How users read translated web pages: occupational and purpose-based differences

Aquest estudi vol demostrar diferències en els patrons de lectura d'una pàgina web en base a les diferències ocupacionals dels participants i la finalitat de lectura. La recerca es realitza amb 20 participants dividits en dos grups: un grup de lectors professionals, on els participants són professionals de la lectura com traductors, editors i correctors, i un grup de lectura recreativa, on les seves professions no impliquen lectura detallada, com xefs, enginyers i personal militar. Tots els participants van completar quatre tasques dissenyades amb quatre finalitats de lectura: 1) sense objectiu específic, 2) per estudiar el tema, 3) per obtenir informació, i 4) per compartir informació. El text de partida en anglès presenta iOS 7. Per al test es va usar la versió web oficial en coreà, després d'inserir-li cinc tipus d'error segons el model d'avaluació LISA. Es va gravar la pantalla dels participants amb programari específic i es van usar Protocols en Veu Alta (TAP) per als seus informes verbals. L'anàlisi suggereix que els errors de traducció es perceben de diferent manera quan la finalitat lectora i la professió dels lectors varien. El grup de lectura professional va aplicar una lectura lineal i meticulosa, mentre que el grup de lectura recreativa va optar per una lectura circular i no rigorosa. El primer grup va detectar gran quantitat d'errors, mentre que el segon va mostrar un baix percentatge de detecció d'errors. Malgrat això, el grup professional mostra major nivell de tolerància als errors de traducció en el procés de comprensió i el grup recreatiu major nivell de frustració a la falta de comprensió. L'autoritat de la companyia encarregada de la web va exercir gran influència en el nivell de confiança del grup de lectura recreativa.Este estudio investiga diferencias en la lectura de una página web traducida en base a las diferencias ocupacionales de los participantes y la finalidad de lectura. La investigación se realiza con 20 participantes divididos en dos grupos: un grupo de lectores profesionales, cuyos participantes son profesionales de la lectura como traductores, editores y correctores, y un grupo de lectura recreativa, cuyas profesiones no implican lectura detallada, como chefs, ingenieros y personal militar. Todos los participantes completaron cuatro tareas diseñadas con cuatro finalidades de lectura: 1) sin objetivo específico, 2) para estudiar el tema, 3) para obtener información, y 4) para compartir información. Para estudiar como los lectores perciben los errores de traducción y la relación entre patrones de lectura y finalidad lectora, se introdujeron cinco tipos de errores de traducción en una web. Se grabó la pantalla de los participantes con software específico y se usaron Protocolos en Voz Alta (TAP) para sus informes verbales. El análisis sugiere que los errores de traducción se perciben de diferente manera cuando la finalidad lectora y la profesión de los lectores varían. El grupo de lectura profesional aplicó una lectura lineal y concienzuda, mientras que el grupo de lectura recreativa optó por una lectura circular y no rigurosa. El primer grupo detectó gran cantidad de errores, mientras que el segundo mostró un bajo porcentaje de detección de errores. Pese a ello, el grupo profesional muestra mayor nivel de tolerancia a los errores de traducción en el proceso de comprensión y el grupo recreativo mayor nivel de frustración a la falta de comprensión. La autoridad de la compañía encargada de la web ejerció gran influencia en el nivel de confianza del grupo de lectura recreativa.As a part of process-oriented research efforts, the study aimed to test occupational differences and purpose-based differences in reading pattern of a translated web page. The research used two reading groups with ten participants in each: a heavy-reading group, whose participants were reading professionals such as translators, editors and proofreaders, and a light-reading group, whose professions did not involve intensive reading, such as chefs, engineers, and military personnel. The participants in both groups completed four different tasks that were designed to provoke four different reading purposes: 1) reading without a specific task, 2) reading for studying subject matter, 3) reading for retrieving information, and 4) reading for sharing information. In order to learn more about how readers perceive translation errors and to test the relations between the reading patterns and the reading purposes, five different types of translation errors were planted in a web page. The participants’ screen activity was recorded by a screen recording software, and TAP is used for their verbal reports. In-depth analysis of the results suggests that occupations and reading purposes have meaningful impacts on the reading patterns of the translated web page. The heavy-reading group displayed very strict bottom-up approaches, with linear and thorough reading, whereas the light-reading group showed relaxed top-down approaches, with circular and not-thorough reading. The heavy group showed critical attitudes in detecting errors, while the light-reading group showed extremely low error-detection rates, with relaxed attitudes. Surprisingly, in spite of the critical error detection pattern, the tolerance level of translation errors in the process of comprehension was much higher in the heavy-reading group, and the frustration level of incomprehension was much higher in the light-reading group. The authority of the company producing the web page also heavily influenced the trust level of the light-reading group

