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Nowadays, COVID - 19 outbreak still exists throughout the world and seriously affects people's lives, since the new crown vaccine on all kinds of media information about the vaccine, and people also never stopped, the discussions of the vaccine in this paper, the authors take the form of a random questionnaire, exploring a certain number of people. This paper investigated the relationship between the publics cognitive demand for vaccine information and attention level on the amount of vaccine knowledge they acquire and the degree of relevant thinking, and used the Cognitive Mediation Model (CMM) to conduct a series of data analyses, and observe some phenomena. For example, the publics perception of vaccine information demand positively related to public attention, focus on epidemic information level, and the relationship between the publics perception of vaccine information demand was positively associated with the degree of involvement with the public to think. The public of vaccine information and relational thinking levels was positively related to the level of attention level and public attention to vaccine information for vaccine utility were positively correlated

Financial risks are characterized by complexity, concealment, abruptness, infectivity and harmfulness. In the 40 years since the establishment of China's Special Economic Zone, Shenzhen's financial industry has become the third largest financial center on the mainland. At present, the financial industry has developed into one of the four pillar industries in Shenzhen. The significance of this paper is to explore and evaluate the regional financial risks in Shenzhen, and put forward targeted suggestions for Shenzhen's banking, securities and insurance, and real estate markets according to the quantitative results. Based on the annual data of Shenzhen from 2000 to 2020, entropy weight method and CRITIC method are used to determine the weight of grading indicators. This paper proposes three innovative scenarios using Holt Winters three exponential smoothing method to predict data. Finally, the risk scoring system is constructed according to the scenario analysis results, and optimization suggestions are put forward according to the early warning results.

Synthesizing ring structure aviation fuels from biomass-derived platform molecules is challenging, especially for bridged ring structure aviation fuels which are typically achieved from fossil-derived chemicals. Herein, we report the synthesis of a series of ring structure biofuels in two steps by a combination of a solvent-free Michael-cyclization reaction and a hydrodeoxygenation (HDO) reaction from lignocellulose-derived 5,5-dimethyl-1,3-cyclohexanedione. These biofuels are obtained with high overall yields up to 90%, which exhibit high densities of 0.81 g cm−3-0.88 g cm−3 and high volumetric neat heat of combustion (VNHOC) values of 36.0 MJ L−1-38.6 MJ L−1. More importantly, bridged-ring structure hydrocarbons can also be achieved in two steps by a combination of a Robinson annulation reaction and an HDO reaction to afford the final products at high overall yields up to 90%. The bridged-ring structure products have comparable high densities and high VNHOC values to the best artificial fuel JP-10 (0.94 g cm−3 and 39.6 MJ L−1). The results demonstrate a promising way for the synthesis of high-density aviation fuels with different fuel properties at high yields.

Idiopathic pulmonary fibrosis (IPF) is a poorly understood, progressive lethal lung disease with no known cure. In addition to alveolar epithelial cell (AEC) injury and excessive deposition of extracellular matrix proteins, chronic inflammation is a hallmark of IPF. Literature suggests that the persistent inflammation seen in IPF primarily consists of monocytes and macrophages. Recent work demonstrates that monocyte-derived alveolar macrophages (moAMs) drive lung fibrosis, but further characterization of critical moAM cell attributes is necessary. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an important epidermal growth factor receptor ligand that has essential roles in angiogenesis, wound healing, keratinocyte migration, and epithelial-mesenchymal transition. Our past work has shown HB-EGF is a primary marker of profibrotic M2 macrophages, and this study seeks to characterize myeloid-derived HB-EGF and its primary mechanism of action in bleomycin-induced lung fibrosis using

Background To summarize the characteristics and treatment, and analyze the prognosis of large number of infants with retinoblastoma (RB) in China through a multicenter, 10-year retrospective analysis. Methods The data of RB infants were collected from multiple centers. The characteristics and survival prognosis were analyzed. The overall survival (OS) rate was estimated by the Kaplan–Meier method. Multivariate Cox survival analysis was to evaluate the independent risk factors affecting the prognosis of RB infants. Results A total of 373 RB infants (202 boys and 171 girls) were included, the median age was 6.22 months (10 days to 11.93 months). The median follow-up time of RB infants was 18.4 (1.02–122.81 months). After excluding the lost to follow-up cases, the OS rate was 97.7% (345/353). Kaplan–Meier survival analysis indicated that 9 cases died and the median survival time was not reached. Univariate analysis of prognostic factors revealed eye affected, presenting signs, left eye stage and recurrence to be poor prognostic factors for OS rate in RB infants (all P P = 0.048) was an independent factor for prognosis of infants with RB. The median survival time of infants underwent chemotherapy + intra-arterial chemotherapy (IAC) + enucleation + vitrectomy was the longest than other treatments (n = 9, 47.64 months, OS = 100%, all P Conclusion Recurrence is an independent factor for prognosis of RB infants, which still needs attention after treatment. Early screening, comprehensive treatments and follow-up of patients may lead to improvements of prognosis of RB infants.

