Phosphorylation-Regulated Dynamic Phase Separation of HIP-55 Protects Against Heart Failure.

BACKGROUND: Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF. METHODS: Fluorescence recovery after photobleaching assay, differential interference contrast analysis, pull-down assay, immunofluorescence, and immunohistochemical analysis were used to investigate the liquid-liquid phase separation capacity of HIP-55 and its dynamic regulation in vivo and in vitro. Mice with genetic deletion of HIP-55 and mice with cardiac-specific overexpression of HIP-55 were used to examine the role of HIP-55 on ß-adrenergic receptor hyperactivation-induced HF. Mutation analysis and mice with specific phospho-resistant site mutagenesis were used to identify the role of phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 in HF. RESULTS: Genetic deletion of HIP-55 aggravated HF, whereas cardiac-specific overexpression of HIP-55 significantly alleviated HF in vivo. HIP-55 possesses a strong capacity for phase separation. Phase separation of HIP-55 is dynamically regulated by AKT-mediated phosphorylation at S269 and T291 sites, failure of which leads to impairment of HIP-55 dynamic phase separation by formation of abnormal aggregation. Prolonged sympathetic hyperactivation stress induced decreased phosphorylation of HIP-55 S269 and T291, dysregulated phase separation, and subsequent aggregate formation of HIP55. Moreover, we demonstrated the important role of dynamic phase separation of HIP-55 in inhibiting hyperactivation of the ß-adrenergic receptor-mediated P38/MAPK (mitogen-activated protein kinase) signaling pathway. A phosphorylation-deficient HIP-55 mutation, which undergoes massive phase separation and forms insoluble aggregates, loses the protective activity against HF. CONCLUSIONS: Our work reveals that the phosphorylation-regulated dynamic phase separation of HIP-55 protects against sympathetic/adrenergic system-mediated heart failure.

Nanoparticles Internalization through HIP-55-Dependent Clathrin Endocytosis Pathway.

Nanoparticles are promising tools for biomedicine. Many nanoparticles are internalized to function. Clathrin-mediated endocytosis is one of the most important mechanisms for nanoparticle internalization. However, the regulatory mechanism of clathrin-mediated nanoparticle endocytosis is still unclear. Here, we report that the adapter protein HIP-55 regulates clathrin-mediated nanoparticle endocytosis. CdSe/ZnS quantum dots (QDs), a typical nanoparticle, enter cells through the HIP-55-dependent clathrin endocytosis pathway. Both pharmacological inhibitor and genetic intervention demonstrate that QDs enter cells through clathrin-mediated endocytosis. HIP-55 can interact with clathrin and promote clathrin-mediated QDs endocytosis. Furthermore, HIP-55 ΔADF which is defective in F-actin binding fails to promote QDs endocytosis, indicating HIP-55 promotes clathrin-mediated QDs endocytosis depending on interaction with F-actin. In vivo, HIP-55 knockout also inhibits endocytosis of QDs. These findings reveal that HIP-55 acts as an intrinsic regulator for clathrin-mediated nanoparticle endocytosis, providing new insight into the nanoparticle internalization and a new strategy for nanodrug enrichment in target cells.

A triphenylamine-based fluorescent probe with phenylboronic acid for highly selective detection of Hg2+ and CH3Hg+ in groundwater.

Mercury is a highly toxic heavy metal and it poses a serious threat to the natural environment and human health. Thus, selective detection of trace mercury (e.g. inorganic mercury and methylmercury) in the environment is critical yet challenging. Herein, we describe the rational design and facile synthesis of a new triphenylamine-based phenylboronic acid fluorescent probe (TPA-PBA) for selective detection of Hg2+ and CH3Hg+. Due to the inherent specificity of the displacement reaction between phenylboronic acid and mercury, this probe exhibits exceptionally high selectivity towards Hg2+/CH3Hg+ against other tested ions with ppb-level sensitivity. More importantly, the probe TPA-PBA is effective and selective in detecting Hg2+/CH3Hg+ in tap water and real-world groundwater, indicating its potential practical applications in in situ and online mercury detection in real-world scenarios. With TPA-PBA based test strips Hg2+ can be distinguished from CH3Hg+ by the naked eye. This study could accelerate the development of low-cost, highly efficient and selective fluorescent probes for rapid trace mercury detection.

