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Voltage-gated K+ channels are widely expressed controllers of cellular behavior. Each channel has a gate between the cytosol and its K+ conductive pore to control the flow of potassium. Small molecules that enter through this gate can block the pore. The interface between a channel and its blocker may change during pore closure, producing channel-state-biased blocker affinity or, equivalently, bias of channel state by bound blockers. My findings suggest that RY785, a small molecule which inhibits KV2.1 voltage-gated K+ channels, enters through the cytosolic gate and has biased affinity for closed channels. KV2.1 channels may include KV8.1 subunits which affect the structure and gating of the pore. I also find that RY785 exhibits a similar mechanism of inhibition for KV2.1/KV8.1 channels but with much lower affinity. Interestingly, the voltage dependence of RY785 inhibition suggests opening the cytosolic gate of KV2.1 is not sufficient to permit K+ conduction and that heteromerization with KV8.1 reduces closure of this gate.In addition to my work on potassium channel pharmacology, I include as an appendix a reflection on my experience designing and teaching an undergraduate seminar on modern ion channel research. This reflection was composed in partial satisfaction of the requirements for obtaining a graduate academic certificate in undergraduate education. This scholarly effort yielded proof-of-concept that undergraduate students benefit from instruction on how to locate and analyze original scientific research articles and produced template instructional materials.

Lately, models utilizing channel impulse response (CIR) data for training deep neural networks used for positioning in radio networks have shown promise, particularly in simulated indoor environments. Research has extended to real outdoor setups as well. In this study, deep neural networks originally designed for image classification were employed to estimate positions using both real and simulated outdoor CIR data. A ray tracing simulator was utilized to generate a simulated dataset which corresponded to a real-world dataset. Models were trained and tested on both datasets. To facilitate training on simulated data and testing on real data, a generative adversarial network (GAN) was employed. The thesis concludes that deep neural networks can effectively be used in real outdoor scenarios, but dense data sampling is likely necessary to achieve satisfactory performance across an area. Additionally, it was found that the simulated data used in this study differed significantly from reality, and the employed GAN could not effectively bridge this gap. Consequently, models trained on simulated data performed poorly when tested on real data. However, it was found that deep neural networks significantly outperformed the baseline K-nearest neighbor algorithm when trained and tested on simulated data. However, this was the only case where such a significant advantage for the deep models was observed.

Ocean currents control seafloor morphology and the transport of sediments, organic carbon, nutrients, and pollutants in deep-water environments. A better connection between sedimentary deposits formed by bottom currents (contourites) and hydrodynamics is necessary to improve reconstructions of paleocurrent and sediment transport pathways. Here we use physical modeling in a three-dimensional flume tank to analyse the morphology and hydrodynamics of a self-emerging contourite system. The sedimentary features that developed on a flat surface parallel to a slope are an elongated depression (moat) and an associated sediment accumulation (drift). The moat-drift system can only form in the presence of a secondary flow near the seafloor that transports sediment from the slope toward the drift. The secondary flow increases with higher speeds and steeper slopes, leading to steeper adjacent drifts. This study shows how bottom currents shape the morphology of the moat-drift system and highlights their potential to estimate paleo-ocean current strength.

The voltage-gated potassium channel Kv1.3 plays a crucial role in T-cell activation and is considered a promising target for the treatment of autoimmune diseases. However, the lack of reliable antibodies has prevented its accurate detection and study under endogenous conditions, so that most published studies have been conducted in heterologous systems. To address this limitation, we engineered a Jurkat T-cell line expressing endogenous Kv1.3 channels tagged with a signal peptide to investigate the expression and localization of native Kv1.3 channels, and their role associated to T cell physiological responses. Using the CRISPR-Cas9 tool, we inserted a Flag-Myc peptide at the C terminus of the KCNA3 gene. Basal and activated channel expression were assessed through western blot analysis and imaging techniques. Surprisingly, besides the canonical Kv1.3 channel (54 KDa), we identified two additional isoforms with distinct N termini: a longer isoform (70 KDa) and a truncated isoform (43 KDa). All three isoforms showed upregulation after T-cell activation. Our focus was on characterizing the truncated isoform (short form, SF) as it had not been previously described and could be present in available Kv1.3-/- mouse models. Overexpressing SF in HEK cells generated Kv1.3-like currents with smaller amplitudes, which, unlike canonical Kv1.3, did not induce HEK proliferation. To explore the role of endogenous SF isoform in a native system, we generated both a knockout Jurkat clone and a clone expressing only the SF isoform. While the canonical isoform localized primarily at the plasma membrane, SF remained intracellular, accumulating perinuclearly. Consequently, SF Jurkat cells lacked Kv1.3 currents, exhibited depolarized resting membrane potential (EM), reduced Ca2+ influx, and diminished increases in intracellular calcium ([Ca2+]i) upon stimulation. Functional characterization of these Kv1.3 channel isoforms revealed their differential contributions to signaling pathways inv, El canal de potasio dependiente de voltaje Kv1.3 juega un papel crucial en la activación de las células T y se considera una buena diana terapéutica para el tratamiento de enfermedades autoinmunes. Sin embargo, la falta de anticuerpos específicos de la proteína ha impedido su detección y estudio precisos en condiciones endógenas, por lo que la mayoría de los estudios publicados se han realizado en sistemas heterólogos. Para abordar esta limitación, diseñamos una línea de células T Jurkat que expresa canales Kv1.3 endógenos marcados con un péptido señal para estudiar su expresión y localización además de su papel fisiológico en los linfocitos T. Usando la herramienta CRISPR-Cas9, insertamos un péptido Flag-Myc en el extremo C del gen KCNA3. La expresión del canal basal y activado se evaluó mediante análisis de transferencia Western y técnicas de imagen. Sorprendentemente, además del canal canónico Kv1.3 (54 KDa), identificamos dos isoformas adicionales con extremos N distintos: una isoforma más larga (70 KDa) y una isoforma truncada (43 KDa). Las tres isoformas mostraron un aumento de su expresión después de la activación de las células T. Nuestro objetivo fue caracterizar la isoforma truncada (forma abreviada, SF) ya que no se había descrito previamente y podría estar presente en los modelos de ratón Kv1.3-/- disponibles. La sobreexpresión de SF en células HEK generó corrientes similares a Kv1.3 con amplitudes más pequeñas que, a diferencia del Kv1.3 canónico, no indujeron la proliferación de HEK. Para explorar el papel de la isoforma SF endógena en un sistema nativo, generamos un clon de Jurkat knockout y un clon que expresa solo la isoforma SF. Mientras que la isoforma canónica se localizó principalmente en la membrana plasmática, el SF permaneció intracelular, acumulándose perinuclearmente. En consecuencia, las células SF Jurkat carecían de las corrientes Kv1.3, presentaban un potencial de membrana en reposo (EM) despolarizado, una entrada de Ca2+ reducida y un a, Escuela de Doctorado, Doctorado en Investigación Biomédica

