Search

Abstract The epithelial neutral amino acid transporter B0AT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of B0AT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders, implying a pharmacological approach for their treatment. Here we employ a medicinal chemistry approach to generate B0AT1 inhibitors with IC50-values of 31-90 nM. High-resolution cryo-EM structures of B0AT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.

In the context of sustainable urban development, effective garbage management plays a crucial role. However, traditional methods encounter limitations in terms of data quality and quantity. The research on automatic garbage image recognition and classification methods based on deep learning has been gaining attention. This study proposes an integrated garbage image recognition and classification method that combines ResNet-50, YOLOv5, and weakly supervised CNN algorithms. The aim is to enhance both the accuracy and efficiency of image recognition, optimize intelligent garbage management, and promote urban sustainable development planning. The ResNet-50 model is employed to extract meaningful features from images and train weakly supervised CNN models for subsequent training and prediction. This enables the analysis of urban environmental development trends and the formulation of planning measures. Through evaluation on four representative public datasets, the proposed method outperforms several traditional algorithms in terms of accuracy, efficiency, and stability in garbage image recognition systems. Notably, on the HGI-30 dataset, the algorithm achieves significant improvements by reducing inference time by over 48.6%, FLOPs by over 46.5%, and MAPE by over 41%. These enhancements greatly enhance the accuracy and robustness of garbage image classification, highlighting the substantial significance of this method in the realms of garbage management and environmental protection.

Abstract The Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium-independent transport of small neutral amino acids, including L-Alanine (L-Ala), Glycine (Gly), and D-Serine (D-Ser), within the central nervous system (CNS). D-Ser and Gly are two key endogenous glutamate co-agonists that activate N-methyl-d-aspartate (NMDA) receptors by binding to the allosteric site. Mice deficient in Asc-1 display severe symptoms such as tremors, ataxia, and seizures, leading to early postnatal death. Despite its physiological importance, the functional mechanism of the Asc-1-4F2hc complex has remained elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of the human Asc-1-4F2hc complex in its apo state, D-Ser bound state, and L-Ala bound state, resolved at 3.6 Å, 3.5 Å, and 3.4 Å, respectively. Through detailed structural analysis and transport assays, we uncover a comprehensive alternating access mechanism that underlies conformational changes in the complex. In summary, our findings reveal the architecture of the Asc-1 and 4F2hc complex and provide valuable insights into substrate recognition and the functional cycle of this essential transporter complex.

IntroductionCurrent research on potentially inappropriate prescribing (PIP) in polymedicated older adults with atrial fibrillation (AF) and multimorbidity is predominantly focused on PIP of oral anticoagulants (OAC). Our study aimed to assess (i) the overall prevalence of PIP in older multimorbid adults with AF, (ii) potential associated factors of PIP, and (iii) the association of PIP with adverse health outcomes in a nationwide sample of Swedish older adults.MethodsSwedish national registries were linked to establish a cohort with a 2-year follow-up of older adults (≥65y) who, on 1 January 2017, had a diagnosis of AF and had at least one comorbidity (n = 203,042). PIP was assessed using the reduced STOPP/START version 2 screening tool. The STOPP criteria identify potentially inappropriate prescribed medications (PIM), while the START criteria identify potential prescribing omissions (PPO). PIP is identified as having at least one PIM and/or PPO. Cox regression analyses were conducted to examine the association between PIP and adverse health outcomes: mortality, hospitalisation, stroke, bleeding, and falls.ResultsPIP was highly prevalent in older adults with AF, with both polypharmacy (69.6%) and excessive polypharmacy (85.9%). In the study population, benzodiazepines (22.9%), hypnotic Z-medications (17.8%) and analgesics (8.7%) were the most frequent PIM. Anticoagulants (34.3%), statins (11.1%), vitamin D and calcium (13.4%) were the most frequent PPO. Demographic factors and polypharmacy were associated with different PIM and PPO categories, with the nature of these associations differing based on the specific type of PIM and PPO. The co-occurrence of PIM and PPO, compared to appropriate prescribing, was associated with an increased risk of adverse health outcomes compared to all appropriately prescribed medications: cardiovascular (CV) (Hazard ratio (HR) [95% confidence interval] = 1.97 [1.88–2.07]) and overall mortality (HR = 2.09 [2.03–2.16]), CV (HR = 1.34 [1.30–1.37]) and overall hospitalisation (HR = 1.48 [1.46–1.51]), stroke (HR = 1.93 [1.78–2.10]), bleeding (HR = 1.10 [1.01–1.21]), and falls (HR = 1.63 [1.56–1.71]).ConclusionThe present study reports a high prevalence of PIP in multimorbid polymedicated older adults with AF. Additionally, a nuanced relationship between prescribing patterns, patient characteristics, and adverse health outcomes was observed. These findings emphasise the importance of implementing tailored interventions to optimise medication management in this patient population.

Abstract The mortality rates for patients undergoing hemodialysis (HD) remain unacceptably high compared to the general population, and more specific information about the causes of death is not known. The study aimed to develop and validate a risk prediction model that uses common clinical factors to predict the probability of cardiovascular events in maintenance hemodialysis (MHD) patients. The study involved 3488 adult patients who received regular scheduled hemodialysis treatment at 20 hemodialysis centers in southwest China between June 2015 and August 2020, with follow-up until August 2021. The optimal parameter set was identified by multivariable Cox regression analyses and Cross-LASSO regression analyses and was used to establish a nomogram for predicting the risk of cardiovascular events in maintenance hemodialysis patients at 3 and 5 years. The performance of the model was evaluated using the consistency index (Harrell’s C-index), the area under the receiver operating characteristic (ROC) curve, and calibration plots. The model was validated by tenfold cross-validation and bootstrapping with 1000 resamples. In the derivation cohort, the model yields an AUC of 0.764 [95% confidence interval (CI), 0.737–0.790] and 0.793 [CI, 0.757–0.829] for predicting the risk of cardiovascular events of MHD patients at 3 and 5 years. In the internal validation cohort AUC of 0.803 [95% CI, 0.756–0.849], AUC of 0.766 [95% CI, 0.686–0.846], and the external validation cohort AUC of 0.826 [95% CI, 0.765–0.888], AUC of 0.817 [95% CI, 0.745–0.889] at 3 and 5 years. The model’s calibration curve is close to the ideal diagonal. By tenfold cross-validation analyses, the 3- and 5-year risk of cardiovascular events (AUC 0.732 and 0.771, respectively). By the bootstrap resampling method, the derivation cohort and validation cohort (Harrell’s C-index 0.695 and 0.667, respectively) showed good uniformity with the model. The constructed model accurately predicted cardiovascular events of MHD patients in the 3rd and 5th years after dialysis. And the further research is needed to determine whether use of the risk prediction tool improves clinical outcomes.

