Publications by authors named "Yufeng Wei"

23 Publications

  • Page 1 of 1

A predictive model based on liquid biopsy for non-small cell lung cancer to assess patient's prognosis: Development and application.

Tissue Cell 2022 Aug 14;77:101854. Epub 2022 Jun 14.

Department of Respiratory, Hwa Mei Hospital, University of Chinese Academy of Sciences, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, China.

Background And Objective: Improving ability to predict the prognosis of patients with progressive lung cancer is an important task in the era of precision medicine. Here, a predictive model based on liquid biopsy for non-small cell lung cancer (NSCLC) was established to improve prognosis prediction in patients with progressive NSCLC.

Methods: Clinical data and blood samples of 500 eligible patients were collected and screened from the electronic case database and blood sample center of Hwa Mei Hospital, University of Chinese Academy of Sciences and Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences. Patients were randomly assigned to training set (300 cases) and validation set (200 cases) in a ratio of 3:2 by random number method. Baseline levels of the two datasets were compared. Progression-free survival (PFS) analysis was performed on the training set using Kaplan-Meier method. The independent prognostic factors affecting patients' PFS were determined by multivariate Cox regression analysis. The prognosis predictive model of patients was constructed by using the nomogram. Calibration curve and C-index were used to evaluate the accuracy of the prognosis predictive model in both internal and external validations.

Results: In training set, the age distribution of patients was 59.00 (46.00, 71.00) years, including 137 (45.7 %) females and 163 (54.3 %) males, 198 cases (66.0 %) with Eastern Cooperative Oncology Group (ECOG) score 0-1, and 102 cases (34.0 %) with ECOG score 2. In verification set, the age distribution of patients was 60.00 (48.25, 73.00) years, including 92 females (46.0 %) and 108 males (54.0 %), 130 cases (65.0%) with ECOG score 0-1, and 70 cases (35.0 %) with ECOG score 2. Patients in training set showed PFS differences stratified by gene mutation type (p < 0.0001), differentiation degree (p < 0.0001), circulating tumor cell (CTC) content (p = 0.00026), and brain metastasis (p < 0.0001). Besides, multivariate Cox regression analysis indicated that gene mutation type, differentiation degree, CTC content (p = 0.002), and brain metastasis (p = 0.005) are independent prognostic factors for PFS. These factors were included in the nomogram parameters, and both internally validated calibration curve (C-index = 0.672) and externally validated calibration curve (C-index = 0.657), showing good predictive performance of the model.

Conclusion: The predictive model has a good predictive ability for prognosis of patients with progressive NSCLC. Notably, the differentiation degree and CTC content are both impact factors for PFS of patients, and the performance of these indicators in predicting the survival of patients with progressive NSCLC needs to be clarified in the future.
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http://dx.doi.org/10.1016/j.tice.2022.101854DOI Listing
August 2022

PEA-15 engages in allosteric interactions using a common scaffold in a phosphorylation-dependent manner.

Sci Rep 2022 01 7;12(1):116. Epub 2022 Jan 7.

Department of Chemistry, New Jersey City University, Jersey City, NJ, 07305, USA.

Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) is a death-effector domain (DED) containing protein involved in regulating mitogen-activated protein kinase and apoptosis pathways. In this molecular dynamics study, we examined how phosphorylation of the PEA-15 C-terminal tail residues, Ser-104 and Ser-116, allosterically mediates conformational changes of the DED and alters the binding specificity from extracellular-regulated kinase (ERK) to Fas-associated death domain (FADD) protein. We delineated that the binding interfaces between the unphosphorylated PEA-15 and ERK2 and between the doubly phosphorylated PEA-15 and FADD are similarly composed of a scaffold that includes both the DED and the C-terminal tail residues of PEA-15. While the unphosphorylated serine residues do not directly interact with ERK2, the phosphorylated Ser-116 engages in strong electrostatic interactions with arginine residues on FADD DED. Upon PEA-15 binding, FADD repositions its death domain (DD) relative to the DED, an essential conformational change to allow the death-inducing signaling complex (DISC) assembly.
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http://dx.doi.org/10.1038/s41598-021-04099-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742051PMC
January 2022

Effect of incubation temperature and substrate moisture on embryonic development, hatchling phenotypes and post-hatching growth in the Reeves' Turtle, .

PeerJ 2021 12;9:e10553. Epub 2021 Feb 12.

Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China.

