Analog VLSI system for active drag reduction

We describe an analog CMOS VLSI system that can process real-time signals from surface-mounted shear stress sensors to detect regions of high shear stress along a surface in an airflow. The outputs of the CMOS circuit are used to actuate micromachined flaps with the goal of reducing this high shear stress on the surface and thereby lowering the total drag. We have designed, fabricated, and tested parts of this system in a wind tunnel in laminar and turbulent flow regimes

A wafer-scale MEMS and analog VLSI system for active drag reduction

We describe an analog CMOS VLSI system that can process real-time signals from integrated shear stress sensors to detect regions of high shear stress along a surface in an airflow. The outputs of the CMOS circuit control the actuation of integrated micromachined flaps with the goal of reducing this high shear stress on the surface and thereby lowering the total drag. We have designed, fabricated, and tested components of this system in a wind tunnel in both laminar and turbulent flow regimes with the goal of building a wafer-scale system

A surface-micromachined shear stress imager

A new MEMS shear stress sensor imager has been developed and its capability of imaging surface shear stress distribution has been demonstrated. The imager consists of multi-rows of vacuum-insulated shear stress sensors with a 300 /spl mu/m pitch. This small spacing allows it to detect surface flow patterns that could not be directly measured before. The high frequency response (30 kHz) of the sensor under constant temperature bias mode also allows it to be used in high Reynolds number turbulent flow studies. The measurement results in a fully developed turbulent flow agree well with the numerical and experimental results previously published

Two Decades of Publishing Excellence in Pharmaceutical Biotechnology

Recombinant biological products have revolutionized modern medicine by providing both remarkably effective vaccines to prevent disease and therapeutic drugs to treat a wide variety of unmet medical needs. Since the early 1980s, dozens of new therapeutic protein drugs and macromolecular vaccines have been commercialized, which have benefitted millions of patients worldwide. The pharmaceutical development of these biological products presented many scientific and technical challenges, some of which continue today with newer candidates including recombinant protein-based vaccines with novel adjuvants, peptide and RNA-based drugs, and stem cellular therapies. Compared with small molecule drugs, the characterization, stabilization, formulation, and delivery of biomolecules share common hurdles as well as unique challenges. This area of drug development research has been referred to as “pharmaceutical biotechnology”, in recognition of the critical role that recombinant DNA technology plays in the design and production of most of these biological products. Current research focus areas in this field include (i) determination of structural integrity of the primary sequence, post-translational modifications, and higher-order three dimensional shapes, (ii) assessment of physicochemical degradation pathways and their effects on biological activity and potency, (iii) formulation design and development to optimize stability and delivery, (iv) evaluating and optimizing process development steps including lyophilization and fill-finish, (v) analytical method development and applications of new instruments and data visualization tools, (vi) design and development of drug delivery approaches, and (vii) studies of biological effects including pharmacokinetics, pharmacodynamics, and adverse immunogenicity. During the early days of pharmaceutical biotechnology research, there were numerous scientific challenges because the analytical characterization approaches needed for development of recombinant biological molecules in “real world” pharmaceutical dosage forms were essentially unknown. Furthermore, understanding critical drug product manufacturing issues (e.g., stability of biological compounds during processing, storage, and shipping as well as reproducibility of fill-finish production technologies) and behavior during and after patient administration was often achieved by “on-the-job” training. Fortunately, the pioneers in the field regularly presented research at key conferences and started publishing early in pharmaceutical sciences journals such as Journal of Pharmaceutical Sciences. Recognizing this critically important new field, the then Editor of the journal, Professor Bill Higuchi, instituted a new “pharmaceutical biotechnology” category for research papers. This insightful move was coupled with an equally wise decision to recruit Dr. C. Russell Middaugh as the new Associate Editor for the new research category. As will be detailed below, under Dr. Middaugh’s diligent and expert guidance, pharmaceutical biotechnology papers have grown in number, scope, and impact over the past 20 years, and these days, the Journal of Pharmaceutical Sciences is viewed by scientific leaders in the field as the “go to” place for publication of the most important results and descriptions of innovations in pharmaceutical biotechnology

Novel Gd Nanoparticles Enhance Vascular Contrast for High-Resolution Magnetic Resonance Imaging

