Restricted N-glycan Conformational Space in the PDB and Its Implication in Glycan Structure Modeling

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author’s publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Understanding glycan structure and dynamics is central to understanding protein-carbohydrate recognition and its role in protein-protein interactions. Given the difficulties in obtaining the glycan's crystal structure in glycoconjugates due to its flexibility and heterogeneity, computational modeling could play an important role in providing glycosylated protein structure models. To address if glycan structures available in the PDB can be used as templates or fragments for glycan modeling, we present a survey of the N-glycan structures of 35 different sequences in the PDB. Our statistical analysis shows that the N-glycan structures found on homologous glycoproteins are significantly conserved compared to the random background, suggesting that N-glycan chains can be confidently modeled with template glycan structures whose parent glycoproteins share sequence similarity. On the other hand, N-glycan structures found on non-homologous glycoproteins do not show significant global structural similarity. Nonetheless, the internal substructures of these N-glycans, particularly, the substructures that are closer to the protein, show significantly similar structures, suggesting that such substructures can be used as fragments in glycan modeling. Increased interactions with protein might be responsible for the restricted conformational space of N-glycan chains. Our results suggest that structure prediction/modeling of N-glycans of glycoconjugates using structure database could be effective and different modeling approaches would be needed depending on the availability of template structures

Cooling season full and part load performance evaluation of Variable Refrigerant Flow (VRF) system using an occupancy simulated research building

VRF systems are touted for their superior part-load performance compared to conventional systems. This study compares both the full and part-load performance of a VRF system with a conventional RTU VAV system in a multi-zone office building with emulated occupancy. To accomplish this, full and part-load conditions (i.e., 100%, 75% and 50% loads) in the building are maintained alternately by conditioning either the entire building or selected zones, and emulating the occupancy, accordingly. During the study period, each system is operated alternately under each of the three load conditions for 2-3 days, and the system parameters, indoor and outdoor conditions, loads, and energy use are monitored.  The cooling season performance and energy use of both systems was monitored during the summer of 2015. System performance is compared in terms of weather-normalized HVAC energy consumption and seasonal average COP. In addition, the ability of each system to maintain the indoor temperature in the conditioned zones is also evaluated. Based on the analysis, the energy savings for the VRF system compared with the RTU system for the cooling season are estimated to be 29%, 36%, and 46% under the 100%, 75%, and 50% load conditions, respectively. The average cooling COP was ~4.0-4.5, 3.9, and 3.7 for the VRF system and 3.1, 2.9, 2.5 for the RTU system under the 100%, 75% and 50% load conditions. Both systems maintained the indoor temperature very well. However, the VRF system maintained the indoor temperature in a slightly tighter range compared to the RTU system

Energy-efficient generation of skyrmion phases in Co/Ni/Pt-based multilayers using Joule heating

We have studied the effects of electrical current pulses on skyrmion formation in a series of Co/Ni/Pt-based multilayers. Transmission X-ray microscopy reveals that by applying electrical current pulses of duration and current density on the order of $\tau$=50 $\mu$s and j=1.7x10$^1$$^0$ A/m$^2$, respectively, in an applied magnetic field of $\mu$$_0$Hz=50 mT, stripe-to-skyrmion transformations are attained. The skyrmions remain stable across a wide range of magnetic fields, including zero field. The skyrmions then remain stable across a wide range of magnetic fields, including zero field. We primarily attribute the transformation to current-induced Joule heating on the order of ~125 K. Reducing the magnetic moment and perpendicular anisotropy using thin rare-earth spacers dramatically reduces the pulse duration, current density, and magnetic field necessary to 25 $\mu$s, 2.4x10$^9$ A/m$^2$, and 27 mT, respectively. These findings show that energetic inputs allow for the formation of skyrmion phases in a broad class of materials and that material properties can be tuned to yield more energy-efficient access to skyrmion phases.Comment: 32 pages, 7 figures, 9 supplemental figure

A Control-Oriented Dynamic Model of Air Flow in a Single Duct HVAC System

A model of a variable air volume (VAV) system is developed that can predict air flow rates, fan pressure rise, and fan power consumption in response to changes in fan speed and damper positions. The system consists of a fan, ductwork, and a number of dampers, one in each VAV box. The model can be used for conducting simulation studies of how advanced control algorithms that seek to provide various services (energy efficiency, personalized comfort, and demand-side flexibility to the grid) may behave when deployed in a building with an existing climate control system, or to do model-based control computations for such services. Comparison of the model\u27s predictions with experimental data from a small commercial building is presented for the single-zone version of the model. The multi-zone model structure is described, but its validation is left for future work. Due to the strong non-linearities in the steady state relation between inputs and outputs, and due to the fast transient response observed in experiments, the dynamic model is constructed to be of Hammerstein type, with a linear dynamic system in series with a static nonlinear model

Highly restricted localization of RNA polymerase II within a locus control region of a tissue-specific chromatin domain

