scholarly journals Coordinating the in vivo processes for minicircle production - a novel approach to large scale manufacturing

2018 ◽  
Author(s):  
Peter Mayrhofer ◽  
Hana Jug ◽  
Aleš Štrancar ◽  
Alexandre Di Paolo ◽  
Laurent Jost ◽  
...  
Keyword(s):  
High Performance ◽  
Large Scale ◽  
Process Development ◽  
Scale Up ◽  
Hydrophobic Interaction Chromatography ◽  
Viral Gene ◽  
Novel Approach ◽  
Dna Production ◽  
Minicircle Dna

ABSTRACTSafety as well as efficiency issues in connection with bacterial backbone sequences should be carefully considered when designing new DNA vaccines or non-viral gene therapy approaches. Bacterial backbone sequences like antibiotic resistance markers or regulatory bacterial elements constitute biological safety risks and reduce the overall efficiency of the DNA agent. To overcome these problems the minicircle technology has been developed. But, despite all the obvious advantages, minicircles have so far not replaced their problem laden conventional counterpart in gene transfer applications what can be contributed to efficiency issues in large scale manufacturing. In this article we describe the combined efforts of experts in the field of minicircle development, large scale biomanufacturing and downstream process development to provide a new approach. The Recombination Based Plasmid Separation (RBPS) Technology, which has already solved crucial problems associated with minicircle-DNA production, has been developed further for this purpose. A novel parental plasmid exploiting advanced in vivo process coordination for restriction and subsequent degradation of miniplasmid-DNA will be introduced. Furthermore we describe the scale-up of minicircle-DNA production by fermentation in combination with high performance downstream processes including purification by ion exchange and hydrophobic interaction chromatography on monolithic material.

The Structure and Properties of MoSi2 Thin Film in Mos Process

1980 ◽  
Vol 38 ◽  
pp. 326-327
Author(s):  
C.K. Wu ◽  
P. Chang ◽  
N. Godinho
Keyword(s):  
Thin Film ◽  
Integrated Circuits ◽  
High Performance ◽  
Large Scale ◽  
Process Development ◽  
Structure And Properties ◽  
Metal Silicides ◽  
High Oxidation ◽  
Important Approach ◽  
High Oxidation Resistance

Recently, the use of refractory metal silicides as low resistivity, high temperature and high oxidation resistance gate materials in large scale integrated circuits (LSI) has become an important approach in advanced MOS process development (1). This research is a systematic study on the structure and properties of molybdenum silicide thin film and its applicability to high performance LSI fabrication.

scholarly journals Applying Microfluidics for the Production of the Cationic Liposome-Based Vaccine Adjuvant CAF09b

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1237
Author(s):  
Signe Tandrup Schmidt ◽  
Dennis Christensen ◽  
Yvonne Perrie
Keyword(s):  
Large Scale ◽  
Colloidal Stability ◽  
Scale Up ◽  
Cationic Liposome ◽  
Poly I:C ◽  
Particle Sizes ◽  
Adjuvant Activity ◽  
Lipid Film ◽  
Gmp Production

Subunit vaccines require particulate adjuvants to induce the desired immune responses. Pre-clinical manufacturing methods of adjuvants are often batch dependent, which complicates scale-up for large-scale good manufacturing practice (GMP) production. The cationic liposomal adjuvant CAF09b, composed of dioctadecyldimethylammonium bromide (DDA), monomycoloyl glycerol analogue 1 (MMG) and polyinosinic:polycytidylic acid [poly(I:C)], is currently being clinically evaluated in therapeutic cancer vaccines. Microfluidics is a promising new method for large-scale manufacturing of particle-based medicals, which is scalable from laboratory to GMP production, and a protocol for production of CAF09b by this method was therefore validated. The influence of the manufacture parameters [Ethanol] (20–40% v/v), [Lipid] (DDA and MMG, 6–12 mg/mL) and dimethyl sulfoxide [DMSO] (0–10% v/v) on the resulting particle size, colloidal stability and adsorption of poly(I:C) was evaluated in a design-of-experiments study. [Ethanol] and [DMSO] affected the resulting particle sizes, while [Lipid] and [DMSO] affected the colloidal stability. In all samples, poly(I:C) was encapsulated within the liposomes. At [Ethanol] 30% v/v, most formulations were stable at 21 days of manufacture with particle sizes <100 nm. An in vivo comparison in mice of the immunogenicity to the cervical cancer peptide antigen HPV-16 E7 adjuvanted with CAF09b prepared by lipid film rehydration or microfluidics showed no difference between the formulations, indicating adjuvant activity is intact. Thus, it is possible to prepare suitable formulations of CAF09b by microfluidics.

