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Glioblastoma (GBM) is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable. A variety of treatment options are currently being explored to improve patient survival, including small molecule inhibitors, viral therapies, cancer vaccines, and monoclonal antibodies. Among them, the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma. Currently, the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma, including receptor tyrosine kinase, PI3K/AKT/mTOR pathway, DNA damage response, TP53 and cell cycle inhibitors. This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways. Meanwhile, the recent advances in temozolomide resistance and drug combination are also reviewed. In the last part, due to the constant clinical failure of targeted therapies, this paper reviewed the research progress of other therapeutic methods for glioblastoma, to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma.

Background. Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL. Methods. In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo. Results. As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells. Conclusion. Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients.

In this paper, an improved empirical formula modeling method using neuro-space mapping (Neuro-SM) for coupled microstrip lines is proposed. Empirical formulas with correction values are used for the coarse model, avoiding a slow trial-and-error process. The proposed model uses mapping neural networks (MNNs), including both geometric variables and frequency variables to improve accuracy with fewer variables. Additionally, an advanced method incorporating simple sensitivity analysis expressions into the training process is proposed to accelerate the optimization process. The experimental results show that the proposed model with its simple structure and an effective training process can accurately reflect the performance of coupled microstrip lines. The proposed model is more compatible than models in existing simulation software.

Abstract When underwater pressure wave is generated, moving water particles cut off the geomagnetic field and produce induced currents, which will simultaneously induce electromagnetic field in the whole space. Due to the large distribution range and slow attenuation of this pseudo‐radiation, it is possible to observe above the sea surface. In this work, we introduce a novel long‐ and short‐term memory neural network and the corresponding training algorithm, to model the multi‐physics process instead of solving magneto‐hydrodynamics equations via numerical methods. Compared with commercial software, the proposed approach is much faster and easier to apply, which puts forward a feasible alternative for predicting the electromagnetic field distribution excited by underwater pressure wave.

We investigate the Moiré superlattice structures generated by the interplay between vortex lattice and optical lattice in two-component Bose–Einstein condensates. Square vortex lattices are generated in both components of the rapidly rotating condensates, and an optical lattice with the same geometry as the vortex lattice is acted on the condensates for a short interval. The optical lattice provides a sudden phase imprint, leading to the appearance of a transient phonon lattice. Such lattice, combined with vortex lattice and twisted an angle from each other, results in the generation of transient Moiré superlattice. The possible superlattice patterns under different twist angles are studied, and the corresponding vertex spacing is determined. We also study the relative shift of the Moir é superlattices in two components of the condensates and give the corresponding shift vector. Our results enrich the quantum phases in cold atomic systems, and contribute to the understanding of Moiré physics in these systems.

Calcium ions (Ca2+) play crucial roles in sperm motility and fertilization. The copine (CPNE) family comprises several Ca2+-dependent phospholipid-binding proteins. Of these, CPNE1 is extensively expressed in mammalian tissues; however, its precise role in testicular development and spermatogenesis is yet to be fully characterized. In this study, we used proteomics to analyze testicular biopsies and found that levels of CPNE1 were significantly reduced in patients with non-obstructive azoospermia (defective spermatogenesis) compared to those in patients with obstructive azoospermia (physiological spermatogenesis). In mice, CPNE1 is expressed at various stages of germ cell development and is associated with the Golgi apparatus. Ultimately, CPNE1 is expressed in the flagella of mature sperms. To further examine the role of CPNE1, we developed a Cpne1 knockout mouse model. Analysis showed that the loss of Cpne1 did not impair testicular development, spermatogenesis, or sperm morphology and motility in physiological conditions. When treated with gadolinium (III) chloride or 2-aminoethoxydiphenyl borate, known inhibitors of store-operated Ca2+ entry, Ca2+ signals and sperm motility were significantly compromised in wild-type mice; however, both mechanisms were conserved in KO mice. These results suggested that CPNE1 is dispensable for testicular development, spermatogenesis or sperm motility in physiological conditions. In addition, CPNE1 may represent a target of Ca2+ channel inhibitors and may therefore be implicated in the regulation of Ca2+ signaling and sperm motility. [ABSTRACT FROM AUTHOR]