Abstract The electrochemical carbon dioxide reduction reaction (eCO2RR) can achieve carbon recycling through renewable electrical energy. Before releasing the full potential of eCO2RR, the electrocatalysts still need improvement in terms of catalytic activity, selectivity, and durability. Two‐dimensional (2D) crystalline materials show a high aspect ratio with well‐defined crystal structures, which are promising electrocatalysts for eCO2RR. In this review, we briefly discuss the typical 2D electrocatalysts for eCO2RR. Subsequently, we provide a summary of the different strategies to improve the catalytic performance of 2D crystalline electrocatalysts for creating and modulating active sites. Finally, we end this review with the current challenges and future opportunities of 2D crystalline materials in the eCO2RR.

Background: Prolonged circulatory arrest time is an independent risk factor for postoperative adverse events of type A aortic dissection (TAAD) surgery. Further reduction of the circulatory arrest time is essential to improve surgical outcomes. This study aimed to evaluate the safety and effectiveness of the novel Sutureless Integrated Stented (SIS) graft prosthesis in an animal experiment. Materials and methods: Straight type of the SIS graft prosthesis was implanted into the descending aorta of 10 adult male sheep, and the use of the device was scored on a scale of 1–10. Aortic digital subtraction angiography (DSA) was performed at 4, 14, and 26 weeks to investigate the prostheses. After 26 weeks, the animals were sacrificed for histological analysis. Results: The immediate success rate of the surgery was 100 %, and the overall mean score of the use of the device was 9.65 ± 0.99. Three animals died from non-device-related causes during follow-up. Aortic DSA showed filling defects in 5 animals. Histological analysis revealed that all prostheses were intact. Except for 2 early deaths, the other 8 prostheses were endothelialized with mild inflammation, foreign body reactions, and intimal fibrosis. The mean cross-sectional area of the sutureless region was reduced by 26.4 % (range, 1.3–39.1 %). Conclusions: The safety and effectiveness of the novel SIS graft prosthesis were acceptable, and the delivery system exhibited a promising performance. Using the SIS graft prosthesis in TAAD surgery was expected to simplify the procedures and shorten the circulatory arrest time. Further large-scale clinical trials are required to verify these findings.

Abstract Organ regeneration necessitates precise coordination of accelerators and brakes to restore organ function. However, the mechanisms underlying this intricate molecular crosstalk remain elusive. In this study, the level of proenkephalin-A (PENK-A), expressed by renal proximal tubular epithelial cells, decreases significantly with the loss of renal proximal tubules and increased at the termination phase of zebrafish kidney regeneration. Notably, this change contrasts with the role of hydrogen peroxide (H2O2), which acts as an accelerator in kidney regeneration. Through experiments with penka mutants and pharmaceutical treatments, we demonstrate that PENK-A inhibits H2O2 production in a dose-dependent manner, suggesting its involvement in regulating the rate and termination of regeneration. Furthermore, H2O2 influences the expression of tcf21, a vital factor in the formation of renal progenitor cell aggregates, by remodeling H3K4me3 in renal cells. Overall, our findings highlight the regulatory role of PENK-A as a brake in kidney regeneration.

Abstract Background The ultimate goal of medical care is to eradicate disease and restore normality to a person’s life. Quality of life (QOL) is a concern as dermatologists and researchers strive to find better drug treatments. However, there have been few reports on the factors associated with QOL among Chinese people with psoriasis. Methods A total of 185 people with psoriasis were surveyed to assess their sociodemographic status, disease-related information, psychosocial status, and QOL. The questionnaires included a sociodemographic questionnaire, the Athens Insomnia Scale, the Hospital Anxiety and Depression Scale, the Perceived Social Support Scale, the Psychosocial Adaptation Questionnaire of Chronic Skin Disease and the Dermatology Life Quality Index. Multiple stepwise regression and path analysis were used to study the factors associated with QOL among Chinese people with psoriasis and to analyse the relationship between them. Results The results showed that the presence of anxiety/depression, lesion area, sleep disorders, psychosocial adaptation, and sex could jointly predict 62.1% of the variance in QOL among Chinese people with psoriasis. According to previous theories and the literature, a path model was established for five variables. Four internal variables could be effectively explained. The values of the explanatory variables were 62.1% (F(1056) = 61.020, p = 0.000) for QOL, 71.8% (F(2433) = 117.370, p = 0.000) for anxiety/depression, 44.0% (F(660) = 36.935, p = 0.000) for sleep disorders, and 66.9% (F(6886) = 93.556, p = 0.000) for psychosocial adaptation. The path analysis confirmed that 9 paths were consistent with the predicted path, and 3 paths were not confirmed. Conclusion To improve QOL among Chinese people with psoriasis, attention should be given to the presence of anxiety/depression, lesion area, sleep disorders, psychosocial adaptation and sex differences. Therefore, health care programs for psoriasis should include physical, psychological and social aspects.

The effective connection of 1050 Al and AZ31 Mg was realized by magnetic pulse welding. The maximum tensile-shear force of the dissimilar Al/Mg metal lap joint reached 97% of that of the 1050 Al alloy base material by optimizing the process parameters. The microstructure of dissimilar Al/Mg welded joints was analysed by Scanning Electron Microscope (SEM), Energy Dispersive Spectrometer (EDS) and Electron Backscattered Diffraction (EBSD). The results show that the key to obtaining high shear strength of Al/Mg dissimilar metal joints is mainly due to the following two reasons. On the one hand, grain refinement and element interdiffusion occur at the interface. On the other hand, no intermetallic compounds are formed at the interface.

This paper proposes a new spacecraft in-orbit launch design using a nonlinear configuration to utilize nonlinear dynamics for the enhancement of vibration isolation and launch performance. The in-orbit launch device has four springs, where the stroke directions of two springs are perpendicular to the launch direction so as to produce nonlinearity with negative stiffness for enhancing the launch velocity. The other two springs are designed to counterbalance the above negative stiffness when the launch outlet is shut down, leading to quasi-zero dynamic stiffness for vibration isolation enhancement. The dynamic equations of the in-orbit launch device for both the on- and off-launch are presented. Then the performance enhancement of both the vibration isolation and launch performance is thoroughly investigated via comparative study and parametric study. The resonance peak is reduced by 4.16 dB, the effective vibration isolation bandwidth is increased by 57%, and the launch speed is increased 1.64 times. This validates the performance improvement of the new launch device design and presents a useful guideline for application.

Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in immunocompromised patients while lack of effective therapeutic options. Oncoproteins Myc and hypoxia-inducible factor-1α (HIF1α) have been found closely related to KSHV infection, replication and oncogenesis. However, the strategies of dual targeting these two oncoproteins have never been developed and tested for treatments of KSHV-related malignancies. In the current study, we report that treatment of echinomycin dramatically regresses cell growth both in vitro-cultured KSHV + tumor cells and in vivo KS or PEL xenograft mice models, through simultaneously inhibiting Myc and HIF1α expression. Echinomycin treatment also induces viral lytic gene expression whereas not increasing infectious virions production from KSHV + tumor cells. Our comparative transcriptomic analysis has identified a bunch of new Echinomycin-regulated, Myc- and HIF1α-related genes contributed to KSHV pathogenesis, including KDM4B and Tau, which are required for the survival of KSHV + tumor cells with functional validation. These data together reveal that dual targeting Myc and HIF1α such as using Echinomycin may represent a new and promising option for treatments of these virus-associated malignancies.

