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Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice

Journal of Genetics and Genomics 2016年第6期43卷 381-391页

作者： Jiangsong Jiang Kanyarat Promchan Hong Jiang Parirokh Awasthi Heather Marshall Adam Harned Ven Natarajan Laboratory of Molecular Cell Biology Leidos Biomedical ResearchInc.Frederick National Laboratory for Cancer ResearchFrederickMD 21702USA Transgenic Mouse Model Laboratory Leidos Biomedical ResearchInc.Frederick National Laboratory for Cancer ResearchFrederickMD 21702USA Electron Microscopy Laboratory Leidos Biomedical ResearehInc.Frederick National Laboratory for Cancer ResearchFrederickMD 21702USA

Bardet-Biedl syndrome（BBS） is a heterogeneous disease characterized by deficiencies in various organs that are caused by defects in genes involved in the genesis, structural maintenance, and protein trafficking of cilia. Leucine zipper transcription factor-like 1（LZTFL1）has been identified as a BBS protein（BBS17）, because patients with mutations in this gene exhibit the common BBS phenotypes. In this study, we generated a knockout mouse model to investigate the effects of LZTFL1 depletion. Lztfl1 knockout mice were born with low birth weight, reached similar weight to those of wild-type mice at 10 weeks of age, and later gained more weight than their wild-type counterparts. LZTFL1 was localized to the primary cilium of kidney cells, and the absence of LZTFL1 inc.eased the ciliary localization of BBS9. Moreover, in the retinas of Lztfl1 knockout mice, the photoreceptor outer segment was shortened, the distal axoneme of photoreceptor connecting cilium was significantly enlarged, and rhodopsin was targeted to the outer nuclear layer. TUNEL assay showed that many of these abnormal photoreceptor cells in Lztfl1 knockout mice underwent apoptosis. Interestingly, the absence of LZTFL1 caused an abnormal inc.ease of the adaptor protein complex 1（AP1） in some photoreceptor cells. Based on these data, we conclude that LZTFL1 is a cilium protein and regulates animal weight and photoreceptor connecting cilium function probably by controlling microtubule assembly and protein trafficking in cilia.

关键词： LZTFL1 Cilium BBSome BBS17 Retina AP-1

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Video-based trajectory extraction with deep learning for High-Granularity Highway Simulation(HIGH-SIM)

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Communications in Transportation Research 2021年第1期1卷 111-120页

作者： Xiaowei Shi Dongfang Zhao Handong Yao Xiaopeng Li David K.Hale Amir Ghiasi Department of Civil and Environmental Engineering University of South FloridaTampaFL33620United States leidos IncSaxton Transportation Operation LaboratoryMcLean22101VirginiaUnited States

High-granularity vehicle trajectory data can help researchers develop traffic simulation models,understand traffic flow characteristics,and thus propose insightful strategies for road traffic *** paper proposes a novel vehicle trajectory extraction method that can extract high-granularity vehicle trajectories from aerial *** proposed method inc.udes video calibration,vehicle detection and tracking,lane marking identification,and vehicle motion characteristics *** particular,the authors propose a Monte-Carlo-based lane marking identification approach to identify each vehicle's *** is a challenging problem for vehicle trajectory extraction,especially when the aerial videos are taken from a high *** authors applied the proposed method to extract vehicle trajectories from several high-resolution aerial videos recorded from *** extracted dataset is named by the High-Granularity Highway Simulation(HIGH-SIM)vehicle trajectory *** demonstrate the effectiveness of the proposed method and understand the quality of the HIGHSIM dataset,we compared the HIGH-SIM dataset with a well-known dataset,the NGSIM US-101 dataset,regarding the accuracy and consistency *** comparison results showed that the HIGH-SIM dataset has more reasonable speed and acceleration distributions than the NGSIM US-101 ***,the internal and platoon consistencies of the HIGH-SIM dataset give lower errors compared to the NGSIM US-101 *** benefit future research,the authors have published the HIGH-SIM dataset online for public use.

