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This paper studies a cooperative modeling framework to reduce the complexity in deriving the governing dynamical equations of complex systems composed of multiple bodies such as biped robots and unmanned aerial and ground vehicles. The approach also allows for an optimization-based trajectory generation for the complex system. This work also studies a fast–slow model predictive control strategy with task prioritization to perform docking maneuvers on cooperative systems. The method allows agents and a single agent to perform a docking maneuver. In addition, agents give different priorities to a specific subset of shared states. In this way, overall degrees of freedom to achieve the docking task are distributed among various subsets of the task space. The fast–slow model predictive control strategy uses non-linear and linear model predictive control formulations such that docking is handled as a non-linear problem until agents are close enough, where direct transcription is calculated using the Euler discretization method. During this phase, the trajectory generated is tracked with a linear model predictive controller and addresses the close proximity motion to complete docking. The trajectory generation and modeling is demonstrated on a biped robot, and the proposed MPC framework is illustrated in a case study, where a quadcopter docks on a non-holonomic rover using a leader–follower topology. [ABSTRACT FROM AUTHOR]

Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2a is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2a, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2a have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission. [ABSTRACT FROM AUTHOR]

Building on recent musicological research that emphasizes the mobility of songs, this article investigates Marseille as a site of cultural encounter and highlights the musical presence of enslaved galley rowers and translators in the city. It focuses on several descriptions of music-making in southern France by the French antiquarian Nicolas-Claude Fabri de Peiresc and his efforts to find materials on Ottoman and Persian music for the music theorist Marin Mersenne. Utilizing the constant influx of goods and people into the city, Peiresc relied on mercantile networks to obtain transcriptions of songs and music theoretical texts, engaging various informers and translators from the eastern Mediterranean. Focusing on a transcription of a single song that has been lost, the article traces the song's connections to cultures of collection, cultural translation, and transcription, with singing constituting a central site in which to negotiate and perform otherness. [ABSTRACT FROM AUTHOR]

Docks are a widespread problem in grassland, necessitating novel management solutions as pesticides become increasingly regulated. The objective was to investigate the role of soil test Potassium (K) concentrations (Morgan's solution; Na acetate + acetic acid, pH 4.8; STK) on competitiveness of docks in grassland. The experimental site (52°21 N, 7°18 W) was reseeded with perennial ryegrass in October 2009. A plot experiment was laid down in a randomised complete block design with seven rates of fertiliser K (0, 50, 100, 150, 200, 250 and 300 kg ha−1) and eight replicates. Dock numbers were measured over 6 years (2010–2015) and herbage production over 5 years (2012–2016). There was poor alignment between fertiliser K and STK in the early years of the study, however this alignment improved over time. While fertiliser K had no effect on dock numbers, there were positive correlations between STK early in the study and dock numbers m−2 throughout the study. Dock numbers m−2 were relatively static between 2010 and 2012 and increased substantially between 2013 and 2015. Between 2013 and 2016 there were strong inverse relationships (r > −.765; p <.001) between dock and grass herbage production. Towards the end of the study the lower annual fertiliser K inputs (0 and 50 kg ha−1) resulted in lower (p <.01) dock root and herbage production with an associated increase (p <.05) in grass herbage production. It is evident there is a threshold STK for permanent grassland infested with docks at which grass is more competitive for plant‐available soil K than the docks to the detriment of the dock component of the sward. [ABSTRACT FROM AUTHOR]

This article introduces a line‐of‐sight (LOS)‐Euler rendezvous and docking (RVD) framework to dock with a tumbling target under several RVD constraints. By a double‐loop control scheme, the chaser's position is controlled to track the target's docking port which is coupled with its rotation. The chaser's attitude is driven to track the target's rotation, while satisfying the field of view constraintwhich is coupled with the LOS range. These complex couplings are linearly described in the proposed framework. To this end, the 6 DoF information interactions among the sensor measurements, states, and RVD constraints need no transformation and linearization. Consider the online piecewise affine (PWA) model predictive controller (MPC) may be unsolvable under complex constraints, which is caused by the accumulated prediction error, a sampling‐based method is proposed. The linear predictions are driven to the closer neighborhoods of the actual nonlinear states by constructing directional sampling intervals. Besides, a singularity free strategy is provided to realize continuous tracking with crossing the singularities of angle states. Detailed numerical simulations illustrate the validity of the proposed methods. [ABSTRACT FROM AUTHOR]

The No.1 and No.2 liquid bulk cargo berths in Jida Port Area of Maoming Port are independent pier type cylinder caisson gravity docks. This paper focuses on the precision control of the prefabricated cover plate on the upper part of the circular caisson and the splitting installation of the berthing components. In the absence of effective cover in the open sea, BIM technology was used to simulate component collision detection, precise alignment of the steel bars of the separate components, and temporary installation stability analysis, in order to optimize the structural type of the separate components and select the optimal lifting plan, refine the positioning and reinforcement construction process, improve the accuracy and efficiency of prefabricated cover plates and berthing components installation through visualization, informatization, and standardization, reduce project costs and maritime lifting safety risks, and provide experience and reference for the installation of large prefabricated components similar to LPG terminals in the future. [ABSTRACT FROM AUTHOR]

The opportunities for leveraging technology to enhance the efficiency of vessel port activities are vast. Applying video analytics to model and optimize certain processes offers a remarkable way to improve overall operations. Within the realm of vessel port activities, two crucial processes are vessel approximation and the docking process. This work specifically focuses on developing a vessel velocity estimation model and a docking mooring analytical system using a computer vision approach. The study introduces algorithms for speed estimation and mooring bitt detection, leveraging techniques such as the Structural Similarity Index (SSIM) for precise image comparison. The obtained results highlight the effectiveness of the proposed algorithms, demonstrating satisfactory speed estimation capabilities and successful identification of tied cables on the mooring bitts. These advancements pave the way for enhanced safety and efficiency in vessel docking procedures. However, further research and improvements are necessary to address challenges related to occlusions and illumination variations and explore additional techniques to enhance the models' performance and applicability in real-world scenarios. [ABSTRACT FROM AUTHOR]

