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As designers push engine efficiency closer to thermodynamic limits, the analysis of flow instabilities developed in a high-pressure turbine (HPT) is crucial to minimizing aerodynamic losses and optimizing secondary air systems. Purge flow, while essential for protecting turbine components from thermal stress, significantly impacts the overall efficiency of the engine and is strictly connected to cavity modes and rim-seal instabilities. This paper presents an experimental investigation of these instabilities in an HPT stage, tested under engine-representative flow conditions in the short-duration turbine rig of the von Karman Institute. As operating conditions significantly influence instability behavior, this study provides valuable insight for future turbine design. Fast-response pressure measurements reveal asynchronous flow instabilities linked to ingress–egress mechanisms, with intensities modulated by the purge rate (PR). The maximum strength is reached at PR = 1.0%, with comparable intensities persisting for higher rates. For lower PRs, the instability diminishes as the cavity becomes unsealed. An analysis based on the cross-power spectral density is applied to quantify the characteristics of the rotating instabilities. The speed of the asynchronous structures exhibits minimal sensitivity to the PR, approximately 65% of the rotor speed. In contrast, the structures’ length scale shows considerable variation, ranging from 11–12 lobes at PR = 1.0% to 14 lobes for PR = 1.74%. The frequency domain analysis reveals a complex modulation of these instabilities and suggests a potential correlation with low-engine-order fluctuations.

Nursing hospitals have a high probability of casualties during a fire disaster because they have many patients with impaired mobility. In this study, fire and egress simulations were conducted to evaluate the egress safety of a typical nursing hospital. The available safe egress time (ASET) of the prototype nursing hospital was calculated using Fire Dynamics Simulator, and the required safe egress time (RSET) was estimated by Pathfinder, reflecting characteristics of the occupants. The egress safety of the nursing hospital was then evaluated by comparing the ASET and RSET, considering the number of egress guides and delay time. According to the simulation results, the RSET increased as the egress delay time increased and the number of egress guides decreased. In addition, it is estimated that at least 20 workers (egress guides) should be on duty in the prototype nursing hospital, even during shiftwork and night duty. Based on the simulation results, egress safety criteria have been proposed in terms of normalized numbers of egress guides and egress delay time. The proposed criteria can be very easily applied to evaluate the egress safety of a typical nursing hospital in operation.

The formation of microbial biofilms enables single planktonic cells to assume a multicellular mode of growth. During dispersion, the final step of the biofilm life cycle, single cells egress from the biofilm to resume a planktonic lifestyle. As the planktonic state is considered to be more vulnerable to antimicrobial agents and immune responses, dispersion is being considered a promising avenue for biofilm control. In this Review, we discuss conditions that lead to dispersion and the mechanisms by which native and environmental cues contribute to dispersion. We also explore recent findings on the role of matrix degradation in the dispersion process, and the distinct phenotype of dispersed cells. Last, we discuss the translational and therapeutic potential of dispersing bacteria during infection.In this Review, Rumbaugh and Sauer discuss the environmental cues and microorganism-derived signals that lead to the biofilm dispersal response, recent findings of matrix-degrading enzymes required for cells to liberate themselves from the biofilm matrix, novel insight into the mechanisms and regulation of dispersal, and the implications of these insights for biofilm control efforts.

In recent years, the number of studio residential buildings has increased significantly in Korea, as well as in many other countries, due to changes in living patterns. In Korea especially, there have been many fire accidents in studio residential buildings, which have caused a huge number of casualties and property damages, because the buildings were not adequately equipped for firefighting. In this study, the egress safety of a typical studio residential building in Korea is analyzed. Fire simulations were performed with variables of the fire location and the capacity of the smoke exhaust system to estimate the available safe egress time (ASET); egress simulations were also performed with the variable of egress delay time, and the required safe egress time (RSET) was determined. Then, the egress safety was evaluated, and the criteria for egress safety evaluation were proposed based on the simulation results. A studio residential building with a floor plan different from the prototype was used to validate the proposed egress safety criteria. Finally, a simple evaluation model is presented to estimate the required safe egress time (RSET) without simulation and to examine the impact of bottlenecks.

