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Chronic heat stress caused by global warming can have serious implications for fish survival. The kidney plays a central role in many homeostatic functions, including water and electrolyte regulation, as well as acid-base balance. However, there is limited knowledge about the effect of heat stress on fish kidneys, especially in cold-water fish species. In this study, we investigated the effects of mild heat stress (24℃, M) and high heat stress (28℃, H) on A. baerii kidneys using histological observation, flow cytometry detection, and RT-qPCR. Our histological observations revealed that heat stress significantly caused infiltration of inflammatory cells in the kidney, especially at 28℃. The flow cytometry assay demonstrated a significant increase in the number of apoptotic cells after heat stress at 28°C compared to the control group at 20°C (P < 0.05). Meanwhile, the mRNA expression levels of inflammation factors (IL-1β and TNF-α) did not differ significantly. However, the mRNA expression levels of heat shock proteins (HSP70, HSP90, and GRP75) were increased in A. baerii. In summary, this study provides insight into the effect of heat stress on A. baerii kidneys and contributes to understanding the coping strategies of cold-water fish to chronic heat stress.

Background COVID-2019 has become a public health crisis, and as a vulnerable group, people with disabilities (PWDs) might be more seriously affected. However, the overall impact of COVID-19 on PWDs is unclear in Mainland China. Thus, we aimed to analyze the overall impact on PWDs from the early remission stage to the regular control stage of the COVID-19 pandemic in Mainland China. Methods In March 2020 and March 2021, anonymous questionnaires were distributed in the WeChat group of the PWDs using a convenient sampling method. The personal and family characteristics, perceived risk of COVID-19 infection, and the overall impact of COVID-19 on daily life and medical services needs were collected. The descriptive analysis, chi-square test, and multiple logistic regression analysis were used. Results 311 and 1083 PWDs were enrolled in 2020 and 2021, respectively. In 2020, 82.0% of the participants reported a negative impact on their daily life, and the proportion of big impact was 20.3%. In 2021, 73.1% of PWDs reported a negative impact on their daily life. Multivariate analysis found the impact on medical services needs was the common associated factor of the overall impact on daily life in 2020 and 2021, and PWDs with lower annual household income or chronic diseases were more likely to suffer bigger negative effects in 2020, while being in quarantine or not at work, having items in shortage and with less disability severity (without multiple disabilities or spinal cord injury) were the associated factors in 2021. Based on the matching method, we found that the overall impact on the daily life of PWDs decreased in 2021. Conclusions A majority of the PWDs reported a negative impact on their daily life in Mainland China at the early remission stage of the COVID-19 pandemic, and the impact has significantly weakened during the normal control period in 2021. It is recommended to fulfill the medical service needs of PWDs in a timely manner, and those being in quarantine or not at work, without SCI or multiple disabilities, and reporting some items in shortage suffered a bigger major overall COVID-19 impact on daily life.

Ischemic stroke is one of the world's leading causes of death and disability. During ischemic stroke, neuronal death is caused by inflammation, oxidative stress, apoptosis, and excitatory toxicity. For a long time, there has been a lot of interest in various studies to promote the repair of nerve damage after stroke. However, the mechanisms underlying the complex pathophysiological processes remain to be fully elucidated. Cerebral Ras-related C3 botulinum toxin substrate (Rac) 1 was initially associated with poor prognosis after stroke. However, some recent studies suggest that Rac1 may contribute to the repair process of nerve injury after stroke and promote the recovery of nerve function. However, the current conflicting findings may be related to the timing of Rac1 interventions. Our study found that post-acute Rac1 activation contributes to ischemic recovery. Here, we first investigated the specific role of neuron Rac1 in neuroprotection and recovery of neurological function in the post-acute phase of stroke. We found that intraventricular injection of Rac1 activator beginning one week after MACO significantly improved brain atrophy and neurological function after MACO. Considering the important role of Rac1 in cell migration. In vitro experiments, we found that Rac1 induced NSCs migration after exogenous and endogenous activator stimulation. In vivo, the addition of Rac1 activator in the post-acute phase helped promote the migration of NSCs in SVC to the lesion area and differentiation into mature nerve cells. It is worth noting that Pak1 is an essential downstream protein of Rac1. Our results suggest that while Rac1 activates Pak1, Pak1 can promote the migration and differentiation of neural stem cells through the downstream p38/β-catenin signalling pathway. While promoting neurogenesis, we found that Rac1 promoted angiogenesis and axon remodelling, and enhanced the synaptic plasticity to support the process of nerve repair during the post-acute phase via downstream Pak1/p38/β-catenin signalling. It suggests that Rac1/Pak1/p38/β-catenin signalling may be a potential therapeutic target in the recovery stage of ischemic stroke.