Background: Reeves' Turtles () are economically important in aquaculture in China. Understanding the effects of incubation temperature and substrate moisture on embryos and hatchlings is of great significance for improving the artificial culture of . However, available studies have not yet determined the thermal and hydric optima for eggs, and the potential interaction between the two factors.

Methods: In this study, eggs of were incubated at five temperature levels (23, 26, 29, 32 and 35 °C, fluctuation range ± 0.5 °C). In each temperature level, there were three substrate moisture levels (1:0.5, 1:0.9 and 1:1.2, weight ratio of vermiculite to water). Thus, a total of 15 combinations of temperature and moisture were used to examine the effects of incubation temperature and substrate moisture on incubation duration, hatching success, hatchling phenotypes, post-hatching growth and hatchling survival.

Results: Substrate moisture did not significantly affect most development parameters (except incubation duration and carapace width of hatchlings). Eggs incubated at low moisture level (1:0.5) had a longer incubation duration and produced hatchlings with smaller carapace widths than those incubated at medium (1:0.9) or high (1:1.2) moisture levels. Incubation temperature had a significant effect on incubation duration, hatching success, hatchling phenotypes and hatchling survival. Incubation duration decreased as incubation temperature increased. Eggs incubated at 23, 26 and 29 °C showed higher hatching success than those incubated at 32 and 35 °C. Hatchlings incubated at 32 °C were smaller in body size and mass than those incubated at 23, 26 and 29 °C. At 12 months of age, incubation temperature had no long-lasting effect on body mass, but hatchlings incubated at 23 and 35 °C had lower survival rates than those incubated at 26, 29 and 32 °C. For the development of embryos and hatchlings, the interaction between incubation temperature and substrate moisture was not significant.

Conclusions: Our results indicate that incubation temperature has a significant influence on the development of embryos and hatchlings of , while substrate moisture only significantly affects the incubation duration and carapace width of hatchlings. The combination of an incubation temperature of 29 ± 0.5 °C and a substrate moisture level of 1:1.2 represented optimal incubation conditions in this experiment. Such incubation conditions are helpful in obtaining higher hatching success, shorter incubation duration and higher survival rates for this aquaculture species.
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http://dx.doi.org/10.7717/peerj.10553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883692PMC
February 2021

Substance Use Disorder in the COVID-19 Pandemic: A Systematic Review of Vulnerabilities and Complications.

Pharmaceuticals (Basel) 2020 Jul 18;13(7). Epub 2020 Jul 18.

Department of Chemistry, New Jersey City University, Jersey City, NJ 07305, USA.

As the world endures the coronavirus disease 2019 (COVID-19) pandemic, the conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by underlying health conditions, such as cardiovascular and lung diseases and undermined immune systems. During the pandemic, access to the healthcare systems and support groups is greatly diminished. Current research on COVID-19 has not addressed the unique challenges facing individuals with SUDs, including the heightened vulnerability and susceptibility to the disease. In this systematic review, we will discuss the pathogenesis and pathology of COVID-19, and highlight potential risk factors and complications to these individuals. We will also provide insights and considerations for COVID-19 treatment and prevention in patients with SUDs.
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http://dx.doi.org/10.3390/ph13070155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407364PMC
July 2020

Observations on carapace color change in the juvenile big-headed turtle ().

PeerJ 2019 26;7:e7331. Epub 2019 Jul 26.

Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Guangdong Institute of Applied Biological Resources, Guangzhou, China.

The carapace color of newborn big-headed turtles () is polymorphic and usually consists of two phenotypes: yellowish brown and olive green. As the turtles grew, over the first year of life, its carapace gradually turned from yellowish brown to chestnut brown, or from olive green to dark brown, depending on the phenotype. Meanwhile, the turtle's plastron remained an orange and black pattern and did not change much. In this study, we primarily used HE staining to observe the carapace color change with age in big-headed turtle juveniles. We took the carapace marginal scute tissues twice from the same turtles before and after the carapace color change. Histological observations show that in the marginal scutes of the four tested turtles with different carapace color phenotypes, melanin granules are all concentrated in the dermal layer underneath the dorsal corneous layer, but rarely on the ventral side. Melanin deposits in the dorsal corneous layer were found to increase as the corneous layers thickened, while the melanin deposits in the ventral corneous layer did not change significantly. However, there was no significant difference in melanin deposition in the epidermis and dermis of the carapace among the yellowish brown, chestnut brown, olive green, and dark brown big-headed turtles. The results of our study indicate that the carapace color darkening in big-headed turtles may not be due to changes in melanin content of the carapace, but is the result of melanin accumulation and superposition in the dorsal corneous layer.
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http://dx.doi.org/10.7717/peerj.7331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662560PMC
July 2019

PEA-15 C-Terminal Tail Allosterically Modulates Death-Effector Domain Conformation and Facilitates Protein-Protein Interactions.

