Li Zhang

Chronic back pain (CBP) is a leading cause of disability and results in considerable socio-economic burdens worldwide. Although CBP patients are commonly diagnosed and treated with a focus on the ‘end organ dysfunction’ (i.e., peripheral nerve injuries or diseases), the evaluation of CBP remains flawed and problematic with great challenges. Given that the peripheral nerve injuries or diseases are insufficient to define the etiology of CBP in some cases, the evaluation of alterations in the central nervous system becomes particularly necessary and important. With the development of advanced neuroimaging techniques, extensive studies have been carried out to identify the cortical abnormalities in CBP patients. Here, we provide a comprehensive overview on a series of novel findings from these neuroimaging studies to improve our understanding of the cortical abnormalities originated in the disease. First, CBP patients normally exhibit central sensitization to external painful stimuli, which is indexed by increased pain sensitivity and brain activations in pain-related brain regions. Second, long-term suffering from chronic pain leads to emotional disorders, cognitive impairments, and the abnormalities of the relevant brain networks among CBP patients. Third, CBP is associated with massive cortical reorganization, including structural, functional, and metabolic brain changes. Overall, a deep insight into the neural mechanisms underlying the development and outcome of CBP through more sophisticated neuroimaging investigations could not only improve our current understanding of the etiology of CBP but also facilitate the diagnosis and treatment of CBP based on precision medicine.

© 2016 Elsevier B.V.The evaporative-cooling roof is a popular passive energy conservation technique. This article presents a novel approach for modelling and analysing the influence of evaporation on roof thermal performance. A multivariate nonlinear model was developed for the prediction of the evaporation rate from porous tile. A computer program was then developed based on the one-dimensional roof unsteady heat transfer theory. Finally, the computer program and hourly weather data of Guangzhou, China, were used to analyse the impacts of evaporation and slope orientation on roof thermal performance. Evaporation beginning at 11:00 can reduce the external surface temperatures of a horizontal roof and 30°-inclined east-sloping and west-sloping roofs by up to 11.3, 10.7, and 9.8 °C, respectively, from those of a non-evaporative roof. This, in turn, can reduce the peak-hour internal surface heat flux. Additionally, with the horizontal roof, the reduction in the peak-hour heat flux can be doubled if the evaporative layer is frequently replenished with water.

© 2015 Elsevier Ltd.Age-related macular degeneration is the leading cause of blindness among the elderly in developed countries. AMD is classified as either neovascular or non-neovascular. Cumulative damage to the retinal pigment epithelium, Bruch's membrane, and choriocapillaris leads to dysfunction and loss of RPE cells. This causes degeneration of the overlying photoreceptors and consequential vision loss in advanced NNV-AMD. In NV-AMD, abnormal growth of capillaries under the retina and RPE, which leads to hemorrhage and fluid leakage, is the main cause of photoreceptor damage. Although a number of drugs are in use for NV-AMD, there is currently no treatment for advanced NNV-AMD. However, replacing dead or dysfunctional RPE with healthy RPE has been shown to rescue dying photoreceptors and improve vision in animal models of retinal degeneration and possibly in AMD patients. Differentiation of RPE from human embryonic stem cells and from induced pluripotent stem cells has created a potentially unlimited source for replacing dead or dying RPE. Such cells have been shown to incorporate into the degenerating retina and result in anatomic and functional improvement. However, major ethical, regulatory, safety, and technical challenges have yet to be overcome before stem cell-based therapies can be used in standard treatments. This review outlines the current knowledge surrounding the application of hESC-RPE and iPSC-RPE in AMD. Following an introduction on the pathogenesis and available treatments of AMD, methods to generate stem cell-derived RPE, immune reaction against such cells, and approaches to deliver desired cells into the eye will be explored along with broader issues of efficacy and safety. Lastly, strategies to improve these stem cell-based treatments will be discussed.