Contract energy management model is a new energy saving mode based on single market mechanism. Due to its externality, the energy efficiency market cannot realize the optimal allocation of resources. Government energy-saving subsidy can solve the market failure of energy-saving service market and improve the performance level of energy-saving services company. However, due to the unbalanced support fields and single incentive tools in the government incentive policy, the incentive effect of the government subsidy policies for contract energy management projects is not satisfactory. Based on a two-stage dynamic decision-making model, this article analyzes the impact of different forms of government subsidy policies on the performance level decision-making of Energy Service Company, and draws the following conclusions. (1) The effect of the government's variable subsidy policy with payment conditions is better than the fixed subsidy policy without payment conditions. (2) Government incentive policy for contract energy management needs to be directed against different energy saving fields. (3) The government should adopt different forms of incentive policies for energy saving service companies with different energy saving levels in the same energy saving field. (4) When the government implements the variable subsidy policy with preset energy saving target, each within a reasonable range, with the increase of which, the incentive effect on energy saving service companies with lower energy saving level decreases. When the subsidy policy has no incentive effect, it is more unfavorable for the energy saving service companies which are below the average level of the industry.

Background Maintaining osmotic balance plays an important role in the normal operation and survival of cold-water fish. High water temperature has been proven to reduce the activity of NA+-K+-ATPase in the gill. However, the mechanism of megatemperature affect gill osmoregulation has not been fully elucidated. Results In this study, A.baerii, as a kind of iconic cold-water fish, was used to analyze histological alterations, plasma ion content, and transcriptional responses of gill of A.baerii, subjected to 20℃, 24℃and 28℃. We found that ROS levels in gill tissue increased and the gill damage deteriorated along with the temperature rising. Moreover, plasma Cl− levels at 28℃ were much lower than those in the other two groups, and there were no significant differences in Na+ and K+ ions among all trials. At the same time, the transcriptome data indicated that there were significant changes in injury-related pathways and genes at 24℃and 28℃. Meanwhile, GO enrichment analysis showed a large number of genes related to ion transport function changed with temperature increasing during cell processes. We discovered that as temperature increased, the expression of genes that regulate ion outflow (OCLN) and active ion absorption (AE2, NHE3, CLC-2) increased, while NKA-a expression decreased. Furthermore, the changes in osmotic regulation genes and the degree of tissue damage at 28℃ were significantly higher than those in the other two groups, indicating that the degree of heat stress-induced injury affects the osmotic regulation function of gill tissue. Conclusions this study reveals for the first time that the tissue damage caused by high temperature affects the function and the response mechanism of the osmotic regulation in gill of cold-water fish. It provides reference data for the study on the physiological function of cold-water fish under global warming.

In this study, we aimed to find the targets of resveratrol in nasopharyngeal carcinoma (NPC) by network target prediction and investigate the possible mechanisms through experimental verification. Firstly, resveratrol and NPC-specific targets were combined with protein-protein interactions to construct a systematical resveratrol targets-NPC network. Consistently, molecular docking was performed to predict the molecular determinants of resveratrol against NPC. In order to clarify this point, the anti-cancer effects of resveratrol were investigated in the CNE2 cell lines in vitro and NPC cases in vivo. Functional enrichment results suggested that resveratrol played anti-NPC role mainly through MAPK pathway and the potential targets were MAPK1, MAPK3, STAT3, TP53, PIK3CA, PIK3R1, SRC, MAPK8, RELA and VEGFA. In vitro, resveratrol inhibited proliferation, invasion, migration and eventually induced apoptosis in CNE2 cells on time-and dose-dependent manner. Meanwhile, western blot confirmed that resveratrol exerted apoptotic activity of NPC cells by inhibiting MAPK cell signaling activation. Clinically, Immuno-histochemical staining showed significant differential p-ERK1/2, p-JNK and p-P38 activation between tumor-surrounding and NPC cases. Altogether, our findings identified resveratrol could play potent inhibition and apoptosis on human NPC cells possibly by targeting MAPK pathways and suggested that resveratrol had the potential to be an effective bioactive compound in NPC patients.

