Sex difference in nocturnal blood pressure dipping in adolescents with varying degrees of adiposity.

BACKGROUND: For adolescents, abnormal dipping patterns in blood pressure (BP) are associated with early-onset organ damage and a higher risk of cardiovascular disorders in adulthood. Obesity is one of the most common reasons for abnormal BP dipping in young people. However, it is unknown whether the severity of obesity is associated with BP dipping status and whether this association is sex-dependent. METHODS: 499 participants between 12 and 17 years old with overweight or obesity underwent ambulatory blood pressure monitoring (ABPM) between April 2018 and January 2019 in Beijing and Baoding. Participants were grouped by body mass index (BMI) into overweight (BMI 85th-95th percentile), obese (BMI ≥ 95th percentile) and severely obese (BMI ≥ 120% of 95th percentile or ≥ 35 kg/m2) groups. Non-dipping was defined as a < 10% reduction in BP from day to night. The interaction effect between sex and obesity degree was also analyzed. RESULTS: 326 boys and 173 girls were included, of whom 130 were overweight, 189 were obese, and 180 were severely obese. Girls with severe obesity had a higher prevalence of non-dipping, but boys showed no significant differences in BP dipping status between obesity categories. In addition, as obesity severity went up, a more evident increase in night-time SBP was observed in girls than in boys. CONCLUSIONS: Severely obese is associated with a higher prevalence of non-BP dipping patterns in girls than in boys, which suggests that the relationship between the severity of obesity and BP dipping status might be sex-specific.

Keeping obesity status is a risk factor of hypertension onset: evidence from a community-based longitudinal cohort study in North China.

Objective: The purpose of our study was to investigate the association of obesity status change with hypertension onset based on a community-based longitudinal cohort study in North China. Methods: This longitudinal study included 3,581 individuals free of hypertension at baseline in the first survey (2011-2012). All participants were followed up (2018-2019). According to the criteria, a total of 2,618 individuals were collected for analysis. We used adjusted Cox regression models and Kaplan-Meier survival analysis to estimate the association between obesity status change and hypertension onset. Additionally, we applied the forest plot to visualize the subgroup analysis including age, gender, and the differences in some variables between baseline and follow-up. Finally, we conducted a sensitivity analysis to examine the stability of our results. Results: Over nearly 7 years of follow-up, a total of 811 (31%) developed hypertension. The new hypertension incidence was mostly observed in those who were obese all the time (P for trend < 0.01). In the fully adjusted Cox regression model, being obese all the time increased the risk of hypertension by 30.10% [HR 4.01 (95% CI 2.20-7.32)]. The Kaplan-Meier survival analysis revealed the change in obesity status as an important feature to predict the occurrence of hypertension. Sensitivity analysis shows a consistent trend between the change in obesity status and hypertension onset in all populations. Subgroup analysis showed that age above 60 years was an important risk factor for hypertension onset, that men were more likely than women to develop hypertension, and that weight control was beneficial in avoiding future hypertension in women. There were statistically significant differences in ΔBMI, ΔSBP, ΔDBP, and ΔbaPWV between the four groups, and all variables, except baPWV changes, increased the risk of future hypertension. Conclusion: Our study shows that obese status was notably associated with a significant risk of hypertension onset among the Chinese community-based cohort.

Flocking Behaviors under Hierarchical Leadership of Thermodynamic Cucker-Smale Particles with Multiplicative White Noise and Perturbation.

The thermodynamic Cucker-Smale model (TCS model) describes dynamic consistency caused by different temperatures between multi-agent particles. This paper studies the flocking behaviors of the TCS model with multiplicative white noise under hierarchical leadership. First, we introduce the corresponding model of two particles. Then, by using mathematical induction and considering the properties of differential functions, it is proved that, under certain conditions, the group can achieve flocking. Finally, we verify the conclusion through numerical simulation results. Similarly, this paper studies the above model with perturbation functions.

Association between length of daily siesta and brachial-ankle pulse wave velocity (baPWV): a community-based cross sectional study in North China.

