gebhart/patrepeval huggingface dataset:
Abstract 79: Caveolin-1 Knockout Mice Have Salt-Sensitive Hypertension and Dopamine-1 Receptor Defects in Renal Cortex and Isolated Renal Proximal Tubule Cells (2013)

Dopamine-1 receptors (D1R) are necessary for kidney proximal tubule-dependent natriuresis and maintenance of normal blood pressure, especially under high salt conditions. G-protein coupled receptor kinase 4 (GRK4) is a negative regulator of D1R function and single nucleotide polymorphisms in GRK4 have been associated with both hypertension and salt sensitivity in humans. Caveolin-1 (CAV1) directly binds to GRK4 and decreases kinase activity. We hypothesized that CAV1 knockout mice (CAV1KO) would have increased GRK4 kinase activity due to lack of physical interaction and inhibition of GRK4; thus overactive GRK4 would inactivate the D1R. Mean arterial blood pressure (MAP, in mmHg ±SEM) measured over 5 days was not significantly different for Wild-type mice (WT, 128.9±4.2 mmHg, n=4) vs CAV1KO (129.5±3.5 mmHg, n=4) on normal chow (0.3% sodium). However, on a 4% high sodium diet, the MAP of CAV1KO mice increased in just 2 days by 20.1±4.2 mmHg (p&lt;0.05 vs either Day 0 CAV1KO or Day 2 WT, n=4). The CAV1KO MAP increased by 25.9±6.6 mmHg by day 7 (p&lt;0.05 vs either Day 0 CAV1KO or Day 7 WT, n=4). Hyperphosphorylation and inactivation of the D1R in renal cortex was examined by looking at phospho-serine D1R by immuno-precipitation and Western dot blotting. A 92.5% ± 18.8 SEM increase in phospho-D1R was found in the CAV1KO renal cortex (n=4, p&lt;0.01 vs WT; 14,574/7570 RFU). Cortical slices were made and incubated for 30 minutes with fenoldopam (FEN, 10 μM) with or without LE300 (D1R-like antagonist, 10 μM) or vehicle (VEH). Cyclic AMP was measured by TR-FRET (Lance, Perkin Elmer). FEN significantly increased cAMP 5.6 fold ± 1.2 SEM (n=4, p&lt;0.01 vs VEH; 7.84/1.4 pmole/mg protein) in WT but not in CAV1KO slices, and this effect was completely blocked by LE300. Primary mouse CAV1KO and WT renal proximal tubule cell lines were established and monensin (sodium ionophore, 5 μM, 30 minutes)-induced plasma membrane D1R recruitment increased as measured by confocal microscopy in WT (30.4% ± 7.4 SEM, n=11, p&lt;0.01 vs VEH; 8990/6894 RFU) but not in CAV1KO proximal tubule cells. In summary, CAV1 is necessary in high salt conditions for maintaining normal blood pressure in mice and for preserving normal D1R function in kidney cortex and in mouse renal proximal tubule cells.
Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes (2019)

Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area-based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m<sup>2</sup>) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day -9/-12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and 124 malignant disorders). The optimal fludarabine exposure was determined as an AUC of 20 mg*h/L. In the overexposed group, EFS was lower (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5; <i>P</i> = .02), due to higher NRM (HR, 3.4; 95% CI, 1.6-6.9; <i>P <</i>001) associated with impaired immune reconstitution (HR, 0.43; 95% CI, 0.26-0.70; <i>P <</i>001). The risks of NRM and graft failure were increased in the underexposed group (HR, 3.3; 95% CI, 1.2-9.4; <i>P</i> = .02; HR, 4.8; 95% CI, 1.2-19; <i>P</i> = .02, respectively). No relationship with relapse was found. Fludarabine exposure is a strong predictor of survival after HCT, stressing the importance of optimum fludarabine dosing. Individualized dosing, based on weight and "renal function" or "therapeutic drug monitoring," to achieve optimal fludarabine exposure might improve survival.
A2A receptor dependent and A2A receptor independent effects of extracellular adenosine on murine thymocytes in conditions of adenosine deaminase deficiency (2000)

Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) and is accompanied by T-cell depletion and accumulation of both intracellular and extracellular adenosine (extAdo) and deoxyadenosine. To better understand the causes of T-cell depletion in vivo and to discriminate between extracellular and intracellular effects of exogenously added adenosine in vitro, we investigated mechanisms of 2 different effects of adenosine on murine thymocytes. These effects of adenosine include direct induction of apoptosis in about 6% to 15% thymocytes and inhibition of T-cell receptor (TCR)-induced activation of the majority of thymocytes with inhibited ADA. A2A adenosine receptors, but not A2B, A1, or A3 receptors, are shown to be mostly responsible for extAdo-triggered signaling (cyclic adenosine monophosphate [cAMP] accumulation) in murine thymocytes and this prompted studies of the effects of extAdo on thymocytes from A2AR gene-deficient mice. It is found that direct apoptotic effects of extAdo on CD4+CD8+ double positive (DP) thymocytes are completely accounted for by signaling through A2AR, with no contribution of intracellular lymphotoxicity or of compensating A2BRs because only A2AR +/+, but not A2AR −/− thymocytes were susceptible to apoptotic effects of extAdo. Studies of the effects of cAMP-raising agents support observations of extAdo/A2AR/cAMP–triggered apoptosis in DP thymocytes. Unexpectedly, the extAdo strongly inhibited TCR-triggered activation of both A2AR +/+ and A2AR −/− thymocytes in the presence of ADA inhibitors. This was confirmed with thymocytes from ADA gene-deficient mice, suggesting the existence of A2AR-independent effects of extAdo on thymocytes. The presented data raises questions about the identity and functional role of A2AR-expressing thymocytes in T-cell differentiation and of the role of TCR-antagonizing effects of extAdo in conditions of ADA SCID.
On performance of long term HSPA evolution: Towards meeting IMT-Advanced requirements (2012)

In this paper, evaluation of HSPA radio technology is provided with the reference to IMT-Advanced requirements. Recent technological advancements are included to verify if HSPA is capable of meeting these requirements. Extensive system-level simulation campaigns are carried out, which shadow IMT-A performance evaluation guidelines and suggested test environments specifications. Respective results are analyzed in the context of spectral efficiency, VoIP capacity and high speed mobility of IMT-A requirements. The presented results indicate that although a single strongly interference-limited environment is unlikely to pass stringent IMT-A spectral efficiency criteria, overall all the IMT-A test requirements are passed.
Defects in GLP-1 Response to an Oral Challenge Do Not Play a Significant Role in the Pathogenesis of Prediabetes (2011)

The lack of association of GLP-1 concentrations with glucose tolerance status and with insulin secretion and action in a cohort encompassing the full spectrum of prediabetes strongly argues against a significant contribution of defects in GLP-1 secretion to the pathogenesis of prediabetes.
Atom-Varied Side Chains in Conjugated Polymers Affect Efficiencies of Photovoltaic Devices Incorporating Small Molecules (2019)

We synthesized three conjugated polymers involving sulfur (S)-inserted and chlorine (Cl)-substituted side chains of the parent two-dimensional conjugated polymer—poly(benzodithiophene–thiophene–benzooxadiazole) (BO)—to form S-inserted (BO2S), Cl-substituted (BO2Cl), and S-inserted with Cl-substituted (BO2S2Cl) polymers for tuning their surface energies and, thus, interaction with IT-4F small molecule in their binary blends. In the BO:IT-4F blend, the bulk heterojunction (BHJ) structure was constituted mainly from the long-rod BO domains along with a few IT-4F domains that dispersed well in the blend; in contrast, favorable networks for charge transport existed in the BO2S or BO2S2Cl with IT-4F blend. The disk sizes of IT-4F in the BO2S2Cl:IT-4F blend were larger than that in the BO2S:IT-4F blend (23.3 vs 18.1 nm). As the extent of atom variation increased from BO to BO2S to BO2S2Cl, the induced IT-4F crystallinity increased, and the orientation of molecular packing of the polymer varied. The highest PCE (12.06%) was that for the device based on the double sulfur-inserted/chlorine-substituted side chain polymer and IT-4F acceptor (BO2S2Cl:IT-4F), owing to the more balanced hole-to-electron mobility, being consistent with the value predicted (11.8%) using the random forest machine learning model. This study not only provides insight into the photovoltaic performance of the polymers with atom-inserted or -substituted side chain but also reveals that the effects of molecular packing.
Simultaneous inhibition of endocytic recycling and lysosomal fusion sensitizes cells and tissues to oligonucleotide therapeutics (2023)