关键词： Video analytics Image processing Vehicle trajectory extraction Deep learning Microsimulation

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Elimination of murine and human T-cell epitopes in recombinant immunotoxin eliminates neutralizing and anti-drug antibodies in vivo

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Cellular & Molecular Immunology 2017年第5期14卷 432-442页

作者： Ronit Mazor Devorah Crown Selamawit Addissie Youjin Jang Gilad Kaplan Ira Pastan Laboratory of Molecular Biology Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA leidos Biomedical Research Inc National Cancer Institute National Institutes of Health Bethesda MD USA

Antibodies against the toxin portion of recombinant immunotoxins （RIT） reduce their efficacy and pose a potential safety risk. To overcome this problem we mutated the very immunogenic immunotoxin SSIP to produce LMB-T20, a de-immunized RIT that has the eight human T-cell epitopes in SSIP modified or removed. To determine the effect of T-cell epitope removal in vivo we mapped the T-cell epitopes in immune-competent BALB/c mice and found that these mice recognize two epitopes. One corresponds to the human immunodominant T-cell epitope and the other to a human subdominant epitope; both were eliminated in LMB-T20. We found that mice immunized with LMB-T20 did not have T-cell activation and did not develop anti-drug antibodies （ADA）, whereas mice immunized with SSIP, showed T-cell activation, and developed ADA detected by both ELISA and drug neutralizing assays. The ability of the mice treated with LMB-T20 to respond to other antigens was not compromised. We conclude that elimination of T-cell epitopes is sufficient to prevent formation of antibodies to an immunogenic foreign protein.

关键词： anti-drug antibodies deimmunization immunogenicity mouse epitopes T-cell epitopes

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Chronotype and self-reported sleep,alertness,and mental health in U.S. sailors

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Military Medical Research 2022年第2期9卷 259-261页

作者： Elizabeth M.Harrison Alexandra P.Easterling Emily A.Schmied Suzanne L.Hurtado Gena L.Glickman Center for Circadian Biology University of California San DiegoSan DiegoUSA leidos Inc.San DiegoUSA Health and Behavioral Sciences Department Naval Health Research CenterSan DiegoUSA School of Public Health San Diego State UniversitySan DiegoUSA Departments of Psychiatry and Neuroscience Uniformed Services University of the Health SciencesBethesdaUSA

Service members are at risk for sleep and psychological conditions affecting their readiness. Chronotype(“morningness”or “eveningness”) is strongly associated with sleep, health and performance. The objective of this study was to examine associations between validated measures of chronotype and sleep quality, daytime functioning, alertness,and symptoms of depression, anxiety, and post-traumatic stress disorder(PTSD) in US service members(n=298).Although predominantly young males(who skew toward eveningness in civilian populations), these Sailors skewed toward morningness(35.6% morning, 51.3% intermediate). Eveningness was associated with symptoms of depression and PTSD(P<0.01), less time in bed(P<0.05), more sleep disruption(P<0.01), and poorer daytime functioning and alertness(P<0.05). Evening types were less likely to consider sleep important for performance(P<0.05). To maximize service member readiness, schedules should be aligned with endogenous rhythms, whenever possible, and evening chronotypes may benefit from targeted interventions. Chronotype should be examined alongside health and readiness in service members.

关键词： Circadian Chronotype Sleep Military Readiness Depression Anxiety Post-traumatic stress disorder

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The multidrug resistance transporter P-glycoprotein confers resistance to ferroptosis inducers

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Cancer Drug Resistance 2023年第3期6卷 468-480页

作者： William J.E.Frye Lyn M.Huff JoséM.González Dalmasy Paula Salazar Rachel M.Carter Ryan T.Gensler Dominic Esposito Robert W.Robey Suresh V.Ambudkar Michael M.Gottesman Laboratory of Cell Biology Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA Protein Expression Laboratory Frederick National Laboratory for Cancer ResearchLeidos Biomedical ResearchIncFrederickMD 21704USA

Aim:Ferroptosis is a non-apoptotic form of cell death caused by lethal lipid *** small molecule ferroptosis inducers(FINs)have been reported,yet little information is available regarding their interaction with the ATP-binding cassette(ABC)transporters P-glycoprotein(P-gp,ABCB1)and *** thus sought to characterize the interactions of FINs with P-gp and ABCG2,which may provide information regarding oral bioavailability and brain penetration and predict drug-drug ***:Cytotoxicity assays with ferroptosis-sensitive A673 cells transfected to express P-gp or ABCG2 were used to determine the ability of the transporters to confer resistance to FINs;confirmatory studies were performed in OVCAR8 and NCI/ADR-RES *** ability of FINs to inhibit P-gp or ABCG2 was determined using the fluorescent substrates rhodamine 123 or purpuin-18,***:P-gp overexpression conferred resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin.P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of *** FINs ML-162,GPX inhibitor 26a,and PACMA31 at 10µM were able to inc.ease intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 *** inhibitor 26a was able to inc.ease intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 ***:Expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the *** ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions.