INTRODUCTION: To date, many studies have shown a link between siesta and cardiovascular events. Little is known regarding the connection between siesta and brachial-ankle pulse wave velocity (baPWV) levels, even though baPWV can determine the degree of atherosclerosis and vascular stiffness. Thus, we examined the relationship between siesta time and baPWV in a cross-sectional study. METHODS: Interviews, physical examinations, lab testing, and electron beam computed tomography were all part of the baseline evaluation for participants aged older than 35. Baseline data were compared for 3 different siesta habits: irregular or no siestas, daily short siestas (1 h or less), and daily long siestas (> 1 h). Utilizing logistic regression models and multivariate linear regression, the link between siesta time and baPWV was determined. RESULTS: Among all 6566 participants, the different siesta groups had a significant difference of the degrees of AS (P < 0.001). The same outcome was true for both males (P < 0.001) and females (P < 0.001). Numerous cardiovascular risk variables and markers of subclinical atherosclerosis were positively correlated with daily extended siestas. Results from the fully adjusted model showed that long siestas (> 60 min, OR = 1.18, 95%CI: 1.06-1.31, P = 0.002) were linked to a more severe level of the baPWV. For age or gender stratification, we found significant differences between non-siesta and > 60 min siesta groups. Multiple linear regression analysis revealed a positive connection between siesta duration and baPWV (ß = 0.197, P = 0.038). CONCLUSIONS: An elevated risk of atherosclerosis was shown to accompany prolonged siestas. These results need to be followed up on with prospective studies and additional lab work.

Nanoparticles Targeting Delivery Antagomir-483-5p to Bone Marrow Mesenchymal Stem Cells Treat Osteoporosis by Increasing Bone Formation.

BACKGROUND: Promoting bone marrow mesenchymal stem cell (BMSC) osteoblastic differentiation is a promising therapeutic strategy for osteoporosis (OP). The present study demonstrates that miR- 483-5p inhibits the osteogenic differentiation of BMSCs. Therefore, selectively delivering the nanoparticles carrying antagomir-483-5p (miR-483-5p inhibitor) to BMSCs is expected to become an effective treatment drug for OP. METHODS: Real-time PCR assays were used to analyze miR-483-5p, ALP and Bglap levels in BMSCs of ovariectomized and aged osteoporotic mice. Immunoglobulin G and poloxamer-188 encapsulated the functional small molecules, and a BMSC-targeting aptamer was employed to confirm the direction of the nanoparticles to selectively and efficiently deliver antagomir-483-5p to BMSCs in vivo. Luciferase assays were used to determine the target genes of miR-483-5p. Western blot assays and immunohistochemistry staining were used to detect the targets in vitro and in vivo. RESULTS: miR-483-5p levels were increased in BMSCs of ovariectomized and aged osteoporotic mice. Inhibiting miR-483-5p levels in BMSCs by antagomir-483-5p in vitro promoted the expression of bone formation markers, such as ALP and Bglap. The FAM-BMSC-aptamer-nanoparticles carrying antagomir- 483-5p were taken up by BMSCs, resulting in stimulation of BMSC osteoblastic differentiation in vitro and osteoporosis prevention in vivo. Furthermore, our research demonstrated that mitogen-activated protein kinase 1 (MAPK1) and SMAD family member 5 (Smad5) were direct targets of miR-483-5p in regulating BMSC osteoblastic differentiation and osteoporosis pathological processes. CONCLUSIONS: The important therapeutic role of FAM-BMSC-aptamer-nanoparticles carrying antagomir- 483-5p in osteoporosis was established in our study. These nanoparticles are a novel candidate for the clinical prevention and treatment of osteoporosis. The optimized, targeted drug delivery platform for small molecules will provide new ideas for treating clinical diseases.

Seasonal variation of ambulatory blood pressure in Chinese hypertensive adolescents.