Focusing on the construction of London's West India Docks in 1802, I argue that this project established a feedback loop with conditions of production in the Caribbean. Through an analysis of committee minutes, letters, parliamentary papers and visual art, I move beyond economic accounts of slavery's impact to demonstrate how geographies of security and surveillance—first developed on the sugar plantation—were imported into the design and function of London's port. As such, I argue that London's docks produced a geography of segregation which offers a unique insight into the workings of racial capitalism and its exploitation of group‐differentiated vulnerabilities. Positioning my discussion alongside London's contemporary landscape, I excavate Britain's repressed memories of slavery to illustrate how they still scar the urban environment. [ABSTRACT FROM AUTHOR]

By focusing on love and humour, this article examines the role of positive emotions in the making and remaking of solidarity on the docks in Liverpool to demonstrate that solidarity was, and still is, embedded within power dynamics that shaped daily life. After outlining the persistent insecurities dock workers and their families faced due to the casual system of employment in place until 1967, the dangerous nature of work and the impact of containerisation, I assess how experiences during this period were remembered. A combination of oral history interviews and archival records of the National Dock Labour Board and the Mersey Docks and Harbour Company are used to highlight the significance of family support, the dockers' bucket and nicknames to understanding the emotional dimensions of class. Ultimately, I outline that solidarity action should not be understood as overt moments of political struggle alone as it was sustained by creating moments of happiness and joy. [ABSTRACT FROM AUTHOR]

This paper presents a novel algorithm to dock a non-holonomic Autonomous Underwater Vehicle (AUV) into a funnel-shaped Docking Station (DS), in the presence of ocean currents. In a previous work, the authors have compared several docking algorithms through Monte Carlo simulations. In this paper, a new control algorithm is presented with a goal to improve over the previous ones to fulfil the specific needs of the ATLANTIS project. Performance of the new proposed algorithm has been compared with the results of the previous study, using the same environemnt on the Stonefish hardware-in-the-loop simulator. [ABSTRACT FROM AUTHOR]

The trans‐Golgi Network (TGN) sorts molecular "addresses" and sends newly synthesized proteins to their destination via vesicular transport carriers. Despite the functional significance of packaging processes at the TGN, the sorting of soluble proteins remains poorly understood. Recent research has shown that the Golgi resident protein Cab45 is a significant regulator of secretory cargo sorting at the TGN. Cab45 oligomerizes upon transient Ca2+ influx, recruits soluble cargo molecules (clients), and packs them in sphingomyelin‐rich transport carriers. However, the identity of client molecules packed into Cab45 vesicles is scarce. Therefore, we used a precise and highly efficient secretome analysis technology called hiSPECs. Intriguingly, we observed that Cab45 deficient cells manifest hypersecretion of lysosomal hydrolases. Specifically, Cab45 deficient cells secrete the unprocessed precursors of prosaposin (PSAP) and progranulin (PGRN). In addition, lysosomes in these cells show an aberrant perinuclear accumulation suggesting a new role of Cab45 in lysosomal positioning. This work uncovers a yet unknown function of Cab45 in regulating lysosomal function. [ABSTRACT FROM AUTHOR]

This study investigated model predictive control (MPC) for close-proximity maneuvering of spacecraft. It is essential for a designed MPC to effectively handle collision avoidance between the servicer spacecraft and the client spacecraft, especially while the client is rotating. The rotating motion of the client leads to dynamic changes in the collision avoidance constraints, which increases the difficulty of optimizing the control input in the MPC framework. Therefore, this study presents a method to improve the performance and computational efficiency of MPC for rendezvous and docking with a nonrotating or rotating client. An ellipsoid is adopted to model the client's keep-out zone (KOZ). Given the spherical KOZ of the servicer, an expanded ellipsoid is introduced to describe the KOZ for the center of mass of the servicer and modeled as a nonlinear constraint. The linearization method for reference points located at the expanded ellipsoid is adopted to convexify the nonlinear constraints. The reference points are adaptively determined according to the positions of the servicer, client, and expanded ellipsoidal KOZ. The resulting hyperplanes are then used to describe the collision avoidance constraints. By utilizing the aforementioned strategies, combined with the calculated reference points, an adaptive convex programming algorithm suitable for real-time implementation of MPC is derived. The performance of the proposed method is demonstrated through numerical simulations. [ABSTRACT FROM AUTHOR]