Transcriptional dynamics of the circulating chicken primordial germ cells revealing key genes in cell adhesion and proliferation prior to gonad colonization.

Primordial germ cells (PGCs), precursors to sperms and oocytes, are responsible for the transfer of genetic information to the next generation. The PGCs arise far away from the developing gonad and thus have to migrate across the embryo to reach their site of function. The migration of PGCs from extraembryonic regions to the genital ridges is accomplished through distinct routes among different species. In particular, the birds PGCs utilized the developing circulation system to travel long distance before settling within the gonad. This study screened the transcriptome profile of chicken PGCs isolated from the bloodstream and the genital ridges to identify the cell intrinsic signals that could guide the unique migration path through circulation. We found cell adhesion and extracellular matrix (ECM) associated pathways were highly enriched in the PGCs from blood but not gonads. The platelet-derived growth factor receptors (PDGFRA and PDGFRB) were downregulated during gonad colonization and knockdown of either PDGFRA or PDGFRB inhibit the proliferation of blood PGCs. Furthermore, the migration of blood PGCs was impaired by the suppression of PDGFRA but not PDGFRB. Hence, the chicken PGCs show dynamic transcriptional remodeling during the blood-to-gonad migration and colonization. The free-floating PGCs in the circulation already express genes associated with cell-cell and cell-ECM interactions and therefore prepare for gonadal colonization.

Scutellarin-mediated autophagy activates exosome release of rat nucleus pulposus cells by positively regulating Rab8a via the PI3K/PTEN/Akt pathway.

To provide a basis for promising exosome-based therapies against intervertebral disc degeneration (IDD), our present research aimed to identify a mechanism underlying the vesicle release from nucleus pulposus cells (NPCs). Scutellarin (SC) is a natural chemotherapeutic agent isolated from Erigeron breviscapus with a variety of biological activities. Here, we observed the significantly elevated autophagy levels in rat NPCs under the stimulation of SC, leading to a concomitant enhancement of intracellular vesicle release, which could be attributed to the inactivation of the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (Akt) pathway. To ensure that exosome release was driven by SC via the autophagic pathway, we implemented gain-of-function and loss-of-function studies by additionally using insulin-like growth factor-1 (IGF-1) and small-interfering RNA of autophagy-related gene 5 (ATG5), and the exosome secretion decreased in the case of attenuated autophagy. Evidently, the treatment with SC exerted the remarkable upregulation of Rab8a through the overexpression of ATG5. After the respective knockdown of ATG5 and Rab8a, the increased release of exosomes induced by SC was reversed, whereas the number of intracellular vesicles was restored. Overall, it can be concluded that SC contributes to the autophagy activation in NPCs by acting on the PI3K/PTEN/Akt pathway, which upregulates the expression of Rab8a and promotes the release of exosomes, inspiring novel therapeutic strategies in preventing IDD that might be fruitfully investigated.

Dynamics of cardiomyocyte and muscle stem cell proliferation in pig.

The cardiac and skeletal muscle tissues are both striated and contractile but their intrinsic cellular properties are distinct. The minimal cardiomyocyte proliferation and the lack of cardiac stem cells directly leads to poor heart repair in adult mammals. But in skeletal muscle, the robust proliferation of widespread muscle stem cells support efficient muscle regeneration. The endogenous cardiomyocyte and muscle stem cell proliferation has been analyzed in common laboratory animals but not in large mammals including pigs, which are more comparable to human. In this study, we rigorously examined the cell cycle dynamics of porcine cardiomyocytes and muscle stem cells through different developmental stages. Proliferative cardiomyocytes and muscle stem cells were broadly observed in the embryonic heart and limb muscle respectively. Muscle stem cells continue to proliferate postnatally but cardiomyocyte proliferation was drastically reduced after birth. However, robust cardiomyocyte cell cycle activity was detected around postnatal day 20, which could be attributed to the binucleation but not cell division. Increased proliferating cells were detected in maternal heart during early pregnancy but they represent non-cardiomyocyte cell types. The islet1 expressing cells were only identified in the embryonic and new born porcine hearts. Furthermore, the accumulated oxidative DNA damage in the cardiac but not skeletal muscle during development could be responsible for the diminished cardiomyocyte proliferation in adult pig. Similarities and differences in the proliferation of heart and skeletal muscle cells are identified in pigs across different developmental stages. Such cellular proliferative features must be taken into account when using porcine models for cardiovascular and muscular research.