Extensive use of drainage ditches in European boreal forests and in some parts of North America has resulted in a major change in wetland and soil hydrology and impacted the overall ecosystem functions of these regions. An increasing understanding of the environmental risks associated with forest ditches makes mapping these ditches a priority for sustainable forest and land use management. Here, we present the first rigorous deep learning-based methodology to map forest ditches at regional scale. A deep neural network was trained on airborne laser scanning data (ALS) and 1,607 km of manually digitized ditch channels from 10 regions spread across Sweden. The model correctly mapped 86% of all ditch channels in the test data, with a Matthews correlation coefficient of 0.78. Further, the model proved to be accurate when evaluated on ALS data from other heavily ditched countries in the Baltic Sea Region. This study leads the way in using deep learning and airborne laser scanning for mapping fine-resolution drainage ditches over large areas. This technique requires only one topographical index, which makes it possible to implement on national scales with limited computational resources. It thus provides a significant contribution to the assessment of regional hydrology and ecosystem dynamics in forested landscapes.

COMPSs és un model de programació que s'encarrega de paral·lelitzar i distribuir aplicacions, convertint l'execució d'unes funcions escollides per l'usuari en tasques asíncrones que s'executaran sobre la mateixa infraestructura distribuïda. Un dels problemes de rendiment de COMPSs és la ineficiència de la capa de comunicacions. Aquesta capa funciona mitjançant la creació de connexions TCP entre els nodes que s'han de transferir dades, el qual resulta ser bastant ineficient a causa de l'elevat número de connexions que es realitzen i el cost de la creació d'aquestes. L'objectiu del projecte serà tractar de solucionar aquesta ineficiència. Per assolir el nostre objectiu, s'han plantejat dues possibilitats diferents. La primera és aprofitar els sockets TCP per eliminar el temps perdut en realitzar els TCP handshake, amb la qual hem arribat a obtenir fins a un 43% de millora, el qual és una millora molt notable. La segona seria tractar d'implementar un protocol alternatiu com seria RDMA el qual creiem que ens pot brindar resultats positius. Tractarem de detallar la situació inicial, tots els processos de les implementacions, les conclusions a les quals arribem i en general allò que considerem remarcable en el desenvolupament del projecte., COMPS is a programming model that is responsible for parallelizing and distributing applications; thereby converting the execution of chosen functions by the user in asynchronous tasks that are executed according to their own distributed infrastructure. One of the problems in the performance of COMPSs is its inefficiency in the area of communications. This particular area works by way of the creation of TCP connections amongst nodes that must transfer data, which proves to be quite inefficient. This is due to a high number of connections that are carried out and their creation cost. The objective of the project is to deal with solving this inefficiency. In order for our objective to be achieved, two different possibilities have been proposed. The first one is to make use of the TCP sockets in order to eliminate lost time in carrying out the TCP handshake. According to the results obtained, there has been an up to 43% improvement due to the newly implemented solution. A quite significant improvement. The second one deals with implementing an alternative protocol: RDMA. We believe that this will produce excellent results. We will provide details of the initial situation, all the processes of the implementations, results which are obtained and in general everything that is considered noteworthy in the development of the project.

Proteins are biological machines composed of a single or multiple threads of amino acids which fold into three-dimensional shapes. These shapes and surfaces directly participate in many of the molecular interactions essential to life. Some proteins exist in lipid membranes and thus have been termed membrane proteins. Membranes serve as sites of import, export, and signaling and allow for compartmentalization; all critical functions for living organisms. After decades of research throughout the 20th century, many families of membrane proteins were revealed to form transport proteins that facilitate movement of substrates across membranes. The general group of transport proteins can be further divided into two groups: active and passive transporters. Passive transport proteins have been called channels, given their observed activity of opening to allow substrate diffusion down an electrochemical gradient. Channels are diverse both in their architecture and substrates, which include ions, small molecules, and other proteins. Despite the broad importance of channels in a vast array of biology many aspects of how these machines operate at a molecular level are yet to be revealed. Determining the structures of channels, which in many cases was not technically feasible until recently, has provided key insights into the form and function of these intricate machines. Presented here are studies of two different channels: the Translocase of the Outer Mitochondrial Membrane (TOM complex) and the light-gated ion channel, ChRmine. The first study in this thesis examines the long-awaited architecture and transport mechanisms of the major protein gate of the outer mitochondrial membrane. The high-resolution structure of the TOM complex revealed its overall organization-- including all its core subunits, multiple assemblies of the complex, and a glimpse at the pore which provides insights into mechanisms of protein transport. The subsequent study examines the first ever structures o

This work studies the flow of a non-Newtonian power-law fluid with viscous dissipation through a pipe with a variable expand ratio (B).The influence of the power law index (n), expand ratio (B), Darcy number (Da) and  Brinkman number(Br) on heat transfer and thermodynamics irreversibility is investigated. Equations of the problem are solved numerically using COMSOL software. Results show that heat transfer and entropy generation are deeply affected by selected governing parameters. Both thermal entropy generation and average Nusselt number are maximal at low power index and at high medium permeability. Power index effect is insignificant at relatively low Darcy number. Considering viscous dissipation with high Brinkman number, heat transfer direction can be reversed at moderate Darcy number and high power index.