Contactin-Associated protein-like 2 is a large multidomain neuronal adhesion molecule implicated in a number of neurological disorders, including epilepsy, schizophrenia, autism spectrum disorder, intellectual disability, and language delay. We reveal here by electron microscopy that the architecture of CNTNAP2 is composed of a large, medium, and small lobe that flex with respect to each other. Using epitope labeling and fragments, we assign the F58C, L1, and L2 domains to the large lobe, the FBG and L3 domains to the middle lobe, and the L4 domain to the small lobe of the CNTNAP2 molecular envelope. Our data reveal that CNTNAP2 has a very different architecture compared with neurexin 1α, a fellow member of the neurexin superfamily and a prototype, suggesting that CNTNAP2 uses a different strategy to integrate into the synaptic protein network. We show that the ectodomains of CNTNAP2 and contactin 2 bind directly and specifically, with low nanomolar affinity. We show further that mutations in CNTNAP2 implicated in autism spectrum disorder arenot segregated but are distributed over the whole ectodomain. The molecular shape and dimensions of CNTNAP2 place constraints on how CNTNAP2 integrates in the cleft of axo-glial and neuronal contact sites and how it functions as an organizing and adhesive molecule.

Knowledge of three-dimensional structures of each individual particles of asymmetric and flexible proteins is essential in understanding those proteins' functions; but their structures are difficult to determine. Electron tomography provides a tool for imaging a single and unique biological object from a series of tilted angles, but it is challenging to image a single protein for three-dimensional reconstruction due to the imperfect mechanical control capability of the specimen goniometer under both a medium to high magnification and an optimized beam coherence condition. Here, we report a fully mechanical control method for automating ET data acquisition without using beam tilt/shift processes. This method could reduce the accumulation of beam tilt/shift that used to compensate the error from the mechanical control, but downgraded the beam coherence. Our method was developed by minimizing the error of the target object center during the tilting process through a closed-loop proportional-integral control algorithm. The validations by both negative staining and cryo-electron microscopy suggest that this method has a comparable capability to other ET methods in tracking target proteins while maintaining optimized beam coherence conditions for imaging.

DNA base pairing has been used for many years to direct the arrangement of inorganic nanocrystals into small groupings and arrays with tailored optical and electrical properties. The control of DNA-mediated assembly depends crucially on a better understanding of three-dimensional structure of DNA-nanocrystal-hybridized building blocks. Existing techniques do not allow for structural determination of these flexible and heterogeneous samples. Here we report cryo-electron microscopy and negative-staining electron tomography approaches to image, and three-dimensionally reconstruct a single DNA-nanogold conjugate, an 84-bp double-stranded DNA with two 5-nm nanogold particles for potential substrates in plasmon-coupling experiments. By individual-particle electron tomography reconstruction, we obtain 14 density maps at ~ 2-nm resolution. Using these maps as constraints, we derive 14 conformations of dsDNA by molecular dynamics simulations. The conformational variation is consistent with that from liquid solution, suggesting that individual-particle electron tomography could be an expected approach to study DNA-assembling and flexible protein structure and dynamics.

Cholesteryl ester transfer protein mediates cholesteryl ester transfer from the atheroprotective high density lipoprotein cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up a CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases.

Commonly used methods for determining protein structure, including X-ray crystallography and single-particle reconstruction, often provide a single and unique three-dimensional structure. However, in these methods, the protein dynamics and flexibility/fluctuation remain mostly unknown. Here, we utilized advances in electron tomography to study the antibody flexibility and fluctuation through structural determination of individual antibody particles rather than averaging multiple antibody particles together. Through individual-particle electron tomography 3D reconstruction from negatively-stained ET images, we obtained 120 ab-initio 3D density maps at an intermediate resolution from 120 individual IgG1 antibody particles. Using these maps as a constraint, we derived 120 conformations of the antibody via structural flexible docking of the crystal structure to these maps by targeted molecular dynamics simulations. Statistical analysis of the various conformations disclosed the antibody 3D conformational flexibility through the distribution of its domain distances and orientations. This blueprint approach, if extended to other flexible proteins, may serve as a useful methodology towards understanding protein dynamics and functions.

Cholesteryl ester transfer protein mediates the transfer of cholesterol esters from atheroprotective high-density lipoproteins to atherogenic low-density lipoproteins. CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases. Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.