Cilia are ubiquitous eukaryotic organelles impotant for cellular motility, signaling, and sensory reception. Cilium formation requires intraflagellar transport of structural and signaling components and involves 22 different proteins organized into intraflagellar transport (IFT) complexes IFT‐A and IFT‐B that are transported by molecular motors. The IFT‐B complex constitutes the backbone of polymeric IFT trains carrying cargo between the cilium and the cell body. Currently, high‐resolution structures are only available for smaller IFT‐B subcomplexes leaving > 50% structurally uncharacterized. Here, we used Alphafold to structurally model the 15‐subunit IFT‐B complex. The model was validated using cross‐linking/mass‐spectrometry data on reconstituted IFT‐B complexes, X‐ray scattering in solution, diffraction from crystals as well as site‐directed mutagenesis and protein‐binding assays. The IFT‐B structure reveals an elongated and highly flexible complex consistent with cryo‐electron tomographic reconstructions of IFT trains. The IFT‐B complex organizes into IFT‐B1 and IFT‐B2 parts with binding sites for ciliary cargo and the inactive IFT dynein motor, respectively. Interestingly, our results are consistent with two different binding sites for IFT81/74 on IFT88/70/52/46 suggesting the possibility of different structural architectures for the IFT‐B1 complex. Our data present a structural framework to understand IFT‐B complex assembly, function, and ciliopathy variants. Synopsis: Construction and maintenance of cilia is mediated by the the bidirectional trafficking of 22 different proteins organized into IFT‐A and IFT‐B complexes, with only structures of smaller IFT‐B assemblies solved. Here, a combination of Alphafold structural modeling and biochemical analysis offers a structural model of the 15‐subunit IFT‐B complex. Validated structural model for 15‐subunit IFT‐B reveals an elongated and highly flexible complex consistent with cryo‐electron tomographic reconstructions of IFT trains.The IFT‐B complex divides into IFT‐B1 and IFT‐B2 parts with binding sites for ciliary cargo and the inactive IFT dynein motor, respectively.Structural modeling and biochemical data are consistent with two different binding sites for IFT81/74 on IFT88/70/52/46 suggesting the possibility of two different conformations of the IFT‐B1 complex. [ABSTRACT FROM AUTHOR]

Nucleocytoplasmic transport (NCT) is affected in several neurodegenerative diseases including C9orf72-ALS. It has recently been found that arginine-containing dipeptide repeat proteins (R-DPRs), translated from C9orf72 repeat expansions, directly bind to several importins. To gain insight into how this can affect nucleocytoplasmic transport, we use coarse-grained molecular dynamics simulations to study the molecular interaction of poly-PR, the most toxic DPR, with several Kapβs (importins and exportins). We show that poly-PR–Kapβ binding depends on the net charge per residue (NCPR) of the Kapβ, salt concentration of the solvent, and poly-PR length. Poly-PR makes contact with the inner surface of most importins, which strongly interferes with Kapβ binding to cargo-NLS, IBB, and RanGTP in a poly-PR length-dependent manner. Longer poly-PRs at higher concentrations are also able to make contact with the outer surface of importins that contain several binding sites to FG-Nups. We also show that poly-PR binds to exportins, especially at lower salt concentrations, interacting with several RanGTP and FG-Nup binding sites. Overall, our results suggest that poly-PR might cause length-dependent defects in cargo loading, cargo release, Kapβ transport and Ran gradient across the nuclear envelope. [ABSTRACT FROM AUTHOR]

Ru‐porphyrins act as convenient pedestals for the assembly of N‐heterocyclic carbenes (NHCs) on solid surfaces. Upon deposition of a simple NHC ligand on a close packed Ru‐porphyrin monolayer, an extraordinary phenomenon can be observed: Ru‐porphyrin molecules are transferred from the silver surface to the next molecular layer. We have investigated the structural features and dynamics of this portering process and analysed the associated binding strengths and work function changes. A rearrangement of the molecular layer is induced by the NHC uptake: the NHC selective binding to the Ru causes the ejection of whole porphyrin molecules from the molecular layer on silver to the layer on top. This reorganisation can be reversed by thermally induced desorption of the NHC ligand. We anticipate that the understanding of such mass transport processes will have crucial implications for the functionalisation of surfaces with carbenes. [ABSTRACT FROM AUTHOR]

Ru‐porphyrins act as convenient pedestals for the assembly of N‐heterocyclic carbenes (NHCs) on solid surfaces. Upon deposition of a simple NHC ligand on a close packed Ru‐porphyrin monolayer, an extraordinary phenomenon can be observed: Ru‐porphyrin molecules are transferred from the silver surface to the next molecular layer. We have investigated the structural features and dynamics of this portering process and analysed the associated binding strengths and work function changes. A rearrangement of the molecular layer is induced by the NHC uptake: the NHC selective binding to the Ru causes the ejection of whole porphyrin molecules from the molecular layer on silver to the layer on top. This reorganisation can be reversed by thermally induced desorption of the NHC ligand. We anticipate that the understanding of such mass transport processes will have crucial implications for the functionalisation of surfaces with carbenes. [ABSTRACT FROM AUTHOR]

The autonomous operations of marine vehicles have recently attracted significant attention. In particular, automation of harbor operations, such as autonomous docking or berthing, is a challenging target. In low-speed harbor operations, the external disturbance of wind is a non-negligible factor. Therefore, the stochastic behavior of gusty wind should be considered in numerical simulations. This study presents a practical computational scheme for generating random wind velocity fields. In the proposed method, the von Kármán's spectrum [1] and Hino's wind speed spectrum [2] were fitted by a degree of freedom (1DoF) filter driven by the Wiener process. The corresponding Itô's equation had the form of the Ornstein–Uhlenbeck process. By employing the analytical solution of the Ornstein–Uhlenbeck process, the wind process was successfully generated without time series repetition. Furthermore, the wind speed and direction processes were also generated from the measured drift and diffusion terms. The spectra of these numerical results are consistent with the observed spectra. [ABSTRACT FROM AUTHOR]

Ethical livestock production is currently a major concern for consumers. In parallel, research has shown that transport duration is an important factor affecting animal welfare and has a negative impact on the final product quality and on the production cost. This study applied proteomics methods to the animal stress/welfare problem in pigs muscle-exudate with the aim to identify proteins indicative of molecular processes underpinning transport stress and to better characterise this species as a biomedical model. A broader perspective of the problem was obtained by applying label-free LC-MS to characterise the proteome response to transport stress (short or long road transportation) in pigs within the same genetic line. A total of 1,464 proteins were identified, following statistical analysis 66 proteins clearly separating pigs subject to short road transportation and pigs subject long road transportation. These proteins were mainly involved in cellular and metabolic processes. Catalase and stress-induced phosphoprotein-1 were further confirmed by Western blot as being involved in the process of self-protection of the cells in response to stress. This study provide an insight into the molecular processes that are involved in pig adaptability to transport stress and are a step-forward for the development of an objective evaluation method of stress in order to improve animal care and management in farm animals. [ABSTRACT FROM AUTHOR]