A single-model quality assessment method for poor quality protein structure.

BACKGROUND: Quality assessment of protein tertiary structure prediction models, in which structures of the best quality are selected from decoys, is a major challenge in protein structure prediction, and is crucial to determine a model's utility and potential applications. Estimating the quality of a single model predicts the model's quality based on the single model itself. In general, the Pearson correlation value of the quality assessment method increases in tandem with an increase in the quality of the model pool. However, there is no consensus regarding the best method to select a few good models from the poor quality model pool. RESULTS: We introduce a novel single-model quality assessment method for poor quality models that uses simple linear combinations of six features. We perform weighted search and linear regression on a large dataset of models from the 12th Critical Assessment of Protein Structure Prediction (CASP12) and benchmark the results on CASP13 models. We demonstrate that our method achieves outstanding performance on poor quality models. CONCLUSIONS: According to results of poor protein structure assessment based on six features, contact prediction and relying on fewer prediction features can improve selection accuracy.

Risk Factors for Incidence and Prognosis in Chondrosarcoma Patients with Pulmonary Metastasis at Initial Diagnosis.

BACKGROUND The incidence and prognostic factors of chondrosarcoma patients have been reported in early studies. However, the association between risk factors and the incidence or prognosis of chondrosarcoma patients with pulmonary metastasis remains unclear. Therefore, we assessed these risk factors among chondrosarcoma patients with pulmonary metastasis. MATERIAL AND METHODS From 1365 chondrosarcoma patients in the Surveillance, Epidemiology, and End Results (SEER) database, we collected the information of 69 patients with pulmonary metastasis at the initial diagnosis of chondrosarcoma from 2010 to 2016. We investigated the incidence, risk factors, and prognostic factors for pulmonary metastasis patients by using multivariate logistic regression and multivariate Cox regression analyses. RESULTS Data from a total of 69 (6.8%) chondrosarcoma patients with pulmonary metastasis at initial diagnosis were extracted. Patients with the following characteristics were positively associated with higher risk of pulmonary metastasis: dedifferentiated subtype, high grade of malignancy, extracompartmental tumor (Enneking B), presence of regional lymph nodes, local recurrence, large tumor size (larger than 15 cm), and being married. Older patients (older than 67 years), and patients with clear cell chondrosarcoma or large tumor size (larger than 15 cm) exhibited the worse prognosis and survival (overall and cancer-specific). Resection of the primary tumor tended to be correlated with a better prognosis. CONCLUSIONS The incidence of pulmonary metastasis in chondrosarcoma was approximately 6.8%, with poor prognosis. Identifying risk factors and their associations with the incidence and prognosis in chondrosarcoma patients with pulmonary metastasis could provide a reference for clinical surveillance and guide the design of personalized treatment plans.

Gax suppresses chemerin/CMKLR1-induced preadipocyte biofunctions through the inhibition of Akt/mTOR and ERK signaling pathways.

Adipose tissue is closely associated with angiogenesis and vascular remodeling. Chemerin is involved in inflammatory reaction and vascular dysfunction. However, the mechanisms of chemerin participating in vascular remodeling and whether Growth arrest-specific homeobox (Gax) can effectively intervene it remain obscured. Here, 3T3-F442A preadipocytes were cultured, injected into athymic mice to model fat pads, and treated respectively with Ad-chemerin, Ad-Gax, or specific inhibitors in vitro and in vivo. MTT, flow cytometry, Western blotting, and imunohisto(cyto)-chemistry analyses showed that chemerin enhanced the expression of FABP4 and VEGF, activated Akt/mTOR and ERK pathways, increased the cell percent of S phase, decreased the percent of G0-G1 phase and apoptotic cells, and augmented neovascular density in fat pads. Inversely, Gax suppressed the expression of these adipogenic and vasifactive markers and these signaling proteins, decreased the percent of S phase cells, and increased those of G0-G1 phase and apoptotic cells, and reduced the neovascular density. Our results indicate that chemerin-CMKLR1 activates Akt/mTOR and ERK pathways and facilitates preadipocyte proliferation, adipogenesis, and angiogenesis. Contrarily, Gax weakens the effect of chemerin on preadipocyte biofunctions.