The awareness of climate change has grown worldwide in the past years. Possible consequences of climate change are sea level rise, heavier storms and high river discharges, but also prolonged drought. For a country such as the Netherlands, these water level variations, high discharges and droughts could have a great impact. Therefore, solutions of flood protection and water management are required to cope with these possible consequences. The Delta21 project proposes a solution for flood protection of the Southwest delta in the Netherlands, while contributing to energy storage and nature preservation. The Delta21 project is a dam structure located in the Haringvliet mouth and, when constructed, results in a large change of the environment in the Haringvliet mouth. The remaining area of the Haringvliet mouth becomes the tidal lake. The important functions of the tidal lake are to be navigable and to have the capacity for extreme discharges to flow through the lake, without posing threats to safety. The functions are fulfilled by a channel through the tidal lake. The current channel (Slijkgat) requires highly frequent maintenance to allow for navigability and contains bottlenecks to meet the discharge capacity function. Hence, the objective of this research is to determine a suitable channel configuration in the tidal lake of Delta21, considering navigability and discharge capacity. A suitable channel configuration is determined by designing a channel, accompanied by a morphological modelling study. The functional requirements and criteria for the design are defined based on the stakeholders interests. The requirements and the expected hydrodynamic and morphodynamic conditions in the tidal lake have resulted in three channel concepts that are considered for the design process. One of the concepts is the current bathymetry of the Slijkgat. The other concepts are Channel Concept 1 and Channel Concept 2, which are the same in cross-sectional area but di, DELTA21, Civil Engineering | Hydraulic Engineering | Coastal Engineering

Law 2/2023, of February 20, aimed at guaranteeing the protection of people who report some of the non-compliance -actions or omissions constituting violations of the regulations- included in its material scope of application, obliges the companies with more than fifty workers and public law entities, as well as political parties, unions, business organizations and foundations created by them, that receive or manage public funds, to implement internal and external information channels for the communication of said relevant information. The legislator has chosen to define a broader material scope of application than that provided for in the Directive, which may raise doubts in relation to labour matters, which, sometimes, have their own reporting mechanisms inside and outside companies and public entities., La Ley 2/2023, de 20 de febrero, dirigida a garantizar la protección de las personas que informen sobre algunos de los incumplimientos -acciones u omisiones constitutivas de infracciones de la normativa– comprendidas en su ámbito material de aplicación, obliga a las empresas de más de cincuenta trabajadores y a las entidades de derecho público, así como a partidos políticos, sindicatos, organizaciones empresariales y fundaciones creadas por ellos, que reciban o gestionen fondos públicos, a implantar canales internos y externo de información para la comunicación de dichas informaciones relevantes. El legislador ha optado por definir un ámbito material de aplicación más amplio que el previsto en la Directiva, lo que puede generar dudas en relación con las infracciones laborales, que, en ocasiones, cuentan con sus propios mecanismos de denuncia dentro y fuera de las empresas y entidades públicas. Con este estudio pretendemos aclarar qué informaciones, o más bien, denuncias, si consideramos la terminología de la Directiva, deben ser canalizadas por los sistemas de información de las organizaciones, así como qué incidencia tendrá la existencia de un canal externo sobre otros canales de información a la autoridad laboral competente para la vigilancia del cumplimiento de la legislación laboral.

This study was conducted at C. K. Tedam University of Applied Sciences and Technology. It was guided by education and communication model as propounded by Shanon and Weaver (1949). This study was designed to investigate the influence of communication channels on education management practices in Ghanaian public universities. The study specifically investigated the types of communication channels used in the university and related the channels to the constraints faced in communicating messages in the university. Literature was reviewed in relation to the above stated objective. The study sample was drawn from CKT-UTAS and involved both academic and administrative staff. The sample size was one hundred and fifty two (152) which represents 77.6% of the target population. Stratified random sampling techniques based on the respondents’ job descriptions were used. The instruments for data collection involved use of questionnaires and information from secondary data materials for instance the University Act 2019, Act 1000 and the employee survey findings of 2006. Data was analyzed using descriptive statistics. The major findings revealed that CKT-UTAS had few channels of communication and that the communication policy framework was in place. However, the study identified that CKT-UTAS relies on Head of Departments, Group representatives, memos, notice boards, face to face and telephone to communicate. The study therefore, recommended that CKT-UTAS embraces new channels of communication (i.e. use of email) for efficiency purposes in addition to the already existing ones. Also the university should adopt strategies of enhancing communication between the staff and administration.

This work produces a unique microfluidic device that acts as a “lab on a chip,” conducting separation, mixing, and concentration of microparticles similar to that required by cell sorting flow cytometry applications. The passive two-dimensional device shows to be successful at separating polystyrene (PS) beads between 5 and 20 µm in diameter, mixing them with an external media, and concentrating them by 250% continuously with minimal sample preparation, while still being inexpensive, and effective. By implementing the microfluidic device, the processing steps are done within seconds due to its high throughput of 2 mL min−1, wherein different hydrodynamic phenomena such as Dean's forces, inertial lift forces, and enhanced diffusion are taken advantage of.

Estuaries and deltas worldwide are facing land loss and drowning due to sea-level rise (SLR). Commonly home to ports, their channels are dredged and deepened for navigation. However, little is known about how such sediment management will interact with changing sediment transport patterns due to SLR. Using scale experiments, empirical relations and real world examples from global estuaries and deltas, we identify that dredging and SLR combined enhance bend migration whereas SLR alone leads to decentralizing of channels and drowning of intertidal area. In estuaries where channels are fixed, excess energy due to increasing tidal prism will manifest as bed and bank erosion, placing flood safety measures like dikes at risk. SLR increases dredging volumes in upstream reaches due to the rapid collapse of shoals and river banks along the whole estuary. Channel deepenings are ineffective under SLR conditions due to sediment import induced by increasingly flood-dominant tides. Non-dredged systems which have more regular and level elevations will lose intertidal area more quickly than dredged systems that have disconnected higher intertidal flats and a single deep channel. Mid-size dredged European systems are more likely to drown due to dredging in the present century than from SLR. Effects can be avoided by pursuing sediment management strategies that help restore the morphology disrupted by dredging.

