gebhart/patrepeval huggingface dataset:
Light-Activated siRNA Endosomal Release (LASER) by Porphyrin Lipid Nanoparticles (2023)

Lipid nanoparticles (LNPs) have achieved clinical success in delivering small interfering RNAs (siRNAs) for targeted gene therapy. However, endosomal escape of siRNA into the cytosol remains a fundamental challenge for LNPs. Herein, we report a strategy termed light-activated siRNA endosomal release (LASER) to address this challenge. We established a porphyrin-LNP by incorporating porphyrin-lipids into the clinically approved Onpattro formulation. The porphyrin-LNP maintained the physical properties of an LNP and generated reactive oxygen species (ROS) when irradiated with near-infrared (NIR) light. Using confocal microscopy, we revealed that porphyrin-lipids within the LNP translocate to endosomal membranes during endocytosis. The translocated porphyrin-lipids generated ROS under light irradiation and enabled LASER through endosomal membranes disruption as observed through GAL-9 recruitment and transmission electron microscopy (TEM). By establishing a quantitative confocal imaging method, we confirmed that porphyrin-LNPs can increase siRNA endosomal escape efficiency by up to 2-fold via LASER and further enhance luciferase target knockdown by 4-fold more in luciferase-transfected prostate cancer cells. Finally, we formulated porphyrin-LNPs encapsulated with gold nanoparticles (GNP) and visualized the LASER effect within prostate tumors via TEM, confirming the light-activated endosomal membrane disruption and subsequent GNP release into cytosols <i>in vivo</i>. Overall, porphyrin-LNPs and the LASER approach enhanced siRNA endosomal escape and significantly improved knockdown efficacy. We believe the versatility of this technology could be applied to various LNP-based RNA therapeutics.
Molecular Level-Crossing Spectroscopy: thegValue for an Excited State of Nitric Oxide (1967)

Zero-field level-crossing effects have been optically detected in the nitric oxide molecule by observing the change in intensity of molecular fluorescence from a specified state with magnetic field. The intensity follows an inverted Lorentzian with a field strength at half-maximum of 0.379\ifmmode\pm\else\textpm\fi{}0.030 G. Together with the radiative lifetime as recently determined by Jeunehomme, this gives for the molecular $g$ factor for this level a value of 0.762\ifmmode\pm\else\textpm\fi{}0.060. This places an upper limit on the magnitude of $\ensuremath{\gamma}$, the molecular $\ensuremath{\rho}$-type doubling constant, of $|\ensuremath{\gamma}|&lt;~1.3\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}5}$ ${\mathrm{cm}}^{\ensuremath{-}1}$ (390 KHz).
Loss of SFRP4 Alters Body Size, Food Intake, and Energy Expenditure in Diet-Induced Obese Male Mice (2015)

Secreted frizzled-related protein 4 (SFRP4) is an extracellular regulator of the wingless-type mouse mammary tumor virus integration site family (WNT) pathway. SFRP4 has been implicated in adipocyte dysfunction, obesity, insulin resistance, and impaired insulin secretion in patients with type 2 diabetes. However, the exact role of SFRP4 in regulating whole-body metabolism and glucose homeostasis is unknown. We show here that male Sfrp4(-/-) mice have increased spine length and gain more weight when fed a high-fat diet. The body composition and body mass per spine length of diet-induced obese Sfrp4(-/-) mice is similar to wild-type littermates, suggesting that the increase in body weight can be accounted for by their longer body size. The diet-induced obese Sfrp4(-/-) mice have reduced energy expenditure, food intake, and bone mineral density. Sfrp4(-/-) mice have normal glucose and insulin tolerance and β-cell mass. Diet-induced obese Sfrp4(-/-) and control mice show similar impairments of glucose tolerance and a 5-fold compensatory expansion of their β-cell mass. In summary, our data suggest that loss of SFRP4 alters body length and bone mineral density as well as energy expenditure and food intake. However, SFRP4 does not control glucose homeostasis and β-cell mass in mice.
Measuring Work of Adhesion of Polystyrene Microspheres (2018)