HIERARCHICAL MAPPING FOR HPC APPLICATIONS

2011 ◽  
Vol 21 (03) ◽  
pp. 279-299 ◽  
Author(s):  
I-HSIN CHUNG ◽  
CHE-RUNG LEE ◽  
JIAZHENG ZHOU ◽  
YEH-CHING CHUNG
Keyword(s):  
High Performance ◽  
Large Scale ◽  
Scale Up ◽  
Matrix Multiplication ◽  
Spectral Graph Theory ◽  
Communication Patterns ◽  
Fine Tuning ◽  
Mapping Algorithm ◽  
Communication Time ◽  
Run Time

As the high performance computing systems scale up, mapping the tasks of a parallel application onto physical processors to allow efficient communication becomes one of the critical performance issues. Existing algorithms were usually designed to map applications with regular communication patterns. Their mapping criterion usually overlooks the size of communicated messages, which is the primary factor of communication time. In addition, most of their time complexities are too high to process large scale problems. In this paper, we present a hierarchical mapping algorithm (HMA), which is capable of mapping applications with irregular communication patterns. It first partitions tasks according to their run-time communication information. The tasks that communicate with each other more frequently are regarded as strongly connected. Based on their connectivity strength, the tasks are partitioned into supernodes based on the algorithms in spectral graph theory. The hierarchical partitioning reduces the mapping algorithm complexity to achieve scalability. Finally, the run-time communication information will be used again in fine tuning to explore better mappings. With the experiments, we show how the mapping algorithm helps to reduce the point-to-point communication time for the PDGEMM, a ScaLAPACK matrix multiplication computation kernel, up to 20% and the AMG2006, a tier 1 application of the Sequoia benchmark, up to 7%.

scholarly journals Cloning and Characterization of a Novel Subunit of Protein Serine/Threonine Phosphatase 4 from Mesangial Cells

2001 ◽  
Vol 12 (12) ◽  
pp. 2601-2608 ◽  
Author(s):  
Takehiko Wada ◽  
Toshio Miyata ◽  
Reiko Inagi ◽  
Masaomi Nangaku ◽  
Masako Wagatsuma ◽  
...  
Keyword(s):  
Amino Acid ◽  
Large Scale ◽  
Cultured Cells ◽  
Mesangial Cells ◽  
Spindle Pole ◽  
Regulatory Subunit ◽  
Glomerular Diseases ◽  
Regulatory Subunits ◽  
Novel Approach

ABSTRACT. Mesangial cells play an important role in maintaining glomeruli structure and function and in the pathogenesis of glomerular diseases. With a novel approach using a rapid large-scale DNA sequencing strategy and computerized data processing, a new human gene, PP4Rmegwas cloned. The full-length cDNA clone of human PP4Rmegcoded for a novel 950-amino acid protein, which was similar to a subunit of protein serine/threonine phosphatase 4 (PP4). Recombinant PP4Rmegproduced in COS-7 cells bound to the catalytic subunit of PP4. PP4Rmegis therefore structurally and functionally related to the recently reported regulatory subunit of PP4, PP4R1. Amino acid sequence analysis of rat PP4Rmeghomologue revealed that the sequences were well conserved between human and rat (86.3% identity). Northern blot analyses of human tissues and cultured cells demonstrated that the regulatory subunits were expressed abundantly in human cultured mesangial cells, although their expression was relatively ubiquitous.In situhybridization studies in normal human renal tissues confirmed their expression in glomeruliin vivo. The expression was upregulated in glomeruli of anti-Thy1 glomerulonephritis rats before mesangial proliferation. These data demonstrate that PP4Rmegis a novel regulatory subunit of PP4, which is expressed ubiquitously but abundantly in mesangial cells. Its pathophysiologic role in mesangial cells and glomerulus remains unknown. As PP4 is an essential protein for nucleation, growth, and stabilization of microtubules at centrosomes/spindle pole bodies during cell division, PP4Rmegmay play a role in regulation of mitosis in mesangial cells.

