Delay In Migration Research Articles

Cooperative interference to achieve interval many-objective evolutionary algorithm for association privacy secure computing migration

In this paper, we study secure computing migration scenarios in uncertain environments with the presence of multiple malicious eavesdroppers (MEs). Specifically, when edge servers (ESs) execute tasks delivered by smart devices (SDs), SDs may move beyond the coverage of ESs, and computing migration (CM) of unfinished tasks is required to ensure service continuity. There is a risk of privacy leakage during task migration, and MEs use colluding eavesdropping to eavesdrop on the migrated tasks, and we consider eavesdropping on the associated tasks through data sharing among MEs to improve the eavesdropping efficiency. For eavesdropping in MEs, we achieve eavesdropping strikes using cooperative interference by jammers, which benefit by providing jamming services. In addition, uncertain computational scenarios directly affect the efficiency of task execution, and we consider the uncertainty factor in the malicious eavesdropping environment. To this end, this paper proposes the secure computational migration of associative privacy in uncertain environments (SCMAPUE) model, which transforms uncertainties into interval parameters, and optimizes the five objectives of migration delay, maximum completion time, energy consumption, load balancing and migration reliability to achieve efficient task execution and reliable migration. Aiming at the model characteristics, this paper designs an interval many-objective evolutionary algorithm for reliable migration (IMaOEA-RM), which employs a condition-based interval confidence strategy and a multi-access secure migration selection strategy to improve the convergence of the algorithm, and utilizes a dual-migration crossover strategy in order to adjust the jammer partners and improve the population diversity. Simulation results show that our proposed IMaOEA-RM algorithm can provide a more reliable and efficient migration scheme than existing algorithms.

Activating A1 adenosine receptor signaling boosts early pulmonary neutrophil recruitment in aged mice in response to Streptococcus pneumoniae infection

BackgroundStreptococcus pneumoniae (pneumococcus) is a leading cause of pneumonia in older adults. Successful control of pneumococci requires robust pulmonary neutrophil influx early in infection. However, aging is associated with aberrant neutrophil recruitment and the mechanisms behind that are not understood. Here we explored how neutrophil recruitment following pneumococcal infection changes with age and the host pathways regulating this.ResultsFollowing pneumococcal infection there was a significant delay in early neutrophil recruitment to the lungs of aged mice. Neutrophils from aged mice showed defects in trans-endothelial migration in vitro compared to young controls. To understand the pathways involved, we examined immune modulatory extracellular adenosine (EAD) signaling, that is activated upon cellular damage. Signaling through the lower affinity A2A and A2B adenosine receptors had no effect on neutrophil recruitment to infected lungs. In contrast, inhibition of the high affinity A1 receptor in young mice blunted neutrophil recruitment to the lungs following infection. A1 receptor inhibition decreased expression of CXCR2 on circulating neutrophils, which is required for trans-endothelial migration. Indeed, A1 receptor signaling on neutrophils was required for their ability to migrate across endothelial cells in response to infection. Aging was not associated with defects in EAD production or receptor expression on neutrophils. However, agonism of A1 receptor in aged mice rescued the early defect in neutrophil migration to the lungs and improved control of bacterial burden.ConclusionsThis study suggests age-driven defects in EAD damage signaling can be targeted to rescue the delay in pulmonary neutrophil migration in response to bacterial pneumonia.

