Dimerization and antidepressant recognition at noradrenaline transporter.

The noradrenaline transporter has a pivotal role in regulating neurotransmitter balance and is crucial for normal physiology and neurobiology1. Dysfunction of noradrenaline transporter has been implicated in numerous neuropsychiatric diseases, including depression and attention deficit hyperactivity disorder2. Here we report cryo-electron microscopy structures of noradrenaline transporter in apo and substrate-bound forms, and as complexes with six antidepressants. The structures reveal a noradrenaline transporter dimer interface that is mediated predominantly by cholesterol and lipid molecules. The substrate noradrenaline binds deep in the central binding pocket, and its amine group interacts with a conserved aspartate residue. Our structures also provide insight into antidepressant recognition and monoamine transporter selectivity. Together, these findings advance our understanding of noradrenaline transporter regulation and inhibition, and provide templates for designing improved antidepressants to treat neuropsychiatric disorders.

Integrated 2D multi-fin field-effect transistors.

Vertical semiconducting fins integrated with high-κ oxide dielectrics have been at the centre of the key device architecture that has promoted advanced transistor scaling during the last decades. Single-fin channels based on two-dimensional (2D) semiconductors are expected to offer unique advantages in achieving sub-1 nm fin-width and atomically flat interfaces, resulting in superior performance and potentially high-density integration. However, multi-fin structures integrated with high-κ dielectrics are commonly required to achieve higher electrical performance and integration density. Here we report a ledge-guided epitaxy strategy for growing high-density, mono-oriented 2D Bi2O2Se fin arrays that can be used to fabricate integrated 2D multi-fin field-effect transistors. Aligned substrate steps enabled precise control of both nucleation sites and orientation of 2D fin arrays. Multi-channel 2D fin field-effect transistors based on epitaxially integrated 2D Bi2O2Se/Bi2SeO5 fin-oxide heterostructures were fabricated, exhibiting an on/off current ratio greater than 106, high on-state current, low off-state current, and high durability. 2D multi-fin channel arrays integrated with high-κ oxide dielectrics offer a strategy to improve the device performance and integration density in ultrascaled 2D electronics.

Local corticosteroid injection versus physical therapy for the treatment of carpal tunnel syndrome: A systematic review and meta-analysis of randomized controlled trials.

The comparative effect of commonly used conservative treatments for carpal tunnel syndrome remained controversial. The purpose of this study was to compare the clinical effect of local corticosteroid injection and physical therapy for the treatment of carpal tunnel syndrome. A systematic literature search of PubMed, EMBASE, and Cochrane library was conducted to identify relevant randomized clinical trials published before 21st Mar 2023. Two independent reviewers assayed quality of included studies using the Cochrane collaboration risk of bias tool. Relevant data were extracted and pooled analyses were conducted. Outcome measurements included Boston Carpal Tunnel Syndrome Questionnaire, visual analogue scale and some electrophysiology tests, while the former two were set as the primary outcomes. Subgroup analysis and sensitive analysis were performed and publication bias was evaluated. Heterogeneity among the included studies was examined using the I2 statistic. After selection, 12 studies were identified eligibility for inclusion. Only one study was found to have a high risk of bias. Pooled data of primary outcomes did not show any differences between treatments, and subgroup analysis supported the results. However, patients treated with local corticosteroid injection showed better improvement in distal motor latency (p = 0.002) and compound muscle action potential (p = 0.04). Some studies failed to pass the sensitive analysis, indicating the related analysis might be not so stable. A slight publication bias was observed in subgroup analysis of function scales, among three publication bias test. In conclusion, compared to physical therapy, local corticosteroid injection might have better treatment effects on carpal tunnel syndrome.

Growth of single-crystal black phosphorus and its alloy films through sustained feedstock release.