Int J Mol Sci 2019 Jul 7;20(13). Epub 2019 Jul 7.

Department of Chemistry, New Jersey City University, Jersey City, NJ 07305-1596, USA.

Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) exerts its regulatory roles on several critical cellular pathways through protein-protein interactions depending on its phosphorylation states. It can either inhibit the extracellular signal-regulated kinase (ERK) activities when it is dephosphorylated or block the assembly of death-inducing signaling complex (DISC) and the subsequent activation of apoptotic initiator, caspase-8, when it is phosphorylated. Due to the important roles of PEA-15 in regulating these pathways that lead to opposite cellular outcomes (cell proliferation vs. cell death), we proposed a phosphostasis (phosphorylation homeostasis) model, in which the phosphorylation states of the protein are vigorously controlled and regulated to maintain a delicate balance. The phosphostasis gives rise to the protective cellular functions of PEA-15 to preserve optimum cellular conditions. In this article, using advanced multidimensional nuclear magnetic resonance (NMR) techniques combined with a novel chemical shift (CS)-Rosetta algorithm for de novo protein structural determination, we report a novel conformation of PEA-15 death-effector domain (DED) upon interacting with ERK2. This new conformation is modulated by the irregularly structured C-terminal tail when it first recognizes and binds to ERK2 at the d-peptide recruitment site (DRS) in an allosteric manner, and is facilitated by the rearrangement of the surface electrostatic and hydrogen-bonding interactions on the DED. In this ERK2-bound conformation, three of the six helices (α2, α3, and α4) comprising the DED reorient substantially in comparison to the free-form structure, exposing key residues on the other three helices that directly interact with ERK2 at the DEF-docking site (docking site for ERK, FxF) and the activation loop. Additionally, we provide evidence that the phosphorylation of the C-terminal tail leads to a distinct conformation of DED, allowing efficient interactions with Fas-associated death domain (FADD) protein at the DISC. Our results substantiate the allosteric regulatory roles of the C-terminal tail in modulating DED conformation and facilitating protein-protein interactions of PEA-15.
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http://dx.doi.org/10.3390/ijms20133335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651876PMC
July 2019

Glucose monitoring in living cells with single fluorescent protein-based sensors.

RSC Adv 2018 Jan 10;8(5):2485-2489. Epub 2018 Jan 10.

Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology 130 Mei Long Road Shanghai 200237 China.

Glucose is the main source of energy and carbon in organisms and plays a central role in metabolism and cellular homeostasis. However, the sensitive fluctuation of glucose in living cells is difficult to monitor. Thus, we developed a series of ratiometric, highly responsive, single fluorescent protein-based glucose sensors of wide dynamic range by combining a circularly permuted yellow fluorescent protein with a bacterial periplasmic glucose/galactose-binding protein. We used these sensors to monitor glucose transport in living cells, and found that the cells take up glucose within 10 min to maintain physiological glucose levels, and observed the differences in glucose uptake and glucose metabolism between wild-type and Mlc knockout cells. These sensors can be specific and simple tools for glucose detection and non-invasive tools for real-time monitoring of glucose metabolism .
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http://dx.doi.org/10.1039/c7ra11347aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9077360PMC
January 2018

Melanin deposition ruled out as cause of color changes in the red-eared sliders (Trachemys scripta elegans).

Comp Biochem Physiol B Biochem Mol Biol 2018 Mar 18;217:79-85. Epub 2017 Dec 18.

Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Guangdong Institute of Applied Biological Resources. Guangzhou 510260, China.