P11 A role for keratinocyte arginase in skin wound healing and barrier function

Abstract Introduction and aims Delayed cutaneous wound healing is a major problem that can result in social isolation and significant morbidity including amputation. There are many changes in cellular function in a chronic wound. Notably, the enzyme arginase (ARG)1 is markedly changed in wound healing. We have identified a role for ARG1 in keratinocyte re-epithelialization during wound closure, but the underlying mechanism driving re-epithelialization was not known. We aimed to determine the role of ARG1 in keratinocyte migration, differentiation and barrier formation. Methods Two-dimensional scratch and differentiation assays using immortalized keratinocytes (NTERT cells) treated with the ARG1 inhibitor, nor-NOHA, and short hairpin RNA-based knockdown cells were assessed. Gene and protein expression changes were highlighted. Expression of proteins was further validated using immunohistochemical profiling of human skin equivalents and human wound lesions by spatial transcriptomics. Results ARG1 was strongly expressed both 2–4h postscratching and at late stages of keratinocyte differentiation. Dysregulation of ARG1 expression was spatially highlighted in chronic lesions, further suggesting an involvement in keratinocyte migration and differentiation. ARG1 inhibition led to a significant delay in postscratch keratinocyte migration. Furthermore, upon ARG1 inhibition, a significant decrease was seen in the expression of late differentiation markers involucrin and filaggrin. ARG1 inhibition significantly decreased the expression of host defence genes β-defensin 3, lipocalin 2 and kallikrein 6. ARG1 triggers production of multiple downstream products and we confirmed a role for the pathway involving production of putrescine and urea, as the addition of these metabolites led to the rescue of these phenotypes. Conclusions ARG1 and its downstream metabolites play a major role in keratinocyte migration, differentiation, and barrier formation, which are vital functions for re-epithelialization and wound closure. Therefore, manipulation of the ARG1 pathway may be crucial in the management of chronic lesions.

The neuroprotective effect of exogen melatonin upon fetal hippocampus damage caused by high-dose caffeine administration in pregnant rats.

The aim of this study is to evaluate whether exogenous melatonin (MEL) mitigates the deleterious effects of high-dose caffeine (CAF) administration in pregnant rats upon the fetal hippocampus. A total of 32 adult Wistar albino female rats were divided into four groups after conception (n = 8). At 9-20 days of pregnancy, intraperitoneal (i.p.) MEL was administered at a dose of 10mg/kg/day in the MEL group, while i.p. CAF was administered at a dose of 60 mg/kg/day in the CAF group. In the CAF plus MEL group, i.p. CAF and MEL were administered at a dose of 60 and 10mg/kg/day, respectively, at the same period. Following extraction of the brains of the fetuses sacrificed on the 21st day of pregnancy, their hippocampal regions were analyzed by hematoxylin and eosin and Cresyl Echt Violet, anti-GFAP, and antisynaptophysin staining methods. While there was a decrease in fetal and brain weights in the CAF group, it was found that the CAF plus MEL group had a closer weight average to that of the control group. Histologically, it was observed that the pyramidal cell layer consisted of 8-10 layers of cells due to the delay in migration in hippocampal neurons in the CAF group, while the MEL group showed similar characteristics with the control group. It was found that these findings decreased in the CAF plus MEL group. It is concluded that high-dose CAF administration causes a delay in neurogenesis of the fetal hippocampus, and exogenous MEL is able to mitigate its deleterious effects.

ROS‐sensitive selenium‐containing cationic brush polymer with potent gene transfection efficiency and biocompatibility

AbstractSmart gene delivery vectors are gaining increasing attention in gene therapy, owing to their low cytotoxicity and intrinsic responsiveness. Our previously fabricated novel cationic brush polymer, comprising CSe bonds and tertiary amine EGIn‐g‐PDMAEMA, shows potential for gene transfection. In this study, its high efficiency for siRNA/pDNA transfection and low cytotoxicity in reactive oxygen species (ROS)‐rich microenvironments is substantiated in vitro. Its superior binding capacity with siRNA/pDNA is confirmed by agarose gel electrophoresis assay. The threshold weight ratios for siRNA/pDNA migration delay are 15 and 3 (polymer‐to‐nucleic acid, w/w), respectively. Fluorescence microscopy and ribonucleotide reductase regulatory subunit M2 gene silencing essay verify the biodegradability and responsive control release of nucleic acids under hydrogen peroxide stimulation in Huh‐7 cells. Compared with the gold standard, polyethylenimine 25 kDa, the target polymer displays superior transfection efficiency in ROS‐rich tumor cells under serum‐free conditions. Furthermore, the vector–nucleic acid complexes exhibit over 90% cell viability at a high concentration of 12 μg mL−1 and good colloidal stability in phosphate‐buffered saline (PBS) and 10% fetal bovine serum‐PBS for 24 h. The efficient control release and expression of nucleic acids in ROS environments and reduced cytotoxicity highlight the superiority of EGIn‐g‐PDMAEMA as a gene delivery platform for tumor gene therapy.