Backgrounds: Autoimmune thyroiditis (AIT) is closely associated with major depressive disorder (MDD). However, its association with suicide attempts (SA) in this population remains unexplored. The study aimed to assess the prevalence and correlates of SA in first-episode drug-naïve (FEDN) MDD patients with AIT. Methods: We recruited 1718 FEDN MDD outpatients and assessed depressive, anxiety, and psychotic symptoms by the Hamilton Rating Scale for Depression (HAMD), the Hamilton Rating Scale for Anxiety, and the Positive and Negative Syndrome Subscale positive subscale, respectively. The serum levels of free triiodothyronine, free thyroxine, thyroid stimulating hormone (TSH), anti-thyroglobulin, thyroid peroxidases antibody (TPOAb), and several other metabolic parameters were assessed. Multiple logistic regression model was applied to identify the correlates of SA in AIT MDD patients. The Area Under the Curve (AUC) was used to test the performance of this model. Results: The prevalence of SA was higher in AIT patients than in non-AIT patients (34% vs 14%, pConclusions: Taken together, AIT was closely associated with SA. Regular thyroid examination may help detect SA in MDD patients.

Synthesizing high-density fuels from non-food biomass is of great interest in the field of biomass conversion because they can increase the loading capability and travel distance of vehicles and aircraft as compared to conventional low-density biofuels (0.78 g/cm

At present, the number of watershed eco-compensations in China is increasing. And the area covered by a single project is also increasing. Under the current model, governments are the primary source of funding. It is difficult to meet the growing funding gap of subsidies. Researches on watershed eco-compensation need to reform and explore a new model for it, expand the fund source of watershed eco-compensation expense, and establish a sustainable "hematopoietic" model. This paper clarifies the concept of watershed eco-compensation and then compares the design principles of eco-compensation projects, definitions of stakeholders, analysis, and summary of watershed eco-compensation models in different regions. It can be found that the model in which the government dominates is still the mainstream. However, the considerable cost of this model will be a heavy burden for governments. Therefore, it becomes an important option to involve more stakeholders in these projects, and governments should transfer part of the lead to dilute costs. How to reduce the expenditures of governments in watershed eco-compensation projects under the premise of maintaining normal operation of the projects has become an important exploration direction concerning watershed eco-compensation in China, which requires transforming from "blood transfusion" to "hematopoiesis."

Huali Gu,1 Yizhuo Wang,1 Dongsheng Huang,1 Xunda Ji,2 Yi Zhang,1 Jianmin Ma,3 Mei Li,4 Weiling Zhang,1 Huimin Hu,1 Jing Li,1 Pinwei Zhang1 1Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Ophthalmology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Ophthalmic Oncology, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Nuclear Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Dongsheng Huang, Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, West South Road 2, Yizhuang Economic and Technological Development Zone, Daxing District, Beijing, 100176, People’s Republic of China, Tel +86 01058266032, Email hds5180@sina.com Xunda Ji, Department of Ophthalmology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Kong Jiang Road 1665, Shanghai, 200092, People’s Republic of China, Tel +86 15921670980, Email jixunda@xinhuamed.com.cnPurpose: Retinoblastoma (RB) is the most common intraocular malignancy in infancy and childhood. This study evaluated the clinical and imaging features, treatment, and prognosis of patients with recurrent RB with limb bone metastases and without central nervous system involvement.Patients and Methods: The clinical data of five patients with RB with limb bone metastases who were diagnosed at the Department of Pediatrics in Beijing Tongren Hospital between January 2015 and January 2021 were analyzed retrospectively.Results: Three males and two females were included (seven eyes: four group E and one each of group D, C, and B). The most common symptom was pain. Three patients had bone marrow and lymph node metastases. Three patients had single and two had multiple skeletal lesions. The main bones that were involved were the femur, humerus, talus, and ulna. The simultaneous involvement of the bone marrow and cortex was also observed. Serum neuron-specific enolase (NSE) levels were significantly elevated in four cases and slightly elevated in one case; primary intravenous chemotherapy resulted in a decrease in NSE levels and the gradual resolution of the bone lesions. Two patients died at the time of follow-up and three were in complete remission. The results of the statistical analysis showed that anterior chamber invasion was correlated with prognosis, and there was significant difference in the decrease in the serum NSE levels after intravenous chemotherapy.Conclusion: Regular lifelong follow-up of patients with RB is warranted to identify bone metastases earlier. Anterior chamber invasion may be a risk factor. The simultaneous involvement of the bone marrow and cortex is characteristic manifestations in images of RB with bone metastases. Multidisciplinary treatment especially intravenous chemotherapy is useful, at least at the beginning.Keywords: recurrent, NSE, SRE, pathological fracture, pamidronate, osteoclast inhibitors

