An activity-regulated transcriptional program directly drives synaptogenesis.

Although the molecular composition and architecture of synapses have been widely explored, much less is known about what genetic programs directly activate synaptic gene expression and how they are modulated. Here, using Caenorhabditis elegans dopaminergic neurons, we reveal that EGL-43/MECOM and FOS-1/FOS control an activity-dependent synaptogenesis program. Loss of either factor severely reduces presynaptic protein expression. Both factors bind directly to promoters of synaptic genes and act together with CUT homeobox transcription factors to activate transcription. egl-43 and fos-1 mutually promote each other's expression, and increasing the binding affinity of FOS-1 to the egl-43 locus results in increased presynaptic protein expression and synaptic function. EGL-43 regulates the expression of multiple transcription factors, including activity-regulated factors and developmental factors that define multiple aspects of dopaminergic identity. Together, we describe a robust genetic program underlying activity-regulated synapse formation during development.

Rewritable Surface-Grafted Polymer Brushes with Dynamic Covalent Linkages.

Surface grafting of polymer brushes drastically modifies surface properties, including wettability, compatibility, responsiveness, etc. A broad variety of functionalities can be introduced to the surface via different types of polymers. Bringing together properties of two or more types of polymer brushes to one surface opens up even more possibilities in brush-modified materials. However, while it is generally feasible to introduce several chemical compositions along the brushes via copolymerization, it is challenging to vary the types of polymer brushes along a surface. Although previous studies have demonstrated binary brushes via orthogonal polymerization techniques or partial deactivation/regrafting, they commonly limit the number of polymer types to two. Here, we propose a strategy to introduce dynamic covalent diketoenamine linkages at the root of polymer brushes. The grafting density could be precisely tuned during surface functionalization. The surface-anchored polymer brushes were cleaved by the addition of small molecule amines. New polymer brushes can be regrafted from the surface following refunctionalization of exposed sites. The maneuverability allows tuning of the types and densities of the polymer brushes, pointing the way to the preparation of a new generation of well-defined brush-modified materials with mixed grafts, with potential applications in the design of smart materials and surfaces.

Iodine concentration, HU accuracy, and metal artifacts evaluation on second-generation dual-layer spectral detector CT images with metal implants: a phantom study.

BACKGROUND: Metal implants may affect the image quality, iodine concentration (IC), and CT Hounsfield unit (HU) quantification accuracy. PURPOSE: To investigate the quantitative accuracy of IC and HU from dual-layer spectral detector (DLCT) in the presence of metal artifacts. MATERIAL AND METHODS: An experimental cylindrical phantom containing eight iodine inserts and two metal inserts was designed. The phantom underwent scanning at three radiation dose levels and two tube voltage settings. A set of conventional images (CIs), virtual monoenergetic images (VMIs), and iodine concentration maps (ICMs) were generated and measured for all the eight iodine inserts. Quantitative indicators of mean absolute percentage error (MAPE), artifact index (AI), contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and standard deviation (SD) on CIs and VMIs were calculated for IC and HU. Subjective score evaluation was also conducted. RESULTS: The MAPEiodine values of all regions of interest across different scanning configurations were all <5%. Almost all APEiodine values were <5%, indicating that metal artifacts had little impact on IC measurements. When the tube voltage was fixed, the SD value of attenuation decreased with the increase of the tube current; this is also true when the tube current was fixed. The middle energy reconstructions seemed to give a good balance between reducing artifacts and improving contrast. CONCLUSION: VMIs from DLCT can reduce metal artifacts, the accuracy of IC quantification is not sensitive to imaging parameters. In summary, metal implants exhibit minimal impact on image quality and IC quantification accuracy in reconstructed images from DLCT.

Artificial intelligence-based joint attenuation and scatter correction strategies for multi-tracer total-body PET.