Animal coloration primarily depends on the presence of pigments and the mixing ratio of eumelanin and pheomelanin. The color of red-eared slider's carapace varies with age, from an olive green to a yellow green, and then to a yellow brown in juveniles, generally. The purpose of the present study was to investigate whether this color change is related to the difference in melanin expression. Melanin deposition levels were examined in the carapace, skin, eye and muscle of the three color-types using hematoxylin and eosin staining. Moreover, the full-length coding sequence (CDS) of red-eared slider turtle melanin biosynthesis regulatory genes TYR, TYRP1, MITF and SLC24A5 were cloned, sequenced and quantitatively analyzed. Both histological view of melanin deposition and quantitative real-time PCR test of melanin-regulated gene expressions showed that there are significant differences among different tissues of red-eared slider, but no significant difference among different color-types, indicating that melanin deposition is not associated with ontogenetic color change in the carapace of red-eared slider. This study initially explore the melanin deposition and the mRNA expression of melanin biosynthesis regulatory genes in red-eared slider, which serve as a foundation for further insight into the pigmentation patterns and the mechanism of body color change in turtles.
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http://dx.doi.org/10.1016/j.cbpb.2017.12.011DOI Listing
March 2018

Involvement of the Hippocampus in Binge Ethanol-Induced Spleen Atrophy in Adolescent Rats.

Alcohol Clin Exp Res 2016 07 6;40(7):1489-500. Epub 2016 Jun 6.

Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, New Jersey.

Background: Ethanol (EtOH) affects the immune system. Binge drinking of hard liquor initiates a stress response. This form of drinking is popular during adolescence, which involves maturation of the immune system. The spleen is a key immune organ, and spleen atrophy is associated with immunosuppression. While the hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the initial stress response, the hippocampus may be involved in stress beyond the HPA axis.

Methods: Blood ethanol concentration (BEC), blood endotoxin levels, and plasma corticosterone levels were measured following binge EtOH treatment. Absolute and relative spleen sizes were analyzed, and stress-related gene expression was compared in the hypothalamus and hippocampus. Polymerase chain reaction array was performed to analyze the expression profile of EtOH metabolism and immune regulation-related genes in the spleen. Relationships among variables were analyzed using the Pearson correlation.

Results: At 24 hours following a 3-day EtOH treatment, no significant difference in BEC was detected between EtOH-treated and control rats. Average plasma endotoxin levels in EtOH-treated animals were significantly higher than in controls, and spleen size was significantly lower. Spleen size did not correlate with plasma endotoxin levels; however, it did significantly negatively correlate with plasma corticosterone levels. Spleen size significantly negatively correlated with hippocampal CRH expression and significantly positively correlated with hippocampal MR expression. No correlation was observed in the hypothalamus. Significantly higher hippocampal CRH and significantly lower MR expression was seen in low spleen/body weight (sp-wt) ratio rats. No gene was found to decrease expression ≥1.5-fold (p < 0.05) in the spleen of high sp-wt group, whereas expression of several genes, including Gabra1, Gabra5, Ifnb1, Irf9, Il12b, and Cx3cr1, decreased significantly in the low sp-wt group.

Conclusions: Our findings suggest that binge EtOH exposure causes lower spleen size in adolescents and that the hippocampus and stress may be associated with alterations in spleen structure and gene expression.
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http://dx.doi.org/10.1111/acer.13109DOI Listing
July 2016

Facile Synthesis of Fe3O4/GCs Composites and Their Enhanced Microwave Absorption Properties.

ACS Appl Mater Interfaces 2016 Mar 25;8(9):6101-9. Epub 2016 Feb 25.

Institute for Superconducting and Electronic Materials, Australian Institute for Innovative Materials, University of Wollongong , North Wollongong 2500, Australia.

Graphene has good stability and adjustable dielectric properties along with tunable morphologies, and hence can be used to design novel and high-performance functional materials. Here, we have reported a facile synthesis method of nanoscale Fe3O4/graphene capsules (GCs) composites using the combination of catalytic chemical vapor deposition (CCVD) and hydrothermal process. The resulting composite has the advantage of unique morphology that offers better synergism among the Fe3O4 particles as well as particles and GCs. The microwave-absorbing characteristics of developed composites were investigated through experimentally measured electromagnetic properties and simulation studies based on the transmission line theory, explained on the basis of eddy current, natural and exchange resonance, as well as dielectric relaxation processes. The composites bear minimum RL value of -32 dB at 8.76 GHz along with the absorption bandwidth range from 5.4 to 17 GHz for RL lower than -10 dB. The better performance of the composite based on the reasonable impedance characteristic, existence of interfaces around the composites, and the polarization of free carriers in 3D GCs that make the as-prepared composites capable of absorbing microwave more effectively. These results offer an effective way to design high-performance functional materials to facilitate the research in electromagnetic shielding and microwave absorption.
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http://dx.doi.org/10.1021/acsami.6b00388DOI Listing
March 2016

On the Quest of Cellular Functions of PEA-15 and the Therapeutic Opportunities.