AbstractIn this study, we demonstrated the label-free continuous separation and enrichment of Bacillus subtilis populations based on length using viscoelastic microfluidics. B. subtilis, a gram-positive, rod-shaped bacterium, has been widely used as a model organism and an industrial workhorse. B. subtilis can be arranged in different morphological forms, such as single rods, chains, and clumps, which reflect differences in cell types, phases of growth, genetic variation, and changing environmental factors. The ability to prepare B. subtilis populations with a uniform length is important for basic biological studies and efficient industrial applications. Here, we systematically investigated how flow rate ratio, poly(ethylene oxide) (PEO) concentration, and channel length affected the length-based separation of B. subtilis cells. The lateral positions of B. subtilis cells with varying morphologies in a straight rectangular microchannel were found to be dependent on cell length under the co-flow of viscoelastic and Newtonian fluids. Finally, we evaluated the ability of the viscoelastic microfluidic device to separate the two groups of B. subtilis cells by length (i.e., 1–5 μm and >5 μm) in terms of extraction purity (EP), extraction yield (EY), and enrichment factor (EF) and confirmed that the device could separate heterogeneous populations of bacteria using elasto-inertial effects.

The human genome codes only a few thousand druggable proteins, mainly receptors and enzymes. While this pool of available drug targets is limited, there is an untapped potential for discovering new drug-binding mechanisms and modes. For example, enzymes with long binding cavities offer numerous prerequisite binding sites that may be visited by an inhibitor during migration from a bulk solution to the destination site. Drug design can use these prerequisite sites as new structural targets. However, identifying these ephemeral sites is challenging. Here, we introduce a new method called NetBinder for the systematic identification and classification of prerequisite binding sites at atomic resolution. NetBinder is based on atomistic simulations of the full inhibitor binding process and provides a networking framework on which to select the most important binding modes and uncover the entire binding mechanism, including previously undiscovered events. NetBinder was validated by a study of the binding mechanism of blebbistatin (a potent inhibitor) to myosin 2 (a promising target for cancer chemotherapy). Myosin 2 is a good test enzyme because, like other potential targets, it has a long internal binding cavity that provides blebbistatin with numerous potential prerequisite binding sites. The mechanism proposed by NetBinder of myosin 2 structural changes during blebbistatin binding shows excellent agreement with experimentally determined binding sites and structural changes. While NetBinder was tested on myosin 2, it may easily be adopted to other proteins with long internal cavities, such as G-protein-coupled receptors or ion channels, the most popular current drug targets. NetBinder provides a new paradigm for drug design by a network-based elucidation of binding mechanisms at an atomic resolution.

In this research work, a 5G-based OFDM signal transmission is performed in order to analyze to what extent optical-wireless impairments affect the communication in a Radio-over-Fiber transmission scenario. By using MATLAB software, both quali-tative and quantitative analysis of the information degradations due to an optical-wireless channel were performed. Simulations results allowed it to be demonstrated that it is possible to carry out OFDM transmissions under New Radio guidelines ensuring low bit error rates in the 0 to 20 km fiber link range allocated for low-latency 5G New Radio applications., En este trabajo de investigación se llevó a cabo la transmisión de señales OFDM, basadas en el estándar 5G New Radio, con el fin de establecer qué tanto los impedimentos óptico-inalámbricos afectan la comunicación en un escenario de transmisión de radio-sobre-fibra. Con el software Matlab se hicieron análisis cualitativo y cuantitativo de las degradaciones en la información debidas a un canal óptico-inalámbrico. Los resultados permitieron demostrar que es posible realizar transmisiones OFDM bajo los lineamientos de 5G New Radio garantizando bajas tasas de error de bits en el rango de 0 a 20 km de fibra óptica, designado para aplicaciones 5G New Radio de baja latencia.

This report presents the results of the second inter-laboratory tests (ILT) carried out in the context of the WFD on eelgrass beds (Zostera noltei) on the French Channel-Atlantic coast. The first test, also carried out as part of the work of the Aquaref consortium, highlighted a critical point concerning the estimation of the coverage of eelgrass leaves in the quadrats, as this estimation was highly variable between operators. The need for recurrent exercises on this subject had then been highlighted. The objective of this second EIL, also devoted to the “coverage estimation” part of the protocol, was to characterise the variability of the estimate by the various operators and to try to understand the causes, and to propose methodological solutions to reduce this variability, which will be integrated into an updated version of the protocol., Ce rapport présente les résultats des seconds essais inter-laboratoires (EIL) réalisés dans le contexte de la DCE sur les herbiers de zostères (Zostera noltei) des côtes françaises de Manche-Atlantique. Le premier essai, également réalisé dans le cadre des travaux du consortium Aquaref, avait permis de mettre en évidence un point critique touchant à l’estimation du recouvrement des feuilles de zostères dans les quadrats, cette estimation présentant une forte variabilité entre les opérateurs. La nécessité d’exercices récurrents à ce sujet avait alors été mise en évidence. L’objectif de ce second EIL, également consacré à ce volet « estimation du recouvrement » du protocole, visait à caractériser la variabilité de l’estimation par les différents opérateurs et à tenter d’en comprendre les causes, et de proposer des solutions méthodologiques permettant de réduire cette variabilité, qui seront ultérieurement intégrées dans une mise à jour du protocole.

Silicon is a beneficial element for plant growth and production, especially in rice. Plant roots take up silicon in the form of silicic acid. Silicic acid channels, which belong to the NIP subfamily of aquaporins, are responsible for silicic acid uptake. Accumulated experimental results have deepened our understanding of the silicic acid channel for its uptake mechanism, physiological function, localization, and other aspects. However, how the silicic acid channel efficiently and selectively permeates silicic acid remains to be elucidated. Recently reported crystal structures of the silicic acid channel enabled us to discuss the mechanism of silicic acid uptake by plant roots at an atomic level. In this mini-review, we focus on the crystal structures of the silicic acid channel and provide a detailed description of the structural determinants of silicic acid permeation and its transport mechanism, which are crucial for the rational creation of secure and sustainable crops.