RNA polymerase II (Pol II) can associate with regulatory elements far from promoters. For the murine β-globin locus, Pol II binds the β-globin locus control region (LCR) far upstream of the β-globin promoters, independent of recruitment to and activation of the βmajor promoter. We describe here an analysis of where Pol II resides within the LCR, how it is recruited to the LCR, and the functional consequences of recruitment. High-resolution analysis of the distribution of Pol II revealed that Pol II binding within the LCR is restricted to the hypersensitive sites. Blocking elongation eliminated the synthesis of genic and extragenic transcripts and eliminated Pol II from the βmajor open reading frame. However, the elongation blockade did not redistribute Pol II at the hypersensitive sites, suggesting that Pol II is recruited to these sites. The distribution of Pol II did not strictly correlate with the distributions of histone acetylation and methylation. As Pol II associates with histone-modifying enzymes, Pol II tracking might be critical for establishing and maintaining broad histone modification patterns. However, blocking elongation did not disrupt the histone modification pattern of the β-globin locus, indicating that Pol II tracking is not required to maintain the pattern

Sub-nanosecond signal propagation in anisotropy engineered nanomagnetic logic chains

Energy efficient nanomagnetic logic (NML) computing architectures propagate and process binary information by relying on dipolar field coupling to reorient closely-spaced nanoscale magnets. Signal propagation in nanomagnet chains of various sizes, shapes, and magnetic orientations has been previously characterized by static magnetic imaging experiments with low-speed adiabatic operation; however the mechanisms which determine the final state and their reproducibility over millions of cycles in high-speed operation (sub-ns time scale) have yet to be experimentally investigated. Monitoring NML operation at its ultimate intrinsic speed reveals features undetectable by conventional static imaging including individual nanomagnetic switching events and systematic error nucleation during signal propagation. Here, we present a new study of NML operation in a high speed regime at fast repetition rates. We perform direct imaging of digital signal propagation in permalloy nanomagnet chains with varying degrees of shape-engineered biaxial anisotropy using full-field magnetic soft x-ray transmission microscopy after applying single nanosecond magnetic field pulses. Further, we use time-resolved magnetic photo-emission electron microscopy to evaluate the sub-nanosecond dipolar coupling signal propagation dynamics in optimized chains with 100 ps time resolution as they are cycled with nanosecond field pulses at a rate of 3 MHz. An intrinsic switching time of 100 ps per magnet is observed. These experiments, and accompanying macro-spin and micromagnetic simulations, reveal the underlying physics of NML architectures repetitively operated on nanosecond timescales and identify relevant engineering parameters to optimize performance and reliability.Comment: Main article (22 pages, 4 figures), Supplementary info (11 pages, 5 sections

The rat intervertebral disk degeneration pain model: relationships between biological and structural alterations and pain

INTRODUCTION: Degeneration of the interverterbral disk is as a cause of low-back pain is increasing. To gain insight into relationships between biological processes, structural alterations and behavioral pain, we created an animal model in rats. METHODS: Disk degeneration was induced by removal of the nucleus pulposus (NP) from the lumbar disks (L4/L5 and L5/L6) of Sprague Dawley rats using a 0.5-mm-diameter microsurgical drill. The degree of primary hyperalgesia was assessed by using an algometer to measure pain upon external pressure on injured lumbar disks. Biochemical and histological assessments and radiographs of injured disks were used for evaluation. We investigated therapeutic modulation of chronic pain by administering pharmaceutical drugs in this animal model. RESULTS: After removal of the NP, pressure hyperalgesia developed over the lower back. Nine weeks after surgery we observed damaged or degenerated disks with proteoglycan loss and narrowing of disk height. These biological and structural changes in disks were closely related to the sustained pain hyperalgesia. A high dose of morphine (6.7 mg/kg) resulted in effective pain relief. However, high doses of pregabalin (20 mg/kg), a drug that has been used for treatment of chronic neuropathic pain, as well as the anti-inflammatory drugs celecoxib (50 mg/kg; a selective inhibitor of cyclooxygenase 2 (COX-2)) and ketorolac (20 mg/kg; an inhibitor of COX-1 and COX-2), did not have significant antihyperalgesic effects in our disk injury animal model. CONCLUSIONS: Although similarities in gene expression profiles suggest potential overlap in chronic pain pathways linked to disk injury or neuropathy, drug-testing results suggest that pain pathways linked to these two chronic pain conditions are mechanistically distinct. Our findings provide a foundation for future research on new therapeutic interventions that can lead to improvements in the treatment of patients with back pain due to disk degeneration

CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis

Macrophages abundantly found in the tumor microenvironment enhance malignancy(1). At metastatic sites a distinct population of metastasis associated macrophages (MAMs) promote tumor cell extravasation, seeding and persistent growth(2). Our study has defined the origin of these macrophages by showing Gr1+ inflammatory monocytes (IMs) are preferentially recruited to pulmonary metastases but not primary mammary tumors, a process also found for human IMs in pulmonary metastases of human breast cancer cells. The recruitment of these CCR2 (receptor for chemokine CCL2) expressing IMs and subsequently MAMs and their interaction with metastasizing tumor cells is dependent on tumor and stromal synthesized CCL2 (FigS1). Inhibition of CCL2/CCR2 signaling using anti-CCL2 antibodies blocks IM recruitment and inhibits metastasis in vivo and prolongs the survival of tumor-bearing mice. Depletion of tumor cell-derived CCL2 also inhibits metastatic seeding. IMs promote tumor cell extravasation in a process that requires monocyte-derived VEGF. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer (Fig S2)(3-6). Our data provides the mechanistic link between these two clinical associations and indicates new therapeutic targets for treating metastatic breast disease