BACKGROUND: Low-dose ungated CT is commonly used for total-body PET attenuation and scatter correction (ASC). However, CT-based ASC (CT-ASC) is limited by radiation dose risks of CT examinations, propagation of CT-based artifacts and potential mismatches between PET and CT. We demonstrate the feasibility of direct ASC for multi-tracer total-body PET in the image domain. METHODS: Clinical uEXPLORER total-body PET/CT datasets of [18F]FDG (N = 52), [18F]FAPI (N = 46) and [68Ga]FAPI (N = 60) were retrospectively enrolled in this study. We developed an improved 3D conditional generative adversarial network (cGAN) to directly estimate attenuation and scatter-corrected PET images from non-attenuation and scatter-corrected (NASC) PET images. The feasibility of the proposed 3D cGAN-based ASC was validated using four training strategies: (1) Paired 3D NASC and CT-ASC PET images from three tracers were pooled into one centralized server (CZ-ASC). (2) Paired 3D NASC and CT-ASC PET images from each tracer were individually used (DL-ASC). (3) Paired NASC and CT-ASC PET images from one tracer ([18F]FDG) were used to train the networks, while the other two tracers were used for testing without fine-tuning (NFT-ASC). (4) The pre-trained networks of (3) were fine-tuned with two other tracers individually (FT-ASC). We trained all networks in fivefold cross-validation. The performance of all ASC methods was evaluated by qualitative and quantitative metrics using CT-ASC as the reference. RESULTS: CZ-ASC, DL-ASC and FT-ASC showed comparable visual quality with CT-ASC for all tracers. CZ-ASC and DL-ASC resulted in a normalized mean absolute error (NMAE) of 8.51 ± 7.32% versus 7.36 ± 6.77% (p < 0.05), outperforming NASC (p < 0.0001) in [18F]FDG dataset. CZ-ASC, FT-ASC and DL-ASC led to NMAE of 6.44 ± 7.02%, 6.55 ± 5.89%, and 7.25 ± 6.33% in [18F]FAPI dataset, and NMAE of 5.53 ± 3.99%, 5.60 ± 4.02%, and 5.68 ± 4.12% in [68Ga]FAPI dataset, respectively. CZ-ASC, FT-ASC and DL-ASC were superior to NASC (p < 0.0001) and NFT-ASC (p < 0.0001) in terms of NMAE results. CONCLUSIONS: CZ-ASC, DL-ASC and FT-ASC demonstrated the feasibility of providing accurate and robust ASC for multi-tracer total-body PET, thereby reducing the radiation hazards to patients from redundant CT examinations. CZ-ASC and FT-ASC could outperform DL-ASC for cross-tracer total-body PET AC.

A comparative study on 3D printing-assisted arthroscopic IDEAL point femoral tunnel positioning for anterior cruciate ligament reconstruction versus conventional arthroscopic positioning.

BACKGROUND: This study aimed to investigate the feasibility and precision of using a 3D-printed template for femoral tunnel placement in guiding the optimal positioning of the Internal anatomical stop and Low tension maintenance (IDEAL) bone tunnel during single-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: A retrospective analysis was conducted on 40 patients who underwent arthroscopic single-bundle ACL reconstruction at our hospital between April 2021 and November 2021. In the direct vision group, the IDEAL bone tunnel was positioned using radiofrequency localization directly visualized at the stump. In the 3D-printed positioning group, preoperative CT scans and Digital Imaging and Communications in Medicine (DICOM) data were employed. Following the Quadrant method by Bernard, the femoral tunnel's depth was set at 25% and its height at 29%. Postoperative plain CT scans enabled the reconstruction of 3D models for both groups. The accuracy of femoral tunnel placement was then compared. RESULTS: The central locations of the bone tunnels in the direct vision group were at a mean depth of 25.74 ± 1.84% and a height of 29.22 ± 2.97%. In the 3D printing localization group, these values were 25.39 ± 2.98% for depth and 28.89 ± 2.50% for height, respectively. No significant differences were found in tunnel positioning between the groups. Both groups demonstrated statistically significant improvements in International Knee Documentation Committee Subjective Knee Form (IKDC) and Lysholm scores postoperatively, with no significant differences observed 12 months post-surgery. CONCLUSION: The findings of this study suggest that 3D printing-assisted arthroscopic IDEAL point femoral tunnel positioning and conventional arthroscopic positioning are feasible and effective for ACL reconstruction. Using 3D printing technology to design femoral anchor points in ACL reconstruction allows for the customization of anterior fork reconstruction and precise bone tunnel positioning, supporting the goal of individualized and accurate reconstruction.

