Structural Insights into Sphingosine-1-phosphate Receptor Activation

As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1-5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or non-lipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its non-redundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here we reported four atomic resolution cryo-EM structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod ((S)-FTY720-P), or non-lipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step "shallow to deep" transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1P receptors.

Instability and Transition of a Boundary Layer over a Backward-Facing Step

The development of secondary instabilities in a boundary layer over a backward-facing step is investigated numerically. Two step heights are considered, h/δo*=0.5 and 1.0 (where δo* is the displacement thickness at the step location), in addition to a reference flat-plate case. A case with a realistic freestream-velocity distribution is also examined. A controlled K-type transition is initiated using a narrow ribbon upstream of the step, which generates small and monochromatic perturbations by periodic blowing and suction. A well-resolved direct numerical simulation is performed. The step height and the imposed freestream-velocity distribution exert a significant influence on the transition process. The results for the h/δo*=1.0 case exhibit a rapid transition primarily due to the Kelvin–Helmholtz instability downstream of step; non-linear interactions already occur within the recirculation region, and the initial symmetry and periodicity of the flow are lost by the middle stage of transition. In contrast, case h/δo*=0.5 presents a transition road map in which transition occurs far downstream of the step, and the flow remains spatially symmetric and temporally periodic until the late stage of transition. A realistic freestream-velocity distribution (which induces an adverse pressure gradient) advances the onset of transition to turbulence, but does not fundamentally modify the flow features observed in the zero-pressure gradient case. Considering the budgets of the perturbation kinetic energy, both the step and the induced pressure-gradient increase, rather than modify, the energy transfer.

Extension of the KDO turbulence/transition model to account for roughness

Wall roughness significantly influences both laminar-turbulent transition process and fully developed turbulence. A wall roughness extension for the KDO turbulence/transition model is developed. The roughness effect is introduced via the modification of the k and νt boundary conditions. The wall is considered to be lifted to a higher position. The difference between the original position and the higher position, named as equivalent roughness height, is linked to the actual roughness height. The ratio between the two heights is determined by reasoning. With such a roughness extension, the predictions of the KDO RANS model agree well with the measurements of turbulent boundary layer with a sand grain surface, while the KDO transition model yields accurate cross-flow transition predictions of flow past a 6:1 spheroid.

Transition of adolescents with severe asthma from pediatric to adult care in Spain: the STAR consensus

Objective: To assess the consensus level among a multidisciplinary expert panel on the transition of adolescents with severe asthma from pediatric to adult care. Methods: A 61-item survey was developed based on guidelines for other chronic pathologies, covering transition planning, preparation, effective transfer, and follow-up. A two-round Delphi process assessed the consensus level among 98 experts (49 pediatricians, 24 allergists and 25 pulmonologists). Consensus was established with ≥70% agreement. Results: Forty-two items (70%) reached consensus. No age range to initiate the transition was agreed upon by the panelists. The main goal to achieve during the transition identified by the experts is that adolescents gain autonomy to manage their severe asthma and prescribed treatments. The panelists agreed on the importance of developing an individualized plan, promoting patient’s autonomy, and identifying home environment factors. They agreed that the adult healthcare team should have expertise in severe asthma, biologics and management of adolescent patients. Pediatric and adult healthcare teams should share clinical information, agree on the criteria to maintain the biological therapy, and have an on-site joint visit with the patient before the effective transfer. Adult healthcare professionals should closely follow the patient after the effective transfer to ensure correct inhaler technique, treatment adherence and attendance to healthcare appointments. Conclusions: This consensus document provides the first roadmap for Spanish pediatric and adult teams to ensure that key aspects of the transition process in severe asthma are covered. The implementation of these recommendations will improve the quality of care offered to the patient.

Learning self-driven collective dynamics with graph networks

Despite decades of theoretical research, the nature of the self-driven collective motion remains indigestible and controversial, while the phase transition process of its dynamic is a major research issue. Recent methods propose to infer the phase transition process from various artificially extracted features using machine learning. In this thesis, we propose a new order parameter by using machine learning to quantify the synchronization degree of the self-driven collective system from the perspective of the number of clusters. Furthermore, we construct a powerful model based on the graph network to determine the long-term evolution of the self-driven collective system from the initial position of the particles, without any manual features. Results show that this method has strong predictive power, and is suitable for various noises. Our method can provide reference for the research of other physical systems with local interactions.

