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Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody. This open-label, multicenter Phase 1 trial assessed the safety, tolerability, pharmacokinetic (PK) profile, and efficacy of envafolimab as a single agent in Japanese patients with advanced solid tumors. In the dose-escalation phase, 10 patients received subcutaneous (SC) envafolimab QW at 1.0 mg/kg, 2.5 mg/kg and 5.0 mg/kg. In the dose-expansion phase, 16 patients were treated at 2.5 or 5.0 mg/kg Q2W in part-1 and 9 patients received SC envafolimab 300 mg Q4W in part-2. No dose-limiting toxicities (DLTs) were reported. Envafolimab was well tolerated and no new safety signals were identified compared with other marketed products of the same class. Three patients reported Grade ≥ 3 envafolimab-related treatment-emergent adverse events (TEAE), including adrenal insufficiency, cerebral infarction, and immune-mediated enterocolitis. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve (AUC) and maximum serum concentration (C

This study aimed to elucidate the effects of Gentiopicroside (Gent) on epileptogenesis and underlying mechanisms.The status epilepticus (SE) model was established by intraperitoneal (i.p.) injection of lithium chloride (127 mg/kg) and pilocarpine (50 mg/kg) in immature rats. HAPI microglial cellular inflammation model was induced by lipopolysaccharide (LPS, 1 μg/ml) and adenosine triphosphate (ATP, 5 mM). The differential concentrations of Gent were used to pretreat animal (200, 400, and 800 mg/kg) and model cells (50, 100, and 200 μM). Epileptic discharges were assessed by electroencephalography (EEG) and Racine scale. Changes in spatial memory function were measured using the Morris water maze task test. Nissl and FJB staining were employed to assess the damage to hippocampus tissues. ELISA was used to detect the production of IL-1β, IL-18, and TNF-α. The expressions of P2X7R and NLRP3 were detected by q-PCR, immunofluorescence staining, and Western blot, and cell viability was determined by cell counting kit-8 (CCK-8).Lithium chloride and pilocarpine (LICL-PILO) induced abnormal EEG activities, behavioral alterations, brain damage, and inflammatory responses in immature rats. However, Gent pretreatment significantly reduced the neuronal damage and spatial memory dysfunction induced by LICL-PILO. Additionally, Gent suppressed the production of inflammatory cytokines and inhibited the expression of P2X7R, NLRP3, ASC, and Caspase-1 in LPS/ATP-induced HAPI microglial cells.Gent intervention could improve epileptogenesis in immature rats partially due to suppressing P2X7R and NLRP3 inflammasome.

Lessons Learned Subcutaneous injection was an effective route of administration for envafolimab with a favorable pharmacokinetic profile in patients with previously treated advanced solid tumors. Subcutaneous envafolimab was well tolerated and had durable antitumor activity at a wide range of doses and schedules. Envafolimab has the potential to be a more convenient option than currently approved intravenous PD-1/PD-L1 inhibitors. Background Envafolimab is a novel fusion of a humanized single-domain PD-L1 antibody and human IgG1 Fc fragment formulated for subcutaneous injection. This study explored the safety and feasibility of subcutaneous administration of envafolimab as an alternative to intravenous administration of PD-1/PD-L1 inhibitors in the treatment of advanced, refractory solid tumors. Methods This was a first-in-human, open-label phase I trial. In a dose-escalation phase, patients received subcutaneous envafolimab 0.01–10 mg/kg once weekly following a modified 3+3 design. In a dose-exploration phase, patients received subcutaneous envafolimab 300 mg once every 4 weeks. Results Twenty-eight patients were enrolled (dose escalation n = 18, dose exploration n = 10, median age 66 years; 71% male; ECOG performance score = 0 [21%] or 1 [79%]). No dose-limiting toxicities or injection-site reactions were reported. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve and maximum plasma concentration. Median time to maximum plasma concentration was 4–7 days. In the dose-exploration phase, terminal half-life was 14 days after dose 1 in cycle 1 and 23 days at steady state. Three patients experienced a confirmed partial response. Conclusion Subcutaneous envafolimab had a favorable safety and pharmacokinetic profile, with promising preliminary antitumor activity in patients with advanced solid tumors.