Authors:
Yufeng Wei

Pharmaceuticals (Basel) 2015 Jul 31;8(3):455-73. Epub 2015 Jul 31.

Department of Chemistry, New Jersery City University, 2039 Kennedy Blvd, Jersey City, NJ 07305, USA.

Phosphoprotein enriched in astrocytes, 15 KDa (PEA-15), a ubiquitously expressed small protein in all mammals, is known for decades for its potent interactions with various protein partners along distinct biological pathways. Most notable interacting partners of PEA-15 include extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the mitogen activated protein kinase (MAPK) pathway, the Fas-associated death domain (FADD) protein involving in the formation of the death-inducing signaling complex (DISC), and the phospholipase D1 (PLD1) affecting the insulin sensitivity. However, the actual cellular functions of PEA-15 are still mysterious, and the question why this protein is expressed in almost all cell and tissue types remains unanswered. Here we synthesize the most recent structural, biological, and clinical studies on PEA-15 with emphases on its anti-apoptotic, anti-proliferative, and anti-inflammative properties, and propose a converged protective role of PEA-15 that maintains the balance of death and survival in different cell types. Under conditions that this delicate balance is unsustainable, PEA-15 may become pathological and lead to various diseases, including cancers and diabetes. Targeting PEA-15 interactions, or the use of PEA-15 protein as therapeutics, may provide a wider window of opportunities to treat these diseases.
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http://dx.doi.org/10.3390/ph8030455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588177PMC
July 2015

Photophoretic trapping of multiple particles in tapered-ring optical field.

Opt Express 2014 Sep;22(19):23716-23

We demonstrate the photophoretic trapping of more than several hundreds of absorbing particles by tapered-ring optical traps diffracted from a circular aperture. The experiments with different laser powers show the influence of air flow acting on particles. Three kinds of particles with different densities (about 1~7 g/cm(3)) and different shapes (spherical, non-spherical) can be trapped. The non-spherical particles (toner particles) disperse in optical field, while the spherical particles (ink droplets and iron particles) arrange as a straight line. More importantly, in the experiments of two counter-propagating tapered-ring beams, the agglomeration of particles is achieved and can help research the dynamics of aerosols.
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http://dx.doi.org/10.1364/OE.22.023716DOI Listing
September 2014

NeuroHIV and use of addictive substances.

Int Rev Neurobiol 2014 ;118:403-40

Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, USA.

In the past three decades, substance abuse has been identified as a key comorbidity of human immunodeficiency virus-1 (HIV-1) infection. Many studies have found that the use and abuse of addictive substances hastens the progression of HIV-1 infection and HIV-associated neurocognitive disorders. Advances in highly active antiretroviral therapy (HAART) in the mid-1990s have been successful in limiting the HIV-1 viral load and maintaining a relatively healthy immune response, allowing the life expectancy of patients infected with HIV to approach that of the general population. However, even with HAART, HIV-1 viral proteins are still expressed and eradication of the virus, particularly in the brain, the key reservoir organ, does not occur. In the post-HAART era, the clinical challenge in the treatment of HIV infection is inflammation of the central nervous system (CNS) and its subsequent neurological disorders. To date, various explicit and implicit connections have been identified between the neuronal circuitry involved in immune responses and brain regions affected by and implicated in substance abuse. This chapter discusses past and current medical uses of prototypical substances of abuse, including morphine, alcohol, cocaine, methamphetamine, marijuana, and nicotine, and the evidence that systemic infections, particularly HIV-1 infection, cause neurological dysfunction as a result of inflammation in the CNS, which can increase the risk of substance abuse.
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http://dx.doi.org/10.1016/B978-0-12-801284-0.00013-0DOI Listing
May 2015

Substantial conformational change mediated by charge-triad residues of the death effector domain in protein-protein interactions.

PLoS One 2013 31;8(12):e83421. Epub 2013 Dec 31.

Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, New Jersey, United States of America.