The sphingosine 1-phosphate (S1P) signalling pathways have important and diverse functions. S1P receptors (S1PRs) have been proposed as a therapeutic target for various diseases due to their involvement in regulation of lymphocyte trafficking, brain and cardiac function, vascular permeability, and vascular and bronchial tone. S1PR modulators were first developed to prevent rejection by the immune system following renal transplantation, but the only currently approved indication is multiple sclerosis. The primary mechanism of action of S1PR modulators in multiple sclerosis is through binding S1PR subtype 1 on lymphocytes resulting in internalisation of the receptor and loss of responsiveness to the S1P gradient that drives lymphocyte egress from lymph nodes. The reduction in circulating lymphocytes presumably limits inflammatory cell migration into the CNS. Four S1PR modulators (fingolimod, siponimod, ozanimod, and ponesimod) have regulatory approval for multiple sclerosis. Preclinical evidence and ongoing and completed clinical trials support development of S1PR modulators for other therapeutic indications.

Herpesviruses use a vesicle-mediated transfer of intranuclearly assembled nucleocapsids through the nuclear envelope (NE) for final maturation in the cytoplasm. The molecular basis for this novel vesicular nucleo-cytoplasmic transport is beginning to be elucidated in detail. The heterodimeric viral nuclear egress complex (NEC), conserved within the classical herpesviruses, mediates vesicle formation from the inner nuclear membrane (INM) by polymerization into a hexagonal lattice followed by fusion of the vesicle membrane with the outer nuclear membrane (ONM). Mechanisms of capsid inclusion as well as vesicle-membrane fusion, however, are largely unclear. Interestingly, a similar transport mechanism through the NE has been demonstrated in nuclear export of large ribonucleoprotein complexes during Drosophila neuromuscular junction formation, indicating a widespread presence of a novel concept of cellular nucleo-cytoplasmic transport.

Malaria is caused by unicellular Plasmodium parasites. Plasmodium relies on diverse microtubule cytoskeletal structures for its reproduction, multiplication, and dissemination. Due to the small size of this parasite, its cytoskeleton has been primarily observable by electron microscopy (EM). Here, we demonstrate that the nanoscale cytoskeleton organisation is within reach using ultrastructure expansion microscopy (U-ExM). In developing microgametocytes, U-ExM allows monitoring the dynamic assembly of axonemes and concomitant tubulin polyglutamylation in whole cells. In the invasive merozoite and ookinete forms, U-ExM unveils the diversity across Plasmodium stages and species of the subpellicular microtubule arrays that confer cell rigidity. In ookinetes, we additionally identify an apical tubulin ring (ATR) that colocalises with markers of the conoid in related apicomplexan parasites. This tubulin-containing structure was presumed to be lost in Plasmodium despite its crucial role in motility and invasion in other apicomplexans. Here, U-ExM reveals that a divergent and considerably reduced form of the conoid is actually conserved in Plasmodium species.

Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.

This paper presents a methodology to evaluate life safety risk of coastal communities vulnerable to seismic and tsunami hazards. The work explicitly incorporates two important aspects in tsunami evacuation modeling: (1) the effect of earthquake-induced damage to buildings on building egress time, (2) the effect of earthquake-induced debris on horizontal evacuation time. The city of Seaside, Oregon, is selected as a testbed community. The hazard is based on a megathrust earthquake and tsunami from the Cascadia Subduction Zone that was defined in a previous study. The built environment consists of buildings and the transportation network for the city. Fragility analysis is used to estimate the seismic damage to buildings and resulting debris that covers portions of the road network. The horizontal evacuation time is determined based on the shortest path to shelters, including the increased travel time due to the earthquake-generated debris. The effects of different mitigation strategies are quantified. Results indicate the fatality and life safety risk of a near-field tsunami increases by 4.2–8.3 times when the effects of building egress and earthquake-induced debris are considered. The choice of population layer affects the life safety risk and thus the maximum risk is obtained when daytime populations are considered. Use of mitigation strategies result in a significant decrease in the number of fatalities. For hazards with recurrence intervals larger than 500- to 1000-years, the seismic retrofit is comparable to vertical evacuation and an effective strategy in reducing fatalities and associated risks. Implementing all mitigation strategies reduces the life safety risk by 90%.

Sphingosine 1-phosphate (S1P) is an important circulating lipid mediator that is derived from the metabolism of cell membranes. Its diverse homeostatic roles, particularly in immunology and vascular biology, can go awry in numerous diseases, including multiple sclerosis, cardiovascular diseases, and fibrosis. The centrality of S1P signaling has led to the development of several drugs, including two approved for treatment of multiple sclerosis. In a Review, Cartier and Hla discuss the current understanding of how one mediator can carry out so many signaling roles in different tissues, how these become dysregulated in disease, and efforts in drug development to target S1P signaling. Science , this issue p. eaar5551 Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein–coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.