Peptides show much promise as potent and selective drug candidates. Fusing peptides to a scaffold monoclonal antibody produces a conjugated antibody which has the advantages of peptide activity yet also has the pharmacokinetics determined by the scaffold antibody. However, the conjugated antibody often has poor binding affinity to antigens that may be related to unknown structural changes. The study of the conformational change is difficult by conventional techniques because structural fluctuation under equilibrium results in multiple structures co-existing. Here, we employed our two recently developed electron microscopy techniques: optimized negative-staining EM and individual-particle electron tomography. Two-dimensional image analyses and three-dimensional maps have shown that the domains of antibodies present an elongated peptide-conjugated conformational change, suggesting that our EM techniques may be novel tools to monitor the structural conformation changes in heterogeneous and dynamic macromolecules, such as drug delivery vehicles after pharmacological synthesis and development.

Since the discovery and implication of N-ethylmaleimide-sensitive factor -attachment protein receptor proteins in membrane fusion almost two decades ago, there have been significant efforts to understand their involvement at the molecular level. In the current study, we report for the first time the molecular interaction between full-length recombinant t-SNAREs and v-SNARE present in opposing liposomes, leading to the assembly of a t-/v-SNARE ring complex. Using high-resolution electron microscopy, the electron density maps and 3D topography of the membrane-directed SNARE ring complex was determined at nanometre resolution. Similar to the t-/v-SNARE ring complex formed when 50 nm v-SNARE liposomes meet a t-SNARE-reconstituted planer membrane, SNARE rings are also formed when 50 nm diameter isolated synaptic vesicles meet a t-SNARE-reconstituted planer lipid membrane. Furthermore, the mathematical prediction of the SNARE ring complex size with reasonable accuracy, and the possible mechanism of membrane-directed t-/v-SNARE ring complex assembly, was determined from the study. Therefore in the present study, using both lipososome-reconstituted recombinant t-/v-SNARE proteins, and native v-SNARE present in isolated SV membrane, the membrane-directed molecular assembly of the neuronal SNARE complex was determined for the first time and its size mathematically predicted. These results provide a new molecular understanding of the universal machinery and mechanism of membrane fusion in cells, having fundamental implications in human health and disease. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Immune cells, including natural killer cells, recognize transformed cells and eliminate them in a process termed immunosurveillance. It is thought that tumor cells evade immunosurveillance by shedding membrane ligands that bind to the NKG2D-activating receptor on NK cells and/or Tcells, and desensitize these cells. In contrast, we show that in mice, a shed form of MULT1, a high-affinity NKG2D ligand, causes NK cell activation and tumor rejection. Recombinant soluble MULT1 stimulated tumor rejection in mice. Soluble MULT1 functions, at least in part, by competitively reversing a global desensitization of NK cells imposed by engagement of membrane NKG2D ligands on tumor-associated cells, such as myeloid cells. The results overturn conventional wisdom that soluble ligands are always inhibitory and suggest a new approach for cancer immunotherapy.

© 2014 American Chemical Society.Attempts to apply artificial nano/micromotors for diverse biomedical applications have inspired a variety of strategies for designing motors with diverse propulsion mechanisms and functions. However, existing artificial motors are made exclusively of synthetic materials, which are subject to serious immune attack and clearance upon entering the bloodstream. Herein we report an elegant approach that turns natural red blood cells into functional micromotors with the aid of ultrasound propulsion and magnetic guidance. Iron oxide nanoparticles are loaded into the RBCs, where their asymmetric distribution within the cells results in a net magnetization, thus enabling magnetic alignment and guidance under acoustic propulsion. The RBC motors display efficient guided and prolonged propulsion in various biological fluids, including undiluted whole blood. The stability and functionality of the RBC motors, as well as the tolerability of regular RBCs to the ultrasound operation, are carefully examined. Since the RBC motors preserve the biological and structural features of regular RBCs, these motors possess a wide range of antigenic, transport, and mechanical properties that common synthetic motors cannot achieve and thus hold considerable promise for a number of practical biomedical uses.

Various cytokines have been evaluated as potential anticancer drugs; however, most cytokine trials have shown relatively low efficacy. Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors. NK cell anergy was accompanied by impaired early signal transduction and was locally imparted by the presence of MHC class I-deficient tumor cells, even when such cells were a minor population in a tumor mixture. These results demonstrate that MHC class I-deficient tumor cells can escape from the immune response by functionally inactivating NK cells, and suggest cytokine-based immunotherapy as a potential strategy for MHC class I-deficient tumors. These results suggest that such cytokine therapies would be optimized by stratification of patients. Moreover, our results suggest that such treatments may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients.

