Unraveling the immunogenetic landscape of autism spectrum disorder: a comprehensive bioinformatics approach.

Background: Autism spectrum disorder (ASD) is a disease characterized by social disorder. Recently, the population affected by ASD has gradually increased around the world. There are great difficulties in diagnosis and treatment at present. Methods: The ASD datasets were obtained from the Gene Expression Omnibus database and the immune-relevant genes were downloaded from a previously published compilation. Subsequently, we used WGCNA to screen the modules related to the ASD and immune. We also choose the best combination and screen out the core genes from Consensus Machine Learning Driven Signatures (CMLS). Subsequently, we evaluated the genetic correlation between immune cells and ASD used GNOVA. And pleiotropic regions identified by PLACO and CPASSOC between ASD and immune cells. FUMA was used to identify pleiotropic regions, and expression trait loci (EQTL) analysis was used to determine their expression in different tissues and cells. Finally, we use qPCR to detect the gene expression level of the core gene. Results: We found a close relationship between neutrophils and ASD, and subsequently, CMLS identified a total of 47 potential candidate genes. Secondly, GNOVA showed a significant genetic correlation between neutrophils and ASD, and PLACO and CPASSOC identified a total of 14 pleiotropic regions. We annotated the 14 regions mentioned above and identified a total of 6 potential candidate genes. Through EQTL, we found that the CFLAR gene has a specific expression pattern in neutrophils, suggesting that it may serve as a potential biomarker for ASD and is closely related to its pathogenesis. Conclusions: In conclusion, our study yields unprecedented insights into the molecular and genetic heterogeneity of ASD through a comprehensive bioinformatics analysis. These valuable findings hold significant implications for tailoring personalized ASD therapies.

Freestanding Serpentine Silicon Strips with Ultrahigh Stretchability over 300% for Wearable Electronics.

Well-functionalized electronic materials, such as silicon, in a stretchable format are desirable for high-performance wearable electronics. However, obtaining Si materials that meet the required stretchability of over 100% for wearable applications remains a significant challenge. Herein, a rational design strategy is proposed to achieve freestanding serpentine Si strips (FS-Si strips) with ultrahigh stretchability, fulfilling wearable requirements. The self-supporting feature makes the strips get rid of excessive constraints from substrates and enables them to deform with the minimum strain energy. Micrometer-scale thicknesses enhance robustness, and large diameter-to-width ratios effectively reduce strain concentration. Consequently, the FS-Si strips with the optimum design could withstand 300% stretch, bending, and torsion without fracturing, even under rough manual operation. They also exhibit excellent stability and durability over 50,000 cycles of 100% stretching cycles. For wearable applications, the FS-Si strips can maintain conformal contact with the skin and have a maximum stretchability of 120%. Moreover, they are electrically insensitive to large deformations, which ensure signal stability during their daily use. Combined with mature processing techniques and the excellent semiconductor properties of Si, FS-Si strips are promising core stretchable electronic materials for wearable electronics.

Target-Guided Isolation and Purification of Antioxidants from Urtica laetevirens Maxim. by HSCCC Combined with Online DPPH-HPLC Analysis.

Urtica laetevirens Maxim. is used extensively in traditional Chinese medicine (TCM) for its potent antioxidative properties. In this study, three antioxidants were purified from U. laetevirens. using HSCCC guided by online DPPH-HPLC analysis. Firstly, the online DPPH-HPLC analysis was performed to profile out the antioxidant active molecules in U. laetevirens. The ultrasonic-assisted extraction conditions were optimized by response surface methodology and the results showed the targeted antioxidant active molecules could be well enriched under the optimized extraction conditions. Then, the antioxidant active molecules were separated by high-speed countercurrent chromatography ethyl acetate/n-butanol/water (2:3:5, v/v/v) as the solvent system. Finally, the three targets including 16.8 mg of Isovitexin, 9.8 mg of Isoorientin, and 26.7 mg of Apigenin-6,8-di-C-ß-d-glucopyranoside were obtained from 100 mg of sample. Their structures were identified by 1H NMR spectroscopy.

Inversely engineered biomimetic flexible network scaffolds for soft tissue regeneration.