Background: Blood pressure (BP) exhibits seasonal variation with lower levels at higher temperatures and vice versa. This phenomenon affects both sexes and all age groups. So far, only a few research studies have investigated this condition in adolescents and none of them were based on hypertensive population or ever applied ambulatory blood pressure monitor (ABPM). Therefore, we carried out the first study that used ABPM to record seasonal variation of blood pressure in hypertensive adolescents. Methods: From March 2018 to February 2019, 649 ABPMs from hypertensive adolescents between 13 and 17 years who were referred to wear an ABPM device in Beijing and Baoding were extracted. Seasonal change in ambulatory BP value, dipping status, and prevalence of different BP phenotypes were analyzed and compared. Results: Mean age of participants was 14.9 ± 1.5 years and 65.8% of them were boys. Of the participants, 75.3% met the criteria of overweight or obesity. From summer to winter, average 24-hour, day-time, and night-time BP showed significant rise, which was 9.8/2.8, 9.8/3.0, and 10.9/3.4 mmHg, respectively. This seasonal effect on BP was not dependent on the obesity degree. In addition, higher prevalence of nondippers and risers existed in winter while white coat hypertension was more frequent in warmer seasons. Conclusion: Hypertensive adolescents showed evident seasonal change in their ABPM results, which was featured by elevated BP level and more frequent abnormal dipping patterns in winter. On the contrary, higher prevalence of white coat hypertension was found in warmer seasons. Physicians should take seasonal variation into consideration when managing adolescent hypertension.

Construction and In Vitro Evaluation of a Tumor Acidic pH-Targeting Drug Delivery System Based on Escherichia coli Nissle 1917 Bacterial Ghosts.

Synthetic nanocarriers are a promising therapeutic delivery strategy. However, these systems are often hampered by inherent disadvantages such as strong biotoxicity and poor biocompatibility. To overcome these issues, biological carriers with commonly used chemotherapy drugs have been developed. In this work, engineered bacterial ghosts (BGs) originated from probiotic Escherichia coli Nissle 1917 (EcN) were devised to specifically target acidic extracellular environments of tumor tissue. To improve the production efficiency and safety, a novel lysis protein E from phage α3 was applied to produce EcN BGs under high growth densities in high quality. In addition, the acidity-triggered rational membrane (ATRAM) peptides were displayed in EcN BGs to facilitate specific cancer cell internalization within the acidic tumor microenvironment before drug release. In conclusion, the engineered EcN BGs offer a promising means for bionic bacteria construction for hepatocellular carcinoma therapy.

Early Childhood Educators as COVID Warriors: Adaptations and Responsiveness to the Pandemic Across Five Countries.

The ongoing COVID-19 pandemic has seriously impacted countries across the globe. The pandemic has created a completely new teaching-learning environment of interaction for early childhood educators. In many countries, face-to-face teaching has been replaced by remote teaching, while in others, there have been intermittent lockdowns and limited interruptions to regular teaching norms. Given the play-based nature of preschool teaching-learning activities in most countries, educators are required to reimagine the sociocultural relationships to their pedagogical practices in their everyday teaching-learning contexts. This paper sheds light on educators' experiences and the dramatic shift in their indoor-outdoor teaching-learning environment due to the evolving health measures. The study draws on notions of teachers' identities and Vygotsky's cultural-historical concept of social situation of development (Vygotsky, 1994) to capture the new forms of relationships that early childhood educators experienced with their pedagogical environments across different countries during the pandemic. Data were collected from preschool teachers across five countries-Australia, Bangladesh, Norway, Singapore and India using online surveys which included open- and close-ended questions. Findings reveal the on-ground realities and teachers' adaptations to new pedagogies emerging across the five countries. The new digital environments provided an equally new dimension for change. These changes were seen in interactions, relationships within the everyday pedagogical contexts, as well as the shifting physical and social environment of early years educators.