Due to the argued benefits of passenger comfort, cost savings, and road safety, the bus sector is showing increasing interest in advanced driver-assistance systems (ADAS). Despite this growth of interest in ADAS and the fact that work tasks are sometimes complicated (especially docking at bus-stops which may occur several hundred times per shift), there has been little research into ADAS in buses. Therefore, the aim of this study was to develop further knowledge of how professional bus drivers experience and accept an ADAS which can help them dock at bus-stops. The study was conducted on a public route in an industrial area with five different bus-stops. Ten professional bus drivers got to use a narrow navigation system (NNS) that could dock automatically at bus-stops. The participants' experience and acceptance were investigated using objective as well as subjective data (during and after the test-drive) and data were collected using interviews, questionnaires, and video recordings. The participants indicated high levels of trust in and acceptance of the NNS and felt that it had multiple benefits in terms of cognitive and physical ergonomics, safety, and comfort. However, the relatively slow docking process (which was deemed comfortable) was also expected to negatively affect, e.g., timetabling, possibly resulting in high stress levels. Therefore, when investigating users' acceptance of ADAS in a work context, it is important to consider acceptance in terms of the operation, use, and work system levels and how those levels interact and affect each other. [ABSTRACT FROM AUTHOR]

Targeted delivery of therapeutics to specific tissues is critically important for reducing systemic toxicity and optimizing therapeutic efficacy, especially in the case of cytotoxic drugs. Many strategies currently exist for targeting systemically administered drugs, and ultrasound-controlled targeting is a rapidly advancing strategy for externally-stimulated drug delivery. In this non-invasive method, ultrasound waves penetrate through tissue and stimulate gas-filled microbubbles, resulting in bubble rupture and biophysical effects that power delivery of attached cargo to surrounding cells. Drug delivery capabilities from ultrasound-sensitive microbubbles are greatly expanded when nanocarrier particles are attached to the bubble surface, and cargo loading is determined by the physicochemical properties of the nanoparticles. This review serves to highlight and discuss current microbubble–nanoparticle complex component materials and designs for ultrasound-mediated drug delivery. Nanocarriers that have been complexed with microbubbles for drug delivery include lipid-based, polymeric, lipid–polymer hybrid, protein, and inorganic nanoparticles. Several schemes exist for linking nanoparticles to microbubbles for efficient nanoparticle delivery, including biotin–avidin bridging, electrostatic bonding, and covalent linkages. When compared to unstimulated delivery, ultrasound-mediated cargo delivery enables enhanced cell uptake and accumulation of cargo in target organs and can result in improved therapeutic outcomes. These ultrasound-responsive delivery complexes can also be designed to facilitate other methods of targeting, including bioactive targeting ligands and responsivity to light or magnetic fields, and multi-level targeting can enhance therapeutic efficacy. Microbubble–nanoparticle complexes present a versatile platform for controlled drug delivery via ultrasound, allowing for enhanced tissue penetration and minimally invasive therapy. Future perspectives for application of this platform are also discussed in this review. [ABSTRACT FROM AUTHOR]

In this research, we present an intelligent forklift cargo precision transfer system to address the issue of poor pallet docking accuracy and low recognition rate when using current techniques. The technology is primarily used to automatically check if there is any pallet that need to be transported. The intelligent forklift is then sent to the area of the target pallet after being recognized. Images of the pallets are then collected using the forklift's camera, and a deep learning-based recognition algorithm is used to calculate the precise position of the pallets. Finally, the forklift is controlled by a high-precision control algorithm to insert the pallet in the exact location. This system creatively introduces the small target detection into the pallet target recognition system, which greatly improves the recognition rate of the system. The application of Yolov5 into the pallet positional calculation makes the coverage and recognition accuracy of the algorithm improved. In comparison with the prior approach, this system's identification rate and accuracy are substantially higher, and it requires fewer sensors and indications to help with deployment. We have collected a significant amount of real data in order to confirm the system's viability and stability. Among them, the accuracy of pallet docking is evaluated 1000 times, and the inaccuracy is kept to a maximum of 6 mm. The recognition rate of pallet recognition is above 99.5% in 7 days of continuous trials. [ABSTRACT FROM AUTHOR]

The Kirsten rat sarcoma (KRAS) oncoprotein has been on drug hunters list for decades now. Initially considered undruggable, recent advances have successfully broken the jinx through covalent inhibition that exploits the mutated cys12 in the switch II binding pocket (KRASG12C). Though this approach has achieved some level of success, patients with mutations other than cys12 are still uncatered for. KRASG12D is the most frequent KRAS mutated oncoprotein. It is only until recently, MRTX1133 has been discovered as a potential inhibitor of KRASG12D. This study seeks to unravel the structural binding mechanism of MRTX1133 as well as identify potential drug leads of KRASG12D based on structural binding characteristics of MRTX1133. It was revealed that MRTX1133 binding stabilizes the binding site by increasing the hydrophobicity which resultantly induced positive correlated movements of switches I and II which could disrupt their interaction with effector and regulatory proteins. Furthermore, MRTX1133 interacted with critical residues; Asp69 (− 4.54 kcal/mol), His95 (− 3.65 kcal/mol), Met72 (− 2.27 kcal/mol), Thr58 (− 2.23 kcal/mol), Gln99 (− 2.03 kcal/mol), Arg68 (− 1.67 kcal/mol), Tyr96 (− 1.59 kcal/mol), Tyr64 (− 1.34 kcal/mol), Gly60 (− 1.25 kcal/mol), Asp12 (− 1.04 kcal/mol), and Val9 (− 1.03 kcal/mol) that contributed significantly to the total free binding energy of − 73.23 kcal/mol. Pharmacophore-based virtual screening based on the structural binding mechanisms of MRTX1133 identified ZINC78453217, ZINC70875226 and ZINC64890902 as potential KRASG12D inhibitors. Further, structural optimisations and biochemical testing of these compounds would assist in the discovery of effective KRASG12D inhibitors. [ABSTRACT FROM AUTHOR]