Graft-host mechanical mismatch has been a longstanding issue in clinical applications of synthetic scaffolds for soft tissue regeneration. Although numerous efforts have been devoted to resolve this grand challenge, the regenerative performance of existing synthetic scaffolds remains limited by slow tissue growth (comparing to autograft) and mechanical failures. We demonstrate a class of rationally designed flexible network scaffolds that can precisely replicate nonlinear mechanical responses of soft tissues and enhance tissue regeneration via reduced graft-host mechanical mismatch. Such flexible network scaffold includes a tubular network frame containing inversely engineered curved microstructures to produce desired mechanical properties, with an electrospun ultrathin film wrapped around the network to offer a proper microenvironment for cell growth. Using rat models with sciatic nerve defects or Achilles tendon injuries, our network scaffolds show regenerative performances evidently superior to that of clinically approved electrospun conduit scaffolds and achieve similar outcomes to autologous nerve transplantation in prevention of target organ atrophy and recovery of static sciatic index.

Using proteomics and metabolomics to identify therapeutic targets for senescence mediated cancer: genetic complementarity method.

Background: Senescence have emerged as potential factors of lung cancer risk based on findings from many studies. However, the underlying pathogenesis of lung cancer caused by senescence is not clear. In this study, we try to explain the potential pathogenesis between senescence and lung cancer through proteomics and metabonomics. And try to find new potential therapeutic targets in lung cancer patients through network mendelian randomization (MR). Methods: The genome-wide association data of this study was mainly obtained from a meta-analysis and the Transdisciplinary Research in Cancer of the Lung Consortium (TRICL), respectively.And in this study, we mainly used genetic complementarity methods to explore the susceptibility of aging to lung cancer. Additionally, a mediation analysis was performed to explore the potential mediating role of proteomics and metabonomics, using a network MR design. Results: GNOVA analysis revealed a shared genetic structure between HannumAge and lung cancer with a significant genetic correlation estimated at 0.141 and 0.135, respectively. MR analysis showed a relationship between HannumAge and lung cancer, regardless of smoking status. Furthermore, genetically predicted HannumAge was consistently associated with the proteins C-type lectin domain family 4 member D (CLEC4D) and Retinoic acid receptor responder protein 1 (RARR-1), indicating their potential role as mediators in the causal pathway. Conclusion: HannumAge acceleration may increase the risk of lung cancer, some of which may be mediated by CLEC4D and RARR-1, suggestion that CLEC4D and RARR-1 may serve as potential drug targets for the treatment of lung cancer.

Inhibitory activities and rules of plant gallotannins with different numbers of galloyl moieties on sucrase, maltase and α-amylase in vitro and in vivo.

BACKGROUND: α-Glucosidase inhibitors could effectively reduce postprandial blood glucose (PBG) levels and control the occurrence of complications of diabetes. Gallotannins (GTs) in plants have attracted much attention due to their significant α-glucosidase inhibitory activities in vitro. However, there is still a lack of systematic comparative studies to further elucidate inhibitory activities in vivo and in vitro of these compounds against α-glucosidase, especially for mammalian sucrase and maltase, and analyze their structure-activity relationship. PURPOSE: Determine the in vitro and in vivo inhibitory activities of five GTs with different number of galloyl moieties (GMs) on sucrase, maltase and α-amylase, and elucidate the relationship between α-glucosidase inhibitory activities and the number and connection mode of GMs. METHODS: Molecular docking and dynamics were used to study the binding mode and binding ability of five GTs against sucrase, maltase and α-amylase. Then, the inhibitory activities and inhibitory mechanisms of these compounds on sucrase, maltase and α-amylase in vitro were studied using inhibitory assay and enzyme inhibition kinetics. Further, the hypoglycemic effects in vivo of these compounds were demonstrated by three polysaccharides tolerance experiments on diabetes model mice. RESULTS: The results of molecular docking showed that these compounds could bind to enzymes through hydrogen bonds, hydrophobic interactions, etc. In addition, the α-glucosidase inhibition comparative studies in vitro and in vivo demonstrated that the inhibitory activities of these compounds on all three sucrase, maltase and α-amylase were ranked as TA ≈ PGG > TeGG > TGG > 1GG, and their inhibitory activities increases with the increase in the number of GMs. Moreover, the hypoglycemic effects of 1,2,3,4,6-pentagalloylglucose (PGG) and tannic acid (TA) in vitro and in vivo were also confirmed to be equivalent to or even stronger than that of acarbose. CONCLUSION: α-Glucosidase inhibitory activities in vitro and in vivo of GTs were positively correlated with the number of GTs, and the more the number, the stronger the activity. However, PGG with five GTs and TA with ten GTs showed almost identical α-glucosidase inhibitory activities, possibly due to the reduced binding force with the enzyme caused by spatial hindrance.