Mechanism of Electrocatalytic H2 Evolution, Carbonyl Hydrogenation, and Carbon-Carbon Coupling on Cu.

Aqueous-phase electrocatalytic hydrogenation of benzaldehyde on Cu leads not only to benzyl alcohol (the carbonyl hydrogenation product), but Cu also catalyzes carbon-carbon coupling to hydrobenzoin. In the absence of an organic substrate, H2 evolution proceeds via the Volmer-Tafel mechanism on Cu/C, with the Tafel step being rate-determining. In the presence of benzaldehyde, the catalyst surface is primarily covered with the organic substrate, while H* coverage is low. Mechanistically, the first H addition to the carbonyl O of an adsorbed benzaldehyde molecule leads to a surface-bound hydroxy intermediate. The hydroxy intermediate then undergoes a second and rate-determining H addition to its α-C to form benzyl alcohol. The H additions occur predominantly via the proton-coupled electron transfer mechanism. In a parallel reaction, the radical α-C of the hydroxy intermediate attacks the electrophilic carbonyl C of a physisorbed benzaldehyde molecule to form the C-C bond, which is rate-determining. The C-C coupling is accompanied by the protonation of the formed alkoxy radical intermediate, coupled with electron transfer from the surface of Cu, to form hydrobenzoin.

Arthroscopic treatment of osteoid osteoma in the posterior proximal tibia: A case report and literature review.

BACKGROUND: Osteoid osteoma (OO) is a benign lesion characterized by an increased fibrous component in the bone marrow, presence of bone-like structures within the medullary cavity, and a surrounding sclerotic bone rim. Reports on OO located in the posterior proximal tibia are rare. CASE SUMMARY: Herein, we report the case of an 18-year-old male, admitted for the evaluation of right knee pain. The right knee pain had started 6 months prior without any apparent cause, which was notably severe at night, affecting sleep, and was exacerbated while climbing stairs or bearing weight. The patient also experienced pain on flexion. Three-dimensional computed tomography and magnetic resonance imaging revealed a nodular lesion beneath the cortical bone of the posterior medial plateau of the right tibia and an abnormal signal focus on the posterior lateral aspect of the right tibial plateau associated with extensive bone marrow edema. A small amount of fluid was present in the right knee joint capsule. The patient subsequently underwent arthroscopic excision of the OO. Postoperatively, there was significant relief of pain, and the knee range of motion returned to normal. CONCLUSION: Although OO in the posterior proximal tibia is a rare occurrence, it can be effectively excised through minimally invasive arthroscopic visualization.

Fludarabine Enhances Radiosensitivity by Promoting Ferroptosis in B-Cell Lymphoma.

The objective of this study is to investigate the impact of fludarabine, a signal transducer and activator of transcription-1 (STAT1) inhibitor, on the radiosensitivity of B-cell lymphoma (BCL) and to explore the underlying mechanisms. Radiotherapy is one of the primary treatments for BCL, and STAT1 plays a critical role in the transcription of cell proliferation-related genes, which are associated with radiotherapy and ferroptosis. This study aims to determine whether fludarabine can enhance the radiosensitivity of BCL and to elucidate the molecular pathways involved. Various in vitro methodologies, including CCK-8 assays, clonogenic formation assays, immunohistochemistry, immunofluorescence, flow cytometry, qRT-PCR, and Western blot analyses, were employed in B-cell lymphoma cell models to thoroughly investigate the effects of fludarabine on radiosensitivity. Subsequently, the obtained results were further validated through in vivo animal models and by examining human diffuse large B-cell lymphoma (DLBCL) cancer samples. Our findings demonstrate that the combination of fludarabine and irradiation synergistically inhibits cell viability and colony formation, while inducing apoptosis and ferroptosis in B-cell lymphoma cell lines Raji and Su-DHL-10. Moreover, fludarabine was found to enhance the ferroptosis induced by radiation, thereby synergistically impeding the growth of BCL. In vivo experiments confirmed these findings, revealing that the intraperitoneal injection of fludarabine significantly enhanced the inhibitory effects of radiation on Raji cell xenograft models, leading to an increased percentage of ferroptosis compared to models without fludarabine. Additionally, the administration of liproxstatin-1, a ferroptosis inhibitor, attenuated the inhibition of xenograft growth caused by the combination of fludarabine and irradiation. Furthermore, our analysis of clinical data revealed that increased co-expression of STAT1 and GPX4 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. These results highlight the potential of fludarabine to enhance radiosensitivity and ferroptosis induction as a promising therapeutic strategy for BCL. Our results demonstrated that fludarabine promoted radiation-induced BCL death through the ferroptosis pathway. We have identified a previously unrecognized mechanism in the fludarabine and radiation combination, indicating that it is necessary to conduct prospective clinical trials to verify this new treatment regimen in BCL.