Black phosphorus (BP), a fascinating semiconductor with high mobility and a tunable direct bandgap, has emerged as a candidate beyond traditional silicon-based devices for next-generation electronics and optoelectronics. The ability to grow large-scale, high-quality BP films is a prerequisite for scalable integrated applications but has thus far remained a challenge due to unmanageable nucleation events. Here we develop a sustained feedstock release strategy to achieve subcentimetre-size single-crystal BP films by facilitating the lateral growth mode under a low nucleation rate. The as-grown single-crystal BP films exhibit high crystal quality, which brings excellent field-effect electrical properties and observation of pronounced Shubnikov-de Haas oscillations, with high mobilities up to ~6,500 cm2 V-1 s-1 at low temperatures. We further extend this approach to the growth of single-crystal BP alloy films, which broaden the infrared emission regime of BP from 3.7 µm to 6.9 µm at room temperature. This work will greatly facilitate the development of high-performance electronics and optoelectronics based on BP family materials.

2D fin field-effect transistors integrated with epitaxial high-k gate oxide.

Precise integration of two-dimensional (2D) semiconductors and high-dielectric-constant (k) gate oxides into three-dimensional (3D) vertical-architecture arrays holds promise for developing ultrascaled transistors1-5, but has proved challenging. Here we report the epitaxial synthesis of vertically aligned arrays of 2D fin-oxide heterostructures, a new class of 3D architecture in which high-mobility 2D semiconductor fin Bi2O2Se and single-crystal high-k gate oxide Bi2SeO5 are epitaxially integrated. These 2D fin-oxide epitaxial heterostructures have atomically flat interfaces and ultrathin fin thickness down to one unit cell (1.2 nm), achieving wafer-scale, site-specific and high-density growth of mono-oriented arrays. The as-fabricated 2D fin field-effect transistors (FinFETs) based on Bi2O2Se/Bi2SeO5 epitaxial heterostructures exhibit high electron mobility (µ) up to 270 cm2 V-1 s-1, ultralow off-state current (IOFF) down to about 1 pA µm-1, high on/off current ratios (ION/IOFF) up to 108 and high on-state current (ION) up to 830 µA µm-1 at 400-nm channel length, which meet the low-power specifications projected by the International Roadmap for Devices and Systems (IRDS)6. The 2D fin-oxide epitaxial heterostructures open up new avenues for the further extension of Moore's law.

A bibliometric analysis of global trends in the research field of pharmaceutical care over the past 20 years.

Pharmaceutical care is essential in building up the basics of public health and clinical care. A comprehensive understanding of global status in the field of pharmaceutical care is necessary for directing its research frontiers and future trends. Therefore, this study aims to make a bibliometric analysis to track the development of pharmaceutical care research worldwide during the past two decades. The publications regarding pharmaceutical care were culled from the Web of Science Core Collection (WoSCC). Countries, institutions, authors, journals, references, and keywords in this field were visually analyzed by using VOSviewer (version 1.6.17) and CiteSpace (Version 5.8.R3). As a result, 3,597 publications (3,177 articles and 420 reviews) were obtained. The annual yields grew more than three times in the past two decades, from 54 records in 2002 to 379 papers in 2021. The United States played the leading role in this research from multiple aspects, including publication (n = 1,208), citations (n = 28,759), funding agencies, and collaboration worldwide. The University of Sydney in Australia was the most contributed institution with the greatest number of publications (n = 112) in pharmaceutical care research. Hersberger KE from the University of Basel was the most productive author (n = 40). Chen TF from the University of Sydney was the author who owed the highest H-index of 19 and most citations (n = 1,501). They both significantly impacted this field. American Journal of Health System Pharmacy produced the most publications, while Pharmacotherapy had the highest IF (IF2020 = 4.705) in this field. Clusters networks of co-cited references and keywords suggested that clinical pharmacy is an essential theme in pharmaceutical care. Terms of medication safety and critical care recognized by burst analysis of keywords also hint at the recent attention on clinical pharmacy. The present bibliometrics analysis may provide a comprehensive overview and valuable reference for future researchers and practitioners in the research field of pharmaceutical care.

Discovery and characterization of the flavonoids in Cortex Mori Radicis as naturally occurring inhibitors against intestinal nitroreductases.