Communication over the network of binary switches regulates the activation of A2A_{2A} adenosine receptor

Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total $\sim$ 5 $\mu$sec molecular dynamics simulations of A$_{2A}$ adenosine receptor (A$_{2A}$AR) in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs "binary switches" as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield $2^{10}$ microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation.Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.Comment: 28 pages, 17 figure

Link between allosteric signal transduction and functional dynamics in a multi-subunit enzyme: S-adenosylhomocysteine hydrolase

S-adenosylhomocysteine hydrolase (SAHH), a cellular enzyme that plays a key role in methylation reactions including those required for maturation of viral mRNA, is an important drug target in the discovery of antiviral agents. While targeting the active site is a straightforward strategy of enzyme inhibition, evidences of allosteric modulation of active site in many enzymes underscore the molecular origin of signal transduction. Information of co-evolving sequences in SAHH family and the key residues for functional dynamics that can be identified using native topology of the enzyme provide glimpses into how the allosteric signaling network, dispersed over the molecular structure, coordinates intra- and inter-subunit conformational dynamics. To study the link between the allosteric communication and functional dynamics of SAHHs, we performed Brownian dynamics simulations by building a coarse-grained model based on the holo and ligand-bound structures. The simulations of ligand-induced transition revealed that the signal of intra-subunit closure dynamics is transmitted to form inter-subunit contacts, which in turn invoke a precise alignment of active site, followed by the dimer-dimer rotation that compacts the whole tetrameric structure. Further analyses of SAHH dynamics associated with ligand binding provided evidence of both induced fit and population shift mechanisms, and also showed that the transition state ensemble is akin to the ligand-bound state. Besides the formation of enzyme-ligand contacts at the active site, the allosteric couplings from the residues distal to the active site is vital to the enzymatic function.Comment: 35 pages, 14 figures, 3 Table

Analgesic effect of highly reversible ω-conotoxin FVIA on N type Ca2+ channels

<p>Abstract</p> <p>Background</p> <p>N-type Ca²⁺channels (Ca_v2.2) play an important role in the transmission of pain signals to the central nervous system. ω-Conotoxin (CTx)-MVIIA, also called ziconotide (Prialt^®), effectively alleviates pain, without causing addiction, by blocking the pores of these channels. Unfortunately, CTx-MVIIA has a narrow therapeutic window and produces serious side effects due to the poor reversibility of its binding to the channel. It would thus be desirable to identify new analgesic blockers with binding characteristics that lead to fewer adverse side effects.</p> <p>Results</p> <p>Here we identify a new CTx, FVIA, from the Korean <it>Conus Fulmen </it>and describe its effects on pain responses and blood pressure. The inhibitory effect of CTx-FVIA on N-type Ca²⁺channel currents was dose-dependent and similar to that of CTx-MVIIA. However, the two conopeptides exhibited markedly different degrees of reversibility after block. CTx-FVIA effectively and dose-dependently reduced nociceptive behavior in the formalin test and in neuropathic pain models, and reduced mechanical and thermal allodynia in the tail nerve injury rat model. CTx-FVIA (10 ng) also showed significant analgesic effects on writhing in mouse neurotransmitter- and cytokine-induced pain models, though it had no effect on acute thermal pain and interferon-γ induced pain. Interestingly, although both CTx-FVIA and CTx-MVIIA depressed arterial blood pressure immediately after administration, pressure recovered faster and to a greater degree after CTx-FVIA administration.</p> <p>Conclusions</p> <p>The analgesic potency of CTx-FVIA and its greater reversibility could represent advantages over CTx-MVIIA for the treatment of refractory pain and contribute to the design of an analgesic with high potency and low side effects.</p

Diacetyl odor shortens longevity conferred by food deprivation in C. elegans via downregulation of DAF-16/FOXO