Study of the role of evolutionary new enhancers in the development of the <i>corpus callosum</i>

One important aspect of the mammalian brain is the exchange of information between neurons located in different hemispheres. This process evolved during the development of mammals. In marsupial (Marsupialia) and monotreme (Monotremata) mammals, the communication between hemispheres is facilitated through an enlarged anterior commissure. In placental (Eutheria) mammals, a new brain structure, the corpus callosum, emerged during the evolutionary process. The corpus callosum, comprising 80% of the brain’s commissural axons, is the largest commissure in the human body. The corpus callosum is a major contributor to the efficiency of higher neural activities, including memory, decision making, social interaction, and language. A possible explanation for the emergence of a novel structure for interhemispheric interaction is a change in the growth direction of neocortical axons during development. Changes in gene expression levels can regulate this process, which involves controlling axon growth and cell migration in the neocortex. A full comprehension of this process will enable the creation of new animal models for studying cortical malformations and the navigation of axons in the cerebral cortex leading to the formation of interhemispheric connections. Several enhancers were identified for protein-coding genes with differing expression patterns in neocortical cells of placental and non-placental (marsupial) mammals. Throughout the genomes of the house opossum (Monodelphis domestica) and the house mouse (Mus musculus), the acetylation levels of histone H3 on lysine 27 (H3K27ac) were compared. H3K27ac is considered an epigenetic marker for active gene enhancers. Then, a screening of candidate genes was performed to evaluate their localization and expression levels in the cortex during embryonic development. Thus, the Tbr1 gene was identified. Incorrect expression of this gene may result in changes to cortical development. The CRISPR/Cas9 system was combined with in utero electroporation to completely delete the active Tbr1 gene enhancer in developing neocortical cells of mouse embryos at day 14 of embryonic development. The impact of this enhancer deletion was then analyzed on the expression of Tbr1 in the upper layers of the cortex, as well as the direction of axon growth and neuronal migration on the 18th day of embryonic development. A significant reduction in Tbr1 expression was observed in the upper layers of the cortex after deletion of the active enhancer. Only 30% of the electroporated neurons retained Tbr1 expression. Moreover, a considerable delay in neuronal migration was observed in the subventricular zone (41% versus 17% in the control group) and in the upper layers of the cortex (20% versus 35% in the control group). However, the direction of axonal growth remained unchanged: callosal axons effectively crossed the midline and created the corpus callosum. Thus, expression of the evolutionary novel Tbr1 enhancer is important for neuronal migration during corticogenesis. However, its contribution to the development of the corpus callosum is not fully understood. A detailed analysis of the corpus callosum morphology post-enhancer deletion will be the subsequent step.

Workflow migration in uncertain edge computing environments based on interval many-objective evolutionary algorithm

In edge computing (EC), when the edge server (ES) is processing tasks delivered by the mobile devices (MDs), the MDs move outside the coverage of the ES, where task migration is required to ensure service continuity. Most current research on task migration ignores inter-task dependencies and uncertain computing environments, and it focuses mainly on migration scenarios where MDs have a one-to-one or many-to-one relationship with ESs. Aiming at the problem of workflow migration with multi-MDs and multi-ESs in uncertain environments, this paper proposes an interval many-objective optimized workflow migration in uncertain environments (I-MaOWMUE) model that considers transforming uncertainty factors into interval parameters for processing, along with the migration delay, maximum completion time, energy consumption, and load balancing as an objective function, and at the same time, utilize real-time priority scheduling strategies to achieve the fast response of the tasks. Considering the dependency of tasks and the changing characteristics of ES load in a migration environment, this paper designs a migration-based interval many-objective evolutionary algorithm (MI-MaOEA), which adopts an interval confidence strategy to improve algorithm convergence and formulates an objective-value-dominated hierarchical sorting and dual-migration selection strategy based on the migration delay and the success rate of the migration to improve the diversity of the populations. Simulation results show that MI-MaOEA optimizes 27%, 35%, 14%, and 80% in solving the four objective values of I-MaOWMUE, and enables the solution to have faster converse speed and better distribution.