Particle adhesion is relevant in fields ranging from aerospace and energy to civil engineering and medicine. The functions of aerodynamic surfaces, heat exchangers, solar panels, ventilation systems, and blood vessels are affected by the buildup of particulates on their surfaces. Direct measurement of the adhesive force between a particle and a surface is key to understanding and mitigating particle fouling. Approaches such as the Johnson-Kendall-Roberts (JKR) and Derjaguin-Muller-Toporov (DMT) models offer a first approximation of the forces involved but do not account for non-idealities like roughness or plastic deformation. Experimental measurements of adhesive forces often deviate significantly from predictions. One approach to measure adhesion is the colloidal probe technique, which uses a particle attached to the tip of an atomic force microscope (AFM) cantilever. The particle is touched to a surface and then withdrawn and a pull-off force (FPO) determined by cantilever deflection. FPO can be used to estimate work of adhesion (Wa) and other properties from existing models. We describe a new method for producing colloidal probes using wax as an adhesive to attach micrometer-scale spheres to AFM tips. This method can be used with a range of particles and minimizes the potential for changes to the particle surface chemistry or geometry from exposure to heat, chemicals, radiation, or external forces. Particle attachment to AFM tips is robust and reversible, allowing old particles to be replaced with new ones in a few minutes. Pull-off measurements using polystyrene (PS) particles, pristine and modified with myristyltrimethylammonium bromide (14-TAB), were collected from various substrates to demonstrate the viability of this technique and investigate the impact of particle surface modification.
Preoperative Risk Management in Perioperative Medicine and Value-based Care: What the United States Needs to Understand, What the United Kingdom Knows (2019)

In the United States, the economics of health has caused us to recognize that a national strategy is needed to quickly and effectively bend the cost curve of a system that is globally noncompetitive with respect to value and is unsustainable in its current form as a health care delivery model. Heretofore, US national policy and health care reform efforts have principally focused on addressing gaps in coverage. Going forward in the United States the drivers of value for health care will most likely come from re-engineering the delivery system itself. In the setting of perioperative medicine, these value gaps maybe unrecognized and underappreciated.
Application of a composite measure of product adherence, protocol compliance, and semen exposure to a phase III microbicide HIV prevention trial (2021)

Abstract Background Strict adherence to antiretroviral-based microbicide use is important for effective HIV prevention. We previously developed a composite measure of product adherence, protocol compliance, and semen exposure for determining vaginal use of tenofovir (TFV) 1% gel applicators through biomarkers and residual drug analyses. In this study, we tested the ability of the composite measure in vaginally used TFV gel applicators from a Phase III HIV prevention clinical trial. Methods Used vaginal gel applicators from the FACTS 001 study were swabbed for detection of vaginal bacterial markers (vaginal insertion), semen DNA markers (semen exposure), and residual TFV gel (product use). Results Of 1,098 evaluable TFV and placebo applicators, 80% had detectable vaginal insertion biomarkers and 52% had semen biomarkers. Ninety-nine percent of vaginally inserted applicators TFV applicators had detectable residual TFV as measured by liquid chromatography with tandem mass spectroscopy (LC–MS/MS). Residual TFV levels were also successfully detected using Fourier Transform Infrared (FTIR)-based spectroscopy. Conclusions Vaginal insertion and semen exposure biomarkers were detectable on used TFV 1% gel applicators. Residual TFV on these gel applicators was detectable by LC–MS/MS and FTIR-based spectroscopy, which has potential to be a more convenient and quicker method for detecting drug use. With continual improvements, this composite measure of product adherence, protocol compliance, and semen exposure has potential to assess use of not only TFV gel but also other topical microbicides or products.
Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis (2020)

We have used a mouse model, human cells, and liver tissue to test how exposure to fructose can cause the liver to store excess fat and become damaged and scarred. We have then inhibited a key enzyme within the liver that is responsible for fructose metabolism. Our findings show that inhibition of fructose metabolism reduces liver injury and fibrosis in mouse and human livers and thus this may represent a potential route for treating patients with fatty liver disease in the future.
Inherited human group IVA cytosolic phospholipase A 2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation (2015)