We have developed a convenient one-pot multicomponent synthesis of highly functionalized [1,6]-naphthyridines under solvent free condition using [Et3NH][HSO4] in excellent yield. This protocol offers several advantages, including short reaction time, simple experimental workup procedure and no toxic byproducts, avoids the use of toxic organic solvents and anhydrous conditions. Further. we have screened the synthesized naphthyridines for in vitro antibacterial, antifungal and antioxidant activity. Furthermore, a molecular docking study of these compounds was carried out to investigate their binding pattern with the target, β-Ketoacyl-acyl carrier protein synthase III (FabH). Finally, the ADME parameters for these compounds showed good drug like properties and can be developed as oral drug candidates. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 claimed millions of lives, globally. Occurring from Wuhan (wild type) in December, 2019, it constantly mutated to Omicron (B.1.1.529), the predecessor to Delta. Omicron having ~ 32 spike mutations has variable infectivity-multiplicity-immuno-invasive properties. Understanding of its mutational effect on ACE2-binding/disease severity and developing preventive/therapeutic strategies are important. The binding affinities of Wuhan/Delta/Omicron spikes (PDB/GISAID/SWISS-MODEL) were docked (HADDOCK2.4) with ACE2 and compared by competitive-docking (PRODIGY). The protein structural stability was verified by kinetic-data/Ramachandran-plot (Zlab/UMassMedBioinfo). After several trials, a 59 amino acid (453ARG-510VAL) peptide-cut (Expasy-server) of the wild-type spike RBD with some desired mutants (THR500SER/THR500GLY/THR500ALA/THR500CYS) was blindly/competitively docked (PyMOL-V2.2.2) to block the Omicron-ACE2 binding. We examined molecular dynamic simulation (iMOD-server, with 9000 cycles/300 k-heating/1 atm pressure for system equilibration for 50 ns-run) of ACE2 and two CUTs with different SARS-CoV-2 variants. The binding-affinity of Omicron-ACE2 is slightly higher than the rest two in competitive docking setup. During individual (1:1) docking, Omicron showed little higher than wild type but much weaker binding affinity than Delta. Competitive docking suggests ten H-bonding (1.3–2.4 Å) with highly favorable energy values/Van-der-Walls-force/Haddock score for more stable-binding of Omicron-RBD with ACE2. Blind docking of different CUTs (wild/mutants) and Omicron to ACE2 completely rejected the Omicron-RBD from ACE2-target. The best blocking/binding affinity of −16.4 and −13 kcal/mole were observed in the case of THR500SER and THR500GLY, respectively, with multiple H-bonding 1.9–2.2 Å. These are supported by the MD-simulation results. So, the spike binding affinities were Delta > Omicron > wild in 1:1 docking with ACE2. Considering the wild type is non-existing nowadays, Omicron showed less ACE2 binding properties. The 59 cut of spike-RBD and its mutant THR500SER/THR500GLY may be further screened as universal blockers of this virus. [ABSTRACT FROM AUTHOR]

The recent successes of AlphaFold and RoseTTAFold have demonstrated the value of AI methods in highly accurate protein structure prediction. Despite these advances, the role of these methods in the context of small-molecule drug discovery still needs to be thoroughly explored. In this study, we evaluated whether the AI-based models can reliably reproduce the three-dimensional structures of protein–ligand complexes. The structure we chose was NLRP3, a challenging protein target in terms of obtaining a three-dimensional model both experimentally and computationally. The conformation of the binding pockets generated by the AI models was carefully characterized and compared with experimental structures. Further molecular docking results indicated that AI-predicted protein structures combined with molecular dynamics simulations offers a promising approach in small-molecule drug discovery. [ABSTRACT FROM AUTHOR]

The A554 Tower Road connects Wallasey and Birkenhead on the Wirral, north west England. The road crosses the entrance to Birkenhead docks from the River Mersey by way of a moveable bridge, which is of major strategic importance in the local highway network. The previous 'A' bridge, built in 1933, was a Scherzer type bascule lifting bridge with 34.4 m main span, one of four similar bridges that once existed along Tower Road. The deteriorating condition of the bridge, the increasing maintenance costs and the consequential impact of maintenance on the local economy resulted in a decision to replace the bridge with a modern, low-maintenance, lifting bridge. This paper provides the background to the bridge replacement project, including the reasons for replacement with a similar Scherzer bascule bridge. The civil, mechanical and electrical design is described and some of the significant issues encountered during implementation and commissioning are discussed. The new bridge has successfully created a local landmark, contributing to the client Wirral Council's vision for the redevelopment of this dockland area as part of the Wirral Waters regeneration project. [ABSTRACT FROM AUTHOR]