Background Chronic heat stress (CHS) may threaten the survival of cultivated and wild sturgeon by jeopardizing heart function. Methods Therefore, we established a heart damage model for the Siberian sturgeon (Acipenser baerii) using varying degrees of CHS (24°C and 28°C) to explore its effect on the heart structure and function, and their mutual relationship. Results Our research showed that CHS caused systemic heart failure in A. baerii, clinically manifested as severely irregular ventricles, increased myocardial fibrotic in the interstitium of cardiomyocytes, and myocardial necrosis. Echocardiographic imaging of A. baerii revealed an accelerated heart rate, incomplete ventricular contraction, decreased cardiac output, and significantly reduced pumping efficiency under CHS. Generally, the contractility of the heart decreased and the afterload increased under CHS, which is typical of high-resistance and low-output heart failure. However, cooling of cultured water (20°C) can offset the adverse effects of partial or total CHS on tissue structure and function. Conclusion Our results systematically characterized the relationship between the effects of CHS on the heart structure and heart function in sturgeon. This work provides a preliminary reference for future summer breeding pond management and protection of sturgeon.

Backgrounds: The outbreak of coronavirus has had a serious impact on the economy, life and education of virtually all countries around the world. In China, the pandemic continues to pose a great challenge to the traditional in-person education model of schools. Educators in China are facing the agonizing decision of whether to resume in-person instruction while there’s still no effective cure for the new coronavirus. Therefore, in order to ensure the quality of teaching and learning during the period of special time, we explore the "online + offline" blended teaching mode. Methods: Four hundred medical undergraduates from Dalian Medical University in China took part in a simulated teaching model to improve their learning ability of innovation and exploration. Taking molecular biology experiment - cell apoptosis as an example, we experimented with the blending of "online + offline " teaching mode and evaluated the learning outcome under this mode from the perspectives of experiment operation, report writing and group cooperation.Results: Over 95% of them totally agree with this teaching mode and expect to have it applied to other subjects, while less than 10% of the students have the opinion that the traditional teaching mode is better. The result of the innovation project competition also shows that the students trained under this teaching mode perform better than those under the traditional teaching mode in both objective questions and answers and experimental operation.Conclusions: Adoption of this "online + offline" blended teaching mode is effective and provides a new perspective to solve the problems encountered by medical students when they reach a higher level of development. In the process of carrying out this teaching mode, the cultivation of students' independent learning and innovative exploration ability were emphasized. Furthermore, it also helps students to lay a solid foundation for their future study and career development.

The efficient conversion of hemicellulose and cellulose in lignocellulosic biomass to reducing sugars remains as one major challenge for the development of biorefinery. In this work, corncob saccharification in the aqueous phase was realized efficiently via pretreatment by magnetic carbon-based solid acid (MMCSA) catalyst, combined with the subsequent in situ enzymatic hydrolysis (occurring in the same pretreatment system after MMCSA separation). Under the optimized pretreatment conditions (the ratio of corncob, catalyst and water is 1:1:20 (g:g:mL), 160°C for 20 min) and in situ enzymatic hydrolysis (cellulase loading of 20 FPU / g, 24 h), an xylose yield of 88.77% and an enzymatic digestibility of 91.24% were obtained, respectively. Compared with the traditional enzymatic process, the present in situ enzymatic system has advantages of reduced enzyme loading, water consumption, and improved saccharification efficiency. Thus, this study provides a more sustainable and effective method for the saccharification of hemicellulose and cellulose in the corncob to produce reducing sugars.

Triggered by the pioneering research on graphene, the family of two-dimensional layered materials (2DLMs) has been investigated for more than a decade, and appealing functionalities have been demonstrated. However, there are still challenges inhibiting high-quality growth and circuit-level integration, and results from previous studies are still far from complying with industrial standards. Here, we overcome these challenges by utilizing machine-learning (ML) algorithms to evaluate key process parameters that impact the electrical characteristics of MoS2 top-gated field-effect transistors (FETs). The wafer-scale fabrication processes are then guided by ML combined with grid searching to co-optimize device performance, including mobility, threshold voltage and subthreshold swing. A 62-level SPICE modeling was implemented for MoS2 FETs and further used to construct functional digital, analog, and photodetection circuits. Finally, we present wafer-scale test FET arrays and a 4-bit full adder employing industry-standard design flows and processes. Taken together, these results experimentally validate the application potential of ML-assisted fabrication optimization for beyond-silicon electronic materials., Here, the authors demonstrate the application of machine learning to optimize the device fabrication process for wafer-scale 2D semiconductors, and eventually fabricate digital, analog, and optoelectrical circuits.