A biopolymer-carbon nanotube (CNT) composite exhibits a high power factor of >2500 μW m−1 K−2 with a high electrical conductivity of about 7450 S cm−1 at a relatively low CNT concentration.

Communication in multi-agent systems is a key driver of team-level cooperation, for instance allowing individual agents to augment their knowledge about the world in partially-observable environments. In this paper, we propose two reinforcement learning-based multi-agent models, namely FCMNet and FCMTran. The two models both allow agents to simultaneously learn a differentiable communication mechanism that connects all agents as well as a common, cooperative policy conditioned upon received information. FCMNet utilizes multiple directional recurrent neural networks to sequentially transmit and encode the current observation-based messages sent by every other agent at each timestep. FCMTran further relies on the encoder of a modified transformer to simultaneously aggregate multiple self-generated messages sent by all agents at the previous timestep into a single message that is used in the current timestep. Results from evaluating our models on a challenging set of StarCraft II micromanagement tasks with shared rewards show that FCMNet and FCMTran both outperform recent communication-based methods and value decomposition methods in almost all tested StarCraft II micromanagement tasks. We further improve the performance of our models by combining them with value decomposition techniques; there, in particular, we show that FCMTran with value decomposition significantly pushes the state-of-the-art on one of the hardest benchmark tasks without any task-specific tuning. We also investigate the robustness of FCMNet under communication disturbances (i.e., binarized messages, random message loss, and random communication order) in an asymmetric collaborative pathfinding task with individual rewards, demonstrating FMCNet’s potential applicability in real-world robotic tasks.

The higher heating value (HHV) was an important factor for measuring the energy recovery price of sewage sludge, which was commonly determined by oxygen bomb calorimeter; however, there were problems of time consuming and high measurement cost. In this study, a back-propagation neural network (BPNN) model based on proximate and ultimate combination analysis was developed to predict the HHV of sewage sludge and the accuracy of the model was illustrated using statistical analysis. The results showed that the BPNN model had good accuracy, with a regression coefficient of 0.979 and 0.975 for the training and test groups, respectively. Several previously proposed linear models for predicting the HHV of sewage sludge were selected for comparison. The results showed that the BPNN model was the best among all models with the highest regression coefficient (0.975) and the lowest mean absolute deviation (0.385).

The outstanding electrical and mechanical properties remain elusive on macroscopic carbon nanotube (CNT) films because of the difficult material process, which limits their wide practical applications. Herein, we report high-performance multifunctional MWCNT films that possess the specific electrical conductivity of metals as well as high strength. These MWCNT films were synthesized by a floating chemical vapor deposition method, purified at high temperature and treated with concentrated HCl, and then densified due to the developed chlorosulfonic acid-enhanced zipping effect. These large scalable films exhibit high electromagnetic interference shielding efficiency, high thermoelectric power factor, and high ampacity because of the densely packed crystalline structure of MWCNTs, which are promising for practical applications.

Background: Ovarian sensitivity index (OSI) is an accurate index to reflect the ovarian sensitivity to exogenous gonadotropins in in vitro fertilization (IVF). How insulin resistance (IR) affects OSI and pregnancy outcomes during IVF remains unclear. Methods: This was a large retrospective, cohort study. A total of 2055 women with polycystic ovary syndrome (PCOS) undergoing the first fresh IVF cycle were enrolled. They were grouped into terciles based on the homeostasis model assessment of insulin resistance (HOMA-IR) values as control, medium and IR group for comparison. Multivariate regression analysis was also conducted. Results: HOMA-IR had a significantly negative impact on OSI (adjusted β = −0.24; 95% CI, −0.35 to −0.13), especially in lean patients with an adjusted β of −0.33 (95% CI, −0.51 to −0.16). The interaction analysis revealed an interactive association between HOMA-IR and body mass index (BMI) (p = 0.017). IR was related to an increased early miscarriage risk independently with an odds ratio (OR) of 2.21 (95% CI, 1.13 to 4.33), without significant impact on pregnancy and live birth rate. Conclusion: IR decreased the ovarian response in PCOS patients undergoing IVF, especially in the lean subgroup. IR may result in a higher risk of early miscarriage, but did not impair pregnancy and live birth rate.