IntroductionMetacognition and self-directed learning are key components in educational research, recognized for their potential to enhance learning efficiency and problem-solving skills. This study explores the effects of musical feedback training on these competencies.MethodsThe study involved 84 preservice teachers aged 18 to 21. Participants were randomly assigned to either an experimental group, which received musical feedback training, or a control group.ResultsThe findings indicate that musical feedback training effectively improved metacognitive abilities. However, its impact on the readiness for self-directed learning was inconclusive. A notable difference in metacognition and self-directed learning readiness was observed between the experimental and control groups during the session, indicating a significant interaction effect. Furthermore, a positive correlation was identified between metacognition and self-directed learning.DiscussionThese results contribute to educational discourse by providing empirical evidence on the utility of musical feedback training in fostering metacognition. They also highlight the importance of consistent and long-term engagement in self-directed learning practices. The significance of these findings advocates for incorporating music feedback training into music education curricula to enhance metacognition and improve overall learning efficiency.

Background Peritoneal dialysis (PD) patients have a high incidence of cardiovascular events (CVEs). Left ventricular fraction shortening (LVFS), one of the echocardiographic parameters, is an independent risk factor for mortality in previous studies. The aim of this study was to evaluate associations between LVFS and CVEs in PD patients.Methods This was a single-center observational cohort study. Seven hundred and eighty-four PD patients were enrolled from 1 January 2012 to 1 June 2021 and followed until 1 June 2022. The primary outcome was the incidence of CVEs. PD patients were categorized into three groups according to the tertiles of LVFS levels (tertile 1-tertile 3). Kaplan-Meier method, Cox proportional hazard models and competing risk regression models were used for survival analysis. The areas under the curve (AUC) of receiver-operating characteristic analysis was used to determine the predictive values of LVFS for CVEs. A preplanned subgroup analysis was assessed according to age, gender, and the presence of hypertension and dyslipidemia, etc.Results During a median follow-up period of 42.3 months (interquartile range 24.0–79.0 months), 259 CVEs occurred. Compared to the other two groups respectively, patients in tertile 3 group had the lowest incidence of CVEs (24.5% vs 31.6% vs 43.0%, respectively, p

BackgroundFocal cortical dysplasia (FCD) IIb and tuberous sclerosis complex (TSC) are common causes of drug-resistant epilepsy in children. However, the etiologies related to the development of FCD IIb and TSC are not fully understood. α-synuclein (α-syn) is a member of synucleins family that plays crucial roles in modulating synaptic transmission in central nervous system. Here, we explored the expression profiles and potential pathogenic functions of α-syn in cortical lesions of epileptic patients with FCD IIb and TSC.MethodsSurgical specimens from epileptic patients with FCD IIb and TSC, as well as FCD rats generated by in utero X-ray-radiation were adopted in this study and studied with immunohistochemistry, immunofluorescence, western blotting, and co-immunoprecipitation etc. molecular biological techniques.ResultOur results showed that α-syn expression was reduced in FCD IIb and TSC lesions. Specifically, α-syn protein was intensely expressed in dysplastic neurons (DNs) and balloon cells (BCs) in FCD IIb lesions, whereas was barely detected in DNs and giant cells (GCs) of TSC lesions. Additionally, p-α-syn, the aggregated form of α-syn, was detected in DNs, BCs, GCs, and glia-like cells of FCD IIb and TSC lesions. We previous showed that the function of N-methyl-D-aspartate receptor (NMDAR) was enhanced in FCD rats generated by X-ray-radiation. Here, we found the interaction between α-syn and NMDAR subunits NMDAR2A, NMDAR2B were augmented in cortical lesions of FCD patients and FCD rats.ConclusionThese results suggested a potential role of α-syn in the pathogenesis of FCD IIb and TSC by interfering with NMDAR.

Objective: To investigate the effect of heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) on the replication of enterovirus 71 (EV-71) in SK-N-SH cells. Methods: The mRNA and protein expression of HNRNPA2B1 in SK-N-SH cells were detected by real-time quantitative PCR (qRT-PCR) and western blotting (WB), respectively. WB was used to detect HNRNPA2B1 protein expression in the nucleus and cytosol. The localization of HNRNPA2B1 protein in the nucleus and cytosol was detected by immunofluorescence (IF). The expression of HNRNPA2B1 was inhibited by small interfering RNA (si-HNRNPA2B1). Viral RNA, viral structural protein VP1, and viral titer were detected by qRT-PCR, WB, and viral dilution counting, respectively. Results: EV-71 infection significantly upregulates the expression of HNRNPA2B1 in SK-N-SH cells. EV-71 infection promotes HNRNPA2B1 nucleus-cytoplasm redistribution. Down-regulation of HNRNPA2B1 expression significantly inhibited EV-71 replication. Conclusion: HNRNPA2B1 protein redistributed from nucleus to cytoplasm and is highly expressed in the cytoplasm during EV-71 infection. Inhibition of HNRNPA2B1 levels effectively inhibits EV-71 replication in SK-N-SH cells.

IntroductionActinobacillus pleuropneumoniae is an important respiratory pathogen, which can cause porcine contagious pleuropneumonia and lead to great economic losses to worldwide swine industry. High potassium is an adverse environment for bacteria, which is not conducive to providing turgor pressure for cell growth and division. Two-component system CpxAR is an important regulatory system of bacteria in response to environmental changes, which is involved in a variety of biological activities, such as antibiotic resistance, periplasmic protein folding, peptidoglycan metabolism and so on.MethodsHowever, little is known about the role of CpxAR in high potassium stress in A. pleuropneumoniae. Here, we showed that CpxAR is critical for cell division of A. pleuropneumoniae under high potassium (K+) stress.ResultsqRT-PCR analysis found that CpxAR positively regulated the cell division genes ftsEX. In addition, we also demonstrated that CpxR-P could directly bind the promoter region of the cell division gene ftsE by EMSA.DiscussionIn conclusion, our results described a mechanism where CpxAR adjusts A. pleuropneumoniae survival under high-K+ stress by upregulating the expression of the cell division proteins FtsE and FtsX. These findings are the first to directly demonstrate CpxAR-mediated high-K+ tolerance, and to investigate the detailed molecular mechanism.