Features of pink salmon Oncorhynchus gorbuscha (Salmonidae) fishery on the Sakhalin coast of the Tatar strait

Pink salmon is a traditional object of fishing in Sakhalin coastal waters of the Tatar strait, where it was caught for a long time off the southern part of the coast. In the last 20 years, there has been a shift in timing of pink salmon approach to the area of trap-nets a later date, as well as the main fishing sites shifting from the southern to the central areas of the coast. During these years, water cooling has observed in May, which could cause a delay in fish migration to the Tatar Strait. Also, in June and July in the northern regions, due to rapid warming, the water temperature became the same as in the southern regions of the strait. It’s known that such thermal regime changes largely determined by the intensity of penetration of the Tsushima current waters into the Tatar Strait, which apparently caused the shift of pink salmon accumulations in the strait to the north.

Gravitational effects on fibroblasts’ function in relation to wound healing

The spaceflight environment imposes risks for maintaining a healthy skin function as the observed delayed wound healing can contribute to increased risks of infection. To counteract delayed wound healing in space, a better understanding of the fibroblasts’ reaction to altered gravity levels is needed. In this paper, we describe experiments that were carried out at the Large Diameter Centrifuge located in ESA-ESTEC as part of the ESA Academy 2021 Spin Your Thesis! Campaign. We exposed dermal fibroblasts to a set of altered gravity levels, including transitions between simulated microgravity and hypergravity. The addition of the stress hormone cortisol to the cell culture medium was done to account for possible interaction effects of gravity and cortisol exposure. Results show a main impact of cortisol on the secretion of pro-inflammatory cytokines as well as extracellular matrix proteins. Altered gravity mostly induced a delay in cellular migration and changes in mechanosensitive cell structures. Furthermore, 20 × g hypergravity transitions induced changes in nuclear morphology. These findings provide insights into the effect of gravity transitions on the fibroblasts’ function related to wound healing, which may be useful for the development of countermeasures.

Efficient Caching in Vehicular Edge Computing Based on Edge-Cloud Collaboration

In vehicular edge computing (VEC), the execution of offloading task needs not only the task data uploaded by the requesting vehicle, but also the additional data to support the task to be executed successfully, and how to efficiently cache and access these supporting data becomes the key issue for task offloading in VEC. In this paper, we study the efficient caching mechanism to minimize the acquisition delay of the supporting data. Firstly, with the software defined network (SDN) based VEC framework, we analyze the acquisition ways of the supporting data and the caching collaboration between VEC servers. Then, according to the density of the requesting vehicles, we divide the VEC coverage into dense and ordinary areas. With the consideration of the similarity of the requested data and the distance between edge servers, the edge servers are clustered into multiple groups based on K-mean++ algorithm. Finally, each server's storage space is divided into three partitions, and the most beneficial data for itself, its group and the whole system are respectively stored in these partitions. Based on service area dividing, server grouping and storage space partitioning, we propose an efficient edge-cloud collaborative caching strategy, which can reduce the delay of data migration while task execution. Simulation results show that, compared with other schemes, the proposed caching strategy has better performance in terms of average data migration delay and application QoS.