关键词： Ferroptosis drug resistance P-glycoprotein ABCG2

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Chemokines in homeostasis and diseases

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Cellular & Molecular Immunology 2018年第4期15卷 324-334页

作者： Keqiang Chen Zhiyao Bao Peng Tang Wanghua Gong Teizo Yoshimura Ji Ming Wang Cancer and Inflammation Program Center for Cancer ResearchNational Cancer Institute at FrederickFrederickMD 21702USA Department of Pulmonary&Critical Care Medicine Ruijin HospitalShanghai Jiaotong University School of MedicineShanghai 200025P.R.China Department of Breast Surgery Southwest HospitalThird Military Medical UniversityChongqing 400038China Basic Research Program Leidos Biomedical ResearchInc.FrederickMD 21702USA Department of Pathology and Experimental Medicine Graduate School of MedicineDentistry and Pharmaceutical SciencesOkayama UniversityOkayama 700-8558Japan

For the past twenty years,chemokines have emerged as a family of critical mediators of cell migration during immune surveillance,development,inflammation and cancer *** bind to seven transmembrane G protein-coupled receptors(GPCRs)that are expressed by a wide variety of cell types and cause conformational changes in trimeric G proteins that trigger the intracellular signaling pathways necessary for cell movement and *** chemokines have evolved to benefit the host,inappropriate regulation or utilization of these small proteins may contribute to or even cause ***,understanding the role of chemokines and their GPCRs in the complex physiological and diseased microenvironment is important for the identification of novel therapeutic *** review introduces the functional array and signals of multiple chemokine GPCRs in guiding leukocyte trafficking as well as their roles in homeostasis,inflammation,immune responses and cancer.

关键词： chemokines chemotaxis diseases GPCRs homeostasis inflammatory cells

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Development of Neutralizing Antibodies against Zika Virus Based on Its Envelope Protein Structure

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Virologica Sinica 2019年第2期34卷 168-174页

作者： Chunpeng Yang Rui Gong Natalia de Val CAS Key Laboratory of Special Pathogens and Biosafety Wuhan Institute of Virology Chinese Academy of Sciences Wuhan 430071 China University of Chinese Academy of Sciences Beijing 100049 China Center for Molecular Microscopy Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD 20892 USA Cancer Research Tech no logy Program Frederick National Laboratory for Cancer Research Leidos Biomedical Research Inc Frederick MD 21701 USA

As we know more about Zika virus(ZIKV), as well as its linkage to birth defects(microcephaly) and autoimmune neurological syndromes, we realize the importance of developing an efficient vaccine against it. Zika virus disease has affected many countries and is becoming a major public health concern. To deal with the infection of ZIKV, plenty of experiments have been done on selection of neutralizing antibodies that can target the envelope(E) protein on the surface of the virion. However, the existence of antibody-dependent enhancement(ADE) effect might limit the use of them as therapeutic candidates. In this review, we classify the neutralizing antibodies against ZIKV based on the epitopes and summarize the resolved structural information on antibody/antigen complex from X-ray crystallography and cryo-electron microscopy(cryo-EM), which might be useful for further development of potent neutralizing antibodies and vaccines toward clinical use.

关键词： Zika virus (ZIKV Envelope protein Neutralizing antibody X-ray crystallography Cryo-electron microscopy (cryo-EM)

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Optimizing the PMCC Algorithm for Infrasound and Seismic Nuclear Treaty Monitoring

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Open Journal of Acoustics 2014年第4期4卷 204-213页

作者： Anthony M. Runco Jr. James A. Louthain Dean A. Clauter Space and Missile Systems Center United States Air Force Los Angeles Air Force Base El Segundo CA USA leidos inc. Beavercreek OH USA Air Force Technical Applications Center United States Air Force Patrick Air Force Base Cocoa Beach FL USA

We introduce novel methods to determine optimum detection thresholds for the Progressive Multi-Channel Correlation (PMCC) algorithm used by the International Data Centre (IDC) to perform infrasound and seismic station-level nuclear-event detection. Receiver Operating Characteristic (ROC) curve analysis is used with real ground truth data to determine the trade-off between the probability of detection (PD) and the false alarm rate (FAR) at various detection thresholds. Further, statistical detection theory via maximum a posteriori and Bayes cost approaches is used to determine station-level optimum “family” size thresholds before detections should be considered for network-level processing. These threshold-determining methods are extensible for family-characterizing statistics other than “size,” such as a family’s collective F-statistic or signal-to-noise ratio (SNR). Therefore, the reliability of analysts’ decisions as to whether families should be preserved for network-level processing can only benefit from access to multiple, independent, optimum decision thresholds based upon size, F-statistic, SNR, etc.