A battery-less wireless implant for the continuous monitoring of vascular pressure, flow rate and temperature.

Devices for monitoring blood haemodynamics can guide the perioperative management of patients with cardiovascular disease. Current technologies for this purpose are constrained by wired connections to external electronics, and wireless alternatives are restricted to monitoring of either blood pressure or blood flow. Here we report the design aspects and performance parameters of an integrated wireless sensor capable of implantation in the heart or in a blood vessel for simultaneous measurements of pressure, flow rate and temperature in real time. The sensor is controlled via long-range communication through a subcutaneously implanted and wirelessly powered Bluetooth Low Energy system-on-a-chip. The device can be delivered via a minimally invasive transcatheter procedure or it can be mounted on a passive medical device such as a stent, as we show for the case of the pulmonary artery in a pig model and the aorta and left ventricle in a sheep model, where the device performs comparably to clinical tools for monitoring of blood flow and pressure. Battery-less and wireless devices such as these that integrate capabilities for flow, pressure and temperature sensing offer the potential for continuous monitoring of blood haemodynamics in patients.

Combination of Aspergillus niger MJ1 with Pseudomonas stutzeri DSM4166 or mutant Pseudomonas fluorescens CHA0-nif improved crop quality, soil properties, and microbial communities in barrier soil.

Soil salinization and acidification seriously damage soil health and restricts the sustainable development of planting. Excessive application of chemical fertilizer and other reasons will lead to soil acidification and salinization. This study focus on acid and salinized soil, investigated the effect of phosphate-solubilizing bacteria, Aspergillus niger MJ1 combined with nitrogen-fixing bacteria Pseudomonas stutzeri DSM4166 or mutant Pseudomonas fluorescens CHA0-nif on crop quality, soil physicochemical properties, and microbial communities. A total of 5 treatments were set: regular fertilization (T1), regular fertilization with MJ1 and DSM4166 (T2), regular fertilization with MJ1 and CHA0-nif (T3), 30%-reducing fertilization with MJ1 and DSM4166 (T4), and 30%-reducing fertilization with MJ1 and CHA0-nif (T5). It was found that the soil properties (OM, HN, TN, AP, AK, and SS) and crop quality of cucumber (yield production, protein, and vitamin C) and lettuce (yield production, vitamin C, nitrate, soluble protein, and crude fiber) showed a significant response to the inoculated strains. The combination of MJ1 with DSM4166 or CHA0-nif influenced the diversity and richness of bacterial community in the lettuce-grown soil. The organismal system-, cellular process-, and metabolism-correlated bacteria and saprophytic fungi were enriched, which were speculated to mediate the response to inoculated strains. pH, OM, HN, and TN were identified to be the major factors correlated with the soil microbial community. The inoculation of MJ1 with DSM4166 and CHA0-nif could meet the requirement of lettuce and cucumber growth after reducing fertilization in acid and salinized soil, which provides a novel candidate for the eco-friendly technique to meet the carbon-neutral topic.

The comparison of clinical effect, knee function, prognosis of double plate fixation and locking plate internal fixation for tibial plateau fractures.