Mobility-Aware Computation Offloading in Edge Computing Using Machine Learning

Cloudlets are resource-rich computing infrastructures of edge computing that are located at physical proximity of users to provide one-hop, high-bandwidth wireless access to additional computational resources. They enable computation offloading for user applications, which compensates for the resource limitation of user devices by providing ultra-low latency processing for their applications. Although the computation capability of user devices is dramatically augmented by offloading, spatio-temporal uncertainties due to user mobility and changes in application specifications bring the most challenging obstacles in deciding where to offload to provide minimum latency. In this paper, we focus on these challenges by designing efficient offloading approaches that take into account these uncertainties and dynamics in order to minimize the turnaround time of the applications, which is constituted by offloading latency, migration delay, and execution time. We first formulate this NP-hard problem as an integer programming model to obtain optimal offloading decisions. We tackle its intractability by designing two novel offloading approaches, called S-OAMC and G-OAMC, that fully assign applications to cloudlets by considering their expected future locations and specifications predicted by Matrix Completion, a machine learning method. S-OAMC is a sampling-based approximation dynamic programming approach that enhances scalability and obtains near-optimal solutions. G-OAMC is a fast greedy-based approach for finding low-turnaround time offloading decisions. We conduct extensive experiments to assess the performance of our proposed approaches. The results show that S-OAMC and G-OAMC lead to near-optimal turnaround time in a reasonable time, and they both obtain low migration rates.

Evaluation of a fine-spaced angled rack with surface bypass in providing safe and timely downstream passage for salmon smolts and silver eels

Hydropower production can cause migration delay and fish mortality, impeding the safe and timely downstream migration of diadromous fish, such as Atlantic salmon (Salmo salar) and silver eels (Anguilla anguilla). To date, only a few field performance tests, especially for eels, have evaluated the efficiency of fine-spaced angled racks associated to a surface bypass entrance to protect fish. Here, 115 salmon smolts and 65 silver eels were radio-tracked over a 2 yr period to assess passage efficiency and passage time at a hydropower intake (50 m3.s−1) retrofitted with a 20 mm rack associated to a surface bypass (2 m3.s−1). Results showed high impediment (89.6% and 96.9% for smolts and eels, respectively), and passage efficiency for the angled rack (89.1% and 93.3%), with short passage times (median, 3 and 7.5 min). However, our results highlighted a strong influence of hydrological conditions, in enhancing fish passage, especially through the bear-trap gate. We conclude that this fish passage solution, making use of existing spillways on the study site, is highly effective for both species. Special attention must, however, be paid to bar-rack design and its cleaning system to ensure fish guidance and prevent impingement or passage through the rack, especially for salmon smolts.

Identifying the hydrocarbon potential from seismic, geochemical, and wireline data of the Sallum intra-basin, North Western Desert of Egypt

ABSTRACT The current study's objectives are to identify the primary source rock's hydrocarbon potential and, using various approaches, examine the Sallum Concession's petroleum system, which lies in the extreme northwestern part of the Western Desert of Egypt. We integrated seismic, geochemical, and well logging data. As a result, the structure analysis indicates that the area is elevated topographic land, representing a high intra-basin about the surrounding Faghour, Matrouh, and Shushan basins. Therefore, the site is a significant concession with various source rocks; Khatatba (Safa member) and Alam El-Buieb (AEB-3A member) are the oil-prone source rocks of the northern and southern parts of the area with high TOC (up to 11.3%) and mid-mature stage (0.7-1.0% Ro) at depth below 8000 ft. On the other hand, the Paleozoic Desouqy, Zeitoun, and Shiffah formations, located below 12000 ft, are gas-prone source rocks with high organic contents (TOC 1.41-4.64%) and fair potential for gas generation and are currently in the mid-mature stage (0.7-1.0% Ro). We concluded that the concession's low oil production might result from a delay in Kerogen maturity and hydrocarbon migration. Finally, the East of Sallum concession is the only potential area because the wells in the west do not show reservoirs characteristics.

CRSM: Computation Reloading Driven by Spatial-Temporal Mobility in Edge-Assisted Automated Industrial Cyber-Physical Systems

Edge Computing, as an emerging computing mode, transfers computing capacity from the cloud center to the edge of new generation automation sensor networks. However, the surge in the number of sensor devices has resulted in the edge server overload. Fortunately, with the development of hardware technology, the computing capacity of sensor devices has improved. Therefore, we introduce a new concept of computation reloading, that is, resource-rich servers allocate tasks to sensor devices with stronger computing capacity. Most previous real-time EC researches have not considered sensor devices’ higher spatial–temporal mobility, which results in continuous computation migration and high delay. In this article, we expose a computation reloading scheme driven by spatial–temporal mobility (CRSM), for single time slice and multiple time slices cases, computation tasks are allocated in advance by predicting sensor devices locations. The experiments demonstrate that our scheme outperforms other methods in terms of shorting industrial cyber-physical systems delays.