The endoplasmic reticulum (ER) is a major site for protein biosynthesis, required for production of about a third of all proteins in eukaryotic cells. The heterotrimeric Sec61 complex is a protein-conducting channel which mediates the transport or membrane integration of a majority of the ER-targeted proteins, such as secretory proteins and membrane proteins. Using a sophisticated gating mechanism, Sec61 transports soluble amino acid segments through its vertical water filled pore, and integrates hydrophobic transmembrane helices laterally into the membrane. The Sec61 channel translocates client polypeptides either co- or post-translationally. The posttranslational mode requires the formation of a larger complex with the membrane proteins Sec62 and Sec63. Substrate translocation further requires the essential ER resident Hsp70, BiP. The post translational complex in fungal species is additionally associated with the non-essential proteins Sec71 and Sec72. The structure and mechanism by which these proteins activate Sec61 for transport of client proteins has been poorly understood.Using cryo-electron microscopy (cryo-EM), we determined the structures of several variants of the Sec61–Sec62–Sec63–Sec71–Sec72 complex (shortly, the Sec complex) from Saccharomyces cerevisiae and Thermomyces lanuginosus and showed that Sec62 and Sec63 induce opening of the Sec61 channel. The structures reveal that Sec63 is positioned in the back of Sec61 and interacts with Sec61 and Sec71-Sec72, while Sec62 is flexibly associated with the complex in front of the lateral gate. The J-domain of Sec63 is optimally positioned under the channel pore to bind BiP and enable efficient polypeptide translocation. Sec63 associates with Sec61 tightly through interactions in cytosolic, transmembrane, and ER-luminal domains. These extensive interactions pry open Sec61’s lateral gate. Association of Sec62 further opens the luminal end of the lateral gate causing dislocation of the small helix blocking the

Indusketa arkeologikoari esker, erregistratu ahal izan da Arga ibaiko ura noriak mugitzeko bideratzen zuen harlanduzko kanalaren zati handi bat; noria horiek eragiten zieten galdaketa-labeen hauspoei eta gainerako makinen hauspoei, Eugiko Burdinurtuaren Errege Fundizio eta Fabrikan ekoizten ziren munizioak garbitzeko eta aztertzeko lantegietan., The archaeological excavation has made it possible to register an important section of the ashlar stone channel that carried water from the Arga River to move the different waterwheels, which op­erated the bellows of the smelting furnaces and the rest of the existing machinery in thecleaning and recognition workshops of the ammunition produced at Eugi´s Royal Foundry and Cast Iron Factory., La excavación arqueológica ha permitido registrar un importante tramo del canal de piedra de sille­ría que conducía el agua del río Arga para mover las distintas norias, que accionaban los fuelles de los hornos de fundición y el resto de maquinaria existente en los talleres de limpieza y reconocimien­to de las municiones producidas en la Real Fundición y Fábrica de Hierro Colado de Eugi.

An in-depth understanding of multisensory customer experiences could inform and transform service experiences across the touchpoints of customer journeys. Sensory research in service and marketing disciplines mostly refers to individual senses in isolation. However, relevant insights could be gleaned from other disciplines to explore the multisensory nature of customer experiences. Noting the fragmented state of research surrounding such topics, the current article presents a systematic, objective overview of the content and theoretical foundations underlying the notion of multisensory customer experiences. Seeking a holistic understanding and research agenda for service research, the authors adopt both text mining and co-citation analyses overlaying findings from the cross-disciplinary foundation to uncover relevant theoretical, conceptual, and methodological developments. The resulting research agenda encourages scholars to employ diverse theories and methods to investigate multisensory stimuli, their integration, and perception, as well as the link between multisensory customer experiences and emotions. These insights then can inform the design of multisensory omnichannel service experiences.

We performed microwave spectroscopy of an InAs nanowire between superconducting contacts implementing a finite-length, multichannel Josephson weak link. Certain features in the spectra, such as the splitting by spin-orbit interactions of the transition lines among Andreev states, have been already understood in terms of noninteracting models. However, we identify here additional transitions, which evidence the presence of Coulomb interactions. By combining experimental measurements and model calculations, we reach a qualitative understanding of these very rich Andreev spectra.

In 2016, a fishery for whelks (Buccinum undatum) was initiated in the Danish part of Kattegat and the Belt Sea. Until then the whelk had been a pristine resource in Danish fisheries. The inner Danish waters are not covered by EU regulations and very little is known about the whelk population characteristics in the area. Thus, the Danish whelk fishery is at present carried out without any administrative regulations or specific biological knowledge. This work gives novel information about the Danish whelk populations in the Southern Kattegat and Belt Sea. The stock size (shell length 40 mm) in Kattegat was estimated to be in the range of 230,250–921,000 tons. The overall meat percentage in the three studied fishing zones ranged from 58.2–65.6 %. The size at maturity (sexes pooled) ranged from 62.9–70.3 mm corresponding to 4–4.5 years of age. The average shell length of the studied populations ranged from 64.1–73.2 mm and the asymptotic shell length was estimated to be 77.6–83.1 mm. Test fishery showed the CPUE quickly to decrease in a southern direction in the Belt Sea due to the prevailing salinity gradient. Commercial fishermen achieved an average CPUE of 1.3 kg pot-1 in the Southern Kattegat (January 2017–November 2018). Although the three zones studied are adjacent, significant differences were found in several of the measured parameters. This underlines the need of local monitoring of population characteristics in order to advice authorities on possible regulation of whelk fishery. The ongoing whelk fishery in the Southern Kattegat has at present an intensity not believed to cause recruitment overfishing. However, the Danish fishing authority is encouraged to implement a minimum conservation reference sizes (MCRS) based on locally determined size of maturity (SOM)., In 2016, a fishery for whelks (Buccinum undatum) was initiated in the Danish part of Kattegat and the Belt Sea. Until then the whelk had been a pristine resource in Danish fisheries. The inner Danish waters are not covered by EU regulations and very little is known about the whelk population characteristics in the area. Thus, the Danish whelk fishery is at present carried out without any administrative regulations or specific biological knowledge. This work gives novel information about the Danish whelk populations in the Southern Kattegat and Belt Sea. The stock size (shell length > 40 mm) in Kattegat was estimated to be in the range of 230,250-921,000 tons. The overall meat percentage in the three studied fishing zones ranged from 58.2-65.6 %. The size at maturity (sexes pooled) ranged from 62.9- 70.3 mm corresponding to 4-4.5 years of age. The average shell length of the studied populations ranged from 64.1-73.2 mm and the asymptotic shell length was estimated to be 77.6-83.1 mm. Test fishery showed the CPUE quickly to decrease in a southern direction in the Belt Sea due to the prevailing salinity gradient. Commercial fishermen achieved an average CPUE of 1.3 kg pot-1 in the Southern Kattegat (January 2017-November 2018). Although the three zones studied are adjacent, significant differences were found in several of the measured parameters. This underlines the need of local monitoring of population characteristics in order to advice authorities on possible regulation of whelk fishery. The ongoing whelk fishery in the Southern Kattegat has at present an intensity not believed to cause recruitment overfishing. However, the Danish fishing authority is encouraged to implement a minimum conservation reference sizes (MCRS) based on locally determined size of maturity (SOM).(c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BACKGROUND: A range of neurological pathologies may lead to secondary hydrocephalus. Treatment has largely been limited to surgical cerebrospinal fluid (CSF) diversion, as specific and efficient pharmacological options are lacking, partly due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties in physiology and pathophysiology.METHODS: CSF obtained from patients with subarachnoid hemorrhage (SAH) and rats with experimentally inflicted intraventricular hemorrhage (IVH) was analyzed for lysophosphatidic acid (LPA) by alpha-LISA. We employed the in vivo rat model to determine the effect of LPA on ventricular size and brain water content, and to reveal the effect of activation and inhibition of the transient receptor potential vanilloid 4 (TRPV4) ion channel on intracranial pressure and CSF secretion rate. LPA-mediated modulation of TRPV4 was determined with electrophysiology and an ex vivo radio-isotope assay was employed to determine the effect of these modulators on choroid plexus transport.RESULTS: Elevated levels of LPA were observed in CSF obtained from patients with subarachnoid hemorrhage (SAH) and from rats with experimentally-inflicted intraventricular hemorrhage (IVH). Intraventricular administration of LPA caused elevated brain water content and ventriculomegaly in experimental rats, via its action as an agonist of the choroidal transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4 was revealed as a novel regulator of ICP in experimental rats via its ability to modulate the CSF secretion rate through its direct activation of the Na+/K+/2Cl- cotransporter (NKCC1) implicated in CSF secretion.CONCLUSIONS: Together, our data reveal that a serum lipid present in brain pathologies with hemorrhagic events promotes CSF hypersecretion and ensuing brain water accumulation via its direct action on TRPV4 and its downstream regulation of NKCC1. TRPV4 may therefore be a promising future pharmacolog