Long intergenic non-protein coding RNA 1547 (LINC01547) presents a notable relationship with prognosis in patients with ovarian cancer. Herein, we examined the expression of LINC01547 in non-small cell lung cancer (NSCLC) to ascertain its clinical significance. We also explored the detailed functions of LINC01547 in regulating the aggressive phenotype of NSCLC and the molecular mechanism of action underlying its carcinogenic activities events in NSCLC. Furthermore, we applied the data acquired from the tissue specimens and the Cancer Genome Atlas (TCGA) database to analyze the level of LINC01547 in NSCLC and conducted functional assays to address the regulatory effect of LINC01547. Further, we examined the mechanistic interaction among LINC01547, microRNA-195-5p (miR-195-5p), and homeobox C8 (HOXC8) using bioinformatics prediction and luciferase reporter assay. LINC01547 was noticeably overexpressed, as affirmed by data from TCGA and our own cohort; moreover, poor prognosis was associated with increased LINC01547 levels in patients with NSCLC. LINC01547 regulates cell proliferation, colony-forming, migration, and invasion, and its absence produced tumor-repressing effects in NSCLC. Mechanistically, as a competitive endogenous RNA, LINC01547 decoyed miR-195-5p and consequently resulted in the overexpression of HOXC8 in NSCLC cells. Using rescue experiments, we found that the regulatory activities of LINC01547 deficient in repressing the malignant properties of NSCLC cells could be counteracted by hindering miR-195-5p or overexpressing HOXC8. Conclusively, LINC01547 serves as a crucial component to worsen the oncogenicity of NSCLC cells by controlling the miR-195-5p/HOXC8 axis. Thus, the newly identified competing endogenous RNA pathway may potentially be an attractive therapeutic for NSCLC management.

In this experiment, response surface methodology–central composite rotatable design was used to optimize the ratio of hydroxypropyl cellulose, konjac flour, and glycerol to obtain optimal composite film. Taking into account the importance of tensile strength, elongation at break and lactobacillus survivability, to the overall properties of composite film, a comprehensive index was proposed to evaluate comprehensive property by fuzzy comprehensive evaluation method. Optimization experiments showed that the optimal composition of the biocomposite membrane that maximized the combined response value was 0.586% HPC, 0.858% KF, and 1.620% GL. In vitro toxicology experiments were used for the safety evaluation of the membranes. In the 14-day feeding test, the mice in each experimental group grew well, and there were no obvious abnormalities in gross anatomical organs and related blood biochemical indicators. A 14-day mouse feeding experiment showed that the biocomposite film had no short-term toxicity, so the biocomposite film could be considered food-safe.

The Qinling mountains are one of the richest diversity hotspots in the world. This area is remote, and new species remain to be discovered, including macrofungi. In this study, Qinling Mountain of the Shaanxi province was surveyed for macrofungus, and one new species of macrofungi Microstoma ningshanica (Sarcoscyphaceae) was discovered and analyzed by light microscopy and scanning electron microscopy as well as DNA sequence analysis. The description, photographs, and comparisons with morphologically similar and phylogenetically related species are provided. Conclusions of its phylogenetic relationships with similar species are also drawn based on the sequence of the nuclear internal transcribed spacer region, as well as the large subunit rRNA.

Highlights 1. Pathologically impaired periventricular white matter was observed in NEC neonatal rats. 2. Hypoxic-ischemic brain injury can also lead to intestinal inflammation. 3. CXCL1 and CXCR2 were significantly upregulated in intestinal and brain tissues in NEC, HIBI, and NEC+HIBI rats compared to the normal group. 4. Compared with the HIBI group, CXCL1 and CXCR2 expression continued to increase in NEC+HIBI rats.

Introduction In ageing societies, the number of older adults with complex chronic conditions (CCCs) is rapidly increasing. Care for older persons with CCCs is challenging, due to interactions between multiple conditions and their treatments. In home care and nursing homes, where most older persons with CCCs receive care, professionals often lack appropriate decision support suitable and sufficient to address the medical and functional complexity of persons with CCCs. This EU-funded project aims to develop decision support systems using high-quality, internationally standardised, routine care data to support better prognostication of health trajectories and treatment impact among older persons with CCCs.Methods and analysis Real-world data from older persons aged ≥60 years in home care and nursing homes, based on routinely performed comprehensive geriatric assessments using interRAI systems collected in the past 20 years, will be linked with administrative repositories on mortality and care use. These include potentially up to 51 million care recipients from eight countries: Italy, the Netherlands, Finland, Belgium, Canada, USA, Hong Kong and New Zealand. Prognostic algorithms will be developed and validated to better predict various health outcomes. In addition, the modifying impact of pharmacological and non-pharmacological interventions will be examined. A variety of analytical methods will be used, including techniques from the field of artificial intelligence such as machine learning. Based on the results, decision support tools will be developed and pilot tested among health professionals working in home care and nursing homes.Ethics and dissemination The study was approved by authorised medical ethical committees in each of the participating countries, and will comply with both local and EU legislation. Study findings will be shared with relevant stakeholders, including publications in peer-reviewed journals and presentations at national and international meetings.

Background: Computational fluid dynamics (CFD) is a new medical method combining medicine and science. The aim of this study is to summarize and analyze the application of CFD in adult aortic diseases. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search in the PubMed, Cochrane Library and Chinese databases identified 47 highly relevant articles. Studies were included if they assessed biomechanical markers and their potential association with progression or rupture of aortic aneurysms or dissections. Results: There are no randomized controlled trials to examine the direct relationship between all biomechanical parameters and aortic disease progression or rupture. Wall stress and peak wall rupture risk can predict the risk of aortic aneurysm rupture using biomechanics, which is more accurate than the prediction based on “diameter” alone. Areas with lower time averaged wall shear stress (TAWSS) and higher oscillatory shear index (OSI) are at risk for further aortic expansion or dissection. Higher relative residence time (RRT) area can predict platelet activation and thrombosis. In addition, pressure, flow field and other indicators can also roughly predict the risk of aortic disease progression. Conclusions: Contemporary evidence suggests that CFD can provide additional hemodynamic parameters, which have the potential to predict the progression of aortic lesions, the effect of surgical intervention, and prognosis.

BackgroundObstructive sleep apnea (OSA) is a heterogeneous sleep disorder often comorbid with metabolic diseases, and type 2 diabetes (T2DM) is one of them. Although apnea hypopnea index (AHI) is currently the diagnostic criteria for OSA severity, a controversial relationship between AHI and T2DM has been found. On the other hand, the duration of apnea–hypopnea events has been shown to be a useful metric for predicting mortality. This study aimed to test whether average respiratory event duration was associated with prevalence of T2DM.MethodsPatients referred to the sleep clinic were recruited in the study. Baseline clinical characteristics and polysomnography parameters including average respiratory event duration were collected. The association of average respiratory event duration with the prevalence of T2DM was evaluated by univariate and multivariate logistic regression analyses.ResultsA total of 260 participants were enrolled, and 92 (35.4%) had T2DM. Univariate analysis revealed that age, body mass index (BMI), total sleep time, sleep efficiency, history of hypertension, and shorter average respiratory event duration were associated with T2DM. In multivariate analysis, only age and BMI remained significant. While average respiratory event duration was insignificant in multivariate analysis, subtype event analysis showed that shorter average apnea duration was both significant in univariate (OR, 0.95; 95% CI, 0.92–0.98) and multivariate analyses (OR, 0.95; 95% CI, 0.91–0.99). Neither average hypopnea duration nor AHI was associated with T2DM. Significant association (OR, 1.19; 95% CI, 1.12–1.25) was observed between shorter average apnea duration and lower respiratory arousal threshold after multivariate adjustment. However, causal mediation analysis revealed no mediating effect of arousal threshold on average apnea duration and T2DM.ConclusionThe average apnea duration may be a useful metric in the diagnosis of OSA comorbidity. Shorter average apnea duration indicating poor sleep quality and augmented autonomic nervous system responses might be the potential pathological mechanisms leading to T2DM.