The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1β production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic Escherichia coli (UPEC). HDAC7-mediated PPP engagement via 6-phosphogluconate dehydrogenase (6PGD) generates NADPH for antimicrobial ROS production, as well as D-ribulose-5-phosphate (RL5P) that both synergizes with ROS for UPEC killing and suppresses selective inflammatory responses. This dual functionality of the HDAC7-6PGD-RL5P axis prioritizes responses to proximal threats. Our findings thus reveal that the PPP metabolite RL5P has both antimicrobial and immunomodulatory activities and that engagement of enzymes in catabolic versus anabolic metabolic pathways triages responses to different types of danger for generation of inflammatory versus antimicrobial responses, respectively.

Recently, increasing attention has been paid to heavy metals in sludge. However, limited literature could be found on the distribution characteristics of heavy metals in sludge and their potential risks. In this study, sludges from wastewater plants in Jiangsu Province (China) were selected for the investigation of heavy metal loadings, showing that typical heavy metal levels were in the order of Zn > Cu > Cr > Ni > Pb > As > Hg > Cd, ranging from 154 to 2970 mg/kg, 28 to 1150 mg/kg, 10 to 136 mg/kg, 9 to 262 mg/kg, 0 to 79 mg/kg, 12.1 to 41.6 mg/kg, 0.67 to 19.50 mg/kg and 0.21 to 2.77 mg/kg, respectively. Analysis of the typical heavy metal distribution in sludge indicated that Hg, Zn and Cu were obviously influenced by the degree of industrial intensity and exploitation of human activities, while Ni, Cd, Pb, As and Cr were more evenly distributed. Effects of sewage sources and wastewater-treatment processes on heavy metal levels implied that different industrial wastewaters resulted in different metal contents, but the distribution of Ni, Cd, Pb, As and Cr in different treatment processes was similar. Furthermore, Hg and Cd had the strongest ecological risk, with their levels reaching severe, suggesting that sludge was not recommended for agricultural reuse in this study.

Recently, due to the abundance of carbon, nitrogen and phosphorus in municipal sewage sludge (MSS), the energy potential of MSS has become increasingly prominent. Economically developed regions possess more financial and policy support advantages for the development of MSS energy recovery technology; hence, the selection of the appropriate sludge treatment and disposal technologies to maximize the energy potential of MSS is of great importance. In this study, the energy recovery potential of MSS was evaluated on the basis of regional economies, sludge analysis, a main sludge energy reuse technology review and legislative profile analysis. As the most commonly adopted technology, incineration had a lower energy potential, which may be ascribed to the high moisture content, high disposal costs and difficulties in in situ energy recovery. In contrast, the energy potential for anaerobic digestion, pyrolysis and gasification was relatively high. By conducting a SWOT-FAHP analysis, management evaluation of these four technologies was carried out from the following four perspectives: problem solving, technology development, ecological environment and laws and regulations. Pyrolysis was evaluated to be the most suitable technology from the technical and environmental perspectives because its products had high energy potential and avoided heavy metal problems. The obstacles and problems that pyrolysis technology might encounter in commercial applications in the future are discussed. With this energy-generating, low energy consumption, low-pollution sludge energy reuse technology, the potential of sludge pyrolysis would be high in the long run. These results revealed the factors affecting the energy recovery potential of sludge, and comprehensively evaluated the technologies from the aspects of problem solving, environmental impact, technology development and law, the optimal solution obtained could provide reference on the management decision of sludge disposal technology for economically developed areas in the future.