Using High Performance Scientific Computing to Accelerate the Discovery and Design of Nuclear Power Applications

2015 ◽  
pp. 119-148
Author(s):  
Liviu Popa-Simil
Keyword(s):  
Nuclear Power ◽  
High Performance ◽  
Large Scale ◽  
Scientific Computing ◽  
Scale Up ◽  
Development Stage ◽  
Power Structures ◽  
The Road ◽  
Macro Scale ◽  
Current Calculation

Present High Performance Scientific Computing (HPSC) systems are facing strong limitations when full integration from nano-materials to operational system is desired. The HPSC have to be upgraded from the actual designed exa-scale machines probably available after 2015 to even higher computer power and storage capability to yotta-scale in order to simulate systems from nano-scale up to macro scale as a way to greatly improve the safety and performances of the future advanced nuclear power structures. The road from the actual peta-scale systems to yotta-scale computers, which would barely be sufficient for current calculation needs, is difficult and requires new revolutionary ideas in HPSC, and probably the large-scale use of Quantum Supercomputers (QSC) that are now in the development stage.

Practical Considerations for Large-Scale Cryopreservation of a Tissue Engineered Human Dermal Replacement

1999 ◽  
Author(s):  
Dawn R. Applegate ◽  
Kang Liu ◽  
Jonathan Mansbridge
Keyword(s):  
Large Scale ◽  
Stress Proteins ◽  
Scale Up ◽  
Tissue Growth ◽  
Volume Distribution ◽  
Isolated Cells ◽  
Successful Design ◽  
Tissue Systems ◽  
End Use

Abstract Tissue engineering is redefining the field of transplantation by providing a readily available, off-the-shelf supply of consistent, easy to use, safe and effective products. Successful design and scale-up of both tissue growth and preservation processes have enabled maintenance of tissue integrity, functionality and viability from product manufacture to end-use and afforded clinical efficacy, feasibility of large-volume distribution and cost-effectiveness. Advances in tissue preservation are being realized through extension of mathematical models and biological principles for isolated cells to bench-scale tissue systems. Hence, implementation problems inherent to large-scale systems are not often considered. Furthermore, the effects of preservation on tissues are not always tested in vivo. This paper addresses the practical obstacles to the design and implementation of a large-scale cryopreservation process. The effects of cryopreservation on in vivo tissue functionality including alteration of cell signal transduction pathways and expression of stress proteins in response to cryopreservation are also reviewed.

Toward safe and high-performance human–robot collaboration via implementation of redundancy and understanding the effects of admittance term parameters

Robotica ◽  
2021 ◽  
pp. 1-16
Author(s):  
Mert Kanık ◽  
Orhan Ayit ◽  
Mehmet Ismet Can Dede ◽  
Enver Tatlicioglu
Keyword(s):  
High Performance ◽  
Large Scale ◽  
Null Space ◽  
Experimental Studies ◽  
Safety Performance ◽  
Industrial Robots ◽  
Industrial Manufacturing ◽  
Novel Approach ◽  
Human Effort ◽  
Human Robot Collaboration

Summary Today, demandsin industrial manufacturing mandate humans to work with large-scale industrial robots, and this collaboration may result in dangerous conditions for humans. To deal with this situation, this work proposes a novel approach for redundant large-scale industrial robots. In the proposed approach, an admittance controller is designed to regulate the interaction between the end effector of the robot and the human. Additionally, an obstacle avoidance algorithm is implemented in the null space of the robot to prevent any possible unexpected collision between the human and the links of the robot. After safety performance of this approach is verified via simulations and experimental studies, the effect of the parameters of the admittance controller on the performance of collaboration in terms of both accuracy and total human effort is investigated. This investigation is carried out via 8 experiments by the participation of 10 test subjects in which the effect of different admittance controller parameters such as mass and damper are compared. As a result of this investigation, tuning insights for such parameters are revealed.

scholarly journals Process Development and Synthesis of Process-Related Impurities of an Efficient Scale-Up Preparation of 5,2′-Dibromo-2,4′,5′-Trihydroxy Diphenylmethanone as a New Acute Pyelonephritis Candidate Drug

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 468
Author(s):  
Xiu E Feng ◽  
Ke Meng Cui ◽  
Qing Shan Li ◽  
Zi Cheng Wu ◽  
Fei Lei
Keyword(s):  
Acute Pyelonephritis ◽  
High Performance ◽  
Process Development ◽  
Scale Up ◽  
Preparation Process ◽  
Reaction Conditions ◽  
Related Impurities ◽  
Candidate Drug ◽  
Optimal Reaction ◽  
Impurity Profiles