Detection of citrus diseases in complex backgrounds based on image-text multimodal fusion and knowledge assistance.

Diseases pose a significant threat to the citrus industry, and the accurate detection of these diseases represent key factors for their early diagnosis and precise control. Existing diagnostic methods primarily rely on image models trained on vast datasets and limited their applicability due to singular backgrounds. To devise a more accurate, robust, and versatile model for citrus disease classification, this study focused on data diversity, knowledge assistance, and modal fusion. Leaves from healthy plants and plants infected with 10 prevalent diseases (citrus greening, citrus canker, anthracnose, scab, greasy spot, melanose, sooty mold, nitrogen deficiency, magnesium deficiency, and iron deficiency) were used as materials. Initially, three datasets with white, natural, and mixed backgrounds were constructed to analyze their effects on the training accuracy, test generalization ability, and classification balance. This diversification of data significantly improved the model's adaptability to natural settings. Subsequently, by leveraging agricultural domain knowledge, a structured citrus disease features glossary was developed to enhance the efficiency of data preparation and the credibility of identification results. To address the underutilization of multimodal data in existing models, this study explored semantic embedding methods for disease images and structured descriptive texts. Convolutional networks with different depths (VGG16, ResNet50, MobileNetV2, and ShuffleNetV2) were used to extract the visual features of leaves. Concurrently, TextCNN and fastText were used to extract textual features and semantic relationships. By integrating the complementary nature of the image and text information, a joint learning model for citrus disease features was achieved. ShuffleNetV2 + TextCNN, the optimal multimodal model, achieved a classification accuracy of 98.33% on the mixed dataset, which represented improvements of 9.78% and 21.11% over the single-image and single-text models, respectively. This model also exhibited faster convergence, superior classification balance, and enhanced generalization capability, compared with the other methods. The image-text multimodal feature fusion network proposed in this study, which integrates text and image features with domain knowledge, can identify and classify citrus diseases in scenarios with limited samples and multiple background noise. The proposed model provides a more reliable decision-making basis for the precise application of biological and chemical control strategies for citrus production.

Non-targeted metabolomics aids in sex pheromone identification: a proof-of-concept study with the triangulate cobweb spider, Steatoda triangulosa.

Targeted metabolomics has been widely used in pheromone research but may miss pheromone components in study organisms that produce pheromones in trace amount and/or lack bio-detectors (e.g., antennae) to readily locate them in complex samples. Here, we used non-targeted metabolomics-together with high-performance liquid chromatography-mass spectrometry (HPLC-MS), gas chromatography-MS, and behavioral bioassays-to unravel the sex pheromone of the triangulate cobweb spider, Steatoda triangulosa. A ternary blend of three contact pheromone components [N-4-methylvaleroyl-O-isobutyroyl-L-serine (5), N-3-methylbutyryl-O-isobutyroyl-L-serine (11), and N-3-methylbutyryl-O-butyroyl-L-serine (12)] elicited courtship by S. triangulosa males as effectively as female web extract. Hydrolysis of 5, 11 and 12 at the ester bond gave rise to two mate-attractant pheromone components [butyric acid (7) and isobutyric acid (8)] which attracted S. triangulosa males as effectively as female webs. Pheromone components 11 and 12 are reported in spiders for the first time, and were discovered only through the use of non-targeted metabolomics and GC-MS. All compounds resemble pheromone components previously identified in widow spiders. Our study provides impetus to apply non-targeted metabolomics for pheromone research in a wide range of animal taxa.

Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling.

Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind to Wntless (WLS) for intracellular transport and secretion. Mechanisms governing the transfer of these low-solubility Wnts from the ER to the extracellular space remain unclear. Through structural and functional analyses of Wnt7a, a crucial Wnt involved in central nervous system angiogenesis and blood-brain barrier maintenance, we have elucidated the principles of Wnt biogenesis and Wnt7-specific signaling. The Wnt7a-WLS complex binds to calreticulin (CALR), revealing that CALR functions as a chaperone to facilitate Wnt transfer from PORCN to WLS during Wnt biogenesis. Our structures, functional analyses, and molecular dynamics simulations demonstrate that a phospholipid in the core of Wnt-bound WLS regulates the association and dissociation between Wnt and WLS, suggesting a lipid-mediated Wnt secretion mechanism. Finally, the structure of Wnt7a bound to RECK, a cell-surface Wnt7 co-receptor, reveals how RECKCC4 engages the N-terminal domain of Wnt7a to activate Wnt7-specific signaling.

Assessing the impact of trade policy uncertainty on pollution emissions: an analysis of Chinese firms' green transformation.

Oscillations in the global trade milieu have exacerbated the ambiguity experienced by Chinese enterprises, thereby influencing their ecological transition. The ongoing debate over whether trade uncertainty augments corporate emissions, exacerbating pollution, or attenuates emissions, encouraging sustainable production, has yet to reach a consensus. The current investigation employs a textual analysis methodology to explore the influence of trade policy uncertainty on pollution emissions, by sourcing indicators of trade policy uncertainty that echo firm-level uncertainty within the period 2008 to 2021. Utilizing the fixed effects model for our analysis, the findings substantiate that escalated uncertainty at the micro-level catalyzes an increase in pollution emissions originating from firms. Crucially, we find that risk diversification and innovation bolster firms' capacities to manage pollution under escalating uncertainty. Furthermore, our estimation reveals that enterprises with low market competitiveness, high financial constraints, and moderate overseas market share are most significantly impacted, whereas those with robust patent portfolios remain largely unaffected. This study carries considerable implications for firms striving to achieve an ecological transition and offers insights for fostering sustainable and high-quality global economic development.

Structural and functional insights into Spns2-mediated transport of sphingosine-1-phosphate.

Sphingosine-1-phosphate (S1P) is an important signaling sphingolipid that regulates the immune system, angiogenesis, auditory function, and epithelial and endothelial barrier integrity. Spinster homolog 2 (Spns2) is an S1P transporter that exports S1P to initiate lipid signaling cascades. Modulating Spns2 activity can be beneficial in treatments of cancer, inflammation, and immune diseases. However, the transport mechanism of Spns2 and its inhibition remain unclear. Here, we present six cryo-EM structures of human Spns2 in lipid nanodiscs, including two functionally relevant intermediate conformations that link the inward- and outward-facing states, to reveal the structural basis of the S1P transport cycle. Functional analyses suggest that Spns2 exports S1P via facilitated diffusion, a mechanism distinct from other MFS lipid transporters. Finally, we show that the Spns2 inhibitor 16d attenuates the transport activity by locking Spns2 in the inward-facing state. Our work sheds light on Spns2-mediated S1P transport and aids the development of advanced Spns2 inhibitors.

[Progress in diagnosis and hip arthroscopic treatment of borderline developmental dysplasia of hip with Cam-type femoroacetabular impingement].