Polyethylene-glycol-coated gold nanoparticles improve cardiac function after myocardial infarction in mice.

Gold nanoparticles (AuNPs) are widely used for drug delivery because of their unique biological properties, such as their safety and ability to prolong drug action. Some studies have demonstrated that AuNPs accumulate in the heart, especially during pathological processes. Therefore, it is very important to understand the effect of AuNPs on the heart. Myocardial infarction (MI) is a major cause of morbidity and mortality; however, the effect of AuNPs on MI remains unclear. In the present study, we carried out a comprehensive evaluation of AuNPs on acute MI. The results showed that AuNPs accumulated in infarcted hearts, decreased infarction size, improved systolic function, and inhibited cardiac fibrosis and TNF-α accumulation. Our work indicated that AuNPs have cardioprotective effects and can be used in drug delivery systems for the treatment of cardiac diseases.

A prospective randomized trial comparing anterior cervical discectomy and fusion versus plate-only open-door laminoplasty for the treatment of spinal stenosis in degenerative diseases.

OBJECTIVE: For three or more involved cervical levels, there is a debate over which approach yields the best outcomes for the treatment of multilevel cervical degenerative disease. Our objective is to compare the radiological and clinical outcomes of two treatments for multilevel cervical degenerative disease: anterior cervical discectomy and fusion (ACDF) versus plate-only open-door laminoplasty (laminoplasty). METHODS: Patients were randomized on a 1:1 randomization schedule with 17 patients in the ACDF group and 17 patients in the laminoplasty group. Clinical outcomes were assessed by a visual analog scale (VAS), Japanese Orthopedic Association (JOA) scores, operative time, blood loss, rates of complications, drainage volume, discharge days after surgery, and complications. The cervical spine curvature index (CI) and range of motion (ROM) were assessed with radiographs. RESULTS: The mean VAS score, the mean JOA score, and the rate of complications did not differ significantly between groups. The laminoplasty group had greater blood loss, a longer operative time, more drainage volume, and a longer hospital stay than the ACDF group. There were no significant differences in the CI and ROM between the two groups at baseline and at each follow-up time point. ROM in both groups decreased significantly after surgery. CONCLUSIONS: Both ACDF and laminoplasty are effective and safe treatments for multilevel cervical degenerative disease. ACDF causes fewer traumas than laminoplasty.

Single-Level Rigid Fixation Combined with Coflex: A Biomechanical Study.

BACKGROUND: The purpose of this biomechanical in vitro study was to compare the kinematics and intradiscal pressure achieved with 2 methods: L4-L5 pedicle screw-rod fixation (PSRF) with an upper L3-L4 Coflex device and L4-L5 PSRF alone. The results were used to characterize the biomechanics of the topping-off operation with a Coflex device for the lumbar motion segment adjacent to single-level rigid fixation. MATERIAL/METHODS: Six human cadaveric spine specimens were biomechanically tested in vitro (6 males, 0 females). The 3-dimensional specimen motion in response to applied loads during flexibility tests was determined. Loads were applied along anatomic axes to induce flexion-extension, lateral bending, and axial rotation. All specimens were first studied with intact lumbar motion segments, then with L4-L5 PSRF alone, and finally with L4-L5 PSRF with an upper L3-L4 Coflex device. A non-paired comparison of the 3 configurations under 3 different conditions was made. RESULTS: PSRF, with or without a Coflex device, significantly increased the range of motion (ROM) in the upper adjacent motion segments in all directions of loading. The intradiscal pressure (IDP) changed slightly. A correlation analysis showed that the ROM and IDP are significantly positively correlated. The application of the upper motion segment of the Coflex device provided greater stability in all directions of motion than did PSRF alone, particularly for extension (p<0.05), while use of a Coflex device did not significantly decrease the IDP compared with PSRF alone (p>0.05). CONCLUSIONS: These results suggest that L4-L5 PSRF with an L3-L4 Coflex device is more stable than L4-L5 PSRF alone. PSRF with an upper Coflex device is a promising alternative to PSRF alone. Based on these biomechanical tests, it might be considered a protective method to prevent adjacent segment degeneration (ASD), although some limitations with this in vitro study must be addressed in the future.