A Two-Timescale Approach to Mobility Management for Multicell Mobile Edge Computing

Mobile edge computing (MEC) is a promising technology for enhancing the computation capacities and features of mobile users by offloading complex computation tasks to the edge servers. However, mobility poses great challenges on delivering reliable MEC service required for latency-critical applications. First, mobility management has to tackle the dynamics of both user’s location changes and task arrivals that vary in different timescales. Second, user mobility could induce service migration, leading to reliability loss due to the migration delay. In this paper, we propose a two-timescale mobility management framework by joint control of service migration and transmission power to address the above challenges. Specifically, the service migration operates at a large timescale to support user mobility in the multi-cell network, while the power control is performed at a small timescale for real-time task offloading. Their joint control is formulated as an optimization problem aiming at the long-term mobile energy minimization subject to the reliability requirement of computation offloading. To solve the problem, we propose a Lyapunov-based framework to decompose the problem into different timescales, based on which a low-complexity two-timescale online algorithm is developed by exploiting the problem structure. The proposed online algorithm is shown to be asymptotically optimal via theoretical analysis, and is further developed to accommodate the multiuser management. The simulation results demonstrate that our proposed algorithm can significantly improve the energy and reliability performance.

Enabling an inter-operator roaming capability in LoRaWAN networks

LoRaWAN is a promising enabling technology for connected things. Nowadays, it is largely used in many application areas thanks to its relevant features such as long-range, low-cost, and low power consumption. However, as with all wireless technologies, mobility remains a major concern bringing end-devices out of their home operator coverage. In this paper, we investigate the inter-operator roaming capability in mobile scenarios. We proposed a novel LoRaWAN roaming scheme to enable inter-operator roaming based on DNS resolution and end-device context migration between networks. Moreover, we extended the LoRaWAN architecture while maintaining the integrity of the existing mechanisms and with a minimum prior configuration requirements. In order to validate our solution, we designed and implemented a test-bed platform integrating our extensions to Chirpstack. An extensive experimental study under various traffic loads demonstrates that the context migration delay perfectly fits the Class A LoRaWAN requirements. We also designed and implemented a LoRaWAN roaming emulator which states on the effectiveness of our roaming solution in terms of response time required for DNS resolution and end-device context migration, as well as CPU and memory utilization.

Real-time quantification for dynamic heat storage characteristic of district heating system and its application in dispatch of integrated energy system

Utilization of heat storage characteristic of district heating system (DHS) is promising to promote the flexibility of integrated energy system (IES). However, unlike battery with constant capacity, the capacity of DHS is related to heat storage/release rate and needs real-time quantification due to heat migration delay. This work proposes a novel quantification method combining system operation simulation and dichotomy method to evaluate the real-time heat storage characteristic of DHS, where such indicators as heat shifting capability, and available storage/release capacity and depth are defined. Quantification results show that if DHS stores/releases heat rapidly for 1 h to reach the upper/lower capacity limits, the available utilization depth of storage/release process are only 52.65% and 57.60%, respectively, while a longer time duration of storage/release process will increase the available depth until reaching 100%. Then, based on the real-time quantification of DHS capacity, a scheduling strategy of IES is proposed by applying the rolling dispatch method. Comparison results show that the simplification of constant heat storage characteristics of DHS brings the violation of system operation constraints, and the differences of dispatch results are up to 18.9% compared to those considering the dynamic heat storage characteristics of DHS precisely.