关键词： Progressive Multi-Channel Correlation PMCC Infrasound Nuclear Treaty Monitoring Detection Optimization

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LSTM-based lane change prediction using Waymo open motion dataset: The role of vehicle operating space

Digital Transportation and Safety

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Digital Transportation and Safety 2023年第2期2卷 112-123页

作者： Xing Fu Jun Liu Zhitong Huang Alex Hainenand Asad J.Khattak Department of Civil Construction and Environmental EngineeringThe University of AlabamaTuscaloosaAL 35487USA leidos Inc.RestonVA 20190USA Department of Civil and Environmental Engineering The University of TennesseeKnoxvilleTN 37916USA

Lane change prediction is critical for crash avoidance but challenging as it requires the understanding of the instantaneous driving *** cutting-edge artificial intelligence and sensing technologies,autonomous vehicles(AVs)are expected to have exceptional perception systems to capture instantaneously their driving environments for predicting lane *** exploring the Waymo open motion dataset,this study proposes a framework to explore autonomous driving data and investigate lane change *** the framework,this study develops a Long Short-Term Memory(LSTM)model to predict lane changing *** concept of Vehicle Operating Space(VOS)is introduced to quantify a vehicle's instantaneous driving environment as an important indicator used to predict vehicle lane *** examine the robustness of the model,a series of sensitivity analysis are conducted by varying the feature selection,prediction horizon,and training data balancing *** test results show that inc.uding VOS into modeling can speed up the loss decay in the training process and lead to higher accuracy and recall for predicting lane-change *** study offers an example along with a methodological framework for transportation researchers to use emerging autonomous driving data to investigate driving behaviors and traffic environments.

关键词： Long Short-Term Memory Lane change prediction Vehicle Operating Space Waymo open data Sensitivity analysis

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Thr231磷酸化对顺式和反式tau蛋白226-236多肽六聚体结构的影响

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阿尔茨海默病及相关病杂志 2020年第4期3卷 258-266页

作者：孟青青曾鑫成苏玉红白钢钢 Ruth Nussinov 马步勇上海交通大学药学院细胞工程及抗体药物教育部工程研究中心上海200240 Basic Science Program Leidos Biomedical ResearchInc.Frederick National Laboratory for Cancer ResearchNational Cancer Institute at FrederickFrederickMD 21702USA Sackler Inst.of Molecular Medicine Department of Human Genetics and Molecular Medicine Sackler School of Medicine Tel Aviv UniversityTel Aviv 69978Israel

目的:研究Thr231磷酸化对于顺-反式tau异构体构象以及聚集行为的影响,探讨可能的在阿尔茨海默病和相关疾病中的毒性关联。方法:采用副本交换分子动力学模拟分析Tau蛋白226-246多肽片段六聚体的相互作用和结构。采用NAMD和CHARMM36分子... 详细信息

目的:研究Thr231磷酸化对于顺-反式tau异构体构象以及聚集行为的影响,探讨可能的在阿尔茨海默病和相关疾病中的毒性关联。方法:采用副本交换分子动力学模拟分析Tau蛋白226-246多肽片段六聚体的相互作用和结构。采用NAMD和CHARMM36分子力场的隐式溶剂化GBIS模型。使用了温度分布从300K到450K的56个模拟副本,每个模拟副本的模拟时间为200 ns,总模拟时间为11200 ns。结果:天然态时Thr231-Pro232是顺式和反式Tau226-236六聚体的相互作用中心,尽管顺式和反式tau多肽六聚体中肽链间有着不同的主链相互作用。反式比顺式tau多肽更易形成主链间氢键,226VAVVR231T部分在顺反式tau中均有4-10%的²结构,而反式tau多肽²结构略多。虽然反式tau蛋白多肽比顺式更为伸展末端距较长,但顺式和反式Tau226-236六聚体具有类似的表面积和回转半径。Thr231磷酸化完全破坏了顺式tau中主链间的氢键和²结构,反式Tau226-236六聚体中主链间的氢键和²结构也随Thr231磷酸化而减少,但影响较小。磷酸化Thr231在顺-反式Tau226-236六聚体中都易与Arg230形成盐桥。Thr231磷酸化促使顺式Tau226-236六聚体中VAVV部分有较大的疏水暴露面积,而这一作用在反式Tau226-236六聚体中较小。结论:Thr231磷酸化对顺式和反式Tau226-236六聚体结构有不同的影响,但是缺乏清晰的局部结构区别。Thr231磷酸化后六聚体中VAVV部分疏水暴露面积的差异和顺反式Tau226-236末端距的明显差别需要在全长Tau蛋白单体和寡聚体中进一步研究。

关键词：阿尔茨海默病 Tau蛋白淀粉样变性磷酸化分子动力学模拟

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