This study investigated the effectiveness of the teaching design scheme called the Immersive Virtual Reality Teaching Model (IVRTM) on a small learner population at the researcher’s university. The study was based on one-term experimental teaching among the undergraduates. An ecological class was set up, extending classroom teaching to 3-layer teaching space, including a physical layer (classroom-based), an information layer (internet-based), and a virtual-reality layer (VR-based). The research aimed (1) to create an online-offline spatial ecological learning environment for higher learning efficiency with a series of learning activities, (2) to uncover the learning effectiveness of VR assistance in oral English, and (3) to acquire the students’ attitudes toward the IVRTM. The study approaches involved literature review, empirical method, questionnaire, interviews, and data analysis. The findings would have a positive significance for the promotion of new technology applications in SLA teaching and provide novel and preliminary references for teachers pursuing an effective teaching design of ecological classes based on IVR spatial fusion.

Diabetic nephropathy (DN) is a common complication of diabetes. Yishen capsule, composed of Chinese herbs, improves the clinical outcome in DN patients. However, its therapeutic potential and underlying mechanisms require further elucidation. Hence, our study aimed to investigate the underlying mechanisms and therapeutic potential of Yishen capsule in DN. Streptozotocin-induced DN rats were treated with Yishen capsules (1.25 g/kg/day) for 8 weeks. Then, blood glucose and urine protein levels were measured. Hematoxylin and eosin staining and western blot assays were used to examine the histologic changes and gene expression, respectively, in kidney samples. Mouse podocytes were treated with rat serum containing Yishen capsule and transmission electron microscopy was used to examine autophagosome formation. Cell counting kit-8 assay was performed to examine cell proliferation. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses were conducted to detect changes in gene expression. The localization of SIRT1 was examined in the podocytes using immunocytofluorescence assay. We found that Yishen capsule relieved pathological changes, decreased urine protein, increased SIRT1, LC3-II, and Beclin-1 expression, and reduced acetylated NF-κB p65 expression in vivo. In addition, rat serum containing Yishen capsule showed improved podocyte proliferation, promoted the mRNA and protein levels of LC3-II and Beclin-1, and induced nuclear translocation of SIRT1. Furthermore, it increased SIRT1 expression and decreased mRNA level of NF-κB in the serum. SIRT1 inhibitor increased the mRNA level of NF-κB. Our data suggests that Yishen capsule improves DN by promoting podocyte autophagy via the SIRT1/NF-κB pathway.

Blocking the biological functions of scaffold proteins and aggregated proteins is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology may be the solution, considering its ability to selectively degrade target proteins. Recent progress in the PROTAC strategy include identification of the structure of the first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019. These discoveries strongly proved the value of the PROTAC strategy. In this perspective, we summarized recent meaningful research of PROTAC, including the types of degradation proteins, preliminary biological data in vitro and in vivo, and new E3 ubiquitin ligases. Importantly, the molecular design, optimization strategy and clinical application of candidate molecules are highlighted in detail. Future perspectives for development of advanced PROTAC in medical fields have also been discussed systematically. KEY WORDS: Protein degradation, PROTAC, Ubiquitin−proteasome system, E3 ubiquitin ligase, Target protein, Heterobifunctional molecule

The prevention and control of natural gas hydrate (hereinafter, “hydrate” for short) blockage during deepwater gas well production tests is very important in ensuring the test safety. In this paper, the distribution of wellbore temperature and pressure field under different test conditions was analyzed, and the changes of hydrate deposition and blockage degree in the pipe string in the whole process of test under different test systems were evaluated using the hydrate generation–deposition–decomposition calculation method. On this basis, a deepwater gas well production test method based on hydrate prevention and control was proposed. And the following research results were obtained. First, in the process of deepwater gas well tests, the vapor–liquid phase of annular-mist flow pattern with the greatest risk of hydrate blockage is often formed in the wellbore. Therefore, it is more reasonable to take measures to prevent hydrate blockage in the process of tests than to prevent the formation of hydrate. Second, when the conventional four-point test method is used, it is required to set low gas production measurement points with lower flowing temperature. In the wellbore with high temperature and low temperature, however, hydrate tends to form and deposit easily, and a long period of test will increase the risk of test string blockage. Third, the mixed-sequence test system suitable for deepwater gas well tests can change wellbore temperature by adjusting the sequence of measuring points without changing the production rate and duration, so as to decompose hydrate sediment layers and reduce the maximum blockage degree of test string in the process of tests. Fourth, a three-point or two-point test method is recommended for deepwater gas wells without sand production, stress sensitivity, retrograde condensation and water production. Superior to the conventional four-point test method, three-point and two-point test methods can effectively reduce the risk of hydrate deposition and blockage in the test string, and it can shorten the testing time and reduce the test cost on the premise of ensuring the accuracy of the productivity equation. In conclusion, the research results are of help to the field test construction of deepwater gas wells. Keywords: Deepwater gas well, Production test, Natural gas hydrate, Prevention and control method, Mixed-sequence test, Pipe blockage degree, Flow assurance

