gebhart/patrepeval huggingface dataset:
A generalizable pre-clinical research approach for orphan disease therapy (2012)

With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease.
Tumor necrosis factor α induces early morphologic and metabolic alterations in friend leukemia cell tumors and fibrosarcomas in mice (1988)

Morphologic and metabolic studies have been carried out on Friend leukemia cell (FLC) tumors (grown in DBA/2 mice) or fibrosarcomas (grown in C3H/HeN or C3H/HeJ mice) shortly after peritumoral injection of recombinant mouse tumor necrosis factor (TNF) alpha. Marked vascular congestion and focal extravasation of erythrocytes were observed as soon as 1 hr after injection of either FLC tumors or fibrosarcomas with TNF. Focal areas of disaggregation of tumor cells were observed 1 hr after injection of TNF. Intraluminal thrombi (composed of degranulated platelets and fibrin) were detected 3 and 6 hr after TNF treatment, and were associated with areas of depletion of endothelial cell cytoplasm. To correlate these morphologic changes in the tumor with alterations in tumor metabolism, NMR spectroscopy and biochemical studies were undertaken on freshly dissected FLC tumors and fibrosarcomas shortly after injection of TNF. The earliest metabolic alterations observed after 1 hr in TNF-treated FLC tumors of fibrosarcomas were: (i) increase in the average intratumoral pH; (ii) decrease in the levels of ATP. These phenomena were not associated with a reduced glycolytic capacity of TNF-treated tumors as, at these early times after injection, the levels of lactic acid were virtually the same for TNF-treated or control treated tumors. Alterations in the levels of some products of phospholipid degradation (GroPCho, GroPEtn, GroP and Cho) also occurred in these tumors as early as 3 hr after TNF treatment. These metabolic changes were not observed in ascitic FLC tumors after TNF treatment. We suggest that TNF induces alterations in tumor blood vessels which subsequently lead to changes in tumor metabolism and tumor degeneration.
Evaluation of voltages and currents in an IPT system through Kalman Filter (2016)

In this paper, an algorithm for the estimation of the output voltage and current of an Inductive Power Transfer is presented. The algorithm is based on the use of a Kalman filter and only the measurement of the primary and secondary current is necessary to estimate the conditions at the secondary side of the system. The proposed algorithm can be utilized in a fault tolerant control for the recharge of electric vehicles. In order to demonstrate the validity of the proposed algorithm, different numerical simulation are carried out.
Covalently Anchored Polymer Immobilized Co(II) Phthalocyanine as Efficient Catalyst for Oxidation of Mercaptans using Molecular Oxygen as Oxidant (2010)

The present paper describes the covalent immobilization of cobalt phthalocyanine “MEROX catalyst” to polystyrene resin via sulfonamide linkage and its catalytic activity for the oxidation of mercaptans to disulfides using molecular oxygen as an oxidant under alkaline conditions. Polymer-supported cobalt phthalocyanine, wherein the catalyst is chemically bounded to the support which prevents the leaching of the catalyst/ligand, can readily be recovered from the reaction mixture and reused for several runs without significant decrease in catalytic activity.
Age-related changes in cell surface antigens of preleukemic AKR thymocytes. (1976)

Thymocytes from preleukemic AKR mice aged 5-6 mo have an altered pattern of cell surface antigens. The expression of four MuLV-related antigens on the cell surface (GIX, GCSA, gp70, p30) is markedly increased in comparison to 2-mo-old AKR mice and approximates the heightened levels of these antigens found on thymic leukemia cells. H-2 and Thy-1 alloantigens also show characteristic modifications in relation to age and leukemia development. In contrast to the high Thy-1/low H-2 levels on 2-mo-old AKR thymocytes, thymocytes from 6-mo-old mice and thymic leukemia cells frequently show a low Thy-1/high H-2 surface phenotype. As thymocytes from mouse strains with a low incidence of leukemia do not show these changes, they appear to represent a stage in the conversion of normal cells to leukemia cells.
Investigating the Use of Linear Programming and Evolutionary Algorithms for Multi-Objective Electric Vehicle Charging Problem (2022)