The production of distinct sets of T cell receptor γδ+ T cells occurs in an ordered fashion in thymic development. The Vγ3 and Vγ4 genes, located downstream in the TCRγ Cγ1 gene cluster, are expressed by the earliest waves of developing TCRγδ+ T cells in the fetal thymus, destined for intraepithelial locations. Upstream Vγ2 and Vγ5 genes are expressed in later waves in the adult and constitute most TCRγδ + T cells in secondary lymphoid tissue. This developmental pattern is caused in part by a preference for rearrangements of the downstream Vγ3 and Vγ4 genes in the early fetal stage, which switches to a preference for rearrangements of the upstream Vγ2 and Vγ5 gene rearrangements in the adult. Our gene targeting studies show that the downstream Vγ genes rearrange preferentially in the early fetal thymus because of their downstream location, independent of promoter or recombination signal sequences and unrelated to the extent of germline transcription. Remarkably, gene deletion studies show that the downstream Vγ genes competitively inhibit upstream Vγ rearrangements at the fetal stage. These data provide a mechanism for specialization of the fetal thymus for the production of T cells expressing specific Vγ genes. JEM © The Rockefeller University Press.

Copyright © 2014, Lin et al.Circadian clocks serve as internal pacemakers that influence many basic homeostatic processes; consequently, the expression and function of their components are tightly regulated by intricate networks of feedback loops that fine-tune circadian processes. Our knowledge of these components and pathways is far from exhaustive. In recent decades, the nuclear envelope has emerged as a global gene regulatory machine, although its role in circadian regulation has not been explored. We report that transcription of the core clock component BMAL1 is positively modulated by the inner nuclear membrane protein MAN1, which directly binds the BMAL1 promoter and enhances its transcription. Our results establish a novel connection between the nuclear periphery and circadian rhythmicity, therefore bridging two global regulatory systems that modulate all aspects of bodily functions.

Multimodal neuroimaging provides a rich source of data for identifying brain regions associated with disease progression and aging. However, present studies still typically analyze modalities separately or aggregate voxel-wise measurements and analyses to the structural level, thus reducing statistical power. As a central example, previous works have used two quantitative MRI parameters—R2* and quantitative susceptibility —to study changes in iron associated with aging in healthy and multiple sclerosis subjects, but failed to simultaneously account for both. In this article, we propose a unified framework that combines information from multiple imaging modalities and regularizes estimates for increased interpretability, generalizability, and stability. Our work focuses on joint region detection problems where overlap between effect supports across modalities is encouraged but not strictly enforced. To achieve this, we combine L1, total variation, and L2 group lasso penalties. While the TV penalty encourages geometric regularization by controlling estimate variability and support boundary geometry, the group lasso penalty accounts for similarities in the support between imaging modalities. We address the computational difficulty in this regularization scheme with an alternating direction method of multipliers optimizer. In a neuroimaging application, we compare our method against independent sparse and joint sparse models using a dataset of R2* and QS maps derived from MRI scans of 113 healthy controls: our method produces clinically-interpretable regions where specific iron changes are associated with healthy aging. Together with results across multiple simulation studies, we conclude that our approach identifies regions that are more strongly associated with the variable of interest, more accurate, and more stable with respect to training data variability. This work makes progress toward a stable and interpretable multimodal imaging analysis framework for studying disease-related changes in brain structure and can be extended for classification and disease prediction tasks.

The objective of this study was to examine the association between resilience and trajectories of college students’ negative and positive affect during the COVID-19 pandemic. A total of 391 college students recruited from China completed a daily online negative and positive affect scale for 1 week, and their resilience was also measured. Profiles of brief trajectories of negative and positive affect over time were identified using the latent growth mixture model, and the effect of resilience on these trajectories was further explored. Two latent profiles of negative affect were found: a constant high negative affect profile and a slowly decreasing low negative affect profile, while three latent profiles of positive affect were identified: a slowly increasing high positive affect profile, a rapidly decreasing medium positive affect profile, and a constant medium positive affect profile. The optimism dimension of resilience predicted the membership in the various profiles significantly, whereas the prediction of tenacity and strength dimensions of resilience was not significant. Activities that promote resilience, especially optimism, should be included to improve the daily emotions of college students during COVID-19.