La pandémie actuelle de COVID-19 a gravement touché les pays du monde entier. La pandémie a créé un tout nouvel environnement d'interaction enseignement-apprentissage pour les éducateurs de la petite enfance. Dans de nombreux pays, l'enseignement en face à face a été remplacé par l'enseignement à distance, tandis que dans d'autres, il y a eu des blocages intermittents et des interruptions limitées des normes d'enseignement régulières. Étant donné la nature ludique des activités d'enseignement-apprentissage préscolaires dans la plupart des pays, les éducateurs sont tenus de réimaginer les relations socioculturelles avec leurs pratiques pédagogiques dans leurs contextes d'enseignement-apprentissage quotidiens. Cet article met en lumière les expériences des éducateurs et le changement radical de leur environnement d'enseignement-apprentissage intérieur-extérieur en raison de l'évolution des mesures de santé. L'étude s'appuie sur les notions d'identité des enseignants et le concept culturel et historique de Vygotsky de situation sociale de développement (Vygotsky, 1994) pour saisir les nouvelles formes de relations que les éducateurs de la petite enfance ont vécues avec leurs environnements pédagogiques dans différents pays pendant la pandémie. Les données ont été recueillies auprès d'enseignants du préscolaire dans cinq pays­Australie, Bangladesh, Norvège, Singapour et Inde à l'aide d'enquêtes en ligne comprenant des questions ouvertes et fermées. Les résultats révèlent les réalités sur le terrain et les adaptations des enseignants aux nouvelles pédagogies émergentes dans les cinq pays. Les nouveaux environnements numériques ont fourni une dimension tout aussi nouvelle pour le changement. Ces changements ont été observés dans les interactions, les relations au sein des contextes pédagogiques quotidiens, ainsi que dans l'environnement physique et social changeant des éducateurs de la petite enfance.

La pandemia de COVID-19 en curso ha afectado gravemente a países de todo el mundo. La pandemia ha creado un entorno de interacción de enseñanza-aprendizaje completamente nuevo para los educadores de la primera infancia. En muchos países, la enseñanza presencial ha sido reemplazada por la enseñanza a distancia, mientras que en otros, ha habido bloqueos intermitentes e interrupciones limitadas de las normas de enseñanza regulares. Dada la naturaleza basada en el juego de las actividades de enseñanza-aprendizaje preescolar en la mayoría de los países, los educadores deben reinventar las relaciones socioculturales con sus prácticas pedagógicas en sus contextos cotidianos de enseñanza-aprendizaje. Este documento arroja luz sobre las experiencias de los educadores y el cambio dramático en su entorno de enseñanza-aprendizaje interior y exterior debido a la evolución de las medidas de salud. El estudio se basa en las nociones de las identidades de los maestros y el concepto histórico-cultural de Vygotsky sobre la situación social del desarrollo (Vygotsky, 1994) para capturar las nuevas formas de relaciones que los educadores de la primera infancia experimentaron con sus entornos pedagógicos en diferentes países durante la pandemia. Se recopilaron datos de maestros de preescolar en cinco países: Australia, Bangladesh, Noruega, Singapur e India mediante encuestas en línea que incluían preguntas abiertas y cerradas. Los hallazgos revelan las realidades sobre el terreno y las adaptaciones de los profesores a las nuevas pedagogías que surgen en los cinco países. Los nuevos entornos digitales proporcionaron una dimensión igualmente nueva para el cambio. Estos cambios se observaron en las interacciones, las relaciones dentro de los contextos pedagógicos cotidianos, así como en el entorno físico y social cambiante de los educadores de la primera infancia.

An Optimal Geometry Configuration Algorithm of Hybrid Semi-Passive Location System Based on Mayfly Optimization Algorithm.

In view of the demand of location awareness in a special complex environment, for an unmanned aerial vehicle (UAV) airborne multi base-station semi-passive positioning system, the hybrid positioning solutions and optimized site layout in the positioning system can effectively improve the positioning accuracy for a specific region. In this paper, the geometric dilution of precision (GDOP) formula of a time difference of arrival (TDOA) and angles of arrival (AOA) hybrid location algorithm is deduced. Mayfly optimization algorithm (MOA) which is a new swarm intelligence optimization algorithm is introduced, and a method to find the optimal station of the UAV airborne multiple base station's semi-passive positioning system using MOA is proposed. The simulation and analysis of the optimization of the different number of base stations, compared with other station layout methods, such as particle swarm optimization (PSO), genetic algorithm (GA), and artificial bee colony (ABC) algorithm. MOA is less likely to fall into local optimum, and the error of regional target positioning is reduced. By simulating the deployment of four base stations and five base stations in various situations, MOA can achieve a better deployment effect. The dynamic station configuration capability of the multi-station semi-passive positioning system has been improved with the UAV.