Gut bacterial nitroreductases are found to be heavily related with the intestinal toxicity of nitroaromatic compounds in food or medicine, which can be converted into mutagenic and enterotoxic nitroso or N-hydroxyl intermediates. Thus, inhibiting the gut microbe-encoded nitroreductases has become an attractive method to reduce the mutagen metabolites in colon and prevent intestinal diseases. In this study, the inhibitory effects of sixteen constituents in Cortex Mori Radicis on two kinds of gut bacterial nitroreductases (EcNfsA and EcNfsB) were evaluated with nitrofurazone (NFZ) as substrate and NADPH as electron donor. The results clearly demonstrated that four flavonoids including kuwanon G, kuwanon A, sanggenol A and kuwanon C showed dual inhibition on both EcNfsA and EcNfsB mediated NFZ reduction; morusin, morin, and sanggenone C were strong inhibitors towards EcNfsA; kuwanon H and kuwanon E exhibited effective inhibition on EcNfsB. Further inhibition kinetic analysis and molecular docking simulations displayed that all inhibitors above suppressed both EcNfsA and EcNfsB activities in competitive manners, except non-competitive inhibition of morin on EcNfsA and non-competitive inhibition of kuwanon C on EcNfsB, respectively. Taking together, these findings revealed that most flavonoids in Cortex Mori Radicis presented effective inhibition on gut microbial nitroreductases, suggesting that Cortex Mori Radicis might be a promising candidate for ameliorating nitroreductases mediated intestinal mutagenicity.

Current Status and Trends of Research on Anthracycline-Induced Cardiotoxicity from 2002 to 2021: A Twenty-Year Bibliometric and Visualization Analysis.

Anthracyclines constitute the cornerstone of numerous chemotherapy regimens for various cancers. However, the clinical application of anthracyclines is significantly limited to their dose-dependent cardiotoxicity. A comprehensive understanding of the current status of anthracycline-induced cardiotoxicity is necessary for in-depth research and optimal clinical protocols. Bibliometric analysis is widely applied in depicting development trends and tracking frontiers of a specific field. The present study is aimed at revealing the status and trends of anthracycline-induced cardiotoxicity during the past two decades by employing bibliometric software including R-bibliometric, VOSviewer, and CiteSpace. A total of 3504 publications concerning anthracycline-induced cardiotoxicity from 2002 to 2021 were collected from the Web of Science Core Collection database. Results showed significant growth in annual yields from 90 records in 2002 to 304 papers in 2021. The United States was the most productive country with the strongest collaboration worldwide in the field. Charles University in the Czech Republic was the institution that contributed the most papers, while 7 of the top 10 productive institutions were from the United States. The United States Department of Health and Human Services and the National Institutes of Health are the two agencies that provide financial support for more than 50% of sponsored publications. The research categories of included publications mainly belong to Oncology and Cardiac Cardiovascular Systems. The Journal of Clinical Oncology had a comprehensive impact on this research field with the highest IF value and many publications. Simunek Tomas from Charles University contributed the most publications, while Lipshultz Steven E. from the State University of New York possessed the highest H-index. In addition, the future research frontiers of anthracycline-induced cardiotoxicity might include early detection, pharmacogenomics, molecular mechanism, and cardiooncology. The present bibliometric analysis may provide a valuable reference for researchers and practitioners in future research directions.

Association between epicardial adipose tissue density and characteristics of coronary plaques assessed by coronary computed tomographic angiography.

To investigate the relationship between the epicardial adipose tissue density (EATD) and the coronary plaque components as assessed by coronary computed tomographic angiography (CCTA). The study cohort included 240 patients with chest pain or precardiac discomfort (mean age 62.01 ± 7.45 years, 55.83% male). Patients were assigned to the high-risk plaque (HRP) group (n = 133) or non-HRP group (n = 107). All patients underwent CCTA to assess plaque composition, and quantitative analysis of EATD and epicardial adipose tissue volume (EATV). Age, gender, EATV, EATD, diabetes history and family history were all correlated with HRP. There was no linear correlation between EATD and EATV among the subjects (R2 = 0.008, p = 0.177), but there was a curvilinear correlation (R2 = 0.102, p < 0.001). After adjusting other traditional factors, and we observed robust associations of EAT volume and density with HRP (all p < 0.05). For per 1 standard deviation increase in EATD, the risk of HRP was 3.120 times the risk than that of non-HRP. For per 1 standard deviation increase in EATV, the risk of HRP was 1.499 times the risk than that of non-HRP. The receiver operating characteristic curve showed that EATD was more predictive of HRP than EATV (AUC = 0.761, 95% CI 0.701-0.822). Our study found that EATD and EATV are both independent factors affecting the presence of HRPs, and EATD had a high predictive value for the presence of HRP.