Several studies have predicted the molecular interactions of the active ingredient of Spirulina platensis as an anti-inflammatory compound. However, these interaction studies did not review the modulation of the NF-κB activation pathway, which involves various factors. This study demonstrated the potential of the bioactive compounds of S. platensis for modulating immune function by reducing inflammation through the inhibition of the NF-κB activation pathway. Phycocyanobilin was predicted to have good potential for molecular docking with multisubunit IκB kinase (IKK)1/IKKA, IKK2/IKKB, NF-κB-inducing kinase, and the IκBα/NF-κB complex. Furthermore, β-carotene exhibited good potential for interactions with NF-κB essential modulator/IKK and the NF-κB complex, and α-glucan had the potential for interactions with COX-2. Therefore, supplementation with S. platensis and its bioactive compounds is expected to provide optimal benefits. [ABSTRACT FROM AUTHOR]

Plant selective (macro)autophagy is a highly regulated process where eukaryotic cells spatiotemporally degrade some of their constituents that have become superfluous or harmful. The identification and characterization of the factors determining this selectivity make it possible to integrate selective (macro)autophagy into plant cell physiology and homeostasis. The specific cargo receptors and/or scaffold proteins involved in this pathway are generally not structurally conserved, as are the biochemical mechanisms underlying recognition and integration of a given cargo into the autophagosome in different cell types. This review discusses the few specific cargo receptors described in plant cells to highlight key features of selective autophagy in the plant kingdom and its integration with plant physiology, aiming to identify evolutionary convergence and knowledge gaps to be filled by future research. [ABSTRACT FROM AUTHOR]

• Incentivizing users to walk farther is a way of rebalancing a bike-share fleet. • The impact of incentives on willingness-to-walk (WTW) to get a bike was examined. • Half of bike-share users would use a bike located 8.9-minutes away without an incentive. • WTW for incentives at origins and destinations were 3.8 min/US$ and 4.2 min/US$. • Results suggest the potential effectiveness of incentives as a rebalancing policy. Bike-share services will produce more limited benefits if users cannot find bikes when and where they need them. Bike-share operators must thus have process for "rebalancing" the bikes within the system to ensure that they are available where demanded. A potentially cost-effective strategy for rebalancing bikes is to offer incentives of some sort to users to walk farther to get a bike (origin-based incentive) or bring a bike to the undersupplied area (destination-based incentive). This paper aims to examine bike-share users' willingness-to-walk to pick up a bike or drop off a bike at some distance from their origins or destinations if rewarded and to identify characteristics influencing willingness-to-walk. We use data from a survey of dock-less e-bike-share users conducted in the Sacramento region. The analysis shows that half of the respondents use bike-share if the available bike is located 8.9 min away. Our estimates of willingness-to-walk farther than the mean distance for incentives at origins and destinations were 3.8 min and 4.2 min per dollar, respectively. Our results give operators and policy makers insights into the potential effectiveness of incentives as a strategy for spatially rebalancing bike-share fleets. [ABSTRACT FROM AUTHOR]

Trypanosomiases are life-threatening infections of humans and livestock, and novel effective therapeutic approaches are needed. Trypanosoma compartmentalize glycolysis into specialized organelles termed glycosomes. Most of the trypanosomal glycolytic enzymes harbor a peroxisomal targeting signal-1 (PTS1) which is recognized by the soluble receptor PEX5 to facilitate docking and translocation of the cargo into the glycosomal lumen. Given its pivotal role in the glycosomal protein import, the PEX5–PTS1 interaction represents a potential target to inhibit import of glycolytic enzymes and thus kill the parasite. We developed a fluorescence polarization (FP)-based assay for monitoring the PEX5–PTS1 interaction and performed a High Throughput Screening (HTS) campaign to identify small molecule inhibitors of the interaction. Six of the identified hits passed orthogonal selection criteria and were found to inhibit parasite growth in cell culture. Our results validate PEX5 as a target for small molecule inhibitors and provide scaffolds suitable for further pre-clinical development of novel trypanocidal compounds. [ABSTRACT FROM AUTHOR]

Excessive absorption of osteoclasts will break the balance between osteoclasts and osteoblasts, leading to bone loss, decreased bone density, and increased bone fragility. We have shown that Loureirin B (LrB) can inhibit osteoclasts. In this study, we demonstrated the targeting-inhibitory mechanism of LrB acting on osteoclast precursor. Using SPR, HPLC and MALDI-TOF-MS to capture and analyze the target protein of Loureirin B in bone marrow macrophages (BMMs), we used this method to detect all target proteins that LrB acts on BMMs, and analyzed the distribution and enrichment rate of the target protein by DAVID enrichment analysis. Ledock molecular docking was used to detect the binding of LrB. We used Western Blot for verification. The target proteins of LrB acting on BMMs were Serpine1, Atp6ap1, Dvl1, Rhd, Fzd2, MAPK1, MAP2K2, MAPK3 and so on. MAPK1, MAP2K2 and MAPK3 were the most relevant. LrB treatment attenuated the expression of phosphorylated JNK and p38 kinases of the MAPK signaling pathway. Our research further confirmed that LrB affects the MAPK signaling pathway in BMMs, thereby inhibiting the differentiation of BMMs into osteoclasts. This discovery can confirm the mechanism by which LrB acts on BMMs. [ABSTRACT FROM AUTHOR]

The Endosomal Sorting Complexes Required for Transport (ESCRTs) drive membrane remodeling in a variety of cellular processes that include the formation of endosomal intralumenal vesicles (ILVs) during multivesicular body (MVB) biogenesis. During MVB sorting, ESCRTs recognize ubiquitin (Ub) attached to membrane protein cargo and execute ILV formation by controlling the activities of ESCRT‐III polymers regulated by the AAA‐ATPase Vps4. Exactly how these events are coordinated to ensure proper cargo loading into ILVs remains unclear. Here we discuss recent work documenting the ability of Bro1, an ESCRT‐associated Ub‐binding protein, to coordinate ESCRT‐III and Vps4‐dependent ILV biogenesis with upstream events such as cargo recognition. [ABSTRACT FROM AUTHOR]