Dynamic Event-Triggered Predictive Control for Interval Type-2 Fuzzy Systems with Imperfect Premise Matching.

This paper investigates the dynamic event-triggered predictive control problem of interval type-2 (IT2) fuzzy systems with imperfect premise matching. First, an IT2 fuzzy systems model is proposed, including a dynamic event-triggered mechanism, which can save limited network resources by reducing the number of data packets transmitted, and a predictive controller, which can predict the state of the system between the two successful transmitted instants to deal with unreliable communication networks. Then, according to the Lyapunov stability theory and imperfect premise matching method, sufficient conditions for system stabilization and the controller gain are obtained. Finally, the validity of the proposed method is demonstrated by the numerical examples.

Adaptive Event-Triggered Synchronization of Uncertain Fractional Order Neural Networks with Double Deception Attacks and Time-Varying Delay.

This paper investigates the problem of adaptive event-triggered synchronization for uncertain FNNs subject to double deception attacks and time-varying delay. During network transmission, a practical deception attack phenomenon in FNNs should be considered; that is, we investigated the situation in which the attack occurs via both communication channels, from S-C and from C-A simultaneously, rather than considering only one, as in many papers; and the double attacks are described by high-level Markov processes rather than simple random variables. To further reduce network load, an advanced AETS with an adaptive threshold coefficient was first used in FNNs to deal with deception attacks. Moreover, given the engineering background, uncertain parameters and time-varying delay were also considered, and a feedback control scheme was adopted. Based on the above, a unique closed-loop synchronization error system was constructed. Sufficient conditions that guarantee the stability of the closed-loop system are ensured by the Lyapunov-Krasovskii functional method. Finally, a numerical example is presented to verify the effectiveness of the proposed method.

Tumor targeted self-synergistic nanoplatforms for arsenic-sensitized photodynamic therapy.

Development of antitumor agents with high efficiency and low toxicity is one of the most important goals for biomedical research. However, most traditional therapeutic strategies were limited due to their non-specificity and abnormal tumor microenvironments, causing a poor therapeutic efficiency and severe side effects. In this paper, a tumor targeted self-synergistic nanoplatform (designated as PAO@PCN@HA) was developed for chemotherapy sensitized photodynamic therapy (PDT) against hypoxic tumors. The efficient drug loading of phenylarsine oxide (PAO) in porphyrinic metal organic framework of PCN-224 as well as the surface modification of hyaluronic acid (HA) improved the targeted drug delivery and reduced the side effects of PAO at the therapeutic dose. Particularly, PAO as an arsenical-based chemotherapeutic agent could not only induce cell apoptosis by generating reactive oxygen species (ROS), but also regulate tumor microenvironments to improve the PDT effect of PCN-224 by mitigating hypoxia and consuming cellular GSH. Both in vitro and in vivo investigations confirmed an effective self-synergy of PAO@PCN@HA in hypoxic tumor therapy with a low systemic toxicity. This integration of microenvironment adjustment with tumor targeted self-synergistic mechanism might provide a new insight for the development of arsenic-based antitumor strategy for clinical applications.

Chinese siblings with hereditary medullary thyroid carcinoma caused by RET mutation: implications for RET oncogene detection.

BACKGROUND: Hereditary medullary thyroid carcinoma (MTC) is mainly caused by germline mutations in the RET proto-oncogene, which accounts for 20-30% of all MTC according to foreign studies. However, no English literatures have reported Chinese hereditary MTC. Here, we reported two Chinese brothers with MTC that caused by germline RET mutation. CASE PRESENTATION: The younger brother was diagnosed with MTC at 29 years ago and suffered recurrence more than 10 years. For elder brother, the diagnosis of MTC was made by postoperative pathological examination at age 61. Both patients received total thyroidectomy and lymph node dissection. Since they had a significant family history for MTC, genetic detection was performed and identified a germline mutation in RET exon 10 (p.C620Y). This mutation was also detected in their offspring, indicating a moderate risk of MTC. CONCLUSIONS: This is the first report presenting a Chinese family with hereditary MTC caused by the RET p.C620Y variant. This case series emphasize the importance of genetic detection of RET proto-oncogene for MTC patients, and bring out managements for individuals after detection of RET mutations.