With the increasing uptake of electric vehicles (EVs), the need for efficient scheduling of EV charging is increasingly becoming important. A charging station operator needs to identify charging/discharging power of the client EVs over a time horizon while considering multiple objectives, such as operating costs and the peak power drawn from the grid. Evolutionary algorithms (EAs) are a popular choice when faced with problems involving multiple objectives. However, since the objectives and constraints of this problem can be expressed using linear functions, it is also possible to come up with improvised multi-objective formulations which can be solved with exact techniques such as mixed-integer linear programming (MILP). With both approaches having their potential strengths and pitfalls, it is worth investigating their use to inform the algorithmic choices, which the current study aims to address. In doing so, it makes a number of contributions to the topic, including extension of an existing EV charging problem to a multi-objective form; observing some interesting properties of the problem to improve both the MILP and EA solution approaches; and comparing the performance of MILP and EA. The study provides some useful insights into the problem, initial results and quantitative basis for selecting solution approaches, and highlights some areas of further development.
&#x201C;Living and mobility&#x201D;- a novel multipurpose in-house grid interface with plug in hybrid BlueAngle (2008)

The alarming rate at which global energy reserves are depleting, is a major worldwide concern at economic, environmental, industrial and community levels. A partial solution to this crisis is the use of decentralized generations and vehicle-to-grid (or V2G) plug-in electric vehicles. This paper presents a novel dasialiving and mobilitypsila concept, through which plug-in-vehicles can be utilized for harnessing renewable energy, storage, transportation, and providing power for both residential and commercial customers. The proposed concept uses an efficient energy management unit (EEMU), a bidirectional power module with a grid-interface, a Web and wireless communication interface and a hybrid plug-in vehicle, called dasiaBlueAnglepsila. The EEMU overseas the operation of the overall system with real time monitoring of system variables. The power module of the proposed system uses a common DC link for power exchange. The amount and the direction of power flow amongst the sub-systems, which include the grid, renewable energy sources, household load and BlueAngle, is controlled by the EEMU in accordance with the systems variables. The proposed system is versatile, and expected to gain popularity amongst both commercial and residential users interested in resolving the global energy crisis.
Niraparib in Patients With Newly Diagnosed Advanced Ovarian Cancer (2020)

(Abstracted from N Engl J Med 2019;381:2391–2402) The standard treatment for newly diagnosed advanced epithelial ovarian cancer involves cytoreductive surgery and platinum-taxane combination chemotherapy. Unfortunately, recurrence occurs in up to 85% of patients after completing this chemotherapy regimen.
Evolution of activation patterns during long-duration ventricular fibrillation in pigs (2011)

Quantitative analysis has demonstrated five temporal stages of activation during the first 10 min of ventricular fibrillation (VF) in dogs. To determine whether these stages exist in another species, we applied the same analysis to the first 10 min of VF recorded in vivo from two 504-electrode arrays, one each on left anterior and posterior ventricular epicardium in six anesthetized pigs. The following descriptors were continuously quantified: 1) number of wavefronts, 2) wavefront fractionations, 3) wavefront collisions, 4) repeatability, 5) multiplicity index, 6) wavefront conduction velocity, 7) activation rate, 8) mean area activated by the wavefronts, 9) negative peak rate of voltage change, 10) incidence of breakthrough/foci, 11) incidence of block, and 12) incidence of reentry. Cluster analysis of these descriptors divided VF into four stages (stages i-iv). The values of most descriptors increased during stage i (1-22 s after VF induction), changed quickly to values indicating greater organization during stage ii (23-39 s), decreased steadily during stage iii (40-187 s), and remained relatively unchanged during stage iv (188-600 s). The epicardium still activated during stage iv instead of becoming silent as in dogs. In conclusion, during the first 10 min, VF activation can be divided into four stages in pigs instead of five stages as in dogs. Following a 16-s period during the first minute of VF when activation became more organized, all parameters exhibited progressive decreased organization. Further studies are warranted to determine whether these changes, particularly the increased organization of stage ii, have clinical consequences, such as alteration in defibrillation efficacy.
Retinal Microvascular Signs Are Associated with Chronic Kidney Disease in Persons with and without Diabetes (2012)

Retinal microvascular signs, namely retinopathy lesions and venular dilation, are associated with CKD both in persons with, and without diabetes. This supports the concept that retinal microvascular signs are indicators of generalized microvascular disease even in the absence of diabetes, and reinforces the link between retinal and renal microcirculations.
Evaluation of the thermal phonon emission in dynamic fracture of brittle crystals (2011)