The type VI secretion system (T6SS) of Pseudomonas aeruginosa injects effector proteins into neighbouring competitors and host cells, providing a fitness advantage that allows this opportunistic nosocomial pathogen to persist and prevail during the onset of infections. However, despite the high clinical relevance of P. aeruginosa, the identity and mode of action of most P. aeruginosa T6SS-dependent effectors remain to be discovered. Here, we report the molecular mechanism of Tse5-CT, the toxic auto-proteolytic product of the P. aeruginosa T6SS exported effector Tse5. Our results demonstrate that Tse5-CT is a pore-forming toxin that can transport ions across the membrane, causing membrane depolarisation and bacterial death. The membrane potential regulates a wide range of essential cellular functions; therefore, membrane depolarisation is an efficient strategy to compete with other microorganisms in polymicrobial environments.

Experiments are conducted in an open channel with semi-circular patches distributed on one sidewall of the channel in which velocity distribution, turbulent intensity, and vortex generation are analyzed. The resistance force offered by a vegetation patch causes the change in water depth which have a broader application in river management, bank stabilization, and flood control. The measurement is conducted in the laboratory with the help of different measuring devices like Laser doppler velocimeter, particle image velocimeter, measuring scale, and so on. From the experiment, the velocity distribution in a longitudinal direction suggests that the flow is fully developed after a certain distance from a channel inlet. When the flow passes through the vegetation patch, it forms three different regions, i.e., canopy region, interference zone, and canopy free region. The flow velocity is maximum at the interference zone because of canopy patches to the flow. Wake formation is observed behind the canopy patch, which plays a vital role in sediment deposition; further moving away in the flow direction, wake formation decreases. Velocity is unstable and very low inside the canopy region due to the resisting force. It increases while moving away from the canopy patch in the transverse direction and becomes stable in canopy free region until it reaches the sidewall. A dip phenomenon is observed for both wide and narrow channels, but a dip phenomenon for narrow channels always lies lower from the surface than for wider channels. Turbulent intensities vary with different factors like the nature of the channel, vegetation density, and vegetation stem diameter. Turbulent intensity for a wide channel is comparatively higher than the narrow channel in a canopy-free region. Also, turbulent intensity is minimum just behind the midpoint of the canopy patches, whereas it is lower for dense vegetation than sparse vegetation behind the patch. Furthermore, turbulent intensity for smaller st

Biological membranes define the boundaries of cells and compartmentalize the chemical and physical processes required for life. Many biological processes are carried out by proteins embedded in or associated with such membranes. Determination of membrane protein (MP) structures at atomic or near-atomic resolution plays a vital role in elucidating their structural and functional impact in biology. This endeavor has determined 1198 unique MP structures as of early 2021. The value of these structures is expanded greatly by deposition of their three-dimensional (3D) coordinates into the Protein Data Bank (PDB) after the first atomic MP structure was elucidated in 1985. Since then, free access to MP structures facilitates broader and deeper understanding of MPs, which provides crucial new insights into their biological functions. Here we highlight the structural and functional biology of representative MPs and landmarks in the evolution of new technologies, with insights into key developments influenced by the PDB in magnifying their impact.

