Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants

The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.

Early postsurgical lethal outcome due to splenic littoral cell angioma:A case report

BACKGROUND Littoral cell angioma(LCA)is a rare benign vascular tumor of the spleen.Given its rarity,standard diagnostic and therapeutic recommendations have yet to be developed for reported cases.Splenectomy is the only method of obtaining a pathological diagnosis and providing treatment to obtain a favorable prognosis.CASE SUMMARY A 33-year-old female presented with abdominal pain for one month.Computed tomography and ultrasound revealed splenomegaly with multiple lesions and two accessory spleens.The patient underwent laparoscopic total splenectomy and accessory splenectomy,and splenic LCA was confirmed by pathology.Four months after surgery,the patient presented with acute liver failure,was readmitted,rapidly progressed to multiple organ dysfunction syndrome and died.CONCLUSION Preoperative diagnosis of LCA is challenging.We systematically reviewed online databases to identify the relevant literature and found a close relationship between malignancy and immunodysregulation.When a patient suffers from both splenic tumors and malignancy or immune-related disease,LCA is possible.Due to potential malignancy,total splenectomy(including accessory spleen)and regular follow-up after surgery are recommended.If LCA is diagnosed after surgery,a comprehensive postoperative examination is needed.

SAR target detection based on the optimal fractional Gabor spectrum feature

In this paper,an algorithm based on a fractional time-frequency spectrum feature is proposed to improve the accuracy of synthetic aperture radar(SAR)target detection.By extending the fractional Gabor transform(FrGT)into two dimensions,the fractional time-frequency spectrum feature of an image can be obtained.In the achievement process,we search for the optimal order and design the optimal window function to accomplish the two-dimensional optimal FrGT.Finally,the energy attenuation gradient(EAG)feature of the optimal time-frequency spectrum is extracted for high-frequency detection.The simulation results show the proposed algorithm has a good performance in SAR target detection and lays the foundation for recognition.

Seismic impedance inversion based on cycle-consistent generative adversarial network

Deep learning has achieved great success in a variety of research fields and industrial applications.However,when applied to seismic inversion,the shortage of labeled data severely influences the performance of deep learning-based methods.In order to tackle this problem,we propose a novel seismic impedance inversion method based on a cycle-consistent generative adversarial network(Cycle-GAN).The proposed Cycle-GAN model includes two generative subnets and two discriminative subnets.Three kinds of loss,including cycle-consistent loss,adversarial loss,and estimation loss,are adopted to guide the training process.Benefit from the proposed structure,the information contained in unlabeled data can be extracted,and adversarial learning further guarantees that the prediction results share similar distributions with the real data.Moreover,a neural network visualization method is adopted to show that the proposed CNN model can learn more distinguishable features than the conventional CNN model.The robustness experiments on synthetic data sets show that the proposed method can achieve better performances than other methods in most cases.And the blind-well experiments on real seismic profiles show that the predicted impedance curve of the proposed method maintains a better correlation with the true impedance curve.

c.753＿754delAG, a novel CFTR mutation found in a Chinese patient with cystic fibrosis: A case report and review of the literature

BACKGROUND Cystic fibrosis(CF)is rare in Asian populations relative to the Caucasian population.In this paper,we report the cystic fibrosis transmembrane conductance regulator(CFTR)variation in a family of Chinese CF patients,and systematically review the previous literature.CASE SUMMARY Here we report a 30-month-old Chinese girl who was diagnosed with CF based on her history and symptoms such as recurrent productive cough,wheezing with repeated infection of Pseudomonas aeruginosa,and parasinusitis.Chest computed tomography(CT)scanning revealed obvious exudative lesions and bilateral bronchiectasis.Liver CT scanning revealed a low-density lesion in the left lobe of the liver.A diagnosis of CF was made based upon CFTR gene tests.The CFTR gene was sequenced using the blood samples of her and her parents and showed a heterozygous novel missense mutation of c.753_754delAG in exon 7.In addition,a heterozygous c.1240 C>T mutation was found in exon 10 of the CFTR.The mutation c.753_754delAG was verified to have been inherited from her mother,and the c.1240 C>T mutation was from her father who was diagnosed with congenital absence of vas deferens.CONCLUSION A novel mutation of CFTR,c.753_754delAG,was found in a Chinese CF child.c.2909G>A is the most common mutation among Chinese CF patients.