Two-dimensional semiconductors can be used to build integrated circuits for running artificial neural networks (ANN) with higher energy efficiency. The implementation of an ANN with 2D semiconductors has been held back by the large-scale and high-quality transistors required for running machine learning algorithms. Here we demonstrate the first functional MoS2 analog ANN integrated circuit, including memory, multiply-and-accumulate (MAC), activation function, and weight update circuits. The ANN integrated circuit is realized through 818 field effect transistors (FETs) with wafer-scale and high-homogeneity MoS2 film. The large current on/off ratio and output linearity of these MoS2 FETs allow the realization of convolutional and activation function circuits with a few number of transistors. This ANN can be used for recognizing tactile digit, showing the recognition rate exceeding 97%. Our work demonstrates wafer-scale processing of a 2D semiconductor for building integrated circuits with the functions of AI computation.

Background Immune checkpoint inhibitors (ICIs) have become a high-profile treatment regimen for malignancy in recent years. However, only a small piece of patients obtain benefit. How to use reasonable biomarkers to optimally select suitable patients is currently a research hot topic.Methods Paired tissue samples and blood samples from 51 patients with various malignancies were collected for correlation analysis. Dynamic changes in bPD-L1 expression, including PD-L1 mRNA, soluble PD-L1 (sPD-L1) and exosomal PD-L1 (exoPD-L1) protein, were detected in non-small-cell lung cancer (NSCLC) patients treated with ICIs. The best cutoff values for progression-free survival (PFS) and OS of all three biomarkers were calculated with R software.Results In 51 malignancies patients, those with positive tPD-L1 expression had significantly higher PD-L1 mRNA expression than those with negative tPD-L1 expression. For sPD-L1 expression, only the TC1~2/IC1~2 group had higher expression than the TC0/IC0 group. In 40 NSCLC patients, those with a fold change (2 months compared to baseline) of PD-L1 mRNA over 2.03 had a better PFS, a better OS and the best objective response (bOR) rate. In addition, a fold change of exoPD-L1 over 1.85 was also found to be associated with better efficacy and OS in a small cohort. Furthermore, the combination of the biomarkers could better screen patients who could benefit from ICI treatment.Conclusion Blood PD-L1 expression was positively correlated with tPD-L1 expression. Increased expression of exoPD-L1, PD-L1 mRNA, or both during early treatment could serve as biomarkers for predicting efficacy and OS in NSCLC patients treated with ICIs.

Background Breast cancer is the leading cause of cancer mortality in women worldwide. Therefore, it is of great significance to identify the biological mechanism of tumorigenesis and explore the development of breast cancer to achieve a better prognosis for individuals suffering from breast cancer. MicroRNAs (miRNAs) have become a hot topic in cancer research, but the underlying mechanism remains unclear.Methods The miRNA profile between breast cancer stem cells (BCSCs, CD44+CD24−/low) and control MCF-7 breast cancer cells was obtained in a previous study. Based on biological analysis, miR-20b-5p was hypothesized to be a key factor due to the malignant behavior of BCSCs. Then, agomir-20b-5p and antagomir-20b-5p were transfected into MCF-7 and T47D breast cancer cells to detect cell migration, wound healing and proliferation, and lentivirus vectors silencing or overexpressing miR-20b-5p were transfected into T47D-CSCs to detect proliferation and apoptosis. The effect of miR-20b-5p on xenograft growth was investigated in vivo by transfection of a lentivirus overexpression vector in T47D cells. The target genes were predicted by the online programs picTar, miRanda and TargetScan and verified by dual luciferase assay, and changes in protein expression were detected by western blot.Results miR-20b-5p had the highest degree in both the miRNA-gene network and miRNA-GO network to regulate BCSCs. Overexpression of miR-20b-5p significantly promoted the migration and wound healing ability of MCF-7 cells and T47D cells compared with the control (P P P P

Background Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Methods The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ATP-binding cassette transporter G1 (ABCG1) and Wnt signaling in oxaliplatin resistance were confirmed. Results Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. Conclusions These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.