Measurement of the Human Calcaneus In Vivo Using Ultrasonic Backscatter Spectral Centroid Shift.

OBJECTIVES: The aim of this study was to determine the relationship between the backscattered spectral centroid shift and the bone mineral density (BMD) in vivo and investigate the feasibility of using the backscattered spectral centroid shift to characterize the cancellous bone status. METHODS: Ultrasonic backscatter measurements were performed in vivo on 1216 participants at the right calcaneus using an ultrasonic backscattered bone diagnostic system, and the backscattered spectral centroid shift was calculated at central frequencies of 3.5 and 5.0 MHz. The BMD values were measured at the sites of the lumbar spine and left hip by dual energy x-ray absorptiometry. RESULTS: The study population included 592 male and 624 female participants aged 20 to 89 years. The correlations between the backscattered spectral centroid shift in the calcaneus and the spine and hip BMD were found to be statistically significant in both the male and female groups (P < .0001). Linear regression showed that the spectral centroid shift at 3.5 MHz had negative correlations with the spine BMD (R = -0.65 for male participants; R = -0.67 for female participants) and hip BMD (R = -0.64 for male participants; R = -0.64 for female participants). The spectral centroid shift at 5.0 MHz was also found to be closely related to the spine BMD (R = -0.68 for male participants; R = -0.68 for female participants) and hip BMD (R = -0.66 for male participants; R = -0.64 for female participants). CONCLUSIONS: The moderate correlations observed between the spectral centroid shift and the spine and hip BMD demonstrate that the ultrasonic backscattered spectral centroid shift may be a useful measurement for assessment of the cancellous bone status.

Recurrent adamantinoma in the thoracolumbar spine successfully treated by three-level total en bloc spondylectomy by a single posterior approach.

PURPOSE: Adamantinoma is a low-grade primary malignant bone tumour with slow growth and local recurrence. Its occurrence in the spine is extremely rare, particularly with multilevel involvement. This paper wants to present the first case involving a patient with recurrent thoracolumbar spinal adamantinoma, who underwent a successful three-level spondylectomy for en bloc resection. METHODS: A 24-year-old man with osteolytic masses of T11 and T12 vertebral bodies was performed curettage by a posterior approach in 2008. The pathology report showed the excised neoplasm was a rare adamantinoma. This patient underwent a tumorectomy again because of its local recurrence nearly 3 years later. In 2012, it was unfortunately revealed that the excised tumour had relapsed and had spread to the L1 vertebral body. Due to its repeated recurrence and aggressive lesion, total en bloc spondylectomy (TES) for this malignant tumour was thought to be the best option for preventing repeated recurrence and possible cure. TES for T11-L1 thoracolumbar spine was performed and spinal reconstruction was completed with instrumentation and a titanium mesh cage through a one-stage single posterior approach. RESULTS: After three-level TES, neurological deficits of the patient demonstrated good recovery and no evidence of adamantinoma recurrence or deformity was found at 2-year follow-up. CONCLUSIONS: This is the first case involving multilevel thoracolumbar spinal adamantinoma with repeated recurrence to be successfully treated by three-level TES by a single posterior approach.

Prediction of risk factors of sleep disturbance in patients undergoing total hip arthroplasty.