Multisystem smooth muscle dysfunction syndrome in a Chinese girl:A case report and review of the literature

BACKGROUND Multisystemic smooth muscle dysfunction syndrome(MSMDS) is a rare genetic disease worldwide. The main mutation is the actin alpha 2(ACTA2) gene p.R179 H. In this paper, we report a Chinese MSMDS patient and systematically review the previous literature.CASE SUMMARY Here, we report a 9.6-month-old Chinese girl who was diagnosed with MSMDS based on her history and symptoms, such as recurrent cough, wheezing, and complications with congenital fixed dilated pupils. Chest high-resolution computed tomography revealed inhomogeneous lung transparency, obvious exudative lesions, and some lung fissures that were markedly thickened. Cranial magnetic resonance imaging excluded bleeding and infarction but showed abnormal signals in the centrum ovale majus and bilateral periventricular regions. Echocardiography only showed patent foramen ovale, and no patent ductus arteriosus, pulmonary artery dilatation, or pulmonary hypertension was found. Bronchoscopy indicated moderate bronchial malacia. These examinations in conjunction with the typical eye abnormality suggested a diagnosis of MSMDS, and sequencing of exon 6 of the ACTA2 gene demonstrated the heterozygous mutation c.536 G>A, p.R179 H. However, her parents' gene analyses were normal.CONCLUSION MSMDS is a rare genetic disease mainly caused by the mutation of the ACTA2 gene p.R179 H. Early genetic diagnosis should be performed for children presenting with congenital fixed dilated pupils and patent ductus arteriosus.During the process of diagnosis and treatment, clinicians should be on high alert for cerebrovascular, cardiovascular, and pulmonary complications.

Alexa Fluor 488-conjugated cholera toxin subunit B optimally labels neurons 3-7 days after injection into the rat gastrocnemius muscle

Neural tract tracing is used to study neural pathways and evaluate neuronal regeneration following nerve injuries.However,it is not always clear which tracer should be used to yield optimal results.In this study,we examined the use of Alexa Fluor 488-conjugated cholera toxin subunit B(AF488-CTB).This was injected into the gastrocnemius muscle of rats,and it was found that motor,sensory,and sympathetic neurons were labeled in the spinal ventral horn,dorsal root ganglia,and sympathetic chain,respectively.Similar results were obtained when we injected AF594-CTB into the tibialis anterior muscle.The morphology and number of neurons were evaluated at different time points following the AF488-CTB injection.It was found that labeled motor and sensory neurons could be observed 12 hours post-injection.The intensity was found to increase over time,and the morphology appeared clear and complete 3-7 days post-injection,with clearly distinguishable motor neuron axons and dendrites.However,14 days after the injection,the quality of the images decreased and the neurons appeared blurred and incomplete.Nissl and immunohistochemical staining showed that the AF488-CTB-labeled neurons retained normal neurochemical and morphological features,and the surrounding microglia were also found to be unaltered.Overall,these results imply that the cholera toxin subunit B,whether unconjugated or conjugated with Alexa Fluor,is effective for retrograde tracing in muscular tissues and that it would also be suitable for evaluating the regeneration or degeneration of injured nerves.

Theoretical analyses of stock correlations affected by subprime crisis and total assets: Network properties and corresponding physical mechanisms

In the field of statistical mechanics and system science, it is acknowledged that the financial crisis has a profound influence on stock market. However, the influence of total asset of enterprise on stock quote was not considered in the previous studies. In this work, a modified cross-correlation matrix that focuses on the influence of total asset on stock quote is introduced into the analysis of the stocks collected from Asian and American stock markets, which is different from the previous studies. The key results are obtained as follows. Firstly, stock is more greatly correlated with big asset than with small asset. Secondly, the higher the correlation coefficient among stocks, the larger the eigenvector is. Thirdly, in different periods, like the pre-subprime crisis period and the peak of subprime crisis period, Asian stock quotes show that the component of the third eigenvector of the cross-correlation matrix decreases with the asset of the enterprise decreasing.Fourthly, by simulating the threshold network, the small network constructed by 10 stocks with large assets can show the large network state constructed by 30 stocks. In this research we intend to fully explain the physical mechanism for understanding the historical correlation between stocks and provide risk control strategies in the future.

Tyrosine 23 Phosphorylation of Annexin A2 Promotes Proliferation,Invasion,and Stat3 Phosphorylation in the Nucleus of Human Breast Cancer SK-BR-3 Cells