Purpose Colorectal cancer is a high incidence tumor, immunotherapy has become a hot topic of research in recent years, at the same time, the dysregulation of intestinal microbiota is also gaining attention because it can lead to changes in body immunity. So, we want to explore the relationship between gut microbiota and colorectal cancer. Methods We performed 16S rRNA high-throughput sequencing of tumors and paraneoplastic tissues from 30 patients, followed by at least 5 years of follow-up. Microbiome analysis, survival analysis, and then immunohistochemistry and its correlation with microbiota were performed in 19 of these patients. Results OTU13530 and OTU17086, both representing g_Sediminibacterium, showed significant differences in normalized abundance in tumor and paraneoplastic tissues (FDR 2FC > 1). Both of them correlated with T-stage (p = 0.016, p = 0.024) and Her-2 expression (p = 0.034, p = 0.001). The former correlated with HIF expression (p = 0.017), and the latter with EGFR expression (p = 0.003). OTU3504, representing o_Myxococcales, had a correlation with patient survival (p = 0.015, HR = 28.5(1.9–425.0)), its abundance correlated with tumor neural invasion (p = 0.005) and vascular invasion (p = 0.005). Conclusion There is no statistical difference in the diversity and homogeneity of the microbiota between tumor and paraneoplastic tissues. But the abundance of some specific microbiota differed significantly between tumor and paraneoplastic tissues, and these microbiota correlated with patient survival, Her-2, HIF and other proteins expression, T-stage, neurovascular invasion and other clinical traits.

TLRs reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulates both TLR-inducible glycolysis and inflammatory responses. Here, we show that the TLR4 agonist LPS, as well as agonists of other TLRs, rapidly increase enzymatic activity of the class IIa HDAC family (HDAC4, 5, 7, 9) in both primary human and murine macrophages. This response was abrogated in murine macrophages deficient in histone deacetylase 7 (Hdac7), highlighting a selective role for this specific lysine deacetylase during immediate macrophage activation. With the exception of the TLR3 agonist polyI:C, TLR-inducible activation of Hdac7 enzymatic activity required the MyD88 adaptor protein. The rapid glycolysis response, as assessed by extracellular acidification rate, was attenuated in Hdac7-deficient mouse macrophages responding to submaximal LPS concentrations. Surprisingly however, reconstitution of these cells with either wild-type or an enzyme-dead mutant of Hdac7 enhanced LPS-inducible glycolysis, whereas only the former promoted production of the inflammatory mediators Il-1β and Ccl2. Thus, Hdac7 enzymatic activity is required for TLR-inducible production of specific inflammatory mediators, whereas it acts in an enzyme-independent fashion to reprogram metabolism in macrophages responding to submaximal LPS concentrations. Hdac7 is thus a bifurcation point for regulated metabolism and inflammatory responses in macrophages. Taken together with existing literature, our findings support a model in which submaximal and maximal activation of macrophages via TLR4 instruct glycolysis through distinct mechanisms, leading to divergent biological responses.

Chronic wounds remain a worldwide clinical challenge, and bioactive materials that can promote skin regeneration are required. Self-assembling peptide (SAP) hydrogels have shown great potential in tissue repair, but their regenerative efficacy and possible mechanism in chronic wound healing are unclear. Here, we report an SAP (KGH) that enhances extracellular matrix (ECM) remodeling and angiogenesis, thereby promoting chronic wound healing in diabetic mice. In vivo, the KGH hydrogel was retained in wounds up to 7 days after injection, and it was effective in speeding up wound closure by ∼20% compared to the control groups and enhancing angiogenesis (e.g., VEGFA, CD31+ capillaries), cell proliferation (e.g., PCNA+ cells), formation of granulation tissue (e.g., α-SMA), and ECM deposition/remodeling (e.g., collagen I, fibronectin). In vitro, the KGH hydrogel created a 3D microenvironment for skin cells, maintained the sustained growth of cell spheroids, and increased the secretion of ECM proteins (e.g., laminin) and growth factors (e.g., PDGFB, VEGFA, and TGF-β) in skin keratinocytes compared to the conventional 2D culture. Mechanistically, the KGH hydrogel might promote wound tissue regeneration by activating the Rho/ROCK and TGF-β/MEK/MAPK pathways. As a type of designed material, SAP can be further re-engineered with biological motifs, therapeutic reagents, or stem cells to enhance skin regeneration. This study highlights that SAP hydrogels are a promising material platform for advanced chronic wound healing and might have translational potential in future clinical applications. Statement of significance Chronic wounds are a common and serious health issue worldwide, and bioactive dressing materials are required to address this issue. SAP hydrogels have shown certain tissue repair potential, but their regenerative efficacy and underlying mechanism in chronic wound healing remain elusive. Herein, we report that SAP hydrogels create a native 3D microenvironment that can remarkably stimulate angiogenesis and ECM remodeling in diabetic wounds. Mechanistically, the SAP hydrogel promoted ECM proteins and GFs secretion in skin cells through the activation of the Rho/ROCK and TGF-s/MEK/MAPK pathways. Additionally, SAP can be readily engineered with various bioactive motifs or therapeutic drugs/cells. This work highlights SAP hydrogels as a promising biomaterial platform for chronic wound healing and the regeneration of many other tissues.