Inefficient endosomal escape remains the primary barrier to the broad application of oligonucleotide therapeutics. Liver uptake after systemic administration is sufficiently robust that a therapeutic effect can be achieved but targeting extrahepatic tissues remains challenging. Prior attempts to improve oligonucleotide activity using small molecules that increase the leakiness of endosomes have failed due to unacceptable toxicity. Here, we show that the well-tolerated and orally bioavailable synthetic sphingolipid analog, SH-BC-893, increases the activity of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) up to 200-fold in vitro without permeabilizing endosomes. SH-BC-893 treatment trapped endocytosed oligonucleotides within extra-lysosomal compartments thought to be more permeable due to frequent membrane fission and fusion events. Simultaneous disruption of ARF6-dependent endocytic recycling and PIKfyve-dependent lysosomal fusion was necessary and sufficient for SH-BC-893 to increase non-lysosomal oligonucleotide levels and enhance their activity. In mice, oral administration of SH-BC-893 increased ASO potency in the liver by 15-fold without toxicity. More importantly, SH-BC-893 enabled target RNA knockdown in the CNS and lungs of mice treated subcutaneously with cholesterol-functionalized duplexed oligonucleotides or unmodified ASOs, respectively. Together, these results establish the feasibility of using a small molecule that disrupts endolysosomal trafficking to improve the activity of oligonucleotides in extrahepatic tissues.
Cloud aided semi-active suspension control (2014)

This paper considers the problem of vehicle suspension control from the perspective of a Vehicle-to-Cloud-to-Vehicle (V2C2V) distributed implementation. A simplified variant of the problem is examined based on the linear quarter-car model of semi-active suspension dynamics. Road disturbance is modeled as a combination of a known road profile, an unmeasured stochastic road profile and potholes. Suspension response when the vehicle hits the pothole is modeled as an impulsive change in wheel velocity with magnitude linked to physical characteristics of the pothole and of the vehicle. The problem of selecting the optimal damping mode from a finite set of damping modes is considered, based on road profile data. The information flow and V2C2V implementation are defined based on partitioning the computations and data between the vehicle and the cloud. A simulation example is presented.
Efficient dispersion modeling in optical multimode fiber (2023)

Dispersion remains an enduring challenge for the characterization of wavelength-dependent transmission through optical multimode fiber (MMF). Beyond a small spectral correlation width, a change in wavelength elicits a seemingly independent distribution of the transmitted field. Here we report on a parametric dispersion model that describes mode mixing in MMF as an exponential map and extends the concept of principal modes to describe the fiber's spectrally resolved transmission matrix (TM). We present computational methods to fit the model to measurements at only a few, judiciously selected, discrete wavelengths. We validate the model in various MMF and demonstrate an accurate estimation of the full TM across a broad spectral bandwidth, approaching the bandwidth of the best-performing principal modes, and exceeding the original spectral correlation width by more than two orders of magnitude. The model allows us to conveniently study the spectral behavior of principal modes, and obviates the need for dense spectral measurements, enabling highly efficient reconstruction of the multispectral TM of MMF.
Crossover from Rouse to Reptation Dynamics in Salt-Free Polyelectrolyte Complex Coacervates (2020)

Considerable interest in the dynamics and rheology of polyelectrolyte complex coacervates has been motivated by their industrial application as viscosity modifiers. A central question is the extent to which classical Rouse and reptation models can be applied to systems where electrostatic interactions play a critical role on the thermodynamics. By relying on molecular simulations, we present a direct analysis of the crossover from Rouse to reptation dynamics in salt-free complex coacervates as a function of chain length. This crossover shifts to shorter chain lengths as electrostatic interactions become stronger, which corresponds to the formation of denser coacervates. To distinguish the roles of Coulomb interactions and density, we compare the dynamics of coacervates to those of neutral, semidilute solutions at the same density. Both systems exhibit a universal dynamical behavior in the connectivity-dominated (subdiffusion and normal diffusion) regimes, but the monomer relaxation time in coacervates is much longer and increases with increasing Bjerrum length. This is similar to the cage effect observed in glass-forming polymers, but the local dynamical slowdown is caused here by strong Coulomb attractions (ion pairing) between oppositely charged monomers. Our findings provide a microscopic framework for the quantitative understanding of coacervate dynamics and rheology.
Building a better cell trap: Applying Lagrangian modeling to the design of microfluidic devices for cell biology (2008)

