Mistletoe lectin dissociates into catalytic and binding subunits before translocation across the membrane to the cytoplasm

AbstractHybridomas producing monoclonal antibodies (mAbs) against the mistletoe lectin A-chain (MLA) were obtained to investigate the intracellular routing and translocation of ribosome-inactivating proteins. Anti-MLA mAb MNA5 did not bind the holotoxin but interacted with isolated MLA. This epitope was not recognized upon MLA denaturation or conjugation of MLA with the ricin binding subunit (RTB). Furthermore, the mAbs did not appreciably react with a panel of MLA synthetic octapeptides linked to the surface of polyethylene pins. A study of the cytotoxicity of mistletoe lectin, ricin, and chimeric toxin MLA/RTB for the hybridomas revealed that interchain disulfide bond reduction and subunit dissociation are required for cytotoxic activity of mistletoe lectin

The conformational manifolds of drug-like molecules as studied in combination of experimental and computational techniques

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Solvation of conformationally flexible molecules. Experiment and computer simulations

23-2

Novel Biodegradable Polymeric Microparticles Facilitate Scarless Wound Healing by Promoting Re-epithelialization and Inhibiting Fibrosis

Despite decades of research, the goal of achieving scarless wound healing remains elusive. One of the approaches, treatment with polymeric microcarriers, was shown to promote tissue regeneration in various in vitro models of wound healing. The in vivo effects of such an approach are attributed to transferred cells with polymeric microparticles functioning merely as inert scaffolds. We aimed to establish a bioactive biopolymer carrier that would promote would healing and inhibit scar formation in the murine model of deep skin wounds. Here we characterize two candidate types of microparticles based on fibroin/gelatin or spidroin and show that both types increase re-epithelialization rate and inhibit scar formation during skin wound healing. Interestingly, the effects of these microparticles on inflammatory gene expression and cytokine production by macrophages, fibroblasts, and keratinocytes are distinct. Both types of microparticles, as well as their soluble derivatives, fibroin and spidroin, significantly reduced the expression of profibrotic factors Fgf2 and Ctgf in mouse embryonic fibroblasts. However, only fibroin/gelatin microparticles induced transient inflammatory gene expression and cytokine production leading to an influx of inflammatory Ly6C+ myeloid cells to the injection site. The ability of microparticle carriers of equal proregenerative potential to induce inflammatory response may allow their subsequent adaptation to treatment of wounds with different bioburden and fibrotic content

Novel Photosensitizers Trigger Rapid Death of Malignant Human Cells and Rodent Tumor Transplants via Lipid Photodamage and Membrane Permeabilization

BACKGROUND: Apoptotic cascades may frequently be impaired in tumor cells; therefore, the approaches to circumvent these obstacles emerge as important therapeutic modalities. METHODOLOGY/PRINCIPAL FINDINGS: Our novel derivatives of chlorin e(6), that is, its amide (compound 2) and boronated amide (compound 5) evoked no dark toxicity and demonstrated a significantly higher photosensitizing efficacy than chlorin e(6) against transplanted aggressive tumors such as B16 melanoma and M-1 sarcoma. Compound 5 showed superior therapeutic potency. Illumination with red light of mammalian tumor cells loaded with 0.1 µM of 5 caused rapid (within the initial minutes) necrosis as determined by propidium iodide staining. The laser confocal microscopy-assisted analysis of cell death revealed the following order of events: prior to illumination, 5 accumulated in Golgi cysternae, endoplasmic reticulum and in some (but not all) lysosomes. In response to light, the reactive oxygen species burst was concomitant with the drop of mitochondrial transmembrane electric potential, the dramatic changes of mitochondrial shape and the loss of integrity of mitochondria and lysosomes. Within 3-4 min post illumination, the plasma membrane became permeable for propidium iodide. Compounds 2 and 5 were one order of magnitude more potent than chlorin e(6) in photodamage of artificial liposomes monitored in a dye release assay. The latter effect depended on the content of non-saturated lipids; in liposomes consisting of saturated lipids no photodamage was detectable. The increased therapeutic efficacy of 5 compared with 2 was attributed to a striking difference in the ability of these photosensitizers to permeate through hydrophobic membrane interior as evidenced by measurements of voltage jump-induced relaxation of transmembrane current on planar lipid bilayers. CONCLUSIONS/SIGNIFICANCE: The multimembrane photodestruction and cell necrosis induced by photoactivation of 2 and 5 are directly associated with membrane permeabilization caused by lipid photodamage

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

В поисках «выхода из тупика»: транссибирские транспортные проекты конца XIX – начала XX в.

