Serum albumin–protamine conjugate for biocompatible platform for targeted delivery of therapeutic macromolecules

A well‐defined, one‐to‐one conjugate between human serum albumin (HSA) and protamine was synthesized and characterized as a biocompatible carrier for macromolecules. In circulation, the conjugate will camouflage drug molecules upon complex formation, while liberating free drug at the desired location using a triggering mechanism. The N‐terminus of protamine was thiolated and conjugated with the unpaired Cysteine‐34 of HSA, and was purified by ion‐exchange chromatography. The molecular weight of the conjugate was 70.8 kDa, confirming one‐to‐one conjugation between HSA (66.6 KDa) and protamine (4200 Da). Superimposed fluorescence spectra of native HSA and HSA–protamine conjugate indicated no conformational change around the Trp‐214. The conjugate had marked reduction in hemolytic and cytotoxic properties compared to protamine. When therapeutic potential was tested using tissue plasminogen activator as a model drug, HSA–protamine conjugate suppressed the enzymatic activity by 65%, which was fully recovered by a triggering agent, heparin. The construct showed binding characteristics with activated platelets upon conjugation with a targeting peptide, demonstrating flexibility to introduce suitable homing moiety on the surface. The camouflaged construct retained triggered release property in human plasma condition. Overall, the conjugate has a good potential to serve as a biocompatible platform for macromolecular drugs. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2481–2490, 2014.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107561/1/jbma34916.pd

Deregulation of HDAC5 by Viral Interferon Regulatory Factor 3 Plays an Essential Role in Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphangiogenesis.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS), which is one of the most common HIV-associated neoplasms. The endothelium is the thin layer of squamous cells where vascular blood endothelial cells (BECs) line the interior surface of blood vessels and lymphatic endothelial cells (LECs) are in direct contact with lymphatic vessels. The KS lesions contain a prominent compartment of neoplastic spindle morphology cells that are closely related to LECs. Furthermore, while KSHV can infect both LECs and BECs in vitro, its infection activates genetic programming related to lymphatic endothelial cell fate, suggesting that lymphangiogenic pathways are involved in KSHV infection and malignancy. Here, we report for the first time that viral interferon regulatory factor 3 (vIRF3) is readily detected in over 40% of KS lesions and that vIRF3 functions as a proangiogenic factor, inducing hypersprouting formation and abnormal growth in a LEC-specific manner. Mass spectrometry analysis revealed that vIRF3 interacted with histone deacetylase 5 (HDAC5), which is a signal-responsive regulator for vascular homeostasis. This interaction blocked the phosphorylation-dependent cytosolic translocation of HDAC5 and ultimately altered global gene expression in LECs but not in BECs. Consequently, vIRF3 robustly induced spindle morphology and hypersprouting formation of LECs but not BECs. Finally, KSHV infection led to the hypersprouting formation of LECs, whereas infection with a ΔvIRF3 mutant did not do so. Collectively, our data indicate that vIRF3 alters global gene expression and induces a hypersprouting formation in an HDAC5-binding-dependent and LEC-specific manner, ultimately contributing to KSHV-associated pathogenesis.IMPORTANCE Several lines of evidences indicate that KSHV infection of LECs induces pathological lymphangiogenesis and that the results resemble KS-like spindle morphology. However, the underlying molecular mechanism remains unclear. Here, we demonstrated that KSHV vIRF3 is readily detected in over 40% of various KS lesions and functions as a potent prolymphangiogenic factor by blocking the phosphorylation-dependent cytosolic translocation of HDAC5, which in turn modulates global gene expression in LECs. Consequently, vIRF3-HDAC5 interaction contributes to virus-induced lymphangiogenesis. The results of this study suggest that KSHV vIRF3 plays a crucial role in KSHV-induced malignancy

Vascular Proteomics Reveal Novel Proteins Involved in SMC Phenotypic Change: OLR1 as a SMC Receptor Regulating Proliferation and Inflammatory Response

Neointimal hyperplasia of vascular smooth muscle cells (VSMC) plays a critical role in atherosclerotic plaque formation and in-stent restenosis, but the underlying mechanisms are still incompletely understood. We performed a proteomics study to identify novel signaling molecules organizing the VSMC hyperplasia. The differential proteomics analysis in a balloon- induced injury model of rat carotid artery revealed that the expressions of 44 proteins are changed within 3 days post injury. The combination of cellular function assays and a protein network analysis further demonstrated that 27 out of 44 proteins constitute key signaling networks orchestrating the phenotypic change of VSMC from contractile to epithelial-like synthetic. Among the list of proteins, the in vivo validation specifically revealed that six proteins (Rab 15, ITR, OLR1, PDH beta, PTP epsilon) are positive regulators for VSMC hyperplasia. In particular, the OLR1 played dual roles in the VSMC hyperplasia by directly mediating oxidized LDL-induced monocyte adhesion via NF-kappa B activation and by assisting the PDGF-induced proliferation/migration. Importantly, OLR1 and PDGFR beta were associated in close proximity in the plasma membrane. Thus, this study elicits the protein network organizing the phenotypic change of VSMC in the vascular injury diseases such as atherosclerosis and discovers OLR1 as a novel molecular link between the proliferative and inflammatory responses of VSMCs.1133Ysciescopu