BACKGROUND Multiple primary malignant tumors are two or more malignancies in an individual without any relationship between the neoplasms. In recent years, an increasing number of cases have been reported. However, concomitant primary gastric and pancreatic cancer reported a relatively small incidence, involving no pancreatic acinar cell carcinoma reports. Here, we present the first case of concomitant pancreatic acinar cell carcinoma and gastric adenocarcinoma. CASE SUMMARY A 69-year-old male presented to our department with a history of vomiting, epigastric pain, and weight loss. Imaging revealed space-occupying lesions in the stomach and the tail of the pancreas, respectively. The patient underwent laparoscopic radical gastrectomy and pancreatectomy simultaneously. The pathologies of surgical specimens were completely different: The resected gastric specimen was moderate to poorly differentiated adenocarcinoma, whereas the pancreatic tumor was consistent with acinar cell carcinoma. The patient was treated with six cycles of oxaliplatin and S-1 chemotherapy. As of March 2021, the patient was healthy without any recurrence or metastasis. After thoroughly reviewing the literature on simultaneous pancreatic and gastric cancers at home and abroad, we discussed the clinical characteristics of these rare synchronous double cancers. Most of the cases had undergone surgery and adjuvant chemotherapy, and all of the cases were pathologically confirmed by the postoperative specimen. CONCLUSION Synchronous pancreatic acinar cells and gastric adenocarcinoma can occur and should be considered when tumors are found in these organs.

Typically, conducting polymers transfer either electrons or holes. It is rare to see high bipolar (p- and n-type) electrical conductivities within a single bulk doped organic polymer without the as...

Acute kidney injury (AKI) is a serious disease for which effective therapeutic agents are required. The capacity of curcumin (CUR) to resolve renal inflammation/oxidative stress and mitochondrial damage has been reported, but crosstalk between these effects and the consequence of this crosstalk remain elusive. In this study, a hypoxia/reoxygenation (H/R)‐induced renal tubular epithelial cell (TEC) injury model and an ischaemia/reperfusion (I/R)‐induced mouse AKI model were treated with CUR with or without mitochondrial inhibitors (rotenone and FCCP) or siRNA targeting mitochondrial transcription factor A (TFAM). Changes in mitochondrial function, inflammation, the antioxidant system and related pathways were analysed. In vitro, CUR suppressed NFκB activation and cytokine production and induced NRF2/HO‐1 signalling in TECs under H/R conditions. CUR treatment also reduced mitochondrial ROS (mtROS) and mitochondrial fragmentation and enhanced mitochondrial biogenesis, TCA cycle activity and ATP synthesis in damaged TECs. However, the anti‐inflammatory and antioxidant effects of CUR in damaged TECs were markedly abolished upon mitochondrial disruption. In vivo, CUR treatment improved renal function and antioxidant protein (NRF2 and SOD2) expression and reduced oxidative stress (8‐OHdG), tubular apoptosis/death, cytokine release/macrophage infiltration and mitochondrial damage in the kidneys of AKI mice. In vitro, the anti‐inflammatory and antioxidant effects of CUR in damaged kidneys were impaired when mitochondrial function was disrupted. These results suggest mitochondrial damage is a driving factor of renal inflammation and redox imbalance. The therapeutic capacity of CUR in kidneys with AKI is primarily dependent on mitochondrial mechanisms; thus, CUR is a potential therapy for various diseases characterized by mitochondrial damage.

Organ fibrosis is a serious health challenge worldwide, and its global incidence and medical burden are increasing dramatically each year. Fibrosis can occur in nearly all major organs and ultimately lead to organ dysfunction. However, current clinical treatments cannot slow or reverse the progression of fibrosis to end-stage organ failure, and thus advanced anti-fibrotic therapeutics are urgently needed. As a type of naturally derived nanovesicle, native extracellular vesicles (EVs) from multiple cell types (e.g., stem cells, immune cells, and tissue cells) have been shown to alleviate organ fibrosis in many preclinical models through multiple effective mechanisms, such as anti-inflammation, pro-angiogenesis, inactivation of myofibroblasts, and fibrinolysis of ECM components. Moreover, the therapeutic potency of native EVs can be further enhanced by multiple engineering strategies, such as genetic modifications, preconditionings, therapeutic reagent-loadings, and combination with functional biomaterials. In this review, we briefly introduce the pathology and current clinical treatments of organ fibrosis, discuss EV biology and production strategies, and particularly focus on important studies using native or engineered EVs as interventions to attenuate tissue fibrosis. This review provides insights into the development and translation of EV-based nanotherapies into clinical applications in the future.