Referring to a large number of journalistic works of the turn of the 20th century that reflect the views of different business, political, and social groups, the author analyses the narrative strategies underlying the representation of both implemented and hypothetical Trans-Siberian transportation projects. The article aims to explicate the cultural attitudes and political goals of the authors of the transportation projects which formed their strategies of mental appropriation of territories. The author singles out and analyses three aspects related to the perception of Siberian space: imperial, regional, and transnational. According to the first aspect, Siberian space was regarded as an enormous geopolitical bridge meant to connect the centre of the country with remote Russian territories (the Far East) and Russia’s spheres of influence (Manchuria, Northeast China). This approach was implemented when the Great Siberian Railway was built and came to represent a horizontal distribution of power, connecting the imperial centre and the periphery. The regional idea of Siberia was a metaphor of its closedness: this was not induced by its nature but rather by artificial economic reasons. The Russian government favoured the export of Siberian butter but not that of grain. The Great Siberian Railway was thus regarded as a means of improving foreign trade. However, this route for Siberian grain was closed following the introduction of the Chelyabinsk railway tariff in 1896. Under such circumstances, Siberians had to resort to the idea of the 1860s–1870s of organising a transit trade route from Siberia to Europe. At the turn of the 20th century, there appeared two approaches to how this could be fulfilled: by joining the basins of Siberian and Central Russian rivers (Siberian River Routes) or establishing a connection between these rivers by means of the Kara Sea (Northern Sea Route). According to the third – transnational – aspect, all three routes were regarded as elements of global transit routes to be established. Following the 1904–1905 Russo-Japanese War, the Russian authorities considered it a national communication system which was not only of economic but also of military and strategic importance. On the eve of World War I, the idea of the Northern Sea Route as an international route was replaced by the idea of it as a “natural monopoly” of the Russian state.На основе широкого круга публицистических работ конца XIX – начала XX в., отображающих взгляды различных деловых, политических и общественных групп, анализируются нарративные стратегии репрезентации как реализованных, так и оставшихся на бумаге транссибирских транспортных проектов данного периода. Целью исследования является экспликация культурных установок и политических устремлений авторов транспортных проектов, лежащих в основе их стратегий ментального присвоения территории. Выделяются и анализируются три аспекта восприятия сибирского пространства: имперский, областнический и транснациональный. В первом сибирское пространство виделось как гигантский геополитический мост, предназначенный соединить центр с удаленными от него российскими территориями (Дальний Восток) и сферами влияния (Маньчжурия, Северо-Восточный Китай). Этот подход был реализован благодаря строительству Великой Сибирской железнодорожной магистрали, своеобразной «горизонтали власти», связавшей имперский центр и окраины. Центральной метафорой областнического воображения Сибири было представление о «закрытости» последней, вызванной не столько естественными, сколько искусственно созданными экономическими причинами. Российское правительство способствовало сбыту сибирского масла, но не поощряло хлебный экспорт. Надежды на подъем внешней торговли Сибири связывались в первую очередь с Великим Сибирским железнодорожным путем. Однако с введением в 1896 г. Челябинского тарифного перелома этот путь для сибирского хлеба был фактически закрыт. В этих условиях сибирские производители вернулись к идее 1860–1870-х гг. о транзитном торговом пути из Сибири в Европу. На рубеже XIX–XX вв. обозначились два основных подхода к его созданию: соединение бассейнов сибирских и центрально-российских рек (Великий Сибирский речной путь) vs установление сообщения этих рек через Карское море (Северный морской путь). В третьем, транснациональном аспекте, все три названных пути воспринимались как элементы будущих глобальных транзитных сетей. После Русско-японской войны 1904–1905 гг. российские правящие круги все чаще видели в нем национальную коммуникационную систему, имевшую не только экономическое, но и военно-стратегическое значение. Накануне Первой мировой войны характерное для конца XIX в. представление о Северном морском пути как международной магистрали сменилось представлением о нем как о своего рода «естественной монополии» российского государства

Movement supporting soviet union in jewish palestine during the Great patriotic war

В статье рассматривается малоизученная в историографии проблема — история возникновения и развития движения в поддержку Советского Союза в еврейской Палестине в годы Великой Отечественной войны. Говорится, что в основе всех солидарных действий еврейских трудящихся Палестины с СССР лежало стремление преодолеть «прежние разногласия» между сионистским движением и Москвой, заложить фундамент будущих дружественных . In the given article the author considers history of the origin and development of a movement supporting Soviet Union in Jewish Palestine during the Great Patriotic war, which is a little-studied issue in historiography. The author reveals that the basis for all united actions of the Jewish labour and the USSR was their urge towards settling “former disputes” between the Zionist movement and Moscow and forming friendly relations in future