Based on a foregoing gram-scale laboratory process, an efficient scale-up preparation process of 5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone (LM49-API), a new acute pyelonephritis candidate drug, was developed and validated aiming to reduce by-products and achieve better impurity profiles. Meanwhile, the polymorph of LM49-API and process-related impurities were also investigated. Ultimately, the optimal reaction conditions were verified by evaluating the impurity profiles and their formation during the synthesis. Six process-related impurities were synthesized and identified, being useful for the quality control of LM49-API. Its finalized preparation process was further validated at 329–410 g scale-up production in 53.4–57.1% overall yield with 99.95–99.98% high-performance liquid chromatography (HPLC) purity, and it is currently viable for commercial production. LM49-API-imC and LM49-API-imX were identified as the main single impurities in LM49-API, with the content controlled to be less than 0.03%.

scholarly journals Evaluation of VCAM-1 Targeted Naringenin/Indocyanine Green-Loaded Lipid Nanoemulsions as Theranostic Nanoplatforms in Inflammation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1066
Author(s):  
Elena Valeria Fuior ◽  
Cristina Ana Mocanu ◽  
Mariana Deleanu ◽  
Geanina Voicu ◽  
Maria Anghelache ◽  
...  
Keyword(s):  
Indocyanine Green ◽  
High Performance ◽  
Large Scale ◽  
Near Infrared ◽  
Water Solubility ◽  
Mrna Levels ◽  
Efficient Delivery ◽  
Anti Inflammatory ◽  
Reduced Water

Naringenin, an anti-inflammatory citrus flavonoid, is restrained from large-scale use by its reduced water solubility and bioavailability. To overcome these limitations, naringenin was loaded into lipid nanoemulsions directed towards vascular cell adhesion molecule (VCAM)-1, exposed by activated endothelium, and delivered intravenously in a murine model of lipopolysaccharide (LPS)-induced inflammation. To follow the in vivo bio-distribution, naringenin-loaded nanoemulsions were labeled with near-infrared probe Indocyanine Green (ICG). Based on ICG fluorescence, a VCAM-1-dependent retention of nanoemulsions was detected in the heart and aorta, while ultra-high-performance liquid chromatography (UHPLC) measurements showed a target-selective accumulation of naringenin in the heart and lungs. Correlated, fluorescence and UHPLC data indicated a mixed behavior of the VCAM-1 directed nanoparticles, which were driven not only by the targeting moiety but also by passive retention. The treatment with naringenin-loaded nanoemulsions reduced the mRNA levels of some inflammatory mediators in organs harvested from mice with acute inflammation, indicative of their anti-inflammatory potential. The data support a novel theranostic nanoplatform for inflammation, the naringenin/ICG-loaded nanoparticles that either by passive accumulation or effective targeting of the activated endothelium can be employed for imaging inflamed vascular areas and efficient delivery of the encapsulated therapeutic agent.

scholarly journals McrEngine: A Scalable Checkpointing System Using Data-Aware Aggregation and Compression

2013 ◽  
Vol 21 (3-4) ◽  
pp. 149-163 ◽  
Author(s):  
Tanzima Zerin Islam ◽  
Kathryn Mohror ◽  
Saurabh Bagchi ◽  
Adam Moody ◽  
Bronis R. de Supinski ◽  
...  
Keyword(s):  
High Performance Computing ◽  
High Performance ◽  
Large Scale ◽  
File System ◽  
Scale Up ◽  
Parallel File System ◽  
Data Semantics ◽  
Using Data ◽  
Performance Computing ◽  
Compute Time

High performance computing (HPC) systems use checkpoint-restart to tolerate failures. Typically, applications store their states in checkpoints on a parallel file system (PFS). As applications scale up, checkpoint-restart incurs high overheads due to contention for PFS resources. The high overheads force large-scale applications to reduce checkpoint frequency, which means more compute time is lost in the event of failure. We alleviate this problem through a scalable checkpoint-restart system, mcrEngine. McrEngine aggregates checkpoints from multiple application processes with knowledge of the data semantics available through widely-used I/O libraries, e.g., HDF5 and netCDF, and compresses them. Our novel scheme improves compressibility of checkpoints up to 115% over simple concatenation and compression. Our evaluation with large-scale application checkpoints show that mcrEngine reduces checkpointing overhead by up to 87% and restart overhead by up to 62% over a baseline with no aggregation or compression.

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