Protein conformational changes are commonly associated with the formation of protein complexes. The non-catalytic death effector domains (DEDs) mediate protein-protein interactions in a variety of cellular processes, including apoptosis, proliferation and migration, and glucose metabolism. Here, using NMR residual dipolar coupling (RDC) data, we report a conformational change in the DED of the phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) protein in the complex with a mitogen-activated protein (MAP) kinase, extracellular regulated kinase 2 (ERK2), which is essential in regulating ERK2 cellular distribution and function in cell proliferation and migration. The most significant conformational change in PEA-15 happens at helices α2, α3, and α4, which also possess the highest flexibility among the six-helix bundle of the DED. This crucial conformational change is modulated by the D/E-RxDL charge-triad motif, one of the prominent structural features of DEDs, together with a number of other electrostatic and hydrogen bonding interactions on the protein surface. Charge-triad motif promotes the optimal orientation of key residues and expands the binding interface to accommodate protein-protein interactions. However, the charge-triad residues are not directly involved in the binding interface between PEA-15 and ERK2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083421PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877032PMC
August 2014

Manipulation of aerosols revolving in taper-ring optical traps.

Opt Lett 2014 Jan;39(1):100-3

We designed taper-ring optical traps by a weakly focused laser beam through a circular aperture. By railing-like potential barriers, these optical traps are partitioned into enclosed rings, in which irregular light-absorbing microparticles can be driven by photophoretic force to revolve around optical axis in air. The diameter of revolution can reach about 700 μm, which is much larger than that in traditional optical traps based on radiation pressure and gradient force. More importantly, multiple particles were driven to revolve simultaneously in different planes in air for the first reported time to the best of our knowledge.
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http://dx.doi.org/10.1364/OL.39.000100DOI Listing
January 2014

Profound conformational changes of PED/PEA-15 in ERK2 complex revealed by NMR backbone dynamics.

Biochim Biophys Acta 2012 Dec 20;1824(12):1382-93. Epub 2012 Jul 20.

Department of Chemistry and Biochemistry, Seton Hall University, South Orange, NJ 07079, USA.

PED/PEA-15 is a small, non-catalytic, DED containing protein that is widely expressed in different tissues and highly conserved among mammals. PED/PEA-15 has been found to interact with several protein targets in various pathways, including FADD and procaspase-8 (apoptosis), ERK1/2 (cell cycle entry), and PLD1/2 (diabetes). In this research, we have studied the PED/PEA-15 in a complex with ERK2, a MAP kinase, using NMR spectroscopic techniques. MAP Kinase signaling pathways are involved in the regulation of many cellular functions, including cell proliferation, differentiation, apoptosis and survival. ERK1/2 are activated by a variety of external stimuli, including growth factors, hormones and neurotransmitters. Inactivated ERK2 is primarily found in the cytosol. Once the ERK/MAPK cascade is initiated, ERK2 is phosphorylated and stimulated, allowing it to redistribute in the cell nucleus and act as a transcription factor. Previous studies have shown that PED/PEA-15 complexes with ERK2 in the cytoplasm and prevents redistribution into the nucleus. Although the NMR structure and dynamics of PED/PEA-15 in the free form have been documented recently, no detailed structural and dynamic information for the ERK2-bound form is available. Here we report NMR chemical shift perturbation and backbone dynamic studies at the fast ps-ns timescale of PED/PEA-15, in its free form and in the complex with ERK2. These analyses characterize motions and conformational changes involved in ERK2 recognition and binding that orchestrate the reorganization of the DED and immobilization of the C-terminal tail. A new induced fit binding model for PED/PEA-15 is proposed.
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http://dx.doi.org/10.1016/j.bbapap.2012.07.001DOI Listing
December 2012

High-definition NMR structure of PED/PEA-15 death effector domain reveals details of key polar side chain interactions.

Biochem Biophys Res Commun 2012 Jul 23;424(1):141-6. Epub 2012 Jun 23.

Department of Chemistry and Biochemistry, Seton Hall University, South Orange, NJ 07094-2646, USA.

Death effector domain (DED) proteins constitute a subfamily of the large death domain superfamily that is primarily involved in apoptosis pathways. DED structures have characteristic side chain-side chain interactions among polar residues on the protein surface, forming a network of hydrogen bonds and salt bridges. The polar interaction network is functionally important in promoting protein-protein interactions by maintaining optimal side chain orientations. We have refined the solution DED structure of the PED/PEA-15 protein, a representative member of DED subfamily, using traditional NMR restraints with the addition of residual dipolar coupling (RDC) restraints from two independent alignment media, and employed the explicit solvent refinement protocol. The newly refined DED structure of PED/PEA-15 possesses higher structural quality as indicated by WHAT IF Z-scores, with most significant improvement in the backbone conformation normality quality factor. This higher quality DED structure of PED/PEA-15 leads to the identification of a number of key polar side chain interactions, which are not typically observed in NMR protein structures. The elucidation of polar side chain interactions is a key step towards the understanding of protein-protein interactions involving the death domain superfamily. The NMR structures with extensive details of protein structural features are thereby termed high-definition (HD) NMR structures.
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http://dx.doi.org/10.1016/j.bbrc.2012.06.091DOI Listing
July 2012

A TAF4-homology domain from the corepressor ETO is a docking platform for positive and negative regulators of transcription.