Utility of multidetector computed tomography quantitative measurements in identifying sarcopenia: a propensity score matched study.

OBJECTIVE: To evaluate the utility of multidetector computed tomography MDCT quantitative measurements in identifying sarcopenia. MATERIALS AND METHODS: The clinical data and MDCT images of 64 patients of sarcopenia and 184 non-sarcopenic participants between October 2020 and January 2021were retrospectively analyzed. Propensity score matching was used to match the sarcopenic patients with the non-sarcopenic participants. Two radiologists independently measured the cross-sectional area (CSA) of skeletal muscle and intramuscular fat tissue and CT density of skeletal muscle at the middle L3 vertebral level on CT images of all participants. Intra-observer agreement was evaluated via intraclass correlation coefficients (ICC). A receiver operating characteristic (ROC) curve was built for each variable. Correlations between CT parameters and clinical data were assessed via Pearson or Spearman correlation coefficient. RESULTS: A total of 74 participants (mean age 72 ± 4 years, range 66-85 years; 38 men and 36 women) were included, comprising 37 sarcopenic patients and 37 non-sarcopenic participants. There were no significant intergroup differences regarding age, sex ratio, and body mass index (BMI) (P < 0.05). The CSA and density of skeletal muscle measured by two radiologists were reliable (ICC ≥ 0.75, P < 0.001). Compared with the sarcopenic group, the non-sarcopenic group had a significantly greater CSA and CT density of the total skeletal muscle (TSM) and paraspinal skeletal muscle (PSM) and skeletal muscle index at L3 level (L3 SMI) (P < 0.05). The fat infiltration ratio (FIR) of TSM, PSM, and psoas muscle was significantly higher in the sarcopenic group than that in non-sarcopenic participants (P < 0.05). ROC curve analysis showed the PSM FIR + PSM CT density (PSM D) had the best predictive value for sarcopenia (AUC = 0.836). The PSM FIR and age were moderately positively correlated (r = 0.410, P < 0.001). CONCLUSION: Fat infiltration of skeletal muscle had better predictive value than L3 SMI in the diagnosis of sarcopenic. The PSM FIR + PSMD had the best predictive value for sarcopenia, which was moderately positively correlated with age.

Association Between the Cardiometabolic Index and Hyperuricemia in an Asymptomatic Population with Normal Body Mass Index.

BACKGROUND AND PURPOSE: The association between the cardiometabolic index (CMI) and hyperuricemia was investigated to provide theoretical support for the management of hyperuricemia in an asymptomatic population with normal body mass index (BMI). METHODS: A cross-sectional study was carried out among 374 asymptomatic adults with normal BMI. Traditional anthropometric indices and CMI were calculated. Anthropometric indices were divided into four quartiles and multivariate logistic analysis was used to analyze the association between these indices and hyperuricemia. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to evaluate the power of the indices to predict hyperuricemia values. The DeLong test was used to compare the AUC of different anthropometric indices. RESULTS: After adjusting for confounding variables, the CMI exhibited a stronger association with hyperuricemia than other anthropometric indices. The odds ratio (OR) for hyperuricemia in the highest quartile of the CMI was 16.674 (confidence interval [CI]=4.424-62.846). The AUC of the CMI was 0.777 (95% CI=0.719-0.835, p<0.001), which was higher than the values for other anthropometric indices. The differences in AUC between the CMI and other indices were statistically significant; the optimal cutoff value of the CMI was 0.655, with sensitivity of 57.1% and specificity of 84.2%. CONCLUSION: The CMI, which combines waist circumference, height and blood lipid parameters, was more strongly associated with hyperuricemia than other anthropometric indices in asymptomatic population with normal BMI. The CMI may serve as a potential monitoring indicator for hyperuricemia management in asymptomatic populations with normal BMI.

Molecular basis for kinin selectivity and activation of the human bradykinin receptors.