We describe in detail how to quantify, computationally, the contribution of the anisotropic and velocity-dependent thermal phonon emission energy release rate during dynamic crack propagation in brittle crystals. The calculations were performed using a procedure based on combined continuum elastodynamics Freund equation of motion and molecular dynamics computer calculations. We used a precracked strip-like specimen subjected to prescribed displacement on the boundaries, commonly used in atomistic calculations of crack dynamics. Various cleavage planes and directions of silicon-like crystal for a wide range of crack speeds were investigated. It is shown that in addition to being strongly dependant on crack speed and atomistic arrangement, the relative phonon emission energy release rate is size dependent, hence governing the size-dependent terminal crack speed. This speed, however, is not influenced by the specimen's initial temperature, ranging between 10K and 300K.
Design of Interconnection Networks (2007)

Digital systems of all types are rapidly becoming communication limited. Movement of data, not arithmetic or control logic, is the factor limiting cost, performance, size, and power in these systems. Historically used only in high-end supercomputers and telecom switches, interconnection networks are now found in systems of all sizes and all types - from large supercomputers to small embedded systems-on-a-chip (SoC) and from inter-processor networks to router fabrics. Indeed, as system complexity and integration continues to increase, many designers are finding it more efficient to route packets, not wires.
From Multiwave Imaging to Elasticity Imaging (2013)

This chapter focuses mainly on the third approach (multiwave approach), which allows mapping tissue elasticity and viscosity with high precision. All techniques based on wave/wave generation are related to some dissipative processes that transform one part of a pulsed electromagnetic energy in some transient tissue motion that radiates coherent ultrasonic waves. The chapter discusses the concept of wave to wave tagging using two kinds of totally different waves. However, although it is not a multiwave technique, MR imaging can also be interpreted as a tagging technique. A major advantage of this imaging technique, called “supersonic shear imaging” (SSI) or also “shear wave imaging” is that it can be performed using conventional ultrasonic probes and provides an additional imaging modality on a new generation of ultrasound scanners. Shear wave imaging is currently under investigation for many other clinical applications. Controlled Vocabulary Terms elasticity; electromagnetic waves; viscosity
A critical link between Lyn-mediated suppression of the TLR-MyD88-IRF5 pathway and the development of SLE-like disease (2016)

Abstract The transcription factor interferon regulatory factor 5 (IRF5) is critical for innate immune responses downstream of Toll-like receptors (TLRs). IRF5 is also linked to the pathogenesis of systemic lupus erythematosus (SLE) in humans and mice. However, it remains elusive whether and how IRF5 activity can be negatively regulated. The Src family kinase Lyn is also implicated in human SLE, and Lyn −/− mice develop an SLE-like disease. Here we show that Lyn selectively inhibits IRF5 activity, while it does not affect the NF-κB pathway. Lyn physically interacted with IRF5, thereby suppressing the phosphorylation and ubiquitination of IRF5, post-translational modifications important for IRF5 activation. Interestingly, the kinase activity of Lyn was dispensable for the suppression of IRF5 activity. IRF5 was hyper-activated in TLR7/9-stimulated Lyn −/− bone marrow-derived dendritic cells (BMDCs), and these cells hyper-produced IRF5-dependent cytokines especially type-I interferons (IFNs). IRF5 was constitutively activated (phosphorylated and translocated into the nucleus) in splenic DCs isolated from Lyn −/− mice. Importantly, even monoallelic ablation of the Irf5 gene was sufficient to alleviate the hyper-production of type-I IFNs in TLR7/9-stimulated Lyn −/− BMDCs, and to ameliorate the development of SLE-like symptoms, such as autoantibody production and autoimmune glomerulonephritis, in Lyn −/− mice. Our results identify Lyn as a critical suppressor of the TLR-MyD88-IRF5 pathway, and implicate that the selective control of IRF5 activity may contribute to better therapeutics for SLE.
Efficacy of anticoagulants and platelet inhibitors in cancer-induced thrombosis (2007)