Objective To investigate the role of tyrosine 23(Tyr23) phosphorylation of Annexin A2(Anxa2) in regulating the proliferation and invasion of human breast cancer SK-BR-3 cells. Methods A panel of lentivirus plasmids expressing Anxa2-wide type(Ana2-WT),Anxa2-Y23A,and Anxa2-Y23D was generated and infected with SK-BR-3 cells.The monoclonal strains were screened.The expression of Anxa2-WT,Anxa2-Y23A,and Anxa2-Y23D was determined by Western blot analysis.The ability of the cells to proliferate was detected through an MTT[3-(4,5-Dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide]test.Boyden chamber assays were employed to examine migration and invasion abilities. The interaction between Anxa2 and Stat3 was analyzed by immunoprecipitation analyses.Nucleoprotein and cytosolic protein were extracted from SK-BR-3,Anxa2-WT,Anxa2-Y23A,and Anxa2-Y23D cells to analyze the expression and localization of Stat3 phosphorylation. Results The monoclonal strains constitutively expressing Anxa2-WT,Anxa2-Y23A,and Anxa2-Y23D were screened.Both Anxa2-W and Anxa2-Y23D enhanced the proliferation,migration and invasion abilities of SK-BR-3 cells(P<0.05).Immunoprecipitation analy revealed that Anxa2 and Stat3 interacted with each other,and the expression of Stat3 phosphorylation in the nucleus was enhanced Anxa2-Y23D. Conclusions Tyr23 phosphorylation of Anxa2 promotes the proliferation and invasion of human breast cancer SK-BR-3 cells and phosphorylation of Stat3 in the nucleus.

Dehydrocostus lactone exerts the antitumor effect in non-small cell lung cancer H1299 cells

Background:Dehydrocostus lactone(DHC),a sesquiterpene lactone derived from Aucklandiae Radix,has been proved to possess various pharmacological activities.Recently,studies have reported that DHC has potential antitumor activity.However,few studies have reported the effect of DHC on non-small cell lung cancer(NSCLC).Here,we investigated the antitumor effect of DHC in NSCLC H1299 cells.Methods:MTT assay and colony formation assay was used to assess the anti-proliferation effects of DHC in H1299 cells.Wound healing and Transwell assays were utilized to determine the inhibitory effects of migration and invasion,respectively.Apoptosis was detected using the Annexin V/propidium iodide test.Real-time-quantitative PCR(RT-qPCR)was used to detect the mRNA expression level.Results:We demonstrated here that DHC inhibited the proliferation,migration and invasion of H1299 cells in a dose-or time-dependent manner.Additionally,after treating with DHC at the concentration of 32.0μM,the apoptosis of H1299 cells was significantly induced.Moreover,DHC affected the mRNA expression of E-cadherin,N-cadherin,Snail,c-Myc,integrinα2,Survivin and matrix metalloproteinase 2.Conclusion:To summarize,our data support that DHC can inhibit proliferation,invasion,migration and induced apoptosis of NSCLC H1299 cells.DHC should be considered for its potential for adjuvant therapeutic development.

Baicalin,silver titanate,Bletilla striata polysaccharide and carboxymethyl chitosan in a porous sponge dressing for burn wound healing

Objective This study tests the efficacy of Bletilla striata polysaccharide(BSP),carboxymethyl chitosan(CMC),baicalin(BA)and silver titanate(ST)in a wound dressings to fight infection,promote healing and provide superior biocompatibility.Methods The antibacterial activity of BA and ST was evaluated in vitro using the inhibition zone method.BA/ST/BSP/CMC porous sponge dressings were prepared and characterized.The biocompatibility of BA/ST/BSP/CMC was assessed using the cell counting kit-8 assay.The therapeutic effect of BA/ST/BSP/CMC was further investigated using the dorsal skin burn model in Sprague-Dawley rats.Results The wound dressing had good antibacterial activity against Escherichia coli and Staphylococcus aureus through BA and ST,while the combination of BSP and CMC played an important role in promoting wound healing.The BA/ST/BSP/CMC porous sponge dressings were prepared using a freeze-drying method with the concentrations of BA and ST at 20 and 0.83 mg/mL,respectively,and the optimal ratio of 5%BSP to 4%CMC was 1:3.The average porosity,water absorption and air permeability of BA/ST/BSP/CMC porous sponge dressings were measured to be 90.43%,746.1%and 66.60%,respectively.After treatment for 3 and 7 days,the healing rates of the BA/ST/BSP/CMC group and BA/BSP/CMC group were significantly higher than those of the normal saline(NS)group and silver sulfadiazine(SSD)group(P<0.05).Interleukin-1βexpression in the BA/ST/BSP/CMC group at 1 and 3 days was significantly lower than that in the other three groups(P<0.05).After being treated for 3 days,vascular endothelial growth factor expression in the BA/BSP/CMC group and BA/ST/BSP/CMC group was significantly higher than that in the NS group and SSD group(P<0.05).Inspection of histological sections showed that the BA/ST/BSP/CMC group and BA/BSP/CMC group began to develop scabbing and peeling of damaged skin after 3 days of treatment,indicating accelerated healing relative to the NS group and SSD group.Conclusion The optimized concentration of BA/ST/BSP/CMC dressing was as follows:6 mg BSP,14.4 mg CMC,0.5 mg ST and 12 mg BA.The BA/ST/BSP/CMC dressing,containing antibacterial constituents,was non-cytotoxic and effective in accelerating the healing of burn wounds,making it a promising candidate for wound healing.