Dietary restriction extends lifespan in various organisms by reducing the levels of both nutrients and non-nutritional food-derived cues. However, the identity of specific food-derived chemical cues that alter lifespan remains unclear. Here, we identified several volatile attractants that decreased the longevity on food deprivation, a dietary restriction regimen in Caenorhabditis elegans. In particular, we found that the odor of diacetyl decreased the activity of DAF-16/FOXO, a life-extending transcription factor acting downstream of insulin/IGF-1 signaling. We then demonstrated that the odor of lactic acid bacteria, which produce diacetyl, reduced the nuclear accumulation of DAF-16/FOXO. Unexpectedly, we showed that the odor of diacetyl decreased longevity independently of two established diacetyl receptors, ODR-10 and SRI-14, in sensory neurons. Thus, diacetyl, a food-derived odorant, may shorten food deprivation-induced longevity via decreasing the activity of DAF-16/FOXO through binding to unidentified receptors. © 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley &amp; Sons Ltd.1

Development of target-tunable P22 VLP-based delivery nanoplatforms using bacterial superglue

Protein cage nanoparticles are widely used as targeted delivery nanoplatforms, because they have well-defined symmetric architectures, high biocompatibility, and enough plasticity to be modified to produce a range of different functionalities. Targeting peptides and ligands are often incorporated on the surface of protein cage nanoparticles. In this research, we adopted the SpyTag/SpyCatcher protein ligation system to covalently display target-specific affibody molecules on the exterior surface of bacteriophage P22 virus-like particles (VLP) and evaluated their modularity and efficacy of targeted delivery. We genetically introduced the 13 amino acid SpyTag peptide into the C-terminus of the P22 capsid protein to construct a target-tunable nanoplatform. We constructed two different SpyCatcher-fused affibody molecules as targeting ligands, SC-EGFRAfb and SC-HER2Afb, which selectively bind to EGFR and HER2 surface markers, respectively. We produced target-specific P22 VLP-based delivery nanoplatforms for the target cell lines by selectively combining SpyTagged P22 VLP and SC-fused affibody molecules. We confirmed its target-switchable modularity through cell imaging and verified the target-specific drug delivery efficacy of the affibody molecules displaying P22 VLP using cell viability assays. The P22 VLP-based delivery nanoplatforms can be used as multifunctional delivery vehicles by ligating other functional proteins, as well as affibody molecules. The interior cavity of P22 VLP can be also used to load cargoes like enzymes and therapeutic proteins. We anticipate that the nanoplatforms will provide new opportunities for developing target-specific functional protein delivery systems

Diphtheria toxin-based efficient target-switchable anticancer drug

Recombinant immunotoxins (RITs) have been extensively utilized in the field of targeted cancer therapy. RITs are composed of toxins derived from natural bacterial strains and antibodies for target specific killing of cancer cells. The conjugated antibodies have specificities against the surface receptors of target cancer cells, facilitate the toxin internalization and consequently induce fatal effects to the target cell. However, low intracellular penetration and endosomal escape efficiency has limited the application of RITs. Diphtheria toxin is a candidate toxin which has potential of overcoming those limitation of RIT. The diphtheria toxins are produced by Corynebacterium diphtheriae and belong to AB toxin families which consist of catalytic (A) domain, binding (B) domain, and translocation(T) domain. Once binding domain of the diphtheria toxin bind to the specific target receptors, it facilitates the receptor-mediated endocytosis. Translocation domain delivers the catalytic domain from endosome to cytosol, which helps its catalytic domain to escape endosome. By substituting the binding domain with recombinant affinity molecules and using the diphtheria toxin, it is expected to overcome the low endosomal escape efficiency of the conventional RITs. In this study, we designed the diphtheria toxin-based target-switchable modular anticancer drugs by using protein ligation system, killing target cells specifically. To create module toxin and module affibody, the catalytic and translocation domain of diphtheria toxin (DTA), and cancer specific affibodies were prepared, genetically fused with protein ligation modules. By simple mix of module diphtheria toxin and module affibodies, we can easily introduce the target-specific diphtheria toxin (DTA-Afb) within an hour. Finally, we confirmed the targeted toxicity against the specific cancer in vitro as well as in vivo. DTA-Afb shows much higher toxicity than doxorubicin, which is a general anticancer drug. The diphtheria toxin-based RIT is promising method for targeted anticancer drug