ALG13 (asparagine-linked glycosylation 13) plays crucial roles in the process of N-linked glycosylation. Mutations of the ALG13 gene underlie congenital disorders of glycosylation type I (CDG-I), a rare human genetic disorder with defective glycosylation. Epilepsy is commonly observed in congenital disorders of glycosylation type I (CDG-I). In our study, we found that about 20% of adult ALG13KO knockout mice display spontaneous seizures, which were identified in a simultaneous video and intracranial EEG recording. However, the mechanisms of ALG13 by which deficiency leads to epilepsy are unknown. Whole-cell patch-clamp recordings demonstrated that ALG13KO mice show a marked decrease in gamma-aminobutyric acid A receptor (GABAAR)-mediated inhibitory synaptic transmission. Furthermore, treatment with low-dose diazepam (a positive allosteric modulator of GABAA receptors), which enhances GABAAR function, also markedly ameliorates severity of epileptic seizures in ALG13KO mice. Moreover, ALG13 may influenced the expression of GABAARα2 membrane and total protein by changing transcription level of GABAARα2. Furthermore, protein interactions between ALG13 and GABAARα2 were observed in the cortex of wild-type mice. Overall, these results reveal that ALG13 may be involved in the occurrence of epilepsy through the regulation of GABAAR function, and may provide new insight into epilepsy prevention and treatment.

This mixed-methods study examined the impact of the COVID-19 pandemic on 1493 Grades 7, 8, and 9 students’ self-perceived emotional states in Wuhan, China when it was locked down for the pandemic on January 23, 2020 and when the lockdown was lifted on April 8, 2020, as well as the changes of their emotional states over the 1-year period after the lockdown was lifted. A five-point Likert scale survey was administered to the participants between March 1 and April 1, 2020 when Wuhan was blocked down; and three focus group interviews were conducted between May 1 and May 31, 2021, 1 year after the lockdown was lifted. The results showed that these students in Wuhan experienced feelings of loss of control and negative emotions when the city was locked down and they were home quarantined; furthermore, there were significant differences for their self-perceived feelings of loss of control and negative emotions across demographic variables of gender, grade level, physical activity, social economic status, and family cohesion; finally, their emotional states changed substantially at different time nodes during this pandemic. Implications for students, parents, and schools are discussed.

Hadoop Distributed File System (HDFS) performs well when storing and managing large data sets, but its performance is significantly reduced when processing massive small files. In response to this problem, a SequenceFile file storage optimization method based on the pile structure (OPSS) is proposed. The method uses the pile as a unit to merge and merge small files in the pile into SequenceFile based on the worst-fit strategy, reducing the data blocks consumed by the same number of small files. In addition, this method stores the index information of small files in a global index file, and accesses the small files through the global index file, which improves the access efficiency and reduces the memory occupied by the index file. Experimental results show that this method effectively optimizes the performance of HDFS for accessing large amounts of small files.

LOF (Local Outliers Factor) algorithm is a very classic anomaly detection algorithm. In order to detect the outliers more accurately, avoid too much testing error, and ensure the detection can be implemented relatively accurately in the data set without professional knowledge, on the basis of traditional LOF algorithm, an improved detection algorithm LOF Outliers is proposed. According to the different distribution densities of logarithmic data points, all the data point sets A1 that are most likely to become outliers are found out. Then, the information entropy weighted LOF algorithm is used to detect the data set to get the result A2. The point set A1 is intersected with A2 to get the final point set A which is the final result. The experimental results show that the algorithm is feasible, and it is more accurate and contains fewer false detection points.

In order to solve the problems of slow running speed, low classification accuracy and catastrophic forgetting existing in current incremental learning algorithms, a new feature learning model of big data that supports incremental updating was proposed. The model extracted feature vectors through deep convolutional neural network, combined new samples and typical samples in the incremental training process, and then used regular dual average soft confidence weighting algorithm (RDASCW) for online classification. The classification model uses these eigenvectors to generate prediction results. If the predicted results are inconsistent with the actual results, the classification model parameters will be updated; otherwise, the model parameters will be kept unchanged. Experimental results show that the model can dynamically learn data features and improve classification accuracy on the basis of improving data processing speed.

Mutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2fl/wtCre+) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2fl/wtCre+ mice, but not in wild-type mice. Gabrg2fl/wtCre+ mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V–VI and hippocampus of Gabrg2fl/wtCre+ mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2fl/wtCre+ mice compared with wild-type mice. In summary, Gabrg2fl/wtCre+ mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumour that occurs in the superficial tissue of extremities of children and young adults. A painless mass in the deep dermis and subcutaneous tissue is the main clinical manifestation. AFH also occurs infrequently in the central nervous system and is relatively common in the cranium. However, spinal canal AFH has not been described yet. We report a rare case of AFH in the cervical canal of a 20-year-old male patient. Microsurgical gross total resection of the tumour was performed, and the diagnosis was confirmed by postoperative pathology. To our knowledge, this is the first case of AFH in the spinal canal.

With the continuous deepening of electricity market reform and the rapid development of renewable energy in China, a large number of distributed energy resources (DERs) have appeared in the distribution network. Microgrid (MG) can integrate them through advanced technology. As a result, DERs can be safely connected to the grid and participate in market transactions. MG can not only interact with the superior main grid, selling redundant power to it, but also participate in the ancillary service market as an independent ancillary service provider. In this paper, a day-ahead optimal scheduling model of MG participating in both energy market and spinning reserve market is established. There are many kinds of reserve resources in MG, and they are classified according to their different characteristics to participate in spinning reserve markets with different requirements. At the same time, considering the influence of the uncertainty of the renewable energy, the fuzzy parameters are used to fit it. The testing example shows that the microgrid operator weigh their own revenue in the electricity and reserve market to schedule its internal resources, and the results verify the impact of uncertainty of renewable energy on its total revenue.

Bacterial lipopolysaccharide (LPS)-induced acute liver failure (ALF) is a common severe clinical syndrome in intensive care unit. No other methods are available for its prevention apart from supportive treatment and liver transplantation. Tamoxifen (TAM) was reported to attenuate ALF induced by excessive acetaminophen, while its effect on LPS-induced ALF remained unknown. For this, in the present study, we comprehensively assessed whether TAM can attenuate ALF induced by LPS/galactosamine (GaIN). Mice were given TAM once a day for three times. Twelve hours after the last treatment, mice were given LPS/GaIN (intraperitoneally [i.p.]). Survival, plasma transaminases, and histopathology were examined. Serum TNF-α and IL-1β were analyzed by ELISA. Hepatic apoptosis was analyzed by TUNEL and caspase-3 Western blotting, respectively. Compared to the model group, ALF induced by LPS/GaIN was alleviated remarkably following TAM administration, as evidenced by the improvement of survival (87.5% vs. 37.5%), hepatic swell, moderate transaminases, slightly increased serum TNF-α, IL-1β (P < 0.05), and moderate histopathology. In respect of apoptosis, severe hepatocellular apoptosis was reduced notably by TAM treatment confirmed by less TUNEL-positive hepatocytes and decreased caspase-3 cleavage. The results demonstrated that TAM could attenuate LPS/GaIN-induced ALF effectively, probably due to hepatic inflammation and apoptosis antagonism. Furthermore, it was the first report about the effect of TAM on LPS/GaIN-induced ALF.

Network-on-chip (NoC) has been proposed as a better interconnection method than the bus architecture. Recently, a large number of routing algorithms have been proposed to improve the network performance. They usually show their benefits under particular traffic patterns. However, traffic patterns are generally unknown in advance and vary according to the application due to the behavioral diversity between inter-core and memory access communications. In this paper, a local traffic pattern detecting mechanism is proposed to detect the current traffic patterns including uniform, transpose, hotspot and real workloads, and then the routing algorithm will be switched to the most suitable one according to the detection result. Experimental results show that the traffic pattern can be accurately detected. For the hotspot traffic pattern, the success rate of the detector can reach up to 100 percent when the hotspot percentage is larger than 8. With the help of the proposed traffic-robust routing algorithm, the network can always work with a more suitable routing algorithm and achieve better performance.