Bradykinin and kallidin are endogenous kinin peptide hormones that belong to the kallikrein-kinin system and are essential to the regulation of blood pressure, inflammation, coagulation and pain control. Des-Arg10-kallidin, the carboxy-terminal des-Arg metabolite of kallidin, and bradykinin selectively activate two G protein-coupled receptors, type 1 and type 2 bradykinin receptors (B1R and B2R), respectively. The hyperactivation of bradykinin receptors, termed 'bradykinin storm', is associated with pulmonary edema in COVID-19 patients, suggesting that bradykinin receptors are important targets for COVID-19 intervention. Here we report two G protein-coupled complex structures of human B1R and B2R bound to des-Arg10-kallidin and bradykinin, respectively. Combined with functional analysis, our structures reveal the mechanism of ligand selectivity and specific activation of the bradykinin receptor. These findings also provide a framework for guiding drug design targeting bradykinin receptors for the treatment of inflammation, cardiovascular disorders and COVID-19.

Comparison of Bioabsorbable and Metallic Interference Screws for Graft Fixation During ACL Reconstruction: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Bioabsorbable interference screws and metallic interference screws are both widely used for graft fixation, but it remains unclear which screw type is superior. PURPOSE: To compare clinical outcomes and complications between bioabsorbable and metallic interference screws for anterior cruciate ligament reconstruction (ACLR). STUDY DESIGN: Systematic review; Level of evidence, 1. METHODS: The literature was searched for relevant randomized controlled trials published between 1966 and 2020. Two investigators independently assessed risk of bias in the included studies, and data were pooled to calculate mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes, together with 95% CIs. Meta-analysis was performed using a random- or fixed-effects model, depending on the heterogeneity in the data. RESULTS: Included were 14 randomized controlled trials involving 1032 patients who underwent ACLR: 528 patients with bioabsorbable screws and 504 patients with metallic screws. The 2 groups did not differ significantly in International Knee Documentation Committee score (RR, 1.04; 95% CI, 0.97 to 1.11), Lysholm score (MD, 0.59; 95% CI, -0.46 to 1.63), range of motion deficit (RR, 0.95; 95% CI, 0.67 to 1.34), positive pivot-shift test (RR, 0.87; 95% CI, 0.61 to 1.24), positive Lachman test (RR, 0.82; 95% CI, 0.48 to 1.39), or KT-1000 arthrometer value (MD, 0.01; 95% CI, -0.16 to 0.18). However, bioabsorbable screws were associated with a significantly higher risk of complications (RR, 1.70; 95% CI, 1.16 to 2.50), such as graft rupture, joint effusion, and infection. CONCLUSION: The results of this review showed that there was no difference between metallic and bioabsorbable screws for ACLR in terms of subjective knee function or knee laxity, but metallic interference screws had fewer complications.

Association of single-nucleotide polymorphisms in antioxidant genes and their gene-gene interactions with risk of male infertility in a Chinese population.

The antioxidant defense system protects DNA from the damaging effects of oxidative stress and is hypothesized to be associated with an increased risk of male infertility. Polymorphisms in antioxidant genes and the gene-gene interactions associated with the antioxidant system may increase the potential risk of male infertility. In the present case-controlled study, the individual link between seven gene polymorphisms (NQO1 rs1800566, SOD2 rs4880, GSTM3 rs1571858, rs3814309, rs7483, GSTM5 rs11807 and GSTP1 rs1695) and the risk of male infertility was investigated. A total of 248 idiopathic infertility patients and 310 fertile controls were selected, and genotyping was performed using the Mass ARRAY platform. There were no significant associations between the seven polymorphisms and risk of male infertility. However, the analysis of gene-gene interactions showed a decreased risk of male infertility in GSTM3 rs3814309/NQO1 rs1800566 [CC x CT/TT; odds ratio (OR)=0.56, 95% confidence interval (CI)=0.34-0.92; P=0.022), and a significant association between a gene-gene interaction in GSTM3 rs1571858/NQO1 rs1800566 and azoospermia (AG/GG x CC; OR=3.84, 95% CI=1.25-11.81; P=0.019).

Alterations of the oral microbiome in patients treated with the Invisalign system or with fixed appliances.