Nat Struct Mol Biol 2007 Jul 17;14(7):653-61. Epub 2007 Jun 17.

Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, New York, New York, 10021, USA.

The eight twenty-one protein, ETO, is implicated in 12%-15% of acute human leukemias as part of a gene fusion with RUNX1 (also called AML1). Of the four ETO domains related to Drosophila melanogaster Nervy, only two are required to induce spontaneous myeloid leukemia upon transplantation into the mouse. One of these domains is related in sequence to TAF4, a component of TFIID. The structure of this domain, ETO-TAFH, is similar to yeast Rpb4 and to Escherichia coli sigma(70); it is the first TAF-related protein with structural similarity to the multisubunit RNA polymerases. Overlapping surfaces of ETO-TAFH interact with an autonomous repression domain of the nuclear receptor corepressor N-CoR and with a conserved activation domain from the E-box family of transcription factors. Thus, ETO-TAFH acts as a structural platform that can interchange negative and positive coregulatory proteins to control transcription.
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http://dx.doi.org/10.1038/nsmb1258DOI Listing
July 2007

iDC: A comprehensive toolkit for the analysis of residual dipolar couplings for macromolecular structure determination.

J Biomol NMR 2006 May 1;35(1):17-25. Epub 2006 Jun 1.

Laboratory of Molecular Biophysics, Rockefeller University, 1230 York Avenue, NewYork, NY, Box 42, 10021, USA.

Measurement of residual dipolar couplings (RDCs) has become an important method for the determination and validation of protein or nucleic acid structures by NMRf spectroscopy. A number of toolkits have been devised for the handling of RDC data which run in the Linux/Unix operating environment and require specifically formatted input files. The outputs from these programs, while informative, require format modification prior to the incorporation of this data into commonly used personal computer programs for manuscript preparation. To bridge the gap between analysis and publication, an easy-to-use, comprehensive toolkit for RDC analysis has been created, iDC. iDC is written for the WaveMetrics Igor Pro mathematics program, a widely used graphing and data analysis software program that runs on both Windows PC and Mac OS X computers. Experimental RDC values can be loaded into iDC using simple data formats accessible to Igor's tabular data function. The program can perform most useful RDC analyses, including alignment tensor estimation from a histogram of RDC occurrence versus values and order tensor analysis by singular value decomposition (SVD). SVD analysis can be performed on an entire structure family at once, a feature missing in other applications of this kind. iDC can also import from and export to several different commonly used programs for the analysis of RDC data (DC, PALES, REDCAT) and can prepare formatted files for RDC-based refinement of macromolecular structures using XPLOR-NIH, CNS and ARIA. The graphical user interface provides an easy-to-use I/O for data, structures and formatted outputs.
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http://dx.doi.org/10.1007/s10858-006-9009-xDOI Listing
May 2006

The structure of FADD and its mode of interaction with procaspase-8.

Mol Cell 2006 Jun;22(5):599-610

Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, Box 42, New York, New York 10021, USA.

The structure of FADD has been solved in solution, revealing that the death effector domain (DED) and death domain (DD) are aligned with one another in an orthogonal, tail-to-tail fashion. Mutagenesis of FADD and functional reconstitution with its binding partners define the interaction with the intracellular domain of CD95 and the prodomain of procaspase-8 and reveal a self-association surface necessary to form a productive complex with an activated "death receptor." The identification of a procaspase-specific binding surface on the FADD DED suggests a preferential interaction with one, but not both, of the DEDs of procaspase-8 in a perpendicular arrangement. FADD self-association is mediated by a "hydrophobic patch" in the vicinity of F25 in the DED. The structure of FADD and its functional characterization, therefore, illustrate the architecture of key components in the death-inducing signaling complex.
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http://dx.doi.org/10.1016/j.molcel.2006.04.018DOI Listing
June 2006

T4 AsiA blocks DNA recognition by remodeling sigma70 region 4.