Drug-induced renal injury is a serious toxic side effect of 5-fluorouracil (5-FU) treatment. Bu-zhong-yi-qi decoction (BZYQD), a water extract of Chinese traditional herbal medicine, is widely used in Asia as an alternative treatment to reduce the side effects of chemotherapy and also improve cancer survival. However, the mechanism is unknown. This study is designed to investigate the protective effect of BZYQD on 5-FU-induced renal injury in mice.Mice were divided into four groups: the control, 5-FU, 5-FU + low, and high BZYQD group. Mice in the three latter groups were administered 5-FU (100 mg/kg/day, intraperitoneally) for six days, and in the 5-FU + low and high BZYQD groups were given BZYQD (1 or 2 g raw herb/kg/day, intragastrically) beginning four days before 5-FU and continuing until the termination of the experiment. The right kidney fixed in formalin for histological examination and the left was homogenized to measure the levels of apoptosis-related proteins and activities of oxidative stress-related biomarkers. Blood samples were collected for measuring renal function-related biochemical indices.Renal morphology injury, increased urea nitrogen and creatinine concentration, and decreased SOD, CAT, and GSH-Px were all observed in 5-FU-administrated mice. However, BZYQD almost reversed the morphological injury as well as renal function-related indices and antioxidant enzyme activity.These results suggest that BZYQD inhibits 5-FU-induced renal injury, possibly through the reduction of apoptosis and necrosis in renal tubular epithelial cells via the antioxidant mechanism. Henceforth, BZYQD may be a potential antioxidant against drug-induced oxidative stress.

To completely mimic the tactile sensing of natural skin, flexible conductive hydrogels (CHs) have been assembled into bionic skin. However, most CHs cannot perfectly rebuild the feeling of human skin due to their highly linear structure. In addition, CHs are difficult to meet the super-stretchable, rapid self-healing properties at the same time. Here, we innovatively incorporated a proanthocyanins/reduced graphene oxide (PC/rGO) composite with a nerve-like nanonetwork into a glycerol-plasticized polyvinyl alcohol-borax (PVA-borax) hydrogel system to obtain a bionic tactile PC/rGO/PVA hydrogel-based electronic skin, which perfectly simulates the tactual sensation of human skin and integrates excellent stretchability (>5000%), compliance (1 mm), self-healing (3 s, 95.73%) ability for the first time. Due to its unique structure and mechanical properties, this electronic skin has remarkable wearable and strain-sensitive (GF = 14.14) properties, which can mimic and detect some real skin epidermis movements such as finger bending, facial expression changes, and throat vocalization. Interestingly, the hydrogel can also be used as an adhesive electrode for the accurate detection of electrocardiograph (ECG) and electromyography (EMG) signals. More importantly, this work provides a new route in mimicking the natural skin’s tactile ability through a hierarchical design of hydrogel networks.

AIM: To characterize the proliferative capacity of pterygial epithelium in different regions (head, neck and body) of pterygium and explore the function of transcription factor 4 (TCF4) in pterygium proliferation. METHODS: Thirty pterygium tissues and 10 normal conjunctival tissues were obtained from Zhongshan Ophthalmic Center (ZOC) and Guangdong Eye Bank, respectively. Proliferative capacity of head, neck and body in pterygial epithelium was measured using clonal analysis, fold growth analysis and expression profile of proliferative markers revealed by immunofluorescent staining and real-time PCR. The expression of TCF4 was highlighted by double immunofluorescent staining with other proliferation related markers such as proliferating cell nuclear antigen (PCNA) and ATP-binding cassette sub-family G member 2 (ABCG2). RESULTS: The proliferative potential of pterygial epithelium was higher than that of normal conjunctival epithelium. High expression levels of proliferative markers (P63α, PCNA and ABCG2) in pterygial body epithelium were observed in immunofluorescent staining and real-time PCR (P