Myo2, a yeast class V myosin, transports a broad range of organelles and plays important roles in various cellular processes, including cell division in budding yeast. Despite the fact that several structures of Myo2/cargo adaptor complexes have been determined, the understanding of the versatile cargo-binding modes of Myo2 is still very limited, given the large number of cargo adaptors identified for Myo2. Here, we used ColabFold, an AlphaFold2-powered and easy-to-use tool, to predict the complex structures of Myo2-GTD and its several cargo adaptors. After benchmarking the prediction strategy with three Myo2/cargo adaptor complexes that have been determined previously, we successfully predicted the atomic structures of Myo2-GTD in complex with another three cargo adaptors, Vac17, Kar9 and Pea2, which were confirmed by our biochemical characterizations. By systematically comparing the interaction details of the six complexes of Myo2 and its cargo adaptors, we summarized the cargo-binding modes on the three conserved sites of Myo2-GTD, providing an overall picture of the versatile cargo-recognition mechanisms of Myo2. In addition, our study demonstrates an efficient and effective solution to study protein–protein interactions in the future via the AlphaFold2-powered prediction. [ABSTRACT FROM AUTHOR]

Teichoic acids (TA) are crucial for the homeostasis of the bacterial cell wall as well as their developmental behavior and interplay with the environment. TA can be decorated by different modifications, modulating thus their biochemical properties. One major modification consists in the esterification of TA by d-alanine, a process known as d-alanylation. TA d-alanylation is performed by the Dlt pathway, which starts in the cytoplasm and continues extracellularly after d-Ala transportation through the membrane. In this study, we combined structural biology and in vivo approaches to dissect the cytoplasmic steps of this pathway in Lactiplantibacillus plantarum, a bacterial species conferring health benefits to its animal host. After establishing that AcpS, DltB, DltC1 and DltA are required for the promotion of Drosophila juvenile growth under chronic undernutrition, we solved their crystal structure and/or used NMR and molecular modeling to study their interactions. Our work demonstrates that the suite of interactions between these proteins is ordered with a conserved surface of DltC1 docking sequentially AcpS, DltA and eventually DltB. Altogether, we conclude that DltC1 acts as an interaction hub for all the successive cytoplasmic steps of the TA d-alanylation pathway. [ABSTRACT FROM AUTHOR]

The brain is essential to human adaptation to any environment including space. We examined astronauts' brain function through their electrical EEG brain potential responses related to their decision of executing a docking task in the same virtual scenario in Weightlessness and on Earth before and after the space stay of 6 months duration. Astronauts exhibited a P300 component in which amplitude decreased during, and recovered after, their microgravity stay. This effect is discussed as a post-value-based decision-making closing mechanism; The P300 amplitude decrease in weightlessness is suggested as an emotional stimuli valence reweighting during which orbitofrontal BA10 would play a major role. Additionally, when differentiating the bad and the good docks on Earth and in Weightlessness and keeping in mind that astronauts were instantaneously informed through a visual cue of their good or bad performance, it was observed that the good dockings resulted in earlier voltage redistribution over the scalp (in the 150–250 ms period after the docking) than the bad dockings (in the 250–400 ms) in Weightlessness. These results suggest that in Weightlessness the knowledge of positive or negative valence events is processed differently than on Earth. [ABSTRACT FROM AUTHOR]

PADI4 is a peptidyl-arginine deiminase (PADI) involved in the conversion of arginine to citrulline. PADI4 is present in macrophages, monocytes, granulocytes, and several cancer cells. It is the only PADI family member observed within both the nucleus and the cytoplasm. PADI4 has a predicted nuclear localization sequence (NLS) comprising residues Pro56 to Ser83, to allow for nuclear translocation. Recent predictors also suggest that the region Arg495 to Ile526 is a possible NLS. To understand how PADI4 is involved in cancer, we studied the ability of intact PADI4 to bind importin α3 (Impα3), a nuclear transport factor that plays tumor-promoting roles in several cancers, and its truncated species (ΔImpα3) without the importin-binding domain (IBB), by using fluorescence, circular dichroism (CD), and isothermal titration calorimetry (ITC). Furthermore, the binding of two peptides, encompassing the first and the second NLS regions, was also studied using the same methods and molecular docking simulations. PADI4 interacted with both importin species, with affinity constants of ~1–5 µM. The isolated peptides also interacted with both importins. The molecular simulations predict that the anchoring of both peptides takes place in the major binding site of Impα3 for the NLS of cargo proteins. These findings suggest that both NLS regions were essentially responsible for the binding of PADI4 to the two importin species. Our data are discussed within the framework of a cell mechanism of nuclear transport that is crucial in cancer. [ABSTRACT FROM AUTHOR]

The emergence of pandemic situations originated from severe acute respiratory syndrome (SARS)‐CoV‐2 and its new variants created worldwide medical emergencies. Due to the non‐availability of efficient drugs and vaccines at these emergency hours, repurposing existing drugs can effectively treat patients critically infected by SARS‐CoV‐2. Finding a suitable repurposing drug with inhibitory efficacy to a host‐protein is challenging. A detailed mechanistic understanding of the kinetics, (dis)association pathways, key protein residues facilitating the entry–exit of the drugs with targets are fundamental in selecting these repurposed drugs. Keeping this target as the goal of the paper, the potential repurposing drugs, Nafamostat, Camostat, Silmitasertib, Valproic acid, and Zotatifin with host‐proteins HDAC2, CSK22, eIF4E2 are studied to elucidate energetics, kinetics, and dissociation pathways. From an ensemble of independent simulations, we observed the presence of single or multiple dissociation pathways with varying host‐proteins‐drug systems and quantitatively estimated the probability of unbinding through these specific pathways. We also explored the crucial gateway residues facilitating these dissociation mechanisms. Interestingly, the residues we obtained for HDAC2 and CSK22 are also involved in the catalytic activity. Our results demonstrate how these potential drugs interact with the host machinery and the specific target residues, showing involvement in the mechanism. Most of these drugs are in the preclinical phase, and some are already being used to treat severe COVID‐19 patients. Hence, the mechanistic insight presented in this study is envisaged to support further findings of clinical studies and eventually develop efficient inhibitors to treat SARS‐CoV‐2. [ABSTRACT FROM AUTHOR]