Eicosanoids are important vascular regulators, but the phospholipase A2 (PLA2) isoforms supporting their production within the cardiovascular system are not fully understood. To address this, we have studied platelets, endothelial cells, and leukocytes from 2 siblings with a homozygous loss-of-function mutation in group IVA cytosolic phospholipase A2 (cPLA2α). Chromatography/mass spectrometry was used to determine levels of a broad range of eicosanoids produced by isolated vascular cells, and in plasma and urine. Eicosanoid release data were paired with studies of cellular function. Absence of cPLA2α almost abolished eicosanoid synthesis in platelets (e.g., thromboxane A2, control 20.5 ± 1.4 ng/ml vs. patient 0.1 ng/ml) and leukocytes [e.g., prostaglandin E2 (PGE2), control 21.9 ± 7.4 ng/ml vs. patient 1.9 ng/ml], and this was associated with impaired platelet activation and enhanced inflammatory responses. cPLA2α-deficient endothelial cells showed reduced, but not absent, formation of prostaglandin I2 (prostacyclin; control 956 ± 422 pg/ml vs. patient 196 pg/ml) and were primed for inflammation. In the urine, prostaglandin metabolites were selectively influenced by cPLA2α deficiency. For example, prostacyclin metabolites were strongly reduced (18.4% of control) in patients lacking cPLA2α, whereas PGE2 metabolites (77.8% of control) were similar to healthy volunteer levels. These studies constitute a definitive account, demonstrating the fundamental role of cPLA2α to eicosanoid formation and cellular responses within the human circulation.
A pilot study of immune checkpoint inhibition in combination with radiation therapy in patients with metastatic pancreatic cancer. (2017)

e15786 Background: Durvalumab is a human IgG1 monoclonal antibody directed against PD-L1. Tremelimumab is a selective human IgG2 monoclonal antibody against CTLA-4. Several studies have documented an increase in peripheral antitumor immunity following radiation. The hypothesis of this study is that the effect of immune checkpoint inhibition (ICI) can be enhanced by radiation in pancreatic adenocarcinoma (PAC). Methods: Patients with histologically confirmed metastatic PC with primary in-situ or metastatic SBRT-amenable disease are being enrolled to this pilot study. Primary objective to determine safety, tolerability and feasibility of immune checkpoint inhibition [comprising either Durvalumab alone (Cohort A), or combined durvalumab and tremelimumab (Cohort B)] in combination with stereotactic body radiation therapy (SBRT) at two different schedules (8Gy/single fraction or 25Gy in 5 fractions). Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 accessible for biopsy. No limit to the number of prior chemotherapy regimens; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active autoimmune disorders. Results: N = 24 patients with chemorefractory metastatic PC have so far been enrolled; M/F = 13/11; Median age = 61. Treatment was well tolerated. No DLT encountered. The most common toxicity was fatigue (G1/2) in all patients in DL2. 5/24 pts had early discontinuation ( &lt; 4 wks) due to rapid PD. No objective responses have been seen. 5 pts (21%) had SD as best response. Conclusions: Immune checkpoint inhibition in combination with SBRT in advanced pancreatic cancer is safe and feasible. Preliminarily no objective responses have been seen for these schedules of SBRT with durvalumab. The study is continuing with evaluation of SBRT with dual checkpoint inhibition (durvalumab and tremelimumab). Clinical trial information: NCT02311361.
In Vitro Reconstitution of the Highly Active and Natively Folded Recombinant Human Superoxide Dismutase 1 Holoenzyme (2018)

Abstract SOD1 is an antioxidant enzyme that exists as a highly stable dimer in healthy humans. Each subunit contains an intramolecular disulfide bond and coordinates one zinc and one copper ion. The dimer is destabilized in the absence of the ions and disruption of the disulfide bond, which leads to the formation of small oligomers and subsequently larger insoluble aggregates. An acquired toxic function of destabilized SOD1 is postulated to be associated with amyotrophic lateral sclerosis (ALS), which is a neurodegenerative disease characterized by peripheral and central paralysis and by 3‐ to 5‐year median survival after diagnosis. In this study, we present a protocol for heterologous expression of human SOD1 in E. coli and total reconstitution of the holoenzyme, which exhibits the highest reported specific activity (four‐fold higher) of recombinant hSOD1. Biophysical characterization confirms the native state of this protein. The presented protocol provides highly active hSOD1 that will benefit in vitro investigations of this protein.
Effects of Matrix Structure/Acidity on Ion Formation in Matrix-Assisted Laser Desorption Ionization Mass Spectrometry (1997)