In this report, we show how computational fluid dynamics can be applied to the design of efficient hydrodynamic cell traps in microfluidic devices. Modeled hydrodynamic trap designs included a large, multiple-aperture “C-type” sieve for trapping hundreds of cells, flat single-aperture arrays for single cells, and “U-type” hydrodynamic structures with one or two apertures to confine small clusters of cells (∼10–15 cells per trap). Using 3T3 cells as a model system, the motion of each individual cell was calculated using a one-way coupled Lagrangian method. The cell was assumed to be a solid sphere, and interactions with other cells were only considered when a cell sedimented in the trap. The ordinary differential equations were solved along the cell trajectory for the three components of the velocity and location vector by using the Rosenbrock method based on an adaptive time-stepping technique. Validation of the predictive value of modeling, using 3T3 cells flowed through microfluidic devices containing “U-type sieves” under the simulation flow parameters, showed excellent agreement between experiment and simulation with respect to cell number per trap and the uniformity of cell distribution within individual microchambers. For applications such as on-chip cell culture or high-throughput screening of cell populations within a lab-on-a-chip environment, Lagrangian simulations have the potential to greatly simplify the design process.
Nonidentical Continuous-Flow Devices For Biventricular Support (2017)

Although biventricular heart failure has been successfully managed with dual continuous-flow ventricular assist devices, the long-term use of 2 mechanically dissimilar pumps has traditionally been discouraged. We present the case of a 52-year-old man whose treatment with a HeartMate II left ventricular assist device was complicated by right ventricular failure, necessitating the implantation of a long-term right ventricular assist device. A HeartWare left ventricular assist device was placed along the right ventricular base to avoid interference with the HeartMate II housing. The patient was discharged from the hospital after routine postoperative care and dual-device training. This case shows that, despite logistical complexities, nonidentical continuous-flow device pairings can successfully provide long-term biventricular support.
Studies on membrane topology, N-glycosylation and functionality of SARS-CoV membrane protein (2009)

Abstract The glycosylated membrane protein M of the severe acute respiratory syndrome associated coronavirus (SARS-CoV) is the main structural component of the virion and mediates assembly and budding of viral particles. The membrane topology of SARS-CoV M and the functional significance of its N-glycosylation are not completely understood as is its interaction with the surface glycoprotein S. Using biochemical and immunofluorescence analyses we found that M consists of a short glycosylated N-terminal ectodomain, three transmembrane segments and a long, immunogenic C-terminal endodomain. Although the N-glycosylation site of M seems to be highly conserved between group 1 and 3 coronaviruses, studies using a recombinant SARS-CoV expressing a glycosylation-deficient M revealed that N-glycosylation of M neither influence the shape of the virions nor their infectivity in cell culture. Further functional analysis of truncated M proteins showed that the N-terminal 134 amino acids comprising the three transmembrane domains are sufficient to mediate accumulation of M in the Golgi complex and to enforce recruitment of the viral spike protein S to the sites of virus assembly and budding in the ERGIC.
Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response (2018)