A great variety of electrically conductive micro-/nano-helices provide the unique interconversion of torsional rotation and linear deformation, which makes them the excellent elements as electromechanical actuators in artificial muscle. In this paper, a comprehensive theory has been constructed for quantitatively analyzing the electromechanical properties involving coupled torsional rotation and linear deformation of the close packed and non-close packed electrically conductive helices with the aid of the concept of Cosserat curve. The distributed force in our model can be used to describe the resultant electromagnetic force and the internal pressure on the current carrying helices, which agree well with the experimental results. It is revealed that if the designers intend to realize the mechanical actuation of coupled rotational inversion and large axial contraction, they can choose the close packed conductive micro-/nano-helices; while if they want the much larger torsional stroke of unwinding during the contraction process, the non-close packed ones will be a good choice. The currents make both kinds of helices stronger, and decreasing helix angle is an additional option for the non-close packed ones. The present study supplies a reliable theoretical reference for further experimental research on the applications of conductive helices in micro-/nanoelectromechanical systems.

Kidney renal clear cell carcinoma (KIRC) is increasing in incidence worldwide, with poor and unpredictable patient prognosis limited by diagnostic and therapeutic approaches. New genes are urgently needed to improve this situation. The ankyrin repeat and suppressor of the cytokine signaling (SOCS) box (ASB) family are a promising class of tumorigenesis-related genes. We examined the expression and mutation of 18 ASB genes in various tumors for this study. The findings revealed that ASB genes exhibit significant copy number variation (CNV) and single nucleotide variation (SNV). There were substantial variations in ASB gene expression in different tumor tissues, and different levels of methylation of ASB genes affected the gene expression and tumor progression. By applying LASSO regression analysis, we established a KIRC survival model based on five ASB genes (ASB6, ASB7, ASB8, ASB13, and ASB17). Additionally, ROC curve analysis was used to assess the survival model’s accuracy. Through univariate and multivariate COX regression analysis, we demonstrated that the model’s risk score might be an independent risk factor for individuals with KIRC. In summary, our KIRC survival model could accurately predict patients’ future survival. Further, we also quantified the survival model through a nomogram. This series of findings confirmed that ASB genes are potential predictive markers and targeted therapies for KIRC. Our KIRC survival model based on five ASB genes can help more clinical practitioners make accurate judgments about the prognosis of KIRC patients.

In organ regeneration, progenitor and stem cells reside in their native microenvironment, which provides dynamic physical and chemical cues essential to their survival, proliferation, and differentiation. However, the types of cells that form the native microenvironment for renal progenitor cells (RPCs) have not been clarified. Here, single-cell sequencing of zebrafish kidney reveals fabp10a as a principal marker of renal interstitial cells (RICs), which can be specifically labeled by GFP under the control of fabp10a promoter in the fabp10a:GFP transgenic zebrafish. During nephron regeneration, the formation of nephrons is supported by RICs that form a network to wrap the RPC aggregates. RICs that are in close contact with RPC aggregates express cyclooxygenase 2 (Cox2) and secrete prostaglandin E2 (PGE2). Inhibiting PGE2 production prevents nephrogenesis by reducing the proliferation of RPCs. PGE2 cooperates with Wnt4a to promote nephron maturation by regulating β-catenin stability of RPC aggregates. Overall, these findings indicate that RICs provide a necessary microenvironment for rapid nephrogenesis during nephron regeneration.

Primary effusion lymphoma (PEL) caused by Kaposi sarcoma-associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies.

ObjectiveKaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and Primary effusion lymphoma (PEL), which are usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin1 (IL1) family is a major mediator for inflammation response and has functional role in both innate and adaptive immunity. In contrast to the well-studied IL1 molecules, the activation and functional role of IL1 receptor/co-receptor and other related ligands, such as the IL1 receptor accessory protein (IL1RAP), in KSHV pathogenesis and tumorigenesis remain almost unknown.MethodsIn the current study, a series of KSHV negative and positive primary or tumor cells, as well as AIDS-KS tumor samples from cohort HIV+ patients were used to compare and determine the activation status of IL1 signaling molecules, and their functional roles in KSHV pathogenesis.ResultsWe reported the high activation of multiple IL1 signaling molecules, including IL1, IL36, IL1R1, IL1RAP and IRAKs, during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. Directly targeting these molecules especially IL1R1 and IL1RAP significantly impaired the survival and growth of KSHV+ tumor cells, as well as their colony formation on 3-D culture.ConclusionOur data indicate the importance of IL1 signaling molecules in KSHV pathogenesis and tumorigenesis, which may represent attractive therapeutic targets against these virus-associated diseases.

Abstract Background Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Previous studies have revealed that the mutations in PTEN and TP53 are the two most common genetic events in hepatocarcinogenesis. Here, we illustrated the crosstalk between aberrant Pten and Tp53 pathways during hepatocarcinogenesis in zebrafish. Methods We used the CRISPR/Cas9 system to establish several transgenic zebrafish lines with single or double tissue-specific mutations of pten and tp53 to genetically induce liver tumorigenesis. Next, the morphological and histological determination were performed to investigate the roles of Pten and Tp53 signalling pathways in hepatocarcinogenesis in zebrafish. Results We demonstrated that Pten loss alone induces hepatocarcinogenesis with only low efficiency, whereas single mutation of tp53 failed to induce tumour formation in liver tissue in zebrafish. Moreover, zebrafish with double mutations of pten and tp53 exhibits a much higher tumour incidence, higher-grade histology, and a shorter survival time than single-mutant zebrafish, indicating that these two signalling pathways play important roles in dynamic biological events critical for the initiation and progression of hepatocarcinogenesis in zebrafish. Further histological and pathological analyses showed significant similarity between the tumours generated from liver tissues of zebrafish and humans. Furthermore, the treatment with MK-2206, a specific Akt inhibitor, effectively suppressed hepatocarcinogenesis in zebrafish. Conclusion Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening.

With the increasing diversification of human energy consumption forms in the integrated energy market, analyzing the comprehensive energy consumption behavior of user groups according to their changing energy demand characteristics is an important issue to be urgently addressed. To solve this problem, an analysis method of user’s comprehensive energy consumption behavior based on the evolutionary game is proposed in this article. First, three types of users including residents, large industries, and commercial users are considered for this purpose. Then, a utility model which takes into account the energy consumption characteristics of these users and their comfort factors is constructed based on the subjective and objective combination weighting method. Thereafter, an evolutionary game theory is used to analyze the dynamic selection process for users by selecting energy suppliers and then using the selection results when the evolutionary equilibrium is reached. Finally, the model is solved by using a distributed iterative method. The correctness and validity of the proposed method are verified by the simulation results.