The purpose of this study was to assess sleep quality in patients undergoing total hip arthroplasty (THA) from preoperatively to 12 weeks postoperatively and to establish a risk predictor for postoperative sleep disturbance to enable early care and intervention. A self-designed data collection form was used. Patients were assessed preoperatively and at 5 postoperative time points using visual analog scale (VAS) for pain, sleep quality and neuropsychological status with the following assessment tools: the Chinese versions of the Pittsburgh Sleep Quality Index (CPSQI), the Epworth Sleepiness Scale (CESS), the Zung Self-Rating Anxiety Scale (ZSAS) and the Epidemiological Studies Depression Scale (CESD). Univariate and multivariate logistic regression analysis was used for the identification of risk factors for postoperative sleep disturbance. The receiver operating characteristic (ROC) curve was plotted to evaluate the regression model. Of the 290 eligible patients, 193 (133 women) were included in the study. There was a 60.6% prevalence of preoperative sleep disturbance. The CPSQI score increased significantly at 2 weeks postoperatively compared to preoperative baseline, but appeared to decrease at 4 weeks postoperatively. Multivariate logistic regression analysis showed that pain (VAS score: OR = 1.202 [95% CI = 1.002-1.446, P < 0.05]), daytime sleepiness (CESS score: OR = 1.134 [95% CI = 1.015-1.267, P < 0.05]) and anxiety (ZSAS score: OR = 1.396 [95% CI = 1.184-1.645, P < 0.001]) were risk factors associated with postoperative sleep disturbance at 2 weeks. The ROC curve showed that the AUC was 0.762, the sensitivity was 83.19% and the specificity was 64.86%. Postoperative sleep disturbance is highly prevalent in the first 2 weeks after THA. The risk prediction model constructed according to the above factors has good discriminant ability for the risk prediction of sleep disturbance after THA. The use of this risk prediction model can improve the recognition of patients and medical providers and has good ability to guide clinical nursing observation and early screening of sleep disturbance after THA.

Pollution characteristics, distribution and risk level of heavy metals in sediments of the Yangtze River estuary.

Pollution characteristics, distribution, risk and sources of 7 heavy metals in sediments of Yangtze River Estuary were investigated. Total concentration ranges of As, Cr, Cu, Cd, Pb, Zn and Ni were [0, 16.5], [1.48, 51.3], [2.66, 318], [0, 0.99], [35.6, 992], [8, 91.3] and [1.88, 108] mg/kg, respectively. Based on the potential ecological risk index and Geoaccumulation index, it was determined that Pb is the most polluted heavy metal. According to class I standard of "Marine sediment quality" of China, mean baseline levels multiples were Pb (8.34) > Cu (0.57) > Cr (0.37) > Zn (0.355) > Ni (0.352) > As (0.28) > Cd (0.00). The study also found the heavy metal content of Pb is the most serious, but most of the Pb content comes from the residual state, which has minimal impact on the environment. The East Nanhui Shoal was identified as the most polluted sub-area in terms of Pb pollution, followed by other specific locations. Considering the pollution level and transport costs, the study concluded that dredge soils of the Yangtze River Estuary Deepwater Channel are not suitable for the restoration of East Hengsha Shoal.

Strong cathode electroluminescence biosensor based on CeO2 functionalized PCN-222@Ag NPs for sensitive detection of p-Tau-181 protein.

Electrochemiluminescence (ECL) biosensors provide a convenient and high sensitivity method for early disease diagnosis. However, creating luminophore arrays relying on powerful ECL signals remains a daunting task. Porphyrin-centered metal organic frameworks (MOFs) exhibit remarkable potential in ECL sensing applications. In this paper, based on a simple one-pot synthesis method, PCN-222@Ag NPs doped with CeO2 was synthesized to enhance the ECL performance. Due to the strong catalytic ability of CeO2, the ECL signal strength of the new material PCN-222@CeO2@Ag NPs is much higher than that of the PCN-222@Ag NPs and PCN-222. The luminous properties of PCN-222@CeO2@Ag NPs become more intense and stable due to the excellent electronic conductivity of Ag NPs. Based on the fact that CuS@PDA composite can quench the ECL signal of PCN-222@CeO2@Ag NPs, we constructed a novel sandwich ECL immune sensor for the detection of phosphorylated Tau 181 (p-Tau-181) protein. The ECL sensor has a great linear relationship with p-Tau-181 protein concentration, ranging from 1 pg/mL to 100 ng/mL. The detection limit is as low as 0.147 pg/mL. This work provides new ideas for developing sensitive ECL sensors for the p-Tau-181 protein, the marker of Alzheimer's disease.