Gadolinium (Gd), with its 7 unpaired electrons in 4f orbitals that provide a very large magnetic moment, is proven to be among the best agents for contrast enhanced MRI. Unfortunately, the most potent MR contrast agent based on Gd requires relatively high doses of Gd. The Gd-chelated to diethylene-triamine-penta-acetic acid (DTPA), or other derivatives (at 0.1 mmole/kg recommended dose), distribute broadly into tissues and clear through the kidney. These contrast agents carry the risk of Nephrogenic Systemic Fibrosis (NSF), particularly in kidney impaired subjects. Thus, Gd contrast agents that produce higher resolution images using a much lower Gd dose could address both imaging sensitivity and Gd safety.To determine whether a biocompatible lipid nanoparticle with surface bound Gd can improve MRI contrast sensitivity, we constructed Gd-lipid nanoparticles (Gd-LNP) containing lipid bound DTPA and Gd. The Gd-LNP were intravenously administered to rats and MR images collected. We found that Gd in Gd-LNP produced a greater than 33-fold higher longitudinal (T(1)) relaxivity, r(1), constant than the current FDA approved Gd-chelated contrast agents. Intravenous administration of these Gd-LNP at only 3% of the recommended clinical Gd dose produced MRI signal-to-noise ratios of greater than 300 in all vasculatures. Unlike current Gd contrast agents, these Gd-LNP stably retained Gd in normal vasculature, and are eliminated predominately through the biliary, instead of the renal system. Gd-LNP did not appear to accumulate in the liver or kidney, and was eliminated completely within 24 hrs.The novel Gd-nanoparticles provide high quality contrast enhanced vascular MRI at 97% reduced dose of Gd and do not rely on renal clearance. This new agent is likely to be suitable for patients exhibiting varying degrees of renal impairment. The simple and adaptive nanoparticle design could accommodate ligand or receptor coating for drug delivery optimization and in vivo drug-target definition in system biology profiling, increasing the margin of safety in treatment of cancers and other diseases

An integrated MEMS system for turbulent boundary layer control

The goal of this project is a first attempt to achieve active drag reduction using a large-scale integrated MEMS system. Previously, we have reported the successful development of a shear-stress imager which allows us to "see" surface vortices (1996). Here we present the promising results of the interaction between micro flap actuators and vortices. It is found that microactuators can actually reduce drag to values even lower than the drag associated with pure laminar flow, and that the microactuators can reduce shear stress values in turbulent flow as well. Based on these results, we have attempted the first totally integrated system that consists of 18 shear stress sensors, 3 magnetic flap-type actuators and control electronics for use in turbulent boundary layer control studies

Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques

Introduction and methodsTo understand the relationship between immunovirological factors and antiretroviral (ARV) drug levels in lymph nodes (LN) in HIV therapy, we analyzed drug levels in twenty-one SIV-infected rhesus macaques subcutaneously treated with daily tenofovir (TFV) and emtricitabine (FTC) for three months.ResultsThe intracellular active drug-metabolite (IADM) levels (TFV-dp and FTC-tp) in lymph node mononuclear cells (LNMC) were significantly lower than in peripheral blood mononuclear cells (PBMC) (P≤0.005). Between Month 1 and Month 3, IADM levels increased in both LNMC (P≤0.001) and PBMC (P≤0.01), with a steeper increase in LNMC (P≤0.01). The viral dissemination in plasma, LN, and rectal tissue at ART initiation correlated negatively with IADM levels at Month 1. Physiologically-based pharmacokinetic model simulations suggest that, following subcutaneous ARV administration, ART-induced reduction of immune activation improves the formation of active drug-metabolites through modulation of kinase activity and/or through improved parent drug accessibility to LN cellular compartments.ConclusionThese observations have broad implications for drugs that need to phosphorylate to exert their pharmacological activity, especially in the settings of the pre-/post-exposure prophylaxis and efficacy of antiviral therapies targeting pathogenic viruses such as HIV or SARS-CoV-2 replicating in highly inflammatory anatomic compartments

Prospective, multisite, international comparison of \u3csup\u3e18\u3c/sup\u3eF-fluoromethylcholine PET/CT, multiparametric MRI, and \u3csup\u3e68\u3c/sup\u3eGa-HBED-CC PSMA-11 PET/CT in men with high-risk features and biochemical failure after radical prostatectomy: Clinical performance and patient outcomes