Ethnopharmacological relevance: The Scutellaria barbata D.Don and Hedyotis diffusa Willd. (SH) herb pair is extensively used in Traditional Chinese medicine for treating cancer, which has a long history in clinical empirical prescriptions, such as ''kang ai ping wan (抗癌平丸)'', ''er ban er bai decoction (二半二白汤)''. The ambiguous pharmacological ingredients and compatibility mechanism of SH herb pair promoted the exploration. Aim of the study: The characteristics of phytochemicals self-recognition and self-assembly is used to quickly find the active nanoparticles in SH herb pair. And it provides a new strategy for the developing new drugs of TCM. Methods: The SH-extracted nanoparticles (NPs) were gained by centrifugating from the 70% fractionated that the biological activity-guided by D101 macroporous resin column. The micromorphology of active NPs was observed with transmission electron microscopy (TEM). Dynamic light scattering (DLS), Ultraviolet−visible (UV-vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD) and element analysis (EA) were applied for characterizing NPs. The main components were identified by high performance liquid chromatography (HPLC) and HPLC-Q-TOF-MS/MS. Proliferation and migration experiments in vitro as well as tumor growth in vivo were performed to evaluate NPs on triple negative breast cancer (TNBC). Results: The present article quickly discovered the key active ingredients from SH herb pair70%SH-NPs, which were mainly composed of aurantiamide acetate (from HD), scutebarbatine A (from SB) and palmitin (from HD). 70%SH-NPs significantly inhibited proliferation and migration of breast cancer cells in vitro together with tumor growth in nude mice. Conclusions: The results maybe explain the wisdom of SH herb pair compatibility, that is, the active ingredients of the two single drugs self-assemble to form NPs via supramolecular chemical bonds during the decoction process. In summary, the present article might inspire the studies of the relationship between active phytochemicals and NPs in herbs, and the corresponding pharmacological implications.

An advanced Neuro-space mapping (Neuro-SM) multiphysics parametric modeling approach for microwave passive components is proposed in this paper. The electromagnetic (EM) domain model, which represents the EM responses with respect to geometrical parameters, is regarded as a coarse model. The multiphysics domain model, which represents the multiphysics responses with respect to both geometrical parameters and multiphysics parameters, is regarded as a fine model. The proposed model is constructed by the input mapping, the output mapping and the coarse model. The input mapping is used to map multiphysics parameters to EM parameters. The output mapping is introduced to further narrow the gap between the output of the coarse model and the multiphysics data. In addition, a three-stage training method is proposed for efficiently developing the proposed multiphysics model. The proposed technique, which combines the efficiency of EM analysis and the accuracy of multiphysics analysis, can achieve better accuracy with less multiphysics data than existing modeling methods. The developed Neuro-SM multiphysics model provides accurate and fast predictions of multiphysics responses. Therefore, the design cycle of microwave passive components is shortened while the modeling cost is significantly reduced. Two microwave filter examples are utilized to demonstrate the accuracy of the proposed parametric modeling technique.