The efficacy of anticoagulants, low-molecular-weight heparins (LMWHs), the antiplatelet glycoprotein IIb/IIIa antagonist, or combinations on cancer-activated thrombosis was determined using thromboelastography. The LMWHs tinzaparin and enoxaparin (0.179, 1.79, 17.9 microg) were incubated in human citrated whole blood (n = 4) and then activated by calcium chloride (11 mmol/l) or Colo205 (cell count 10). Concentrations of 9.9, 17.9 and 179 microg glycoprotein IIb/IIIa antagonist, XV454, and combinations with each LMWH were carried out and activated under the same conditions. The experiment was repeated with tissue factor substituting for the Colo205 to induce platelet/fibrin clot formation. Parameters tested in the thrombelastography analysis included clotting time, rate of clot formation due to fibrin formation, clot kinetics, and clot strength related to platelet count (maximum amplitude). Tinzaparin (1.79 microg), enoxaparin (1.79 microg), and XV454 (17.9 microg) significantly reduced the angle by 64, 26 and 27%, respectively, in cancer-induced clotting. Significant reductions in the maximum amplitude occurred in tinzaparin 1.79 microg (31%), enoxaparin 1.79 microg (11%), and XV454 17.9 microg (59%). An overall antithrombotic additive effect occurred when each LMWH (1.79 microg) was combined with XV454 (17.9 microg). The results between cancer-activated and tissue factor-activated blood were similar. The study concludes that an additive effect is present between LMWHs and a glycoprotein IIb/IIIa antagonist in reducing cancer-mediated thrombosis.
Evaluation of CO2-EOR and Storage Potential in Mature Oil Reservoirs (2014)

Abstract The selection of candidate reservoirs for future CO2 enhanced oil recovery (EOR) and storage projects greatly relies on methodical screening and detailed site specific evaluations. Once suitable reservoirs are identified in an initial screening for further evaluation, CO2-Prophet screening model could be used for a better understanding of proposed EOR project performance and site specific incidental CO2 storage prior to launching detailed and time consuming reservoir simulation studies. This paper reports on the use of publicly available geological and reservoir data and CO2-Prophet model for performing such analysis for two deep mature light oil reservoirs situated in the Kern County, California. In initial screening, these reservoirs have already been found amenable for CO2-EOR and storage. Often, calibration of CO2-prophet model is either overlooked or just performed for achieving a material balance for oil and water phases. In addition to commonly used calibration step that involves a match for field water cut versus cumulative oil recovery history since waterflooding to achieve material balance for oil and water phases, we propose the use of an average gas-oil ratio match plot for obtaining a reasonable material balance for produced gas phase. A reservoir specific calibration of CO2-Prophet model for obtaining material balance for all three phases is aimed to increase confidence in future performance prediction results. We describe calibration procedure of the CO2-Prophet model in detail and use appropriately calibrated models for predicting CO2-EOR performance and incidental CO2 storage potentials in the reservoirs which have been already found ameable for CO2-EOR and storage in initial screening. Beyond EOR based volumetric predications or other simple estimations made in initial screening of candidate reservoirs, appropriately calibrated CO2-Prophet model can provide more robust and reservoir specific estimates of CO2-EOR and incidental CO2 storage potential for a candidate reservoir. Such approach can be used for making initial business decisions such as selection of propective pilot sites or field acquisition while avoiding the need of detailed reservoir simulation studies. The results presented in the study clearly demonstrate that deep and mature light oil reservoirs of Kern County, California have potential for large scale (injection of more than 1 million metric tons of CO2 per year) CO2-EOR and storage projects.
Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for prostate cancer (2012)

The objective of these studies was to examine the murine pharmacokinetics, pharmacodynamics and metabolism of (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone (Indole 15), a novel tubulin inhibitor for the treatment of cancer. We developed HPLC and LC/MS/MS assays to quantitate Indole 15 and characterize its metabolites in vivo. Pharmacokinetic studies were performed after intravenous (IV), oral (PO) and subcutaneous (SC) administration of 10 mg/kg doses to male ICR mice. Urine and fecal samples were also collected over a 72-h period to identify metabolites. Pharmacodynamic studies were conducted by monitoring the tumor size change during a period of two weeks in PC-3 tumor bearing mice after daily IV administration of Indole 15 at doses of 0, 10, 50, 100 and 150 mg/kg. The pooled plasma concentration data after administration via different dose routes was simultaneously fitted by a two-compartmental model. Indole 15 was moderately well absorbed after PO and SC administration, with a bioavailable fraction of 0.27 and 0.72, respectively. The steady state volume distribution (Vss) and clearance (CL) were estimated to be 7.0 l/kg and 4.36 l/h/kg, respectively. The mean data of PC-3 tumor growth in mice was fitted well by a transduction model using fixed plasma pharmacokinetics as a driving function. Analysis of the metabolites in mice indicated that the compound undergoes extensive oxidative metabolism with subsequent sulfation. These studies demonstrate that favorable pharmacokinetic and pharmacodynamic properties of Indole 15 offer hope for achieving pharmacological activity in early clinical trials.
MicroRNA profiling for the identification of cancers with unknown primary tissue‐of‐origin (2011)