Crystallizing Metal Shrinkage: Automation of High-Pressure Crystallization Control

The properties of bulk metal products are formed when molten metal transforms from an unstructured liquid into a solid crystal state. We suggest a new approach to the automation of the control over crystallized metal shrinkage compensation based on controlling the law of change in pressure applied to crystallizing metal through a program taking into account the transition process in the hydraulic system of the production equipment. We observed the increase in rigidity, durability, and pliability of В95-alloy samples as compared to cast aluminum alloys. The metal utilization rate can be increased up to 0.90 of the liquid metal volume.

Roadmapping the Transition to Water Resource Recovery Facilities: The Two Demonstration Case Studies of Corleone and Marineo (Italy)

The current exploitation of freshwater, as well as the significant increase in sewage sludge production from wastewater treatment plants (WWTPs), represent nowadays a critical issue for the implementation of sustainable development consistent with the circular economy concept. There is an urgent need to rethink the concept of WWTPs from the conventional approach consisting in pollutant removal plants to water resource recovery facilities (WRRFs). The aim of this paper is to provide an overview of the demonstration case studies at the Marineo and Corleone WRRFs in Sicily (IT), with the final aim showing the effectiveness of the resources recovery systems, as well as the importance of plant optimization to reduce greenhouse gas (GHG) emissions from WRRFs. This study is part of the H2020 European Project “Achieving wider uptake of water-smart solutions—Wider-Uptake”, which final aim is to demonstrate the water-smart solution feasibility in the wastewater sector. The main project goal is to overcome the existing barriers that hamper the transition to circularity through the implementation of a governance analysis tool. The preliminary actions in the two demonstration cases are first presented, while, subsequently, the water-smart solutions to be implemented are thoroughly described, highlighting their roles in the transition process. The achieved preliminary results underlined the significant potential of WRRF application, a great chance to demonstrate the feasibility of innovative solutions in the wastewater sector to overcome the existing social, administrative and technical barriers.

Experimental study of the effect of various collision angles and critical conditions on marine engine’s twin-spray collision process

To enhance the fuel-gas mixing and phase transition process, the fuel is injected by twin injectors in a large-bore low-speed two-stroke marine engine, while the cylinder condition has reached the transcritical and supercritical conditions. The twin-injector configuration has a great potential for further optimization, but the exploration on the outcome of collision and phase transition was still limited. Therefore, this work aims to study the effect of various collision angles (60°, 90°, 120°, 150°) and critical conditions (sub/trans/supercritical) on the twin-spray collision process using optical techniques. A wide range of experimental cases are conducted to provide an analysis and database for future modeling validation. The post-collisional spray structures, spatial distribution, and periphery features are analyzed to characterize the droplet’s collision. The results show that with the collision angle increasing, the higher collision velocity enhances the mass transfer while the minor vertical component results in a smaller axial dispersion. Because of the trade-off relationship between the vertical velocity component and pre-collision penetration, a higher reduction in droplet momentum results in a slighter collision behavior. At the collision angle of 150°, the subcritical condition tends to result in an off-axis collision. Under the transcritical (P) condition, the probability of head-on collision increases and presents a wider spatial distribution. But under the supercritical condition, because of the existence of the liquid collision, the thermal conversion among phases is accelerated, while the ambient resistance is reduced. Moreover, an exponential correlation of collision liquid length is formulated to predict the axial dispersion based on various critical conditions.

Institutional Care and Family Reintegration: The Transition Process in the Voices of Young Brazilians

This article aims to present reflections on the transition from being institutionalised to autonomous life, from the perspective of deinstitutionalised young Brazilians. Five young adults participated in the pilot study. The Piagetian clinical method was used. Through semi-structured interviews, the following were investigated: causes of institutionalisation, preparation for transition, deinstitutionalisation and perspectives of present and future life. The results indicate that there was no effective preparation for transition from the institution to the family and/or independent life. Biological families have difficulties in achieving (re) integration and overcoming conflicts between parents and children. In conclusion, when leaving institutions, some young people manage to build their own arrangements for a new life trajectory, while others return to contexts of risk and life on the street. Public policies to assist these young people should be prioritised.