Automated inspection technology based on computer vision is now widely used in the manufacturing industry with high speed and accuracy. However, metal parts always appear in high gloss or shadow on the surface, resulting in the overexposure of the captured images. It is necessary to adjust the light direction and view to keep defects out of overexposure and shadow areas. However, it is too tedious to adjust the position of the light direction and view the variety of parts’ geometries. To address this problem, we design a photometric-stereo-based defect detection system (PSBDDS), which combines the photometric stereo with defect detection to eliminate the interference of highlights and shadows. Based on the PSBDDS, we introduce a photometric-stereo-based defect detection framework, which takes images captured in multiple directional lights as input and obtains the normal map through the photometric stereo model. Then, the detection model uses the normal map as input to locate and classify defects. Existing learning-based photometric stereo methods and defect detection methods have achieved good performance in their respective fields. However, photometric stereo datasets and defect detection datasets are not sufficient for training and testing photometric-stereo-based defect detection methods, thus we create a photometric stereo defect detection (PSDD) dataset using our PSBDDS to eliminate gaps between learning-based photometric stereo and defect detection methods. Furthermore, experimental results prove the effectiveness of the proposed PSBBD and PSDD dataset.

Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer’s disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 ± 0.11 µM; 15j, eqBChE IC50 = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.

Abstract This article examines Meilong animal husbandry cooperatives in the Haixi Prefecture of Qinghai Province, China as a study case, using information gathered through field surveys and questionnaires to explore the systemic structure and operational mechanisms of Meilong Cooperatives, as well as its impacts on pastoral areas and herdsmen. Based on the results, the main contribution of the Meilong Model is providing a new way for pastoral villages to pursue development through joint-stock cooperatives, and thus represents the long-term direction of pastoral area development. This model reforms the traditional cooperative concept that naturally arises among herdsmen; Meilong Share-holding Cooperative guarantees the equal rights of small or poor households to participate in the management of cooperatives on the basis of “one household, one vote”, rather than the principle of “shareholders have the right to manage, vote and speak according to the proportion of shareholding” found in the joint-stock systems of modern enterprises. It localizes the shareholding system theory to be more acceptable and feasible in order to ensure the survival of animal husbandry cooperatives.

The application of paclitaxel (PTX) in clinic has been restricted due to its poor solubility. Several traditional nano-medicines have been developed to improve this defect, while they are still lack of tumor targeting ability and rapid drug release. In this work, an amphiphilic polymeric micelle of hyaluronic acid (HA) – all-trans-retinoid acid (ATRA) with a disulfide bond, was developed successfully for the co-delivery of PTX and ATRA. The combination chemotherapy of PTX and ATRA can strengthen the anti-tumor activity. Along with self-assembling to micelles in water, the delivery system displayed satisfying drug loading capacities for both PTX (32.62% ± 1.39%) and ATRA, due to directly using ATRA as the hydrophobic group. Rapid drug release properties of the PTX-loaded redox-sensitive micelles (HA-SS-ATRA) in vitro were confirmed under reducing condition containing GSH. Besides, HA-CD44 mediated endocytosis promoted the uptake of HA-SS-ATRA micelles by B16F10 cells. Due to these properties, cytotoxicity assay verified that PTX-loaded HA-SS-ATRA micelles showed concentration-dependent cytotoxicity and displayed obvious combination therapy of PTX and ATRA. Importantly, HA-SS-ATRA micelles could remarkably prolong plasma circulation time after intravenously administration. Therefore, redox-sensitive HA-SS-ATRA micelles could be utilized and explored as a promising drug delivery system for cancer combination chemotherapy. Keywords: Redox-sensitive, Hyaluronic acid, All-trans-retinoid acid, Tumor targeting, Combination chemotherapy

Recent studies suggested that Chotosan has ameliorative effects on vascular dementia through antioxidative pathways. Nevertheless, no systematic pharmacological research was conducted to evaluate the contribution of nuclear factor-E2-related factor 2 (Nrf2), a crucial regulator of antioxidative system, on Chotosan-induced neuroprotection invascular dementia. The present study aimed to investigate the neuroprotective effect of Chotosan on vascular dementia and reveal the possible molecular mechanism involving Nrf2. We found that Chotosan treatment could ameliorate memory impairment and reduce neuron cell loss induced by common carotid artery occlusion surgery. Furthermore, Chotosan could significantly reverse reactive oxygen species production, neuronal apoptosis and microglia over-activation in hippocampus. In addition, Chotosan enhanced Nrf2 expression and its nuclear translocation as well as its downstream antioxidant protein expression, NAD(P)H/quinone oxidoreductase 1 and heme oxygenase-1. These findings suggest that Chotosan exert neuroprotection in an animal model of vascular dementia via activating Nrf2-mediated antioxidant pathway. Chotosan may serve as a potential candidate and promising Nrf2 activator for treating vascular dementia. Keywords: Chotosan, Vascular dementia, Nrf2, Oxidative stress, Cognitive deficits