A significant proportion of men with rising prostate-specific antigen (PSA) levels after radical prostatectomy (RP) fail prostate fossa (PF) salvage radiation treatment (SRT). This study was done to assess the ability of F-fluoromethylcholine ( F-FCH) PET/CT (hereafter referred to as F-FCH), Ga-HBED-CC PSMA-11 PET/CT (hereafter referred to as PSMA), and pelvic multiparametric MRI (hereafter referred to as pelvic MRI) to identify men who will best benefit from SRT. Methods: Prospective, multisite imaging studies were carried out in men who had rising PSA levels after RP, high-risk features, and negative/equivocal conventional imaging results and who were being considered for SRT. F-FCH (91/91), pelvic MRI (88/91), and PSMA (31/91) (Australia) were all performed within 2 wk. Imaging was interpreted by experienced local/central interpreters who were masked with regard to other imaging results, with consensus being reached for discordant interpretations. Expected management was documented before and after imaging, and data about all treatments and PSA levels were collected for 3 y. The treatment response to SRT was defined as a reduction in PSA levels of .50% without androgen deprivation therapy. Results: The median Gleason score, PSA level at imaging, and PSA doubling time were 8, 0.42 (interquartile range, 0.29–0.93) ng/mL, and 5.0 (interquartile range, 3.3–7.6) months. Recurrent prostate cancer was detected in 28% (25/88) by pelvic MRI, 32% (29/91) by F-FCH, and 42% (13/31) by PSMA. This recurrence was found within the PF in 21.5% (19/88), 13% (12/91), and 19% (6/31) and at sites outside the PF (extra-PF) in 8% (7/88), 19% (17/91), and 32% (10/31) by MRI, F-FCH, and PSMA, respectively (P, 0.004). A total of 94% (16/17) of extra-PF sites on F-FCH were within the pelvic MRI field. Intra-pelvic extra-PF disease was detected in 90% (9/10) by PSMA and in 31% (5/16) by MRI. F-FCH changed management in 46% (42/91), and MRI changed management in 24% (21/88). PSMA provided additional management changes over F-FCH in 23% (7/31). The treatment response to SRT was higher in men with negative results or disease confined to the PF than in men with extra-PF disease ( F-FCH 73% [32/44] versus 33% [3/9] [P, 0.02], pelvic MRI 70% [32/46] versus 50% [2/4] [P was not significant], and PSMA 88% [7/ 8] versus 14% [1/7] [P, 0.005]). Men with negative imaging results (MRI, F-FCH, or PSMA) had high (78%) SRT response rates. Conclusion: F-FCH and PSMA had high detection rates for extra-PF disease in men with negative/equivocal conventional imaging results and rising PSA levels after RP. These findings affected management and treatment responses, suggesting an important role for PET in triaging men being considered for curative SRT. 18 18 18 68 18 18 18 18 18 18 18 18 1

Taxonomic assignment of uncultivated prokaryotic virus genomes is enabled by gene-sharing networks

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Microbiomes from every environment contain a myriad of uncultivated archaeal and bacterial viruses, but studying these viruses is hampered by the lack of a universal, scalable taxonomic framework. We present vConTACT v.2.0, a network-based application utilizing whole genome gene-sharing profiles for virus taxonomy that integrates distance-based hierarchical clustering and confidence scores for all taxonomic predictions. We report near-identical (96%) replication of existing genus-level viral taxonomy assignments from the International Committee on Taxonomy of Viruses for National Center for Biotechnology Information virus RefSeq. Application of vConTACT v.2.0 to 1,364 previously unclassified viruses deposited in virus RefSeq as reference genomes produced automatic, high-confidence genus assignments for 820 of the 1,364. We applied vConTACT v.2.0 to analyze 15,280 Global Ocean Virome genome fragments and were able to provide taxonomic assignments for 31% of these data, which shows that our algorithm is scalable to very large metagenomic datasets. Our taxonomy tool can be automated and applied to metagenomes from any environment for virus classification

Comprehensive Comparison of the Performance of Autogenous Brachial-Basilic Transposition Arteriovenous Fistula and Prosthetic Forearm Loop Arteriovenous Graft in a Multiethnic Asian Hemodialysis Population

Aim. For patients who have exhausted cephalic vein arteriovenous fistula (AVF) options, controversy exists on whether brachialbasilic AVF with transposition (BBTAVF) or a forearm arteriovenous graft (AVG) should be the next vascular access of choice. This study compared the outcomes of these two modalities. Methods. A retrospective study of 122 Asian multiethnic patients who underwent either a BBTAVF (81) or an AVG (41). Maturation time and intervention rates were analyzed. Functional primary, secondary, and overall patency rates were evaluated. Results. The maturation time for BBTAVFs was significantly longer than AVGs. There was also a longer deliberation time before surgeons abandon a failing BBTAVF compared to an AVG. Both functional primary and secondary patency rates were significantly higher in the BBTAVF group at 1-year follow-up: 73.2% versus 34.1% ( < 0.001) and 71.8% versus 54.3% ( = 0.022), respectively. AVGs also required more interventions to maintain patency. When maturation rates were considered, the overall patency of AVGs was initially superior in the first 25 weeks after creation and then became inferior afterwards. Conclusion. BBTAVFs had superior primary and functional patency and required less salvage interventions. The forearm AVG might have a role in patients who require early vascular access due to complications from central venous catheters or with limited life expectancy