Objectives: The purpose of this study was to investigate the clinical effect, knee function improvement and prognosis of double plate internal fixation and locking plate internal fixation in the treatment of tibial plateau fractures. Methods: Clinical data from 96 tibial plateau fracture patients treated at our hospital were analyzed retrospectively. Of these, 46 had been treated using locking plate internal fixation and 50 were treated with double T-shaped plate fixation. Clinically related indices, Hospital for Special Surgery (HSS) score of knee function, and ability of daily living (ADL) score were evaluated during postoperative follow-up. Results: No significant differences were observed in pre-operative patient characteristics in both groups. Healing time, time to weight-bearing, tibial plateau angle (TPA) and lateral posterior angle (PA) were all superior in the locking plate fixation group compared to the double plate fixation group. At three months post-operative visit, range of motion, knee function, flexion deformity, muscle strength, pain, and stability metrics were all superior in the locking plate fixation group compared to the double plate fixation group. ADL scores were also higher in the locking plate fixation group than in the double plate fixation group at three and six months follow-up. Conclusions: The clinical effect, knee function improvement and prognosis of locking plate internal fixation in the treatment of tibial plateau fractures are better than those of double plate fixation.

The effect of platelet rich plasma combined with celecoxib on knee function and pain in patients with knee osteoarthritis.

Objectives: To analyze the immediate effect of platelet rich plasma, combined with celecoxib, on knee function and pain in patients with knee osteoarthritis. Methods: The clinical data of 86 patients with knee osteoarthritis, treated in our hospital from January 2019 to January 2021, were analyzed retrospectively. According to the treatment records, patients were divided into a control group (n = 43, celecoxib) and a treatment group (n = 43, platelet rich plasma + celecoxib). The knee function, pain and clinical effect in the two groups were compared and analyzed using the Hospital for Special Surgery (HSS) knee score and the visual analog scale (VAS). Results: The treatment group had a higher HSS score, and a lower VAS score compared to the control group (P<0.05). The clinical efficacy in the treatment group was higher than that in the control group (95.35% and 72.09% respectively, P<0.05). Conclusions: Platelet rich plasma combined with celecoxib can promote the recovery of knee function and reduce pain in patients with knee osteoarthritis. This treatment combination also has a high immediate clinical effectiveness but needs further evaluation to find out the long term effects.

A 0.8 V, 5.3-5.9 GHz Sub-Sampling PLL with 196.5 fsrms Integrated Jitter and -251.6 dB FoM.

This paper proposes a hybrid dual path sub-sampling phase-locked loop (SSPLL), including a proportional path (P-path) and an integral path (I-path), with 0.8 V supply voltage. A differential master-slave sampling filter (MSSF), replacing the sub-sampling charge pump (SSCP), composed the P-path to avoid the degraded feature caused by the decreasing of the supply voltage. The I-path is built by a rail-to-rail SSCP to suppress the phase noise of the voltage-controlled oscillator (VCO) and avoid the trouble of locking at the non-zero phase offset (as in type-I PLL). The proposed design is implemented in a 40-nm CMOS process. The measured output frequency range is from 5.3 to 5.9 GHz with 196.5 fs root mean square (RMS) integrated jitter and -251.6 dB FoM.

Delayed specific IgM antibody responses observed among COVID-19 patients with severe progression.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

Small-size effect on wrinkle and fracture of monolayer graphene subjected to in-plane shear.

Controlling surface patterns are useful in a wide range of applications including flexible electronics, biological templates, microelectromechanical systems and device fabrication. The present paper investigates the wrinkling and fracture of graphene subjected to in-plane shear. It is found that the size of a graphene sheet has significant effect on the wrinkle and fracture based on both molecular dynamics simulation and nonlocal plate theory. The analytical expressions for wrinkle amplitude and wavelength are deduced. The nonlocal parameter of nonlocal plate theory is evaluated. Furthermore, the higher aspect ratio has enhanced the wrinkle resistance and shear strength of graphene. Temperature and chirality have insignificant impact on the wrinkling, but significantly influence the fracture of the graphene sheet. This work is expected to provide a better understanding of the mechanism of nanometer scale wrinkles.

Adiponectin is required for cardiac MEF2 activation during pressure overload induced hypertrophy.