Jing Li,* Weiling Zhang,* Huimin Hu, Yi Zhang, Yizhuo Wang, Huali Gu, Dongsheng Huang Department of Pediatrics, Beijing Tongren Hospital of China Capital Medical University, Beijing, 100176, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongsheng HuangDepartment of Pediatrics, Beijing Tongren Hospital of China Capital Medical University, No. 1 Dongjiao Lane, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel +86 10 5826 6032Email huamgdomgshemg@163.comObjective: This study aims to summarize the clinical features and prognoses of the malignant rhabdoid tumor of the kidney (MRTK) in children. It further aims to analyze the high-risk factors affecting MRTK prognosis.Methods: Clinical data from 14 children with MRTK treated in Paediatrics of Beijing Tongren Hospital from January 2010 to December 2019, along with the high-risk factors affecting prognosis, were retrospectively analyzed.Results: There were 14 children with MRTK included in the study, with a median onset age of 13 (3– 46) months. Thirteen patients had distant metastases, the most common site for metastases being inside the lung. A comprehensive treatment protocol combined with chemotherapy was mainly applied during the surgery. A surgical resection of primary tumors was performed on 13 (13/14) patients, and all 14 children received chemotherapy with ifosfamide + carboplatin + etoposide, ifosfamide + etoposide, and vincristine + pirarubicin + cyclophosphamide regimens, alternately. Three patients received radiotherapy and two received oral targeted drugs after partial response. The median follow-up was after 16.5 months (3– 53 months) and the four-year overall survival (OS) was 41.8%. In children aged ≤ 24 months and children aged > 24 months, the two-year OS was 67.2% and 100% (χ2 = 108.998, P< 0.05), respectively. In children with Ki 67 > 70% and children with Ki 67 < 70%, the two-year OS was 52.6% and 86.9% (χ2 = 8.544, P = 0.003), respectively. In children with distant metastases and children without distant metastasis, the two-year OS was 70% and 100% (χ2 = 14.239, P< 0.05), respectively.Conclusion: The most common MRTK distant metastasis site is the lung. Risk factors for poor MRTK prognoses include an age of < 24 months, Ki 67 > 70%, and distant metastases.Keywords: children, malignant rhabdoid tumor of the kidney, MRTK, treatment, prognosis

Kidney diseases are a serious health issue worldwide, and novel therapeutics are urgently needed. Extracellular vesicles (EVs) have emerged as potent drug delivery systems (DDSs), but their therapeutic potential is limited by short circulation times and insufficient renal retention. Here, we report that endogenous ligand (albumin, ALB) binding is an efficient modification strategy to improve the therapeutic potency of EV-based DDSs for kidney diseases. Surface albumin-binding peptide (ABP)-displayed EVs (ABP-EVs) were produced by transfecting parent cells with the ABP-Lamp2b fusion plasmid. Compared with unmodified EVs (NC-EVs), ABP-EVs showed increased binding to ALB in vitro and elevated circulation time and multiple organ retention in vivo after systemic (iv) injection. Moreover, ABP-EVs had higher renal retention than NC-EVs in mice with acute kidney injury through a complex mechanism involving microvascular injury and megalin-mediated endocytosis. As a result, delivery of small molecule drugs (e.g., curcumin) or proteins (e.g., hepatocyte growth factor) by ABP-EVs had superior therapeutic (e.g., anti-apoptotic, antioxidant, anti-inflammatory) effects in vitro and in vivo. This study highlights that ABP-EVs are versatile DDSs for kidney diseases and provides insights into the new strategies of engineering EVs for drug delivery.

Impaired learning and memory ability is one of the characteristics of a variety of neurological diseases, and its molecular mechanisms are complex and diverse and are regulated by a variety of factors. It is generally believed that synaptic plasticity plays an important role in the process of learning and memory. The protein encoded by the

Energy industry is a vital area related to the security and economic development of a sovereign country, and the green and low carbon development is becoming the main development direction of global energy technology innovation (ETI). Driven by the energy revolution and the digital revolution, a new round of global technological revolution and industrial transformation is in the ascendant ...