基于氮,膦配体多孔有机聚合物材料的设计合成及其催化应用

多孔有机聚合物(porous organic polymers,POPs)是近年来涌现出的由纯粹的有机分子砌块,通过共价键连接而成的一类具有高比表面积、丰富的孔结构、低骨架密度和良好热稳定性的新型材料。而N,P配体在均相过渡金属络合物催化的氢甲酰化反应、偶联反应、加氢反应、硅氢加成反应,CO2环加成等反应中具有重要的应用,通过合理的设计和修饰N,P配体的电子效应和立体结构,可有效地调控目标产物的收率和选择性。得益于有机合成策略的多样性,POPs材料也具有合成路径及构建方式多样,可较为方便地在聚合物骨架中定点引入特定功能位点的特点,这为基于N,P配体均相过渡金属催化剂的多相化提供了全新的思路与契机。本文将对国内国外相关课题组及本课题组在基于N,P配体POPs材料的设计合成及其催化应用方面所做的工作进行简要的总结归纳,并对该方向进行相应的工业应用前景展望。

DLPlib： A Library for Deep Learning Processor

Recently, deep learning processors have become one of the most promising solutions of accelerating deep learning algorithms. Currently, the only method of programming the deep learning processors is through writing assembly instructions by bare hands, which costs a lot of programming efforts and causes very low efficiency. One solution is to integrate the deep learning processors as a new back-end into one prevalent high-level deep learning framework （e.g., TPU （tensor processing unit） is integrated into Tensorflow directly）. However, this will obstruct other frameworks to profit from the programming interface, The alternative approach is to design a framework-independent low-level library for deep learning processors （e.g., the deep learning library for GPU, cuDNN）. In this fashion, the library could be conveniently invoked in high-level programming frameworks and provides more generality. In order to allow more deep learning frameworks to gain benefits from this environment, we envision it as a low-level library which could be easily embedded into current high-level frameworks and provide high performance. Three major issues of designing such a library are discussed. The first one is the design of data structures. Data structures should be as few as possible while being able to support all possible operations. This will allow us to optimize the data structures easier without compromising the generality. The second one is the selection of operations, which should provide a rather wide range of operations to support various types of networks with high efficiency. The third is the design of the API, which should provide a flexible and user-friendly programming model and should be easy to be embedded into existing deep learning frameworks. Considering all the above issues, we propose DLPIib, a tensor-filter based library designed specific for deep learning processors. It contains two major data structures, tensor and filter, and a set of operators including basic neural network primitives and matrix/vector operations. It provides a descriptor-based API exposed as a C＋＋ interface. The library achieves a speedup of 0.79x compared with the performance of hand-written assembly instructions.

2022 roadmap on hydrogen energy from production to utilizations

Hydrogen has been always the hot topic,which drives a lot of researchers to study and explore hydrogenrelated projects and fields.The first subfield is hydrogen production with green and cost-effective means.Some methods have been intensively used for high-efficient hydrogen production,i.e.,catalytic chemical hydrogen generation,electrocatalytic hydrogen evolution,photocatalytic hydrogen evolution,photo-electrocatalytic hydrogen evolution.Most of them are driven by various catalysts.Moreover,the hydrogen storage is also an important question,which is also a present research hot topic,although the history is long with several decades.Hydrogen fuel cells have also obtained great attention due to the zero emissions.The related research mainly focuses on the cell systems and electrocatalysts used.Under this background,we invite some excellent research groups to write this progress on hydrogen from production to utilizations.Finally,we believe that this roadmap on hydrogen can give some useful guidance in future research.

保持隐私信息流安全性的服务组合演化方法（英文）

隐私信息流安全的服务组合部署后,用户隐私需求与成员服务的信誉度等级均可能发生变化,保持隐私信息流安全性是非常重要的演化需求。提出一种保持隐私信息流安全性的服务组合演化方法。分析基于Petri网的隐私数据项依赖关系,计算各成员服务的隐私数据使用集及安全范围,最后提出保持隐私信息流安全性的演化操作集。通过操作实施演化,避免演化后隐私信息流安全性的完整验证过程,提高演化效率。通过实例分析说明该方法的有效性,并对其性能进行实验分析。结果表明,与完整安全性验证过程相比,该方法有较高演化效率,能大大降低演化代价。