The involvement of ground and excited state proton transfer reactions in matrix-assisted laser desorption ionization (MALDI) of bradykinin and bovine insulin is examined using a series of p-substituted aniline compounds as matrices. Semiempirical calculations of ground and excited state acidity of the p-substituted aniline and anilinium ions are presented. A linear correlation between log (analyte [A + H]+ ion yield) and matrix acidity is obtained. The behavior of the seven p-substituted anilines is discussed in terms of the relationship between matrix compound structure, reactivity, and ability to act as a MALDI matrix.
Signboard Recognition by Consistency Checking of Local Features (2007)

The problem of recognizing signboards in street scenes is defined as matching the input image to pre-stored 2D signboard images. This problem is not as simple as it appears to be due to arbitrary drawings and relative 3D positions. We approached this problem by matching characteristic local features of input image to those of images in the database. Local decisions are verified by the global viewpoint of the homographic consistency and color consistency. The well-known SIFT feature is used as a local feature and the homographic consistency checking is performed using RANSAC, a random sampling method. In order to handle highly perspective-distorted signboards, several perspective-transformed templates are generated offline. In our experiment, with a database of 35 images, our proposed method achieved 95% recognition rate, showing good results despite the highly distorted input images.
Novel chemical amplification positive-resist material for EB lithography (1992)

This paper reports on a novel three-component chemical amplification positive resist system for EB lithography composed of a novolak resin, an acid generator, and a newly synthesized dissolution inhibitor. We synthesized a novel dissolution inhibitor named CP-TBOC (1), which contains a tert-butoxycarbonyl (t-BOC) group and a lactone ring, to obtain resist materials with high sensitivity and high contrast. The t-BOC group of this dissolution inhibitor effectively decomposed by an acid catalyzed thermal reaction as the other conventional dissolution inhibitors. In addition to this decomposition, the lactone ring of the decomposed product was spontaneously cleft in an aqueous base to generate carboxylic acid, further enhancing the solubility to alkaline developers. The subsequent cleavage in an aqueous developer was investigated by UV-visible spectroscopy. The highest EB sensitivity was obtained at a CP-TBOC concentration of approximately 4.7 X 10-4 mol/g.
Silicon Photonics for Modulation, Switching, and Tuning (2011)

Thermal and electro-refractive silicon photonic modulators, switches, and tunable filters have been demonstrated with ultralow switching energies and high-speed operation. These elements form building blocks that will enable future generations of large-scale microphotonic systems.
Selective DNA-Binding Activity of Interleukin-10-Stimulated STAT Molecules in Human Monocytes (1999)

It has been demonstrated that interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) have various reverse effects on macrophages; however, the molecular mechanism of this difference has not been fully understood. In this study, we analyzed the binding activity of IL-10- and IFN-gamma-activated STAT molecules to two kinds of GAS-motif sequences. IL-10-activated STAT1 could bind to the GAS-motif sequence in the promoter region of the Fcgamma receptor, but not to that in the promoter region of the COX-2 gene, whereas IFN-gamma-activated STAT1 and STAT5 could bind to both sequences. IL-10 inhibited IFN-gamma-induced STAT activation without newly synthesized protein. We further demonstrated that aspirin, but not dexamethasone, suppressed IFN-gamma-induced STAT activation. Taken together, these results suggest that IL-10-activated STAT1 has a specificity in binding to the GAS-motif sequences, whereas IFN-gamma-activated STAT1 and STAT5 have a broader spectrum in binding to the GAS-motif sequences. This may explain the difference between IL-10 and IFN-gamma in biological activity, and the inhibitory effect of IL-10 on IFN-gamma activities.
Kinetically Controlled Formation of Supported Nanoparticles in Low Temperature Supercritical Media for the Development of Advanced Nanostructured Materials (2009)