EMBO J 2004 Aug 15;23(15):2952-62. Epub 2004 Jul 15.

Laboratory of Molecular Biophysics, Rockefeller University, New York, NY 10021, USA.

Bacteriophage T4 AsiA is a versatile transcription factor capable of inhibiting host gene expression as an 'anti-sigma' factor while simultaneously promoting gene-specific expression of T4 middle genes in conjunction with T4 MotA. To accomplish this task, AsiA engages conserved region 4 of Eschericia coli sigma70, blocking recognition of most host promoters by sequestering the DNA-binding surface at the AsiA/sigma70 interface. The three-dimensional structure of an AsiA/region 4 complex reveals that the C-terminal alpha helix of region 4 is unstructured, while four other helices adopt a completely different conformation relative to the canonical structure of unbound region 4. That AsiA induces, rather than merely stabilizes, this rearrangement can be realized by comparison to the homologous structures of region 4 solved in a variety of contexts, including the structure of Thermotoga maritima sigmaA region 4 described herein. AsiA simultaneously occupies the surface of region 4 that ordinarily contacts core RNA polymerase (RNAP), suggesting that an AsiA-bound sigma70 may also undergo conformational changes in the context of the RNAP holoenzyme.
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http://dx.doi.org/10.1038/sj.emboj.7600312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC514929PMC
August 2004

Identification of an expanded binding surface on the FADD death domain responsible for interaction with CD95/Fas.

J Biol Chem 2004 Jan 22;279(2):1474-81. Epub 2003 Oct 22.

Laboratory of Molecular Biophysics, The Rockefeller University, New York, New York 10021, USA.

The initiation of programmed cell death at CD95 (Fas, Apo-1) is achieved by forming a death-inducing signaling complex (DISC) at the cytoplasmic membrane surface. Assembly of the DISC has been proposed to occur via homotypic interactions between the death domain (DD) of FADD and the cytoplasmic domain of CD95. Previous analysis of the FADD/CD95 interaction led to the identification of a putative CD95 binding surface within FADD DD formed by alpha helices 2 and 3. More detailed analysis of the CD95/FADD DD interaction now demonstrates that a bimodal surface exists in the FADD DD for interaction with CD95. An expansive surface on one side of the domain is composed of elements in alpha helices 1, 2, 3, 5, and 6. This major surface is common to many proteins harboring this motif, whether or not they are associated with programmed cell death. A secondary surface resides on the opposite face of the domain and involves residues in helices 3 and 4. The major surface is topologically similar to the protein interaction surface identified in Drosophila Tube DD and the death effector domain of hamster PEA-15, two physiologically unrelated proteins which interact with structurally unrelated binding partners. These results demonstrate the presence of a structurally conserved surface within the DD which can mediate protein recognition with homo- and heterotypic binding partners, whereas a second surface may be responsible for stabilizing the higher order complex in the DISC.
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http://dx.doi.org/10.1074/jbc.M304996200DOI Listing
January 2004

A 2D MAS solid-state NMR method to recover the amplified heteronuclear dipolar and chemical shift anisotropic interactions.

J Magn Reson 2002 Sep-Oct;158(1-2):23-35

Department of Chemistry and Biophysics Research Division and Department of Macromolecular Science and Engineering, The University of Michigan, Ann Arbor, MI 48109, USA.

A two-dimensional solid-state NMR method for the measurement of chemical shift anisotropy tensors of X nuclei (15N or 13C) from multiple sites of a polypeptide powder sample is presented. This method employs rotor-synchronized pi pulses to amplify the magnitude of the inhomogeneous X-CSA and 1H-X dipolar coupling interactions. A combination of on-resonance and magic angle rf irradiation of protons is used to vary the ratio of the magnitudes of the 1H-X dipolar and X-CSA interactions which are recovered under MAS, in addition to suppressing the 1H-1H dipolar interactions. The increased number of spinning sidebands in the recovered anisotropic interactions is useful to determine the CSA tensors accurately. The performance of this method is examined for powder samples of N-acetyl-(15)N-L-valine (NAV), N-acetyl-15N-L-valyl-15N-L-leucine (NAVL), and alpha-13C-L-leucine. The sources of experimental errors in the measurement of CSA tensors and the application of the pulse sequences under high-field fast MAS operations are discussed.
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http://dx.doi.org/10.1016/s1090-7807(02)00056-3DOI Listing
January 2003
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