In the context of smart grid planning and construction, how to tackle the future distribution network, a comprehensive evaluation of smart distribution network planning has become an urgent problem to be solved. To address this issue, this research provides a method for comprehensive evaluation that combines subjective and objective weighing approaches. Firstly, a set of evaluation index system is constructed and quantified based on the characteristics of the future distribution network; after that a comprehensive evaluation model is established and a subjective and objective weighting method combining AHP-entropy weighting method is used to weight the indicators; Finally, the actual data from the distribution network is evaluated and scored. Based on the scoring verification results, the correctness and effectiveness of the method proposed in this paper are verified.

Lower extremity arterial disease (LEAD) is a major vascular complication of diabetes. Vascular endothelial cells dysfunction can exacerbate local ischemia, leading to a significant increase in amputation, disability, and even mortality in patients with diabetes combined with LEAD. Therefore, it is of great clinical importance to explore proper and effective treatments. Conventional treatments of diabetic LEAD include lifestyle management, medication, open surgery, endovascular treatment, and amputation. As interdisciplinary research emerges, regenerative medicine strategies have provided new insights to treat chronic limb threatening ischemia (CLTI). Therapeutic angiogenesis strategies, such as delivering growth factors, stem cells, drugs to ischemic tissues, have also been proposed to treat LEAD by fundamentally stimulating multidimensional vascular regeneration. Recent years have seen the rapid growth of tissue engineering technology; tissue-engineered biomaterials have been used to study the treatment of LEAD, such as encapsulation of growth factors and drugs in hydrogel to facilitate the restoration of blood perfusion in ischemic tissues of animals. The primary purpose of this review is to introduce treatments and novel biomaterials development in LEAD. Firstly, the pathogenesis of LEAD is briefly described. Secondly, conventional therapies and therapeutic angiogenesis strategies of LEAD are discussed. Finally, recent research advances and future perspectives on biomaterials in LEAD are proposed.

Vitamin K and vitamin K-dependent proteins have been reported to be associated with a large spectrum of age-related diseases. While most of these associations have been deduced from observational studies, solid evidence for the direct impact of vitamin K on cellular senescence remains to be proven. As vitamin K status reflects the complexity of interactions between dietary intake, gut microbiome activity and health, we will demonstrate the pivotal role of the diet-microbiome-health axis in human ageing and exemplify how vitamin K is implicated therein. We propose that food quality (i.e., food pattern) should be highlighted beyond the quantity of total vitamin K intake. Instead of focusing on a single nutrient, exploring a healthy diet containing vitamin K may be more strategic. As such, healthy eating patterns can be used to make dietary recommendations for the public. Emerging evidence suggests that dietary vitamin K is a modulator of the diet-microbiome-health axis, and this needs to be incorporated into the investigation of the impact of vitamin K on gut microbial composition and metabolic activities, along with host health outcomes. In addition, we highlight several critical caveats that need to be acknowledged regarding the interplay between diet, vitamin K, gut microbiome and host health that is pivotal for elucidating the role of vitamin K in ageing and responding to the urgent call of healthy eating concerning public health.

Mycobacterium kansasii infections predominantly manifest in immunocompromised people and are primarily responsible for lung disease and systemic disseminated infection. Osteopathy is a rare consequence of M. kansasii infection. Here, we present imaging data from a 44-year-old immunocompetent Chinese woman diagnosed with multiple bone destruction, particularly of the spine, secondary to M. kansasii pulmonary disease, which is easily misdiagnosed. The patient underwent an emergency operation after experiencing unexpected incomplete paraplegia during hospitalization, indicating an aggravation of bone destruction. Preoperative sputum testing and next-generation sequencing of DNA and RNA of intraoperative samples confirmed the diagnosis of M. kansasii infection. Treatment with anti-tuberculosis therapy and the subsequent patient response supported our diagnosis. Given the rarity of osteopathy secondary to M. kansasii infection in immunocompetent individuals, our case offers some insight into this diagnosis.

Although Kaposi’s sarcoma-associated herpesvirus (KSHV) has been reported to cause several human cancers including Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), the mechanisms of KSHV-induced tumorigenesis, especially virus–host interaction network, are still not completely understood, which therefore hinders the development of effective therapies. Histamine, together with its receptors, plays an important role in various allergic diseases by regulating different inflammation and immune responses. Our previous data showed that antagonists targeting histamine receptors effectively repressed KSHV lytic replication. In the current study, we determined that histamine treatment increased cell proliferation and anchorage-independent growth abilities of KSHV-infected cells. Furthermore, histamine treatment affected the expression of some inflammatory factors from KSHV-infected cells. For clinical relevance, several histamine receptors were highly expressed in AIDS-KS tissues when compared to normal skin tissues. We determined that histamine treatment promoted KSHV-infected lymphoma progression in immunocompromised mice models. Therefore, besides viral replication, our data indicate that the histamine and related signaling are also involved in other functions of KSHV pathogenesis and oncogenesis.

Chen et al. find that SARS-CoV-2 encoded proteins and some anti-COVID-19 drugs can induce lytic reactivation of Kaposi’s sarcoma-associated herpesvirus (KSHV), one of the major human oncogenic viruses. This study suggests that KSHV-positive patients exposed to COVID-19 or undergoing its treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19.

Taper implants differ greatly from anatomical teeth in shape. In this study, seven three-dimensional finite element models were established, including a conventional taper implant and six root-analog implants with different root numbers and shapes. Vertical, horizontal, and oblique instantaneous loads of 100 N were applied to the models to obtain stress distribution in the implant, mucosa, cortical bone, and cancellous bone. ANSYS was used to perform the analysis under hypothetical experimental conditions. We find the stresses in all the implants and surrounding tissues varied by loading direction, the sequence of stress magnitude is vertical load, oblique load, and then horizontal load. The maximum stress values in root-analog implants were significantly less than in the taper implant. Moreover, stress distribution in the former was equalized contrary to the concentrated stress in the latter. Root-analog implants with different root geometry also revealed a pattern: stresses in multiple-root implant models were lower than those in single-root implants under the same load. The implant with a long and rounded root distributed the stress more uniformly, and it was mainly concentrated on the implant itself and cancellous bone. However, the opposite effect was observed in the short implant on mucosa and cortical bone. The root geometry of anatomical teeth can modify their functions. A uniform-shaped implant can hardly meet their functional requirements. Thus, the root-analog implant could be a possible solution.