Phospholamban (PLN), a key modulator of Ca2+-homeostasis, inhibits sarcoplasmic reticulum (SR) calcium-ATPase (SERCA2a) and regulates cardiac contractility. The human PLN mutation R14del has been identified in arrhythmogenic cardiomyopathy patients worldwide and is currently extensively investigated. In search of the molecular mechanisms mediating the pathological phenotype, we examined PLN-R14del associations to known PLN-interacting partners. We determined that PLN-R14del interactions to key Ca2+-handling proteins SERCA2a and HS-1-associated protein X-1 (HAX-1) were enhanced, indicating the super-inhibition of SERCA2a's Ca2+-affinity. Additionally, histidine-rich calcium binding protein (HRC) binding to SERCA2a was increased, suggesting the inhibition of SERCA2a maximal velocity. As phosphorylation relieves the inhibitory effect of PLN on SERCA2a activity, we examined the impact of phosphorylation on the PLN-R14del/SERCA2a interaction. Contrary to PLN-WT, phosphorylation did not affect PLN-R14del binding to SERCA2a, due to a lack of Ser-16 phosphorylation in PLN-R14del. No changes were observed in the subcellular distribution of PLN-R14del or its co-localization to SERCA2a. However, in silico predictions suggest structural perturbations in PLN-R14del that could impact its binding and function. Our findings reveal for the first time that by increased binding to SERCA2a and HAX-1, PLN-R14del acts as an enhanced inhibitor of SERCA2a, causing a cascade of molecular events contributing to impaired Ca2+-homeostasis and arrhythmogenesis. Relieving SERCA2a super-inhibition could offer a promising therapeutic approach for PLN-R14del patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2D) constitutes 90% of the diabetes cases, and it is a complex multifactorial disease. In the last decade, genome-wide association studies (GWASs) for T2D successfully pinpointed the genetic variants (typically single nucleotide polymorphisms, SNPs) that associate with disease risk. In order to diminish the burden of multiple testing in GWAS, researchers attempted to evaluate the collective effects of interesting variants. In this regard, pathway-based analyses of GWAS became popular to discover novel multigenic functional associations. Still, to reveal the unaccounted 85 to 90% of T2D variation, which lies hidden in GWAS datasets, new post-GWAS strategies need to be developed. In this respect, here we reanalyze three metaanalysis data of GWAS in T2D, using the methodology that we have developed to identify disease-associated pathways by combining nominally significant evidence of genetic association with the known biochemical pathways, protein-protein interaction (PPI) networks, and the functional information of selected SNPs. In this research effort, to enlighten the molecular mechanisms underlying T2D development and progress, we integrated different in silico approaches that proceed in top-down manner and bottom-up manner, and presented a comprehensive analysis at protein subnetwork, pathway, and pathway subnetwork levels. Using the mutual information based on the shared genes, the identified protein subnetworks and the affected pathways of each dataset were compared. While most of the identified pathways recapitulate the pathophysiology of T2D, our results show that incorporating SNP functional properties, PPI networks into GWAS can dissect leading molecular pathways, and it could offer improvement over traditional enrichment strategies. [ABSTRACT FROM AUTHOR]

In narrow waterways, navigation restrictions are imposed on vessels based on beam and length to safely accommodate two-way traffic. Each transit in a narrow waterway can potentially generate delay for the rest of the vessels in the opposite direction. In this paper, first an algorithm is developed to model the two-way traffic with beam restrictions and to quantify delay due to such restrictions. Next, procedures are presented to determine parameters such as destination docks and vessel arrival and departure times based on the automatic identification system (AIS) and local pilot data. The models and the solution algorithms are applied on three restricted sections of the Houston Ship Channel, and the number of impacted vessels and total delays is presented for each section. The proposed model and solution algorithm can be used in many studies, such as expansion projects, vessel scheduling, and ordering optimization. To show the applicability of the model, a scheduling model is presented in the paper. [ABSTRACT FROM AUTHOR]

Three porous aluminium benzene-1,3,5-tricarboxylates MIL-96(Al), MIL-100(Al) and MIL-110(Al) materials were studied for their hydrothermal stability. The 40-cycles water vapour sorption experiments for the three samples were performed by varying the temperature between 40 and 140 °C at 75% relative humidity to simulate working conditions for materials used in water sorption-based low-T heat storage and reallocation applications. The materials were characterized by powder X-ray diffraction, N2 physisorption, and Nuclear Magnetic Resonance and Infrared spectroscopies before and after the cycling tests. The results showed that the structure of MIL-110(Al) lost its crystallinity and porosity under the tested conditions, while MIL-96(Al) and MIL-100(Al) exhibited excellent hydrothermal stability. The selection of structures, which comprise the same type of metal and ligand, enabled us to attribute the differences in stability primarily to the known variances in secondary building units and the shielding of potential water coordination sites due to the differences in pore accessibility for water molecules. Additionally, our results revealed that water adsorption and desorption at tested conditions (T, RH) is very slow for all three materials, being most pronounced for the MIL-100(Al) structure. [ABSTRACT FROM AUTHOR]