General control nonderepressible 2 (GCN2) plays a major role in the cellular response to amino acid limitation. Although maintenance of amino acid homeostasis is critical for tumor growth, the contribution of GCN2 to cancer cell survival and proliferation is poorly understood. In this study, we generated GCN2 inhibitors and demonstrated that inhibition of GCN2 sensitizes cancer cells with low basal-level expression of asparagine synthetase (ASNS) to the antileukemic agent l-asparaginase (ASNase) in vitro and in vivo. We first tested acute lymphoblastic leukemia (ALL) cells and showed that treatment with GCN2 inhibitors rendered ALL cells sensitive to ASNase by preventing the induction of ASNS, resulting in reduced levels of de novo protein synthesis. Comprehensive gene-expression profiling revealed that combined treatment with ASNase and GCN2 inhibitors induced the stress-activated MAPK pathway, thereby triggering apoptosis. By using cell-panel analyses, we also showed that acute myelogenous leukemia and pancreatic cancer cells were highly sensitive to the combined treatment. Notably, basal ASNS expression at protein levels was significantly correlated with sensitivity to combined treatment. These results provide mechanistic insights into the role of GCN2 in the amino acid response and a rationale for further investigation of GCN2 inhibitors for the treatment of cancer.
Low rank continuous-space graphical models (2012)

Constructing tractable dependent probability distributions over structured continuous random vectors is a central problem in statistics and machine learning. It has proven difficult to find general constructions for models in which efficient exact inference is possible, outside of the classical cases of models with restricted graph structure (chain, tree, etc.) and linear-Gaussian or discrete potentials. In this work we identify a graphical model class in which exact inference can be performed efficiently, owing to a certain “low-rank ” structure in the potentials. While we focus on the case of tree graphical models, the lowrank treatment can also be applied for efficient exact inference in certain sparsely-loopy models. We explore this new class of models by applying the resulting inference methods to neural spike rate estimation and motioncapture joint-angle smoothing tasks. 1
Design of flexural ultrasonic phased array for fluid-coupled applications (2016)

A design of a 4×4 ultrasonic phased array working in flexural mode is presented. The array consists of an elastic metal sheet, a baffle with 16 holes, a back plate and 16 piezoelectric discs. The active area of each flexural array element is defined by the diameter of the holes of the baffle and the back plate provides an additional clamped-edge-like boundary condition through the baffle for each flexural element. A finite element analysis is utilized to investigate the influence of the dimensions and the materials on the performance of the array. Optimal ratios of the radius of piezo disc to the radius of elastic element working at (0, 0) mode and (1, 0) mode are obtained. A direct comparison of the radiation patterns of the flexural transducers working at (0, 0) and (1, 0) modes proves that the (0, 0) mode is preferable as working mode for the array. The dimensions and the materials of the baffle and the back plate are chosen to effectively reduce the mechanical cross talk between the neighboring array elements. A flexural ultrasonic phased array prototype is fabricated and characterized. Experiments indicate that the ultrasonic beam of the array can be continuously steered from 0° to 50°. This proof-of-concept design demonstrates our low-cost flexural ultrasonic phased arrays design to be sufficiently robust for various fluid-coupled applications.
1,2,3-Triazolyl-pyridine derivatives as chelating ligands for blue iridium(iii) complexes. Photophysics and electroluminescent devices (2008)

We report on the study of a new family of neutral heteroleptic Ir(F2ppy)2L (F2ppy = 2-(2,4-difluorophenyl)pyridine) complexes bearing different triazole derivatives (L = 2-(1,2,3-triazol-5-yl)pyridine) as the third ligand. Two of these ligands were used for the first time as ancillary ligands in iridium(III) complexes. A full photophysical and electrochemical study of these complexes is reported here, together with theoretical investigations at the density functional theory (DFT) level. The complexes were also obtained as single crystals and their structures were determined by X-ray crystallography. The newly reported complexes exhibit blue emission with high quantum yields in solution. Photophysical results are also compared to those reported for their 1,2,4-triazole isomer analogues. The emitting state is a mixture between the triplet metal-to-ligand charge transfer (3MLCT) and triplet inter-ligand charge transfer (3ILCT) states, and it is more localized on the F2ppy ligand as supported by DFT calculations. In addition, this paper reports some preliminary tests of polymer light-emitting diodes (PLEDs) doped with these iridium complexes. The results indicate that such molecules are good candidates as blue- and green-emitting dopants in LED devices.
5d Early-Transition-Metal Corroles: a Trioxo-Bridged Binuclear Tungsten(VI) Derivative (2012)

The synthesis and full characterization of the first tungsten corrole reveal that it is a binuclear trioxo-bridged complex of tungsten(VI), a coordination motif without precedence for tungsten chelated by other ligands.