Kaposi’s Sarcoma (KS) caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) continues to be the most common AIDS-associated tumor. Involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. Numerous types of cancer are associated with the alterations of in components of the microbiome. However, little is known about how KSHV coinfection affects the oral microbiome in HIV+ patients, especially in a “pre-cancer” niche. Using 16S rRNA pyrosequencing, we found that oral shedding of KSHV correlated with altered oral microbiome signatures in HIV+ patients, including a reduction in the microbiota diversity, changing the relative composition of specific phyla and species, and regulating microbial functions. Furthermore, we found that Streptococcus sp., one of the most increased species in the oral cavity of HIV+/KSHV+ patients, induced KSHV lytic reactivation in primary oral cells. Together, these data indicate that oral shedding of KSHV may manipulate the oral microbiome to promote viral pathogenesis and tumorigenesis especially in immunocompromised patients.

Gastric cancer is a kind of gastrointestinal tumor with high morbidity and mortality. Finding effective methods for early diagnosis and treatment of gastric cancer has important significance and application prospects. MicroRNAs without protein coding potential affect the occurrence and development of gastric cancer. This study aims to explore the biological function and mechanism of microRNA-107 (miR-107) in gastric cancer. The results show that miR-107 is low expressed in gastric cancer, while TRIAP1 is highly expressed; the overexpression of miR-107 can inhibit the progression of gastric cancer in vivo and in vitro, while the overexpression plasmid of TRIAP1 can restore the miR-107 mimic-induced cell proliferation and metastasis inhibition, and the small interfering RNA of TRIAP1 can inhibit the cell proliferation and invasion induced by miR-107 inhibitor. In conclusion, the results of this study show that miR-107 can inhibit the proliferation of gastric cancer in vivo and in vitro by targeting TRIAP1.

Abstract Background The broken guide wire could get stuck anywhere during coronary artery angiography, but the broken guide wire in the brachial artery is extremely rare. Case presentation In this report, we describe our experience with a case of off-pump coronary artery bypass (OPCABG) concomitant with the retrieval of a broken guide wire stuck in the brachial artery: a 56-year-old male patient was referred to our hospital because of tri-vessel disease and a broken guide wire stuck in the right brachial artery. He received OPCABG concomitant with the retrieval of the broken guide wire stuck in the brachial artery under general anesthesia. The patient was discharged uneventfully, and 12 months follow-up showed an excellent surgical outcome. Conclusion Open surgery is an effective means for treating patients with a guide wire stuck in the brachial artery during percutaneous coronary intervention.

Recent studies have shown human platelets can access the tumor microenvironment by passive diffusion across capillaries or via activated immune cells. In a previous study, we exploited this affinity of platelets for tumor cells as part of a new approach to target tumors with modified platelets. Therefore, the engineering of human nanoplatelets as living vehicles for in vivo tumor-targeted near-infra-red fluorescence (NIRF) imaging and the delivery of cytotoxins to tumor cells by endocytosis are described in this study. Nanoplatelets with an average diameter of 200 nm were prepared by mild sonication of kabiramide C (KabC)-loaded human platelets. The sealed plasma membrane of the nanoplatelets allows them to accumulate and retain membrane-permeable chemicals, such as epidoxorubicin (EPI) and KabC. Tumor-targeted imaging functionalities were engineered on the nanoplatelets by surface-coupling transferrin, Cy5 and Cy7. High-resolution fluorescence imaging and flow cytometry analyses showed that the nanoplatelets loaded with EPI and Cy5 targeted human myeloma cells (RPMI8226 cells) that over-expressed the transferrin receptor. The endocytosis of the nanoplatelets by RPMI8226 cells was transferrin-dependent and induced apoptosis. The test results also showed that the nanoplatelets functionalized with transferrin and Cy7 and injected in mice bearing RPMI8226 cells-derived myeloma xenotransplants accumulated in the tumor tissue and could be used for high-contrast in vivo NIRF imaging of early-stage tumors. Nanoplatelets represent a new class of living nano-vehicles that may efficiently target and deliver therapeutic agents and imaging probes to diseased tissues including tumors.

PurposeCarcinoma of unknown primary (CUP) is a clinically aggressive disorder with early tumor dissemination. Identifying molecular traits of CUP can be not only beneficial for a better therapeutic approach but also potentially valuable for patients with general metastatic dissemination.Patients and MethodsWe retrospectively investigated a total of 35 unique CUP cases. Tumor tissue samples were available in 26 patients, and plasma samples were available in 22 patients. Targeted sequencing was performed with a panel of 416 pan cancer-related genes.ResultsA genomic landscape of the CUP cohort showed that TP53 mutation was the most frequently observed mutation while MYC amplification was the most common CNV. Aberrant TP53, RTK-RAS, and PI3K signaling pathways were also prevalent, identified in more than half of the cases with tumor tissue. Around 58% of the CUP cases harbored homologous recombinant repair (HRR) pathway gene alterations. The tumor mutational load of CUP patients with altered HRR pathway displayed a significant increase than that of patients with intact HRR. Clinically actionable mutations were identified in eight patients, which may benefit from targeted therapies. Eight patients were treated with platinum-based chemotherapy, showing different responses, HRR, and LOH status.ConclusionCollectively, our data have provided much-need insights into the treatment options for patients diagnosed with CUP in the era of precision medicine.

AimsVarious kinds of surgical strategies and prostheses have been advocated to improve short-term and long-term outcomes in type A aortic dissection (TAAD). Large-scale repair of the pathological aorta is hard to generalize due to complex procedures. We aimed to investigate the performance, effectiveness and safety of a novel Sutureless Integrated Stented (SIS) graft prosthesis in TAAD patients undergoing total arch replacement (TAR) and frozen elephant trunk (FET) implantation surgery.MethodsAll patients admitted to Fuwai Hospital were prospectively screened. Urgent or scheduled surgery was arranged for eligible patients. The primary endpoint was operative mortality. Key secondary endpoints included stroke, spinal cord injury, unexpected aortic reoperation, and 1-year survival. Discharged patients were followed up with computed tomography angiography and transthoracic echocardiography at 3 months, 6 months, and 1 year after surgery. Performance, effectiveness and safety analyses were performed in those patients.ResultsBetween August 1 and September 3, 2020, ten TAAD patients were enrolled in this study and successfully implanted with the SIS graft prosthesis. The median (IQR) age was 56.50 (43.75, 66.75) years (range from 31 to 75), and seven patients were male (70.0%). All patients underwent ascending aorta replacement + TAR + FET and additional procedures when necessary. The median (IQR) operation time, cardiopulmonary bypass time and cross clamp time were 270.50 (218.50, 312.50), 110.00 (88.00, 125.75), 69.50 (51.25, 82.75) min, respectively. Of note, the median (IQR) circulatory arrest time was 9.00 (8.00, 9.00) min (range from 4 to 12). The median (IQR) lowest nasopharyngeal temperature was 26.75 (25.98, 27.67) °C. Follow-up was 100% completed. During the 1-year follow-up, no patients died, no severe adverse events occurred, and rate of freedom from aortic reintervention was 100%.ConclusionsThe SIS graft prosthesis was implanted in a novel sutureless way, which simplified the surgical procedure, shortened the circulatory arrest time and avoided deep hypothermia. The preliminary clinical outcomes and follow-up outcomes demonstrated the effectiveness and safety of this prosthesis. A large-scale trial is being conducted to further assess these findings.