Cardiomyocyte (CM) hypertrophy and increased heart mass in response to pressure overload are associated with hyper-activation of the myocyte enhancer factor-2 (MEF2) family of transcriptional regulators, and concomitant initiation of the fetal gene program. Adiponectin, an adipokine that is reduced in individuals with obesity and diabetes, has been characterized both as a negative regulator or permissive factor in cardiac hypertrophy. We therefore sought to analyze temporal regulation of MEF2 activity in response to pressure overload (PO) and changes in adiponectin status. To address this we crossed a well characterized transgenic MEF2 "sensor" mouse (MEF2-lacZ) with adiponectin null mice (Ad-KO) to create compound MEF2 lacZ/Ad-KO mice. Initially, we established that transverse aortic banding induced PO in wild-type (WT) mice increased heart mass and CM hypertrophy from 1 to 4weeks following surgery, indicated by increased CM diameter and heart weight/tibia length ratio. This was associated with cardiac dysfunction determined by echocardiography. Hypertrophic changes and dysfunction were observed in Ad-KO mice 4weeks following surgery. MEF2 lacZ activity and endogenous ANF mRNA levels, used as indicators of hypertrophic gene activation, were both robustly increased in WT mice after MTAB but attenuated in the Ad-KO background. Furthermore, activation of the pro-hypertrophic molecule p38 was increased following MTAB surgery in WT mice, but not in Ad-KO animals, and treatment of primary isolated CM with recombinant adiponectin induced p38 phosphorylation in a time dependent manner. Adiponectin also increased MEF2 activation in primary cardiomyocytes, an effect attenuated by p38 MAPK inhibition. In conclusion, our data indicate that robust hypertrophic MEF2 activation in the heart in vivo requires a background of adiponectin signaling and that adiponectin signaling in primary isolated CM directly enhances MEF2 activity through activation of p38 MAPK. We conclude that adiponectin is required for full induction of cardiomyocyte MEF2 activation, thus contributing to the myocardial hypertrophic gene expression program in response to PO.

Phenomics of Vascular Disease: The Systematic Approach to the Combination Therapy.

Vascular diseases are usually caused by multifactorial pathogeneses involving genetic and environmental factors. Our current understanding of vascular disease is, however, based on the focused genotype/phenotype studies driven by the "one-gene/one-phenotype" hypothesis. Drugs with "pure target" at individual molecules involved in the pathophysiological pathways are the mainstream of current clinical treatments and the basis of combination therapy of vascular diseases. Recently, the combination of genomics, proteomics, and metabolomics has unraveled the etiology and pathophysiology of vascular disease in a big-data fashion and also revealed unmatched relationships between the omic variability and the much narrower definition of various clinical phenotypes of vascular disease in individual patients. Here, we introduce the phenomics strategy that will change the conventional focused phenotype/genotype/genome study to a new systematic phenome/genome/proteome approach to the understanding of pathophysiology and combination therapy of vascular disease. A phenome is the sum total of an organism's phenotypic traits that signify the expression of genome and specific environmental influence. Phenomics is the study of phenome to quantitatively correlate complex traits to variability not only in genome, but also in transcriptome, proteome, metabolome, interactome, and environmental factors by exploring the systems biology that links the genomic and phenomic spaces. The application of phenomics and the phenome-wide associated study (PheWAS) will not only identify a systemically-integrated set of biomarkers for diagnosis and prognosis of vascular disease but also provide novel treatment targets for combination therapy and thus make a revolutionary paradigm shift in the clinical treatment of these devastating diseases.

One-dose vaccination associated with attenuated disease severity of adolescent and adult varicella cases in Beijing's Fengtai District.

BACKGROUND: In recent years, the number of varicella cases in adults has significantly increased in Beijing. However, the effect of the vaccination on varicella-related characteristics among adults has not been studied. METHODS AND RESULTS: Using data from the Infectious Disease Reporting System and the Immunization Information System, we compared the epidemiology and disease severity in breakthrough and unvaccinated varicella cases in adolescents and adults (≥ 15 year-old) from 2008 to 2011 in Beijing's Fengtai district, China. The results showed that the age (P = 0.003),contact history (90% vs. 73%, P = 0.019) and outbreak cases (10% vs. 1%, P < 0.0001) were significantly differently distributed between the two groups and that both the incidence of moderate-to-severe cases (26% vs. 45%, P = 0.035, OR = 0.446) and varicella-associated fever (49% vs. 66%, P = 0.068, OR = 0.534) were either significantly lower or trended to be lower in the breakthrough group than in the unvaccinated group. Additionally,vaccine effectiveness against moderate-to-severe cases of varicella was 55.4%. CONCLUSION: Altogether, these results indicate that vaccination against varicella among adolescents and adults affected the epidemiology and attenuated the disease severity of the cases. The Results from this study will provide useful information for the prevention of varicella in adolescents and adults.