[ES] El canal del ATS conduce un volumen anual de agua de hasta 600 hm3/año de máximo con un promedio de entre 300 y 400 hm3/año. Este trasvase pasa por el río Júcar vertiendo sus aguas en la cola del embalse de Alarcón, para después derivar aguas abajo de este. El canal al aproximarse al embalse de Alarcón desciende una altura de entre 30 y 50 metros mediante 2 rápidas que disipan la energía del agua debida al desnivel existente. En el conjunto de las dos rápidas se estima una energía promedio de 30 a 35 GWh/año. Disponiendo de datos históricos de caudales mensuales en el ATS para el estudio hidrológico. Se propone revisar un estudio de soluciones previo en que se consideren las siguientes alternativas: 1. Aprovechamiento hidroeléctrico fluyente de la 1ª rápida. 2. Aprovechamiento hidroeléctrico fluyente de la 2ª rápida. 3. Aprovechamiento fluyente para el conjunto de las dos rápidas. 4. Aprovechamiento de puntas para cada una de las 3 construcciones anteriores. A continuación se profundizará en el estudio de soluciones y desarrollo del diseño constructivo de la alternativa 2 ya que en esta se prevé sea la idónea por obtener el mayor salto con menor inversión., [EN] The ATS canal carries an annual volume of water of up to 600 hm3 / year maximum, with an average of between 300 and 400 hm3 / year. This transfer passes through the Júcar river, pouring its waters into the tail of the Alarcón reservoir, and then diverting downstream from it. When approaching the Alarcón reservoir, the channel descends between 30 and 50 meters in height using 2 rapids that dissipate the energy of the water due to the unevenness. In the set of the two rapids, an average energy of 30 to 35 GWh / year is estimated. Having historical data on monthly flows in the ATS that can be considered for the hydraulic study. It is proposed to carry out a study of solutions that consider the following alternatives: 1. Construction of 2 flowing plants. One for each fast. 2. Construction of a single flowing plant that saves the two rapids. 3. Construction of a regulated plant for the two rapids. Finally, a constructive design of a power station will be developed in Rapid 2 of Alternative 1 since this is the biggest jump and will mean less construction volume.

[ES] Las ciudades echan raíces en la tierra donde se asientan, y son las variables territoriales y la naturaleza de la zona las que determinan la morfogénesis de las mismas. En este trabajo se reconstruye la historia de un paisaje hidráulico y la huella que ha dejado el agua en la ciudad con el paso de los siglos. Mediante el uso de métodos como la superposición cartográfica y la recomposición del palimpsesto urbano, se muestra como Valencia ha estado desde su fundación relacionada con sus flujos hidráulicos. El análisis se centra en el trazado histórico de la acequia madre de Favara, una de las principales fuentes de abastecimiento tanto para el centro de la ciudad como para las huertas situadas en la zona sur de Valencia. Se estudian sus invariables así como su relación con la morfología de la ciudad contemporánea , y se proponen una serie de intervenciones con el fin de recuperar parte del patrimonio de la Vega y promover un mayor acercamiento del turismo y los valencianos a uno de los elementos más importantes de la historia de Valencia., [EN] Cities take root in the land where they are located, and it is the territorial variables and the nature of the area that determine their morphogenesis. This work reconstructs the history of a hydraulic landscape and the footprint that water has left on the city over the centuries. Through the use of methods such as cartographic superposition and the recomposition of the urban palimpsest, it is shown how Valencia has been related to its hydraulic flows since its foundation. The analysis focuses on the historical layout of the Favara mother canal, one of the main sources of supply both for the city center and for the orchards located in the south of Valencia. Its invariants as well as its relationship with the morphology of the contemporary city are studied, and a series of interventions are proposed in order to recover part of the heritage of the Vega and promote a greater approach of tourism and Valencians to one of the most important elements in the history of Valencia., [CA] Les ciutats tiren arrels en la terra on s’assenten, i són les variables territorials i la naturalesa de la zona les que determinen la morfogènesi d’aquestes. En aquest treball es reconstrueix la història d’un paisatge hidràulic i la petjada que ha deixat l’aigua a la ciutat amb el pas dels segles. Mitjançant l’ús de mètodes com la superposició cartogràfica i la recomposició del palimpsest urbà, es mostra com València ha estat des de la seua fundació relacionada amb els seus fluxos hidràulics. L’anàlisi se centra en el traçat històric de la séquia mare de Favara, una de les principals fonts de proveïment tant per al centre de la ciutat com per a les hortes situades en la zona sud de València. S’estudien els seus invariables així com la seua relació amb la morfologia de la ciutat contemporània , i es proposen una sèrie d’intervencions amb la finalitat de recuperar part del patrimoni de la Vega i promoure un major acostament del turisme i els valencians a un dels elements més importants de la història de València.

[ES] El trabajo se basa en diseñar un canal convergente en el interior de un ala. El objetivo de este elemento es mejorar la eficiencia aerodinámica de la misma. El estudio preliminar del canal se desarrolla en un modelo 2D para luego ser evaluado a l largo de toda un ala en tres dimensiones. La validación de estos resultados se realizan con un estudio experimental complementario con el uso de un túnel de viento., [EN] The work is based on designing a convergent channel inside a wing. The objective of this element is to improve the aerodynamic efficiency. The preliminary study of the channel is developed in a 2D model tand then it is evaluated implementing the device in wing in three dimensions. The validation of these results is carried out with a complementary experimental study with the use of a wind tunnel.

El centre anomenat CPS Francesc Palau és una organització pública que busca acollir, orientar i acompanyar les persones més desfavorides del Prat de Llobregat, per al seu apoderament i inclusió social i comunitària. És un espai on totes les persones vulnerables o amb problemes d'inserció laboral, busquen poder rebre formació i orientació bàsica per poder desenvolupar-se en el nostre país. És important destacar que també ofereix cursos d'un àmbit més social com podrien ser tècniques artístiques com Patchwork i treballs manuals o cursos de salut i benestar per persones grans. Fins ara, tant els professors com els directius del centre requerien una aplicació externa com Whatssap per poder comunicar qualsevol informació rellevant referent als seus cursos. Però amb la proposta d'aquest TFG es busca un canal personalitzat on fer arribar als estudiants qualsevol esdeveniment o comunicat que els treballadors del centre necessitessin notificar als seus alumnes., The center called CPS Francesc Palau is a public organization that searches to help and guide the most disadvantaged people in el Prat de Llobregat, they search for their social empowerment and their community inclusion. It is a space where all vulnerable people seek to receive basic training and guidance in order to be able to develop themselves in our country. It is important to note that it also offers courses in a more social field such as artistic techniques, patchwork and handicrafts or health and wellness courses for the elderly. Until now, the teachers and the directors of the center required an external application such as Whatssap to be able to communicate any relevant information about their courses. But the proposal of this TFG seeks a personalized channel to send students any event or statement that the staff of the center needs to notify their students., El centro llamado CPS Francesc Palau es una organización pública que busca acoger, orientar y acompañar a las personas más desfavorecidas del Prat de Llobregat, para su empoderamiento e inclusión social y comunitaria. Es un espacio en el que todas las personas vulnerables o con problemas de inserción laboral, buscan poder recibir formación y orientación básica para poder desarrollarse en nuestro país. Es importante destacar que también ofrece cursos de un ámbito más social como podrían ser técnicas artísticas como Patchwork y trabajos manuales o cursos de salud y bienestar para personas mayores. Hasta ahora, tanto los profesores como los directivos del centro requerían una aplicación externa como Whatssap para poder comunicar cualquier información relevante en lo referente a sus cursos. Pero con la propuesta de este TFG se busca un canal personalizado donde hacer llegar a los estudiantes cualquier evento o comunicado que los trabajadores del centro necesitaran notificar a sus alumnos.