Diabetic nephropathy is one of the common microvascular complications of diabetes. Iron death is a recently reported way of cell death. To explore the effects of iron death on diabetic nephropathy, iron death score of diabetic nephropathy was analyzed based on the network and pathway levels. Furthermore, markers related to iron death were screened. Using RNA-seq data of diabetic nephropathy, samples were clustered uniformly and the disease was classified. Differentially expressed gene analysis was conducted on the typed disease samples, and the WGCNA algorithm was used to obtain key modules. String database was used to perform protein interaction analysis on key module genes for the selection of Hub genes. Moreover, principal component analysis method was applied to get transcription factors and non-coding genes, which interact with the Hub gene. All samples can be divided into two categories and principal component analysis shows that the two categories are significantly different. Hub genes (FPR3, C3AR1, CD14, ITGB2, RAC2 and ITGAM) related to iron death in diabetic nephropathy were obtained through gene expression differential analysis between different subtypes. Non-coding genes that interact with Hub genes, including hsa-miR-572, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-208a-3p, hsa-miR-153-3p and hsa-miR-29c-3p, may be related to diabetic nephropathy. Transcription factors HIF1α, KLF4, KLF5, RUNX1, SP1, VDR and WT1 may be related to diabetic nephropathy. The above factors and Hub genes are collectively involved in the occurrence and development of diabetic nephropathy, which can be further studied in the future. Moreover, these factors and genes may be potential target for therapeutic drugs.

BackgroundNon-typhoidal Salmonella (NTS), a common cause of diarrheal enterocolitis, may also cause severe invasive diseases. Limited information on NTS infections in children is available in China.MethodsWe performed a retrospective study of children admitted to the Ningbo Women and Children's Hospital with culture-confirmed NTS infections between January 2012 and December 2019. Clinical and microbiological information were collected. We compared demographic, clinical and antibiotic resistance variables of invasive NTS (iNTS) infections and non-invasive NTS (non-iNTS) infections, and explored associations between hospitalizations for pediatric NTS infections and temperature and rainfall.ResultsA total of 166 pediatric hospitalizations due to NTS infection were identified during the 8-year study period. Most of the 166 children were ConclusionNon-iNTS accounts for the majority of infections in this study; infants ≤6 months and children with underlying medical conditions of leukemia are more likely to have invasive infection. The rates of antibiotic resistance in the iNTS isolates are generally lower than those in the non-iNTS isolates. On the other hand, high temperatures and heavy rainfall are positively associated with NTS hospitalizations among children in Ningbo.

Transmembrane protein 16A was involved in the development of the monocrotaline-induced pulmonary arterial hypertension model through ERK1/2 activation, and it was considered as potential target for pulmonary arterial hypertension treatment. A pulmonary arterial hypertension rat model was established by intraperitoneal administration of monocrotaline. Noninvasive pulsed-wave Doppler and histological analysis was performed, and it revealed proliferation and remodeling of pulmonary arterioles and right ventricle hypertrophy. In addition, transmembrane protein 16A, proliferating cell nuclear antigen—a proliferate marker, P-ERK1/2 increased following monocrotaline treatment. Expression of transmembrane protein 16A in the pulmonary arteries was co-localized with a specific marker of vascular smooth muscle α-actin. Then, a specific inhibitor of transmembrane protein 16A-T16A inh -A01 was administered to pulmonary arterial hypertension rats. It was found to alleviate the remodeling of pulmonary arterioles and right ventricle hypertrophy significantly, and decrease the upregulation of proliferating cell nuclear antigen in monocrotaline-induced pulmonary arteries. In addition, T16A inh -A01 could inhibit the activation of ERK1/2 in pulmonary arterial hypertension model. Transmembrane protein 16A mediated the proliferation and remodeling of pulmonary arterioles in the monocrotaline-induced pulmonary arterial hypertension model. ERK1/2 pathway is one of downstream factors. Long-term use of T16A inh -A01 in vivo could alleviate remodeling and pressure in pulmonary arterial hypertension.