Poor downstream passage at a dam creates an ecological trap for migratory fish

Ecological traps can be caused when partial restoration leads organisms to make maladaptive habitat choices. One example of this is fishways (e.g., fish ladders) that provide upstream passage at dams but are not paired with adequate downstream passage. We tested the hypothesis that attracting anadromous fishes to spawn above a dam, but blocking downstream passage of their offspring leads to an ecological trap. Using passive integrated transponder (PIT) tags, we monitored the movements of steelhead ( Oncorhynchus mykiss) at a dam and fishway on the central California coast. We found that downstream passage for juveniles and kelts was limited by four factors: migration delay, loss in the reservoir, avoidance of the downstream bypass, and water depths on the spillway. Based on the spillway-passage depth thresholds, we estimated that the ability for fish to pass downstream was limited to only half of the migration season in 55% of the past 20 years (2002–2021). Our results support the ecological trap hypothesis, which may explain why restoration using fishways has failed to produce recovery gains in this population and elsewhere.

Role of transient receptor potential vanilloid 4 in therapeutic antifibrotic effects of pirfenidone.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal lung disorder characterized by aberrant extracellular matrix deposition in the interstitium. Pirfenidone is an antifibrotic agent used to treat patients with IPF. Pirfenidone shows a pleiotropic mode of action, but its underlying antifibrotic mechanism is unclear. Transient receptor potential vanilloid 4 (TRPV4), which is a mechanosensitive calcium channel, was recently shown to be related to pulmonary fibrosis. To clarify the antifibrotic mechanisms of pirfenidone, we investigated whether TRPV4 blockade has a pharmacological effect in a murine model of pulmonary fibrosis and whether pirfenidone contributes to suppression of TRPV4. Our synthetic TRPV4 antagonist and pirfenidone treatment attenuated lung injury in the bleomycin mouse model. TRPV4-mediated increases in intracellular calcium were inhibited by pirfenidone. In addition, TRPV4-stimulated interleukin-8 release from cells was reduced and a delay in cell migration was abolished by pirfenidone. Furthermore, pirfenidone decreased TRPV4 endogenous ligands in bleomycin-administered mouse lungs and their production by microsomes of human lungs. We found TRPV4 expression in the bronchiolar and alveolar epithelium and activated fibroblasts of the lungs in patients with IPF. Finally, we showed that changes in forced vital capacity of patients with IPF treated with pirfenidone were significantly correlated with metabolite levels of TRPV4 endogenous ligands in bronchoalveolar lavage fluid. These results suggest that the antifibrotic action of pirfenidone is partly mediated by TRPV4 and that TRPV4 endogenous ligands in bronchoalveolar lavage fluid may be biomarkers for distinguishing responders to pirfenidone.

RNA Binding Protein Rbms1 Enables Neuronal Differentiation and Radial Migration during Neocortical Development by Binding and Stabilizing the RNA Message for Efr3a.

Various RNA-binding proteins (RBPs) are key components in RNA metabolism and contribute to several neurodevelopmental disorders. To date, only a few of such RBPs have been characterized for their roles in neocortex development. Here, we show that the RBP, Rbms1, is required for radial migration, polarization and differentiation of neuronal progenitors to neurons in the neocortex development. Rbms1 expression is highest in the early development in the developing cortex, with its expression gradually diminishing from embryonic day 13.5 (E13.5) to postnatal day 0 (P0). From in utero electroporation (IUE) experiments when Rbms1 levels are knocked down in neuronal progenitors, their transition from multipolar to bipolar state is delayed and this is accompanied by a delay in radial migration of these cells. Reduced Rbms1 levels in vivo also reduces differentiation as evidenced by a decrease in levels of several differentiation markers, meanwhile having no significant effects on proliferation and cell cycle rates of these cells. As an RNA binding protein, we profiled the RNA binders of Rbms1 by a cross-linked-RIP sequencing assay, followed by quantitative real-time polymerase chain reaction verification and showed that Rbms1 binds and stabilizes the mRNA for Efr3a, a signaling adapter protein. We also demonstrate that ectopic Efr3a can recover the cells from the migration defects due to loss of Rbms1, both in vivo and in vitro migration assays with cultured cells. These imply that one of the functions of Rbms1 involves the stabilization of Efr3a RNA message, required for migration and maturation of neuronal progenitors in radial migration in the developing neocortex.