Effective identification of the control model is one of the key aspects in improving the performance of the single gimbal control moment gyroscope (SGCMG) servo system. The accuracy and stability of the servo system can be improved by studying system identification and mechanical resonance frequency. In this study, firstly, the SGCMG gimbal servo system was simplified to a two-mass block model. The theoretical mathematical model of the system's transfer function and mechanical resonance frequency was derived. Secondly, this paper studied the effective suppression method for mechanical resonance. Thirdly, the mathematical model of the orthogonal correlation analysis method was deduced for system identification. Then, an experimental platform was investigated to obtain the frequency characteristic curve and the transfer function. Finally, the frequency characteristic curve obtained using the transfer function model was plotted and compared with the frequency characteristic curve obtained experimentally. Our results indicate that the orthogonal correlation analysis has a high identification accuracy.

Rapid release of biopharmaceutical products enables a more efficient drug manufacturing process. Multi-attribute methods that target several product quality attributes (PQAs) at one time are an essential pillar of the rapid-release strategy. The novel, high-throughput, and nondestructive multi-attribute Raman spectroscopy (MARS) method combines Raman spectroscopy, design of experiments, and multivariate data analysis (MVDA). MARS allows the measurement of multiple PQAs for formulated protein therapeutics without sample preparation from a single spectroscopic scan. Variable importance in projection analysis is used to associate the chemical and spectral basis of targeted PQAs, which assists in model interpretation and selection. This study shows the feasibility of MARS for the measurement of both protein purity-related and formulation-related PQAs; measurements of protein concentration, osmolality, and some formulation additives were achieved by a generic multiproduct model for various protein products containing the same formulation components. MARS demonstrates the potential to be a powerful methodology to improve the efficiency of biopharmaceutical development and manufacturing, as it features fast turnaround time, good robustness, less human intervention, and potential for automation.

Abstract Background An increasing number of studies have described the aberrant expression of homeobox (HOX) proteins in gastric cancer (GC), which is critically associated with the prognosis and clinicopathological characteristics of GC. This study was conducted to investigate the clinical value and action mechanisms of HOX proteins in GC. Methods A comprehensive search of PubMed, Embase, Web of Science and Cochrane Library was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) and the pooled odds ratio (OR) with its 95% CI were used to assess the effect of HOX protein expression on the prognosis and clinicopathological features of GC, respectively. Results Nineteen studies containing 3775 patients were selected for this study. Heterogeneity among HRs of overall survival (OS) was markedly high (I2 = 90.5%, p = 0.000). According to the subgroup analysis, increased expression of HOX protein in the downregulated subgroup was associated with a good prognosis for patients with GC (pooled HR: 0.46, 95% CI: 0.36–0.59, I2 = 3.1%, p = 0.377), while overexpression of HOX protein in the upregulated subgroup was correlated with a reduced OS (pooled HR: 2.59, 95% CI: 1.79–3.74, I2 = 73.5%, p = 0.000). The aberrant expression of HOX protein was crucially related to the TNM stage, depth of tumour invasion, tumour size, lymph node metastasis, distant metastasis, vascular invasion, histological differentiation and Lauren classification in patients with GC. In addition, the molecular mechanisms by which HOX proteins regulate tumorigenesis and development of GC were also explored. Conclusions HOX proteins play vital roles in GC progression, which might serve as prognostic markers and therapeutic targets for GC.

Abstract Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide and is characterized by highly hypoxic tumor microenvironment. Hypoxia-inducible factor-1 alpha (HIF-1α) is a major regulator of cellular response to changes in oxygen concentration, supporting the adaptation of tumor cells to hypoxia in an oxygen-deficient tumor microenvironment. Numerous studies revealed the central role of HIF-1α in the carcinogenesis and progression of pancreatic cancer. This article reviewed the molecular mechanisms of how HIF-1α regulated tumorigenesis and progression of pancreatic cancer and suggested that targeting HIF-1α and its signaling pathways could be promising therapeutics for pancreatic cancer.

Abstract Background Vascular calcification (VC) is an independent predictor of cardiovascular disease (CVD) present in 30–70% of patients with chronic kidney disease (CKD). Copeptin is a sensitive surrogate marker of arginine vasopressin (AVP), which is involved in many pathophysiologic processes in CKD. The aim of the present study was to explore the association of copeptin with VC in CKD stage 5. Methods Copeptin was investigated in conjunction with living donor kidney transplantation in 149 clinically stable CKD stage 5 patients (CKD5), including 53 non-dialyzed (CKD5-ND) and 96 dialysis patients treated by peritoneal dialysis (PD) (n = 43) or hemodialysis (HD) (n = 53). We analyzed the association of copeptin with presence and extent of VC ascertained both histologically in biopsies from the inferior epigastric artery (n = 137) and by coronary artery calcification (CAC) score measured by computed tomography. Results Patients with higher copeptin were older, had higher systolic blood pressure, higher prevalence of CVD and their preceding time on chronic dialysis was longer. In Spearman’s rank correlations (Rho), copeptin concentrations were significantly associated with CAC score (Rho = 0.27; p = 0.003) and presence of medial VC (Rho = 0.21; p = 0.016). Multivariate logistic regression analysis showed that 1-SD higher age, male gender, diabetes and 1-SD higher copeptin were significantly associated with the presence of moderate-extensive VC. Conclusions High circulating levels of copeptin in CKD5 patients are independently associated with the degree of medial calcification ascertained by histology of arterial biopsies. Thus, plasma copeptin may serve as a marker of the uremic calcification process.

Objective: The duration of hypothermic circulatory arrest (HCA) is one of the important factors affecting the prognosis of arch surgery, which is still controversial. The purpose of this study was to investigate the effect of HCA duration on early prognosis in type A aortic dissection (TAAD) patients who underwent arch surgery in our center.Methods: All consecutive patients who underwent surgical treatment for TAAD in Fuwai Hospital from January 2013 to December 2018 were included in this study and divided into four quartile groups based on HCA time. Baseline characteristics, perioperative indicators, and early mortality were statistically analyzed by propensity score matching (PSM) and restricted cubic spline (RCS) method. Perioperative adverse events were confirmed according to the American STS database and Penn classification.Results: About 1,018 consecutive patients (mean age 49.11 ± 1.4 years, male 74.7%) with TAAD treated surgically were eventually included in this study. After PSM, with the prolongation of HCA time, the surgical mortality rates of group [2,15], (15,18], (18,22], and (22,73] were 4.1, 6.6, 7.8, and 10.9% with p = 0.041, respectively. As shown in RCS, the mortality rate increased sharply after the HCA time exceeded 22 min. And from the subgroup analysis, the HCA time of 22 min or less was associated with better clinical outcomes (OR 2.09, 95%CI 1.25–3.45, p = 0.004).Conclusions: The early mortality increases significantly with the duration of HCA time when arch surgery was performed. And multiple systems throughout the body can be adversely affected.