Twenty-four-hour ambulatory blood pressure changes in older patients with essential hypertension receiving monotherapy or dual combination antihypertensive drug therapy.

OBJECTIVE: To evaluate the differences in 24-hour ambulatory blood pressure (BP) in older patients with hypertension treated with the five major classes of antihypertensive drugs, as monotherapy or dual combination therapy, to improve daytime and nighttime BP control. METHODS: We enrolled 1920 Chinese community-dwelling outpatients aged ≥ 60 years and compared ambulatory BP values and ambulatory BP control (24-hour BP < 130/80 mmHg; daytime mean BP < 135/85 mmHg; and nighttime mean BP < 120/70 mmHg), as well as nighttime BP dip patterns for monotherapy and dual combination therapy groups. RESULTS: Patients' mean age was 71 years, and 59.5% of patients were women. Calcium channel blockers (CCBs) constituted the most common (60.3% of patients) monotherapy, and renin-angiotensin system (RAS) blockers combined with CCBs was the most common (56.5% of patients) dual combination therapy. Monotherapy with beta-blockers (BB) provided the best daytime BP control. The probabilities of having a nighttime dip pattern and nighttime BP control were higher in patients receiving diuretics compared with CCBs (OR = 0.52, P = 0.05 and OR = 0.41, P = 0.007, respectively). Patients receiving RAS/diuretic combination therapy had a higher probability of having controlled nighttime BP compared with those receiving RAS/CCB (OR = 0.45, P = 0.004). Compared with RAS/diuretic therapy, BB/CCB therapy had a higher probability of achieving daytime BP control (OR = 1.27, P = 0.45). CONCLUSIONS: Antihypertensive monotherapy and dual combination drug therapy provided different ambulatory BP control and nighttime BP dip patterns. BB-based regimens provided lower daytime BP, whereas diuretic-based therapies provided lower nighttime BP, compared with other antihypertensive regimens.

Electrocardiographic criteria for the diagnosis of abnormal hypertensive cardiac phenotypes.

This article compared the performance of 18 electrocardiographic (ECG) left ventricular hypertrophic (LVH) criteria and four P-wave indices for the diagnosis of echocardiographic (ECHO) LVH and left atrial enlargement (LAE), including the deepest S-wave amplitude added to the S-wave amplitude of lead V4 (SD +SV4 ) and P-wave terminal force in lead V1 (PTFV1 ). A total of 152 middle-aged hypertensive patients without evident cardiovascular diseases (CVDs) were enrolled. The gold standard for the diagnosis of LVH and LAE was ECHO left ventricular mass index (LVMI) and largest left atrial volume index (LAVI). For the detection of LVH, Sokolow-Lyon voltage, Cornell voltage, Cornell product, SD +SV4 , Manning, and R+S in any precordial lead had relatively higher sensitivity, especially SD +SV4 criteria. Their combination could further increase sensitivity (43% vs 29% [SD +SV4 ], P = 0.016). PTFV1 was the only criterion that had significant diagnostic value for ECHO LAE (AUC, 0.68; 95% CI: 0.54-0.73, P = 0.008). For middle-aged hypertensive patients without evident cardiovascular diseases, SD +SV4 had the highest sensitivity for the diagnosis of LVH and the combination of several ECG LVH criteria might further increase sensitivity. PTFV1 had significant diagnostic value for ECHO LAE.

Understanding Hong Kong Chinese Families' Experiences of an Autism/ASD Diagnosis.