Data analyses by machine learning (ML) algorithms are gaining popularity in biomedical research. When time-to-event data are of interest, censoring is common and needs to be properly addressed. Most ML methods cannot conveniently and appropriately take the censoring information into consideration, potentially leading to inaccurate or biased results. We aim to develop a general-purpose method for imputing censored survival data, facilitating downstream ML analysis. In this study, we propose a novel method of imputing the survival times for censored observations. The proposal is based on their conditional survival distributions (CondiS) derived from Kaplan-Meier estimators. CondiS can replace censored observations with their best approximations from the statistical model, allowing for direct application of ML methods. When covariates are available, we extend CondiS by incorporating the covariate information through ML modeling (CondiS-X), which further improves the accuracy of the imputed survival time. Compared with existing methods with similar purposes, the proposed methods achieved smaller prediction errors and higher concordance with the underlying true survival times in extensive simulation studies. We also demonstrated the usage and advantages of the proposed methods through two real-world cancer datasets. The major advantage of CondiS is that it allows for the direct application of standard ML techniques for analysis once the censored survival times are imputed. We present a user-friendly R package to implement our method, which is a useful tool for ML-based biomedical research in this era of big data.

Herein, we describe a three-step synthesis strategy starting with a chemical kinetics-governed one-pot two-step reaction. A series of biomass-derived molecules have been converted into ring-structu...

Background: Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in hematologic malignancies but limited success in solid tumors. GCC19CART, the first clinical candidate from the CoupledCAR solid tumor platform, is designed to overcome the limitations of conventional CAR T-cells in solid tumor malignancies by pairing solid tumor CAR T-cells with CD19 targeting CAR T-cells to amplify proliferation and activation of the solid tumor CAR T component. GCC19CART targets guanylate cyclase-C (GCC) which is expressed in the metastatic lesions of 70%-80% of subjects with colorectal cancers. A Phase 1 investigator-initiated clinical trial is underway in China for patients with relapsed or refractory metastatic colorectal cancer who have received at least 2 prior lines of therapy. Based on a data cutoff on October 20, 2022 21 subjects have been enrolled in 2 dose escalation groups at 5 hospitals in China. Methods: Subjects are screened for GCC expression by immunohistochemistry. Eligible subjects undergo leukapheresis, a single dose of lymphodepleting chemotherapy (fludarabine 30mg/m2 and cyclophosphamide 300mg/m2) 3 days prior to infusion, and then administration of a single infusion of GCC19CART at one of two preassigned doses: 1 × 106 or 2 × 106 CAR T-cells/kg. Endpoints are safety and preliminary evidence of efficacy as determined by CT or PET/CT per RECIST 1.1 or PERCIST 1.0. All responses were confirmed by an independent third-party imaging contract research organization (CRO). Results: 13 subjects have been enrolled to dose level 1 (1 × 106 cells/kg) and 8 subjects have been enrolled to dose level 2 (2 × 106 cells/kg). The most common adverse events were cytokine release syndrome (CRS) in 21/21 subjects (Grade 1 19/21 (90.48%) or Grade 2 2/21 (9.52%)) and diarrhea in 21/21 subjects (Grade 1 6/21 (28.57%) Grade 2 5/21 (23.81%) Grade 3 9/21 (42.86%) or Grade 4 1/21 (4.76%)). Neurotoxicity was observed in 2/21 (9.52%) subjects at Grade 3 or 4 and resolved with corticosteroids. The combined overall response rate (ORR) for both dose levels was 28.6% (6/21). For dose level 1, the overall response rate (ORR) per RECIST 1.1 was 15.4% (2/13). Two subjects demonstrated a partial response (PR) while 3 additional subjects had partial metabolic response (PMR) on PET/CT with stable disease (SD) or progressive disease (PD) per RECIST 1.1. For dose level 2, The ORR per RECIST 1.1 was 50% (4/8). 4 subjects demonstrated a PR (3 at month 1, 1 at month 3 after being SD at month 1) and 2 additional subjects had PMR on PET/CT with SD per RECIST 1.1. Conclusions: preliminary data show that GCC19CART has meaningful dose dependent clinical activity and an acceptable safety profile in relapsed or refractory metastatic colorectal cancer. This trial is ongoing and updated data will be presented. A Phase 1 trial of GCC19CART in the US under a cleared IND is expected to enroll patients from mid-2022. Citation Format: Naifei Chen, Chengfei Pu, Lingling Zhao, Ning Li, Chang Wang, Yusheng Huang, Suxia Luo, Xun Li, Zhenzhou Yang, Jun Bie, Ruihong Zhu, Xi Huang, Haiyang Tang, Tingting Liang, Yizhuo Wang, Beibei Jia, Dongqi Chen, Zhao Wu, Yongping Song, Victor Lu, Lei Xiao, Jiuwei Cui. A phase 1 dose escalation study of GCC19CART - a novel CoupledCAR therapy for subjects with metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1130.