Objective: To summarize the biomechanical characteristics, diagnosis, and hip arthroscopic treatment of borderline developmental dysplasia of hip (BDDH) with Cam-type femoroacetabular impingement (Cam FAI). Methods: The literature on BDDH with Cam FAI at home and abroad in recent years was extensively reviewed and analyzed. Results: In patients with BDDH and Cam FAI, the femoral neck anteversion angle and femoral neck shaft angle increase, the pelvis tilts, and the acetabulum rotates, resulting in instability of the hip joint. In order to maintain the stability of the hip joint, the direction of biomechanical action of the hip joint has changed, which further affects the anatomical structures such as the proximal femur and acetabular morphology. BDDH with Cam FAI can be diagnosed clinically by combining lateral center edge angle, anterior center edge angle, and acetabular index. BDDH with Cam FAI can be effectively treated through arthroscopic polishing of the edges of the acetabular proliferative bone, excision of Cam malformations, and minimally invasive repair of the glenoid lip and cartilage of the hip joint. Conclusion: Currently, there is no unified standard for the diagnosis and treatment of BDDH with Cam FAI. Minimally invasive treatment of the hip under arthroscopy can achieve good early- and medium-term effectiveness, and has certain advantages in repairing and maintaining the integrity of the glenoid lip and suturing/compression joint capsule. However, the long-term effectiveness needs to be further followed up to determine. The timing of surgery, intraoperative bone edge depth polishing, and joint capsule suturing/compression techniques also need to be further explored.

Transmembrane protein CD69 acts as an S1PR1 agonist.

The activation of Sphingosine-1-phosphate receptor 1 (S1PR1) by S1P promotes lymphocyte egress from lymphoid organs, a process critical for immune surveillance and T cell effector activity. Multiple drugs that inhibit S1PR1 function are in use clinically for the treatment of autoimmune diseases. Cluster of Differentiation 69 (CD69) is an endogenous negative regulator of lymphocyte egress that interacts with S1PR1 in cis to facilitate internalization and degradation of the receptor. The mechanism by which CD69 causes S1PR1 internalization has been unclear. Moreover, although there are numerous class A GPCR structures determined with different small molecule agonists bound, it remains unknown whether a transmembrane protein per se can act as a class A GPCR agonist. Here, we present the cryo-EM structure of CD69-bound S1PR1 coupled to the heterotrimeric Gi complex. The transmembrane helix (TM) of one protomer of CD69 homodimer contacts the S1PR1-TM4. This interaction allosterically induces the movement of S1PR1-TMs 5-6, directly activating the receptor to engage the heterotrimeric Gi. Mutations in key residues at the interface affect the interactions between CD69 and S1PR1, as well as reduce the receptor internalization. Thus, our structural findings along with functional analyses demonstrate that CD69 acts in cis as a protein agonist of S1PR1, thereby promoting Gi-dependent S1PR1 internalization, loss of S1P gradient sensing, and inhibition of lymphocyte egress.

GPR35 and mediators from platelets and mast cells in neutrophil migration and inflammation.

Neutrophil recruitment from circulation to sites of inflammation is guided by multiple chemoattractant cues emanating from tissue cells, immune cells, and platelets. Here, we focus on the function of one G-protein coupled receptor, GPR35, in neutrophil recruitment. GPR35 has been challenging to study due the description of multiple ligands and G-protein couplings. Recently, we found that GPR35-expressing hematopoietic cells respond to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). We discuss distinct response profiles of GPR35 to 5-HIAA compared to other ligands. To place the functions of 5-HIAA in context, we summarize the actions of serotonin in vascular biology and leukocyte recruitment. Important sources of serotonin and 5-HIAA are platelets and mast cells. We discuss the dynamics of cell migration into inflamed tissues and how multiple platelet and mast cell-derived mediators, including 5-HIAA, cooperate to promote neutrophil recruitment. Additional actions of GPR35 in tissue physiology are reviewed. Finally, we discuss how clinically approved drugs that modulate serotonin uptake and metabolism may influence 5-HIAA-GPR35 function, and we speculate about broader influences of the GPR35 ligand-receptor system in immunity and disease.

Does the economic growth target overweight induce more polluting activities? Evidence from China.

In China, official promotion evaluation based on economic performance motivates local governments to develop high economic growth targets, which has played an active role in boosting China's economic growth in the past decades, whereas its environmental consequences have not been fully exploited. This paper finds that the economic growth target overweight has a stronger positive impact on the output of high-polluting industries than on the output of low-polluting industries, thus inducing more polluting activities. To deal with the issues of reverse causality and omitted variables bias, we take an instrumental variable approach. Examining mechanisms, we show that economic growth target overweight promotes polluting activities through the deregulation of the polluting activities in high-polluting industries. We also find an increase in the impact of the economic growth target overweight after the 2008 global economic crisis. Our study provides new evidence for explaining the dual presence of rapid economic growth and heavy environmental pollution in China.