The formation of surface nanostructures allows assemblies of materials at different scales, opening new routes toward the design of advanced nanostructured materials. The decoration of surfaces with shape- and size-controlled metal nanoparticles can be achieved through the reduction of hexafluoroacetylacetonate complexes [M(hfac)x] with H2 in supercritical CO2/alcohol at low temperature with neither catalyst nor surface prefunctionalization. This paper investigates the influence of different alcohols, methanol, ethanol, and isopropanol, used as cosolvent on the reduction kinetics of Cu(hfac)2·H20 in the supercritical CO2/alcohol/H2 mixtures. The results are applied to the modeling of the decoration process of silica spheres, used as a model substrate, with copper nanoparticles (5−17 nm). The model, using the decomposition kinetics of the precursor, is based on a bimodal process: (i) an initial homogeneous nucleation in the supercritical media and (ii) a fast heterogeneous growth by coalescence on the surface of the silica particles. We demonstrate good agreements between the simulated results and the experimental data showing an advanced kinetically controlled size of the supported nanoparticles in the range of temperature 100−125 °C and residence time 0−120 min.
Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections (2023)

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Co-culturing CD4<sup>+</sup> with autologous CD8<sup>+</sup> T cells from ART-suppressed HIV<sup>+</sup> donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8<sup>+</sup> T cells. This trispecific antibody mediates CD4<sup>+</sup> and CD8<sup>+</sup> T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection.
Guaranteeing service rates for cell-based schedulers with a grouping architecture (2003)

Packet fair queueing (PFQ) algorithms are packetised versions of generalised processor sharing (GPS), which is an idealised fluid scheduling model with desirable properties in terms of delay bound and fairness. To support a large number of sessions with diverse bandwidth requirements, the grouping architecture, which is scalable, has been proposed to approximate PFQ algorithms. The authors analyse the relationship between the guaranteed service rates and utilisation for cell-based schedulers with the grouping architecture. Based on this analysis, call admission control (CAC) schemes are proposed to provide the guaranteed service rate for each session, and their performance is evaluated and compared in terms of computational complexity.
Cathepsin S inhibitors as novel immunomodulators. (2005)

Cathepsin S is one of the major cysteine proteases, and is expressed in the lysosome of antigen presenting cells; primarily dendritic cells, B-cells and macrophages. Cathepsin S is most well known for its critical function in the proteolytic digestion of the invariant chain chaperone molecules, thus controlling antigen presentation to CD4+ T-cells by major histocompatibility complex (MHC) class II molecules or to NK1.1+ T-cells via CD1 molecules. Cathepsin S also appears to participate in direct processing of exogenous antigens for presentation by MHC class II to CD4+ T-cells, or in cross-presentation by MHC class I molecules to CD8+ T-cells. In addition, although direct evidence is still lacking, in its secreted form cathepsin S is implicated in degradation of the extracellular matrix, which may contribute to the pathology of a number of diseases, including arthritis, atherosclerosis and chronic obstructive pulmonary disease. Therefore, inhibition of cathepsin S is a promising target for the development of novel therapeutics for a variety of indications.
ISSLS PRIZE IN BIOENGINEERING SCIENCE 2019: biomechanical changes in dynamic sagittal balance and lower limb compensatory strategies following realignment surgery in adult spinal deformity patients (2019)

Longitudinal changes in DSB following successful multi-level spinal realignment indicate reduced forces on the lower lumbar spine along with altered lower limb dynamics matching that of controls. Inadequate improvement in DSB may indicate increased risk of post-surgical mechanical failure. These slides can be retrieved under Electronic Supplementary Material.
Transverse localization of sound (2013)

We show how disorder can be used to guide a broadband ultrasonic wave. The idea is to exploit the transverse localization regime that has been reported for light. Our waveguide consists of a set of parallel cylindrical scatterers randomly distributed in the transverse plane. An ultrasonic beam propagating along the direction of scatterers is found to remain confined in the two other directions on a size smaller than the waveguide diameter and driven by the localization length. Interestingly, the guided wave is also found to propagate with a very limited temporal dispersion.