In this paper, an unmanned aerial vehicle (UAV)-aided multi-antenna configured downlink mmWave cooperative generalized frequency division multiplexing (GFDM) system is proposed. To provide physical layer security (PLS), a 3D controlled Lorenz mapping system is introduced. Further-more, the combination of T-transformation spreading codes, walsh Hadamard transform, and discrete Fourier transform (DFT) techniques are integrated with a novel linear multi-user multiple-input multiple-output (MU-MIMO) gyre precoding (GP) for multi-user interference reduction. Furthermore, concatenated channel-coding with multi-user beamforming weighting-aided maximum-likelihood and zero forcing (ZF) signal detection schemes for an improved bit error rate (BER) are also used. The system is then simulated with a single base station (BS), eight massive machine-type communications (mMTC) users, and two UAV relay stations (RSs). Numerical results reveal the robustness of the proposed system in terms of PLS and an achievable ergodic rate with signal-to-interference-plus-noise ratio (SINR) under the implementation of T-transformation scheme. By incorporating the 3D mobility model, brownian perturbations of the UAVs are also analyzed. An out-of-band (OOB) reduction of 320 dB with an improved BER of 1 × 10−4 in 16-QAM for a signal-to-noise ratio, Eb /N0, of 20 dB is achieved.

Drag in pipelines is composed almost solely of skin friction drag. The most common technique to achieve drag reduction (DR) is by adding drag-reducing agents. However, in the aerospace industry, various impressive passive drag-reducing techniques have been suggested to reduce skin friction drag in the past decades. Among these techniques, dimpled surfaces form a relatively unexplored terrain. Research into reducing skin friction drag in the turbulent regime by using dimples has been performed in the aviation industry since the '80s. The excessive amount of skin friction drag in pipelines forms an intriguing challenge to break new grounds. Several researchers investigated the potential of DR of turbulent flows using dimpled channels. Even though most of these studies that found DR are disputed, studies published at the National University of Singapore (NUS) obtained positive results time and again. NUS's exact test setup was reconstructed at Delft University of Technology, which has not been done yet as far as the author of this report is aware. Identical pressure measurements were performed, yielding an absolute DR of ≈ 5%, which is slightly less than what was obtained at NUS (>7%). Flat plates return a DR between 8-15%, dimpled test plates returned at DR between 12-20%. The test plates were covered for 99.5% with diamond-shaped dimples of 100 mm long and 50 mm wide. In total, 29 pressure taps were used to determine the change in drag in an 8 m long channel of 20 mm in height. Tests were done at Reynolds numbers, based on half channel width and centerline velocity, between 6,000 and 40,000. Accurate results were perceived up to a Reynolds number of 21,000, likely due to test-setup limitations. Multiple verifications such as two-dimensionality of the ow, comparison of theoretical and experimental skin friction coefficients, and instantaneous pressure tests were used to allow for an objective analysis. The pressure measurements were also supported by 1D hotwire ane

The poster shows the five stages leading up to the professional establishment of the ZB MED YouTube channel. It outlines the ups and downs along the way and names the most important aspects that need to be taken into account when making YouTube films., Das Poster stellt die fünf Stationen bis zum professionellen Aufbau des ZB MED-YouTube-Kanals dar. Es skizziert die Höhen und Tiefen auf dem Weg bis dahin und benennt die wichtigsten Aspekte, die bei YouTube-Filmen beachtet werden müssen.

An animal's decision to accept or reject a prospective food is based only, in part, on its chemical composition. Palatability is also greatly influenced by textural features including smoothness versus grittiness, which is influenced by particle sizes. Here, we demonstrate that Drosophila melanogaster is endowed with the ability to discriminate particle sizes in food and uses this information to decide whether a food is appealing. The decision depends on a mechanically activated channel, OSCA/TMEM63, which is conserved from plants to humans. We found that tmem63 is expressed in a multidendritic neuron (md-L) in the fly tongue. Loss of tmem63 impairs the activation of md-L by mechanical stimuli and the ability to choose food based on particle size. These findings reveal the first role for this evolutionarily conserved, mechanically activated TMEM63 channel in an animal and provide an explanation of how flies can sense and behaviorally respond to the texture of food provided by particles.

Sphingosine-1-phosphate (S1P) is a lipid mediator that is relatively abundant in plasma and plays an important role in the vascular and immune systems. To date, the only known mechanism for removing S1P from plasma has been dephosphorylation by phospholipid phosphatases (PLPPs) on the surface of cells in contact with the plasma. However, there remains a possibility that PLPP-independent dephosphorylation or direct S1P uptake into cells could occur. To examine these possibilities, here we generated triple KO (TKO) HAP1 cells that lacked all PLPPs (PLPP1-3) present in mammals. In the TKO cells, the intracellular metabolism of externally added deuterium-labeled S1P to ceramide was reduced to 17% compared with the WT cells, indicating that most extracellular S1P is dephosphorylated by PLPPs and then taken up into cells. However, this result also reveals the existence of a PLPP-independent S1P uptake pathway. Tracer experiments using [P-32]S1P showed the existence of a direct S1P uptake pathway that functions without prior dephosphorylation. Overexpression of sphingolipid transporter 2 (SPNS2) or of major facilitator superfamily domain containing 2B (MFSD2B), both known S1P efflux transporters, in TKO cells increased the direct uptake of S1P, whereas KO of MFSD2B in TKO cells reduced this uptake. These results suggest that these are channel-type transporters and capable of not only exporting but also importing S1P. Furthermore, we observed that erythroid cells expressing MFSD2B, exhibited high S1P uptake activity. Our findings describing direct S1P uptake may contribute to the elucidation of the molecular mechanisms that regulate plasma S1P concentration.