Emergence of skew distributions in controlled growth processes

Starting from a master equation, we derive the evolution equation for the size distribution of elements in an evolving system, where each element can grow, divide into two, and produce new elements. We then probe general solutions of the evolution quation, to obtain such skew distributions as power-law, log-normal, and Weibull distributions, depending on the growth or division and production. Specifically, repeated production of elements of uniform size leads to power-law distributions, whereas production of elements with the size distributed according to the current distribution as well as no production of new elements results in log-normal distributions. Finally, division into two, or binary fission, bears Weibull distributions. Numerical simulations are also carried out, confirming the validity of the obtained solutions.Comment: 9 pages, 3 figure

A Detailed Monte-Carlo Simulation for the Belle TOF System

We have developed a detailed Monte Carlo simulation program for the Belle TOF system. Based on GEANT simulation, it takes account of all physics processes in the TOF scintillation counters and readout electronics. The simulation reproduces very well the performance of the Belle TOF system, including the dE/dx response, the time walk effect, the time resolution, and the hit efficiency due to beam background. In this report, we will describe the Belle TOF simulation program in detail.Comment: To be submitted to NI

High Mobility Amorphous Polymer-Based 3D Stacked Pseudo Logic Circuits through Precision Printing

Direct printing of conjugated polymer thin-film transistors enables the fabrication of deformable devices with low cost, high throughput, and large area. However, a relatively poor device performance of printed devices remains a major obstacle to their application in high-end display backplanes and integrated circuits. In this study, high-performance and highly stackable printed organic transistors is developed, arrays, and circuits using a near-amorphous polymer, indacenodithiophene-co-benzothiadiazole (IDT-BT). The printed devices exhibited high saturation mobility (>1 cm2 V−1 s−1), high on/off ratio (>107), and low subthreshold slope (245 mV dec−1). In addition, 16 × 16 printed IDT-BT arrays achieved 100% fabrication yield, with excellent device-to-device uniformity and low variations of mobility (9.55%) and threshold voltage (4.51%), and good operational and environmental stability (>365 days). Furthermore, five stacked 3D transistors are demonstrated with an excellent 3D uniformity without compromising device performance due to a low required thermal budget for processing amorphous IDT-BT. Finally, a new concept of 3D universal logic gate with high voltage gain (33.91 V/V) and record density (100 printed transistors per cm2) is proposed and fabricated, which is relevant for the commercialization of low-cost printed display backplanes and high-density integrated circuits based on highly processable polymeric semiconductors

Index for Three Dimensional Superconformal Field Theories and Its Applications

We review aspects of superconformal indices in three dimension. Three dimensional superconformal indices can be exactly computed by using localization method including monopole contribution, and can be applied to provide evidences for mirror duality, AdS_4/CFT_3 correspondence and global symmetry enhancement of strongly coupled gauge theories. After reviewing, we discuss the possibility of global symmetry enhancement in a finite rank of gauge group.Comment: 14 pages, Proceedings of the Seventh International Conference Quantum Theory and Symmetries (QTS-7) in Prague, Czech Republic, August, 2011; v2: minor modifications, discussion of supersymmetry enhancement of abelian ABJM theory by using an index were adde

On the new concept of the available water climatology and its application

We propose a new concept of climatology called the Available Water Climate (AWC). Available water is 'the remained water usable in every moment' that is calculated regardless of any time intervals or the amounts of precipitation. With this concept, the Available Water Resources Index (AWRI) has been digitized following the earlier work of Byun and Lee (2002). The applicability of AWRI not only to the assessment and prediction of water related disasters but also to the academic researches has been tested. Resulted merits are as follows. Firstly, the threshold value of AWRI for the occurrence of all water related disasters like flood, drought, inundation landslide, and drought each region became clear, therefore the assessment and the prediction of them became much more precise than before. It became clear that the more extreme the AWRI value is, the severer the related disasters become. As example, all disasters caused by heavy rains, even though a small inundation, became predictable at the time step of heavy rain warning with the help of the Long-term remained water index(LWI). As another example, the drought intensity and its dates on start and end are defined with more reasonably and precisely than any other drought indexes with help of the Effective drought index (EDI) using sliding time scale. Secondly, the spatiotemporal distribution of water environment were digitized clearly and objectively using AWRI and new concepts of the Water Abundant Season (WAS) and the Little Water Season (LIWAS), their dates on start and end, and their strength were defined, which is very beneficial for agriculture, forestry, and all other water controls. Also, the differences of water environments among regions were clearly digitized and the improvement of the climate classification by Köppen etc. became possible. Thirdly, other merits will be found continuously afterwards

Unassisted photoelectrochemical water splitting exceeding 7% solar to hydrogen conversion efficiency using photon recycling

Various tandem cell configurations have been reported for highly efficient and spontaneous hydrogen production from photoelectrochemical solar water splitting. However, there is a contradiction between two main requirements of a front photoelectrode in a tandem cell configuration, namely, high transparency and high photocurrent density. Here we demonstrate a simple yet highly effective method to overcome this contradiction by incorporating a hybrid conductive distributed Bragg reflector on the back side of the transparent conducting substrate for the front photoelectrochemical electrode, which functions as both an optical filter and a conductive counter-electrode of the rear dye-sensitized solar cell. The hybrid conductive distributed Bragg reflectors were designed to be transparent to the long-wavelength part of the incident solar spectrum (lambda>500 nm) for the rear solar cell, while reflecting the short-wavelength photons (lambda<500 nm) which can then be absorbed by the front photoelectrochemical electrode for enhanced photocurrent generation.114129Ysciescopu