Patent strategy is increasingly recognized as a vital contributor in promoting core competitiveness of an enterprise. A top management team has been indicated as one of the key factors driving changes in patent strategy. Based on upper echelons theory, this study examines how TMT characteristics, including, team diversity, emotional intelligence, and safety climate, influence enterprise patent strategic change and, hence, the business outcome. The data from 930 top managers in 228 enterprises showed that the changes in patent strategies are significantly influenced by the characteristics of top managers. These aforementioned internal TMT factors have diverse effects on the speed and scope of the enterprise patent strategic change, which in turn affects firm performance in a positive and negative way, respectively.

As professional football stadiums continue to grow in popularity worldwide, fans are able to watch the game in closer proximity, but the design of professional football stadiums to shorten the distance between fans and the playing field also exacerbates the impact of the home advantage on the referee’s decision to call a penalty. Studies have confirmed the existence of the home advantage and found that experienced referees can reduce the impact of this interference, but the neural mechanisms behind this phenomenon have not been adequately investigated. In this study, we designed a soccer referee decision making task based on a home field effect scenario in a real soccer game, and used event-related potentials to compare the decision making and EEG differences between individuals with different experience levels when faced with foul actions under spectator noise interference. The experiments showed that individuals with different experience levels triggered a significant ERN EEG component when performing the penalty decision task under the home field effect factor, suggesting that the interference of the home field effect may lead referees to correct their previous decision-making behavior patterns in the penalty decision and reduce unfavorable calls against the home team. In contrast, referees with officiating experience elicited smaller ERN amplitudes compared to other subjects, suggesting that experience factors may inhibit this tendency to change behavioral patterns. This study suggests that in response to the increasing trend of professional football stadiums, policy makers should place more emphasis on enhancing the experience level of referees in the training of referees to ensure the fairness of the game.

With the service-dominant logic gradually replacing the traditional commodity-dominant reason, co-creating value with consumers has become an essential marketing practice for enterprises. As a critical information carrier in enterprise marketing communication, the co-creation signal impacts co-creation observers. Enterprises are now exploring how to effectively release co-creation signals to attract most observers to participate in value creation activities actively. Based on self-determination theory, this study investigates the influence mechanism of co-creation signals on observers’ willingness to co-create and the moderating role of mental simulation through the experimental method. The conclusions are as follows: The co-creation signal has a significant positive effect on the co-creation intention of observers. Self-designed co-creation signals generate more important co-creation willingness than self-produced co-creation signals; Self-determination and its dimensions mediate the relationship between co-creation signals and the observer’s co-creation willingness; and Mental simulation moderates the relationship between co-creation signal and self-determination. This study has important theoretical significance in enriching co-creation signals and mental simulation research. It also provides management implications for enterprises to release co-creation signals and optimize co-creation marketing practices effectively.

A burgeoning body of research has shown that authoritarian leadership embodies the characteristics of “light” and “dark,” meaning that it does not always have a negative impact on employees’ creative activities. However, studies explaining this potential positive effect are insufficient. To extend the AL and creativity literature, we draw on self-determination theory and event system theory, and elicit discipline-focused AL and appointment event criticality to examine whether, when, and how authoritarian leaders affect employee creativity positively. With time-lagged data collected from 435 employees and their direct leaders in China, we found that discipline-focused AL has an indirect positive effect on employee creativity through creative self-efficacy. Additionally, appointment event criticality strengthens the positive relationship between discipline-focused AL and creative self-efficiency, and the indirect impact of discipline-focused AL on employee creativity through creative self-efficiency. The theoretical and practical implications are discussed.

Choice revision is a sort of non-prioritized multiple revision, in which the agent partially accepts the new information represented by a set of sentences. We investigate the construction of choice revision based on a new approach to belief change called descriptor revision. We prove that each of two variants of choice revision based on such construction is axiomatically characterized with a set of plausible postulates, assuming that the object language is finite. Furthermore, we introduce an alternative modelling for choice revision, which is based on a type of relation on sets of sentences, named multiple believability relation. We show without assuming a finite language that choice revision constructed from such relations is axiomatically characterized with the same sets of postulates that we proposed for the choice revision based on descriptor revision, whenever the relations satisfy certain rationality conditions.