Transmembrane protein CD69 acts as an S1PR1 agonist.

The activation of Sphingosine-1-phosphate receptor 1 (S1PR1) by S1P promotes lymphocyte egress from lymphoid organs, a process critical for immune surveillance and T cell effector activity 1-4 . Multiple drugs that inhibit S1PR1 function are in use clinically for the treatment of autoimmune diseases. Cluster of Differentiation 69 (CD69) is an endogenous negative regulator of lymphocyte egress that interacts with S1PR1 in cis to facilitate internalization and degradation of the receptor 5,6 . The mechanism by which CD69 causes S1PR1 internalization has been unclear. Moreover, although there are numerous class A GPCR structures determined with different small molecule agonists bound, it remains unknown whether a transmembrane protein per se can act as a class A GPCR agonist. Here, we present the cryo-EM structure of CD69-bound S1PR1 coupled to the heterotrimeric G i complex. The transmembrane helix (TM) of one protomer of CD69 homodimer contacts the S1PR1-TM4. This interaction allosterically induces the movement of S1PR1-TMs 5-6, directly activating the receptor to engage the heterotrimeric G i . Mutations in key residues at the interface affect the interactions between CD69 and S1PR1, as well as reduce the receptor internalization. Thus, our structural findings along with functional analyses demonstrate that CD69 acts in cis as a protein agonist of S1PR1, thereby promoting G i -dependent S1PR1 internalization, loss of S1P gradient sensing, and inhibition of lymphocyte egress.

Air pollution-induced health impacts and health economic losses in China driven by US demand exports.

Understanding how trade between regions or countries drives the transfer of air pollution has attracted considerable interest recently, but few studies have explored the various transfer pathways or evaluated economic losses due to the health impact of such air pollution. Here, we assess the air pollutant emissions and related health impacts and economic losses in China caused by export trade due to US demand by combining the linked multi-regional input-output (MRIO) model, GEOS-Chem model, integrated exposure-response model, and the willingness to pay method. We show that the air pollutant emissions embedded in China's export due to the US demand reached 5792.38 Kt in 2012 (2.48% of the total), which includes direct exports of intermediate (40.27%) and final (33.61%) products and indirect exports of intermediate products via domestic provinces (16.43%, domestic spillover) and other countries (9.69%, foreign spillover). The resulting increase in PM2.5 (<2.8 µg m-3) leads to additional 27,963 deaths in 30 provinces, with a higher death toll in coastal areas and the corresponding economic loss was higher in more developed regions and reached USD 2.08 billion. This study highlights the region-different air pollution and health impacts in China embedded in the US-demand trade, and provides a framework for the analysis of health and economic losses hidden in global trade, particularly between developing and developed countries.

Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain.

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme in cholesterol synthesis and target of cholesterol-lowering statin drugs. Accumulation of sterols in endoplasmic reticulum (ER) membranes accelerates degradation of HMGCR, slowing the synthesis of cholesterol. Degradation of HMGCR is inhibited by its binding to UBIAD1 (UbiA prenyltransferase domain-containing protein-1). This inhibition contributes to statin-induced accumulation of HMGCR, which limits their cholesterol-lowering effects. Here, we report cryo-electron microscopy structures of the HMGCR-UBIAD1 complex, which is maintained by interactions between transmembrane helix (TM) 7 of HMGCR and TMs 2-4 of UBIAD1. Disrupting this interface by mutagenesis prevents complex formation, enhancing HMGCR degradation. TMs 2-6 of HMGCR contain a 170-amino acid sterol sensing domain (SSD), which exists in two conformations-one of which is essential for degradation. Thus, our data supports a model that rearrangement of the TMs in the SSD permits recruitment of proteins that initate HMGCR degradation, a key reaction in the regulatory system that governs cholesterol synthesis.