Adaptor protein HIP-55-mediated signalosome protects against ferroptosis in myocardial infarction.

Ischemic heart disease is a leading cause of death worldwide. Myocardial infarction (MI) results in cardiac damage due to cell death and insufficient cardiomyocyte self-renewal. Ferroptosis, a novel type of cell death, has recently been shown as a key cause of cardiomyocyte death after MI. However, the complicated regulation mechanisms involved in ferroptosis, especially how ferroptosis is integrated into classical cell survival/death pathways, are still unclear. Here, we discovered that HIP-55, a novel adaptor protein, acts as a hub protein for the integration of the ferroptosis mechanism into the classical AKT cell survival and MAP4K1 cell death pathways for MI injury. The expression of HIP-55 is induced in MI. Genetic deletion of HIP-55 increased cardiomyocyte ferroptosis and MI injury, whereas cardiac-specific overexpression of HIP-55 significantly alleviated cardiomyocyte ferroptosis and MI injury. Mechanistically, HIP-55 was identified as a new AKT substrate. AKT phosphorylates HIP-55 at S269/T291 sites and further HIP-55 directs AKT signaling to negatively regulate the MAP4K1 pathway against MI injury in a site-specific manner. S269A/T291A-mutated HIP-55 (HIP-55AA), which is defective in AKT phosphorylation and significantly decreases the interaction between HIP-55 and MAP4K1, failed to inhibit the MAP4K1/GPX4 ferroptosis pathway. In line with this mechanism, cardiac-specific overexpression of HIP-55WT mice, but not cardiac-specific overexpression of HIP-55AA mice, protected cardiomyocytes against MI-induced ferroptosis and cardiac injury in vivo. These findings suggest that HIP-55 rewired the classical AKT (cell survival) and MAPK (cell death) pathways into ferroptosis mechanism in MI injury. HIP-55 may be a new therapeutic target for myocardial damage.

Is it safe for the spinal metastasis patients with preoperative deep vein thrombosis to use low-molecular-weight heparin before surgery? A prospective study.

Spine surgeons should weigh the risks of anticoagulants against their benefits in preventing deep venous thrombosis (DVT), as they may increase the risk of bleeding. Spinal metastasis patients undergoing decompression with fixation are at a high risk for DVT, which may occur preoperatively. Therefore, anticoagulants should be administered preoperatively. This study aimed to evaluate the safety of the administration of anticoagulants in treating spinal metastasis patients with preoperative DVT. Therefore, we prospectively investigated the prevalence of DVT in these patients. Patients who were diagnosed with preoperative DVT were included in an anticoagulant group. Subcutaneous low-molecular-weight heparin (LMWH) was administered. Patients without DVT were included in a non-anticoagulant group. Data on patient information, clinical parameters, blood test results, and bleeding complications were also collected. Moreover, the safety of anticoagulants was analyzed. The prevalence of preoperative DVT was 8.0%. None of the patients developed pulmonary thromboembolism. Furthermore, no significant differences in blood loss, drainage volume, hemoglobin levels, number of transfusions, or preoperative trans-catheter arterial embolization were observed between the two groups. None of the patients developed major bleeding. However, two patients experienced wound hematoma and one experienced incisional bleeding in the non-anticoagulant group. Therefore, LMWH is safe for spinal metastasis patients. Future randomized controlled trials should be conducted to evaluate the validity of perioperative prophylactic anticoagulation therapy in these patients.

Photo-controllable binding and release of HP2O73- using an azobenzene based smart macrocycle.

Herein, we describe the design and synthesis of an unusual azobenzene-bearing macrocycle 1, whose trans isomer was found able to 100% transform into its cis configuration under photoirradiation, for selectively recognizing HP2O73- with reversibly photo-controllable binding and release properties.