The epidemiology of varicella cases among children in Beijing's Fengtai District from 2008 to 2012.

In recent years, the number of breakthrough cases of varicella (onset >42 days after vaccination) increased each year, and varicella outbreaks continue to occur in Beijing. Data from the Immunization Information System and the Infectious Disease Reporting System demonstrated that in Beijing's Fengtai District, the varicella breakthrough rate increased from 0.7% in 2008 to 2.5% in 2012 and showed an increased trend (P<0.001). Among the varicella cases in children (age of 3-15 years), the number of breakthrough cases increased from 167 in 2008 to 622 in 2012, which was 45.2% (n=1735) of the total child cases (n=3842). From 2008 to 2012, a total of 62 outbreaks occurred; among the 787 affected child outbreak cases, 61% were vaccinated. Altogether, the results from this study indicated that 1-dose vaccination cannot sufficiently prevent the occurrence of breakthrough cases of varicella or control varicella outbreaks in Beijing's Fengtai District.

A report on the first outbreak of a single clone group A Streptococcus (emm-type 89) tonsillopharyngitis in China.

In 2012, 28 out of 140 staff working for a film crew in a Beijing movie and television base experienced a sudden onset of fever, sore throat, and/or tiredness, headache within the 24 hour period of July 26-27. All of the patients visited the hospital and were diagnosed as having tonsillopharyngitis. On July 28, 2012, a team of Centers for Disease Control and Prevention staff arrived and initiated an outbreak investigation. Pharyngeal swabs were obtained from patients for microbiologic analysis. All isolates of the outbreak were analyzed for toxin-genes and drug-resistance genes by polymerase chain reaction, and were performed for the emm typing and pulsed-field gel electrophoresis typing. On July 30, 2012, Group A Streptococcus was isolated from eight of the 16 throat swab specimens obtained on site. These isolates were found to have the same genotype emm 89. This is the first report to identify Group A Streptococcus emm type-89 as a cause of tonsillopharyngitis in Beijing, China.

Predominant role of vasoconstrictors over dilatators derived from arachidonic acid in hypoxic pulmonary vasoconstriction.

Prostanoids derived from arachidonic acid (AA) have been shown to play a permissive role in the regulation of vascular tone and wall tension. Conventionally, epoxyeicosatrienoic acids (EETs) and prostacyclin have been considered as dilatators, whereas thromboxane (TX) and hydroxyeicosatetraenoic acid (HETE) were considered as vasoconstrictors. However, the role of these prostanoids in the mediation of acute hypoxic pulmonary vasoconstriction is not yet clearly understood. In the present study, the role of prostanoids in the acute hypoxic response in rat isolated intrapulmonary arteries (IPAs) was investigated. Exogenous AA directly caused vasoconstriction, but exerted a significant inhibition on hypoxic vasoconstriction. The vasoconstriction by AA was mediated by the endothelium. AA metabolites from lipoxygenase (LOX) had no effect on vascular tone or hypoxic vasoconstriction. Consistent results from the blockage of cytochrome P450 (CYP) or CYP epoxide hydrolase showed that HETE contributed to endothelium­independent hypoxic vasoconstriction. EET via epoxygenase exerted no effect on 80 mM KPSS­induced vessel contraction or hypoxic vasoconstriction. In addition, prostacyclin also failed to inhibit hypoxic pulmonary vasoconstriction (HPV). However, blockage of thromboxane A2/prostanoid (TP) receptors almost eliminated hypoxic vasoconstriction, suggesting the primary role of TP receptors in the regulation of the hypoxic response in rat IPAs. In conclusion, the current data indicate the predominant role of vasoconstrictors instead of dilatators in mediating HPV. These data also highlight a pivotal role for voltage­independent Ca2+ entry in pulmonary hypoxic response and suggest that modulation of these channels by prostanoids underlies their regulatory mechanisms.