Little is known about the experience of Chinese parents of children diagnosed with autism spectrum disorders (ASD) living in the Hong Kong Special Administrative Region. Seventy-five parents of children (aged 6 months-18 years) with ASD diagnoses completed the Family Quality of Life Scale. Forty-five parents from the original surveyed cohort, also participated in semi-structured interviews. Parents' perceptions of their child's disability were influenced both by their cultural background and by the limited and expensive, pre- and post-diagnostic services available. Longer waiting times to diagnosis were associated with lower emotional well-being and perceived disability-related support. Clinicians are encouraged to become part of the support network for parents of children with ASD, to help parents to adjust to caring for their child.

CAT-1 as a novel CAM stabilizes endothelial integrity and mediates the protective actions of L-Arg via a NO-independent mechanism.

Interendothelial junctions play an important role in the maintenance of endothelial integrity and the regulation of vascular functions. We report here that cationic amino acid transporter-1 (CAT-1) is a novel interendothelial cell adhesion molecule (CAM). We identified that CAT-1 protein localized at cell-cell adhesive junctions, similar to the classic CAM of VE-cadherin, and knockdown of CAT-1 with siRNA led to an increase in endothelial permeability. In addition, CAT-1 formed a cis-homo-dimer and showed Ca(2+)-dependent trans-homo-interaction to cause homophilic cell-cell adhesion. Co-immunoprecipitation assays showed that CAT-1 can associate with ß-catenin. Furthermore, we found that the sub-cellular localization and function of CAT-1 are associated with cell confluency, in sub-confluent ECs CAT-1 proteins distribute on the entire surface and function as L-Arg transporters, but most of the CAT-1 in the confluent ECs are localized at interendothelial junctions and serve as CAMs. Further functional characterization has disclosed that extracellular L-Arg exposure stabilizes endothelial integrity via abating the cell junction disassembly of CAT-1 and blocking the cellular membrane CAT-1 internalization, which provides the new mechanisms for L-Arg paradox and trans-stimulation of cationic amino acid transport system (CAAT). These results suggest that CAT-1 is a novel CAM that directly regulates endothelial integrity and mediates the protective actions of L-Arg to endothelium via a NO-independent mechanism.

Constitutively active signaling by the G protein ßγ-subunit mediates intrinsically increased phosphodiesterase-4 activity in human asthmatic airway smooth muscle cells.

Signaling by the Gßγ subunit of Gi protein, leading to downstream c-Src-induced activation of the Ras/c-Raf1/MEK-ERK1/2 signaling pathway and its upregulation of phosphodiesterase-4 (PDE4) activity, was recently shown to mediate the heightened contractility in proasthmatic sensitized isolated airway smooth muscle (ASM), as well as allergen-induced airway hyperresponsiveness and inflammation in an in vivo animal model of allergic asthma. This study investigated whether cultured human ASM (HASM) cells derived from asthmatic donor lungs exhibit constitutively increased PDE activity that is attributed to intrinsically upregulated Gßγ signaling coupled to c-Src activation of the Ras/MEK/ERK1/2 cascade. We show that, relative to normal cells, asthmatic HASM cells constitutively exhibit markedly increased intrinsic PDE4 activity coupled to heightened Gßγ-regulated phosphorylation of c-Src and ERK1/2, and direct co-localization of the latter with the PDE4D isoform. These signaling events and their induction of heightened PDE activity are acutely suppressed by treating asthmatic HASM cells with a Gßγ inhibitor. Importantly, along with increased Gßγ activation, asthmatic HASM cells also exhibit constitutively increased direct binding of the small Rap1 GTPase-activating protein, Rap1GAP, to the α-subunit of Gi protein, which serves to cooperatively facilitate Ras activation and, thereby, enable enhanced Gßγ-regulated ERK1/2-stimulated PDE activity. Collectively, these data are the first to identify that intrinsically increased signaling via the Gßγ subunit, facilitated by Rap1GAP recruitment to the α-subunit, mediates the constitutively increased PDE4 activity detected in asthmatic HASM cells. These new findings support the notion that interventions targeted at suppressing Gßγ signaling may lead to novel approaches to treat asthma.