Conjunctival integrity and preservation is indispensable for vision. The self-renewing capacity of conjunctival cells controls conjunctival homeostasis and regeneration; however, the source of conjunctival self-renewal and the underlying mechanism is currently unclear. Here, we characterize the biochemical phenotype and proliferative potential of conjunctival epithelial cells in adult mouse by detecting proliferation-related signatures and conducting clonal analysis. Further, we show that transcription factor 7-like 2 (T-cell-specific transcription factor 4), a DNA binding protein expressed in multiple types of adult stem cells, is highly correlated with proliferative signatures in basal conjunctival epithelia. Clonal studies demonstrated that Transcription factor 7-like 2 (Tcf7l2) was coexpressed with p63α and proliferating cell nuclear antigen (PCNA) in propagative colonies. Furthermore, Tcf7l2 was actively transcribed concurrently with conjunctival epithelial proliferation in vitro. Collectively, we suggest that Tcf7l2 may be involved in maintenance of stem/progenitor cells properties of conjunctival epithelial stem/progenitor cells, and with the fornix as the optimal site to isolate highly proliferative conjunctival epithelial cells in adult mice.

Phytoremediation is considered to be a promising approach to restore or stabilize soil contaminated by lead (Pb). Turfgrasses, due to their high biomass yields, are considered to be suitable for use in phytoextraction of soil contaminated with heavy metal. It has been demonstrated that centipedegrass (Eremochloa ophiuroides (Munro) Hack., Poaceae) is a good turfgrass for restore of soil contaminated by Pb. However, the enhanced tolerant mechanisms in metallicolous (M) centipedegrass accessions remain unknown. In this study, we made a comparative study of growth performance, Pb accumulation, antioxidant levels, and phytochelatin concentrations in roots and shoots from M and nonmetallicolous (NM) centipedegrass accessions. Results showed that turf quality and growth rate were less repressed in M accessions than in NM accession. Pb stress caused generation of reactive oxygen species in centipedegrass with relatively lower levels in M accessions. Antioxidant activity analysis indicated that superoxide dismutase and catalase played important roles in Pb tolerance in M accessions. M accessions accumulated more Pb in roots and shoots. Greatly increased phytochelatins and less repressed sulfur contents in roots and shoots of M accessions indicated that they correlated with Pb accumulation and tolerance in centipedegrass.

The ocular region is of prime importance for the facial aesthetic outlook. Various anthropometric analyses for the periocular region have developed to ensure a pleasing postoperative appearance. However, little information exists for Chinese young adults. In this study, authors not only analyzed the periocular anthropometric characteristics, but, more importantly, searched out the most meaningful aesthetic indicators of the population. The cross-sectional study was executed using two-dimensional photogrammetry acquired from 162 Chinese young adults (79 males, 83 females) between 20-30 years old. Anthropometric parameters including palpebral fissure length and height, intercanthal and outercanthal width, crease height, angle of endocanthion and exocanthion, axis of palpebral fissure, palpebral fissure index, canthal index, and angular index were acquired from standardized photographs. Then, 134 volunteers (20-30 years old) gave each photograph a score within 1-5 points to evaluate their ocular aesthetic attractiveness. The correlation between anthropometric parameters and aesthetic assessment was analyzed. A statistical difference between genders was found for palpebral fissure length and height, outercanthal width, angle of exocanthion, palpebral fissure index and canthal index (p

With the development of air traffic transportation industry, present design capacity can not meet future demand. Multi-airport system is the research object of this paper. The main influencing factor of multi-airport system capacity is partial route legs have less capacities. This paper combines the restricted optimization method of Simultaneous Perturbation Stochastic Approximation (SPSA) and hierarchical optimization model based on points’ importance level. Through simulate the real situation, the multi-airport system optimization model and algorithm is get. This paper chooses Pearl River Delta Region (PRDR) as the test case to explain the parameters’ setmodes and the steps of optimization. After simulation, the outcome of flights timetable based on decreasing delays was get, and it certifies the validity of simulation and optimization. The delay cost of multi-airport system is decreasing. The operating efficiency and economic benefit are increasing.

Present scheduled flights are arranged between two airports as a pair of flights. This paper proposed a novel and innovative method that one flight executes more scheduled flight plans over more airports and then come back to the departure airport and at the same time another flight execute the opposite scheduled flight from the same departure airport and come back to the airport from the opposite flight route. After a comparative analysis of various heuristic algorithms [1] , ant colony algorithm is selected to solve this problem. In this paper, choose eight airports as the research objects and obtain the results with the help of computer. The outcome indicates the validity of the improved ant colony algorithm.