coordination on the example of Honda supply chain

Współczesne przedsiębiorstwa, funkcjonując w pojedynkę, mają znikome szanse na zdobycie i utrzymanie pozycji istotnego gracza. W związku z tym, decydują się na przystąpienie do rozbudowanej struktury łańcucha dostaw, której podłożem jest większa liczba, zróżnicowanych ogniw. Osiągnięcie określonego stopnia współdziałania przedsiębiorstw wymaga koordynacji. W teorii wyróżnia się na ogół trzy formy koordynacji - rynkową, hierarchiczną i społeczną. Celem artykułu jest identyfikacja rynkowej formy koordynacji działań wielopodmiotowych, która dominuje w spektrum działań koordynacyjnych podejmowanych w łańcuchu dostaw firmy Honda. Identyfikacja form koordynacji pomogła autorom w potwierdzeniu dominacji rynkowej formy koordynacji.Contemporary companies, when operating as a sole entity, have little chances for achieving and sustaining its leading position. Therefore, they decide to participate in the developed structure of a supply chain, constituted by a number of diversified actors. Likewise, achieving a certain level of collaboration requires a coordination mechanism. There are three basic forms of coordination in the theory, namely: market, hierarchical and social. The aim of the paper is identification the essence and the example of using the market coordination that holds a prevailing position in the spectrum of coordinative activities performed in Honda supply chain. Identification form of coordination helps authors to confirm that market for of coordination is dominant