INTRODUCTION: Although the Invisalign system has been used widely in recent years, the influences of this treatment on the oral microbiome and whether or not this influence is different from that of fixed appliances is still unknown. In this study, we investigated the changes in the oral microbiome in patients treated with the Invisalign system or with fixed appliances. METHODS: Fifteen subjects were enrolled, comprising 5 fixed appliance patients, 5 Invisalign patient, and 5 healthy controls. Saliva samples were collected, and high-throughput pyrosequencing was performed based on the 16S rRNA gene. RESULTS: Both fixed and Invisalign orthodontic treatments resulted in dysbiosis of the oral microbiome. Firmicutes and TM7 at the phyla level and Neisseria at the genus level displayed statistically significant differences between the 2 orthodontic groups. The effect of these changes with microbiome on oral health was inconsistent. The inferred microbial function of the Invisalign group suggested this group was more predisposed to periodontal diseases. CONCLUSION: The influence of the Invisalign system on the oral microbiome was no better for oral health compared with fixed appliances. The convenience of maintaining oral hygiene rather than changes in the oral microbiome may be the underlying reason for the performance of the Invisalign system on oral health.

A complex structure of arrestin-2 bound to a G protein-coupled receptor.

Arrestins comprise a family of signal regulators of G-protein-coupled receptors (GPCRs), which include arrestins 1 to 4. While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin, arrestins 2 and 3 (Arr2 and Arr3) are ß-arrestins known to regulate many nonvisual GPCRs. The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs. Here we report the structure of Arr2 in complex with neurotensin receptor 1 (NTSR1), which reveals an overall assembly that is strikingly different from the visual arrestin-rhodopsin complex by a 90° rotation of Arr2 relative to the receptor. In this new configuration, intracellular loop 3 (ICL3) and transmembrane helix 6 (TM6) of the receptor are oriented toward the N-terminal domain of the arrestin, making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3. Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2‒NTSR1 complex. Sequence analysis and homology modeling suggest that the Arr2‒NTSR1 complex structure may provide an alternative template for modeling arrestin-GPCR interactions.

Pretreatment with resveratrol ameliorate trigeminal neuralgia by suppressing matrix metalloproteinase-9/2 in trigeminal ganglion.

Trigeminal neuralgia (TN) is a common type of neuropathic pain whereas the underlying pathogenesis has not been completely elucidated. Recent study suggests that the development of neuroinflammation is responsible for generating and sustaining neuropathic pain. The purpose of our study was to investigate the protective effect of intervening the inflammation in early stages of pain and explore its potential mechanism. MMP-9 and MMP-2 are vital proinflammatory participants and accumulating evidence indicates that they are involved in the early development of neuropathic pain. In this study, we found that MMP-9/2 showed different temporal up regulation in trigeminal ganglion (TG) significantly after chronic constriction injury (CCI) surgery. However, the activation of MMP-9/2 were suppressed by the pretreatment with resveratrol, which delayed and attenuated CCI-induced mechanical allodynia simultaneously. Besides, the expression of proinflammatory cytokines like IL-1ß and TNF-α as well as the excessive neuronal activity induced by CCI were suppressed by resveratrol. Moreover, we believed that the inhibition of MMP-9/2 activation and pain sensitization may be related to the TLR-4/NF-κB signaling pathway, which might be negatively regulated by the induction of SOCS3. In conclusion, pretreatment with resveratrol could be an effective approach to alleviate trigeminal neuralgia in early stages via a powerful inhibition on the activation of MMP-9/2 in TG.

Ligand-induced activation of ERK1/2 signaling by constitutively active Gs-coupled 5-HT receptors.

5-HT4R, 5-HT6R, and 5-HT7AR are three constitutively active Gs-coupled 5-HT receptors that have key roles in brain development, learning, memory, cognition, and other physiological processes in the central nervous system. In addition to Gs signaling cascade mediated by these three 5-HT receptors, the ERK1/2 signaling which is dependent on cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activation downstream of Gs signaling has also been widely studied. In this study, we investigated these two signaling pathways originating from the three Gs-coupled 5-HT receptors in AD293 cells. We found that the phosphorylation and activation of ERK1/2 are ligand-induced, in contrast to the constitutively active Gs signaling. This indicates that Gs signaling alone is not sufficient for ERK1/2 activation in these three 5-HT receptors. In addition to Gs, we found that ß-arrestin and Fyn are essential for the activation of ERK1/2. Together, these results put forth a novel mechanism for ERK1/2 activation involving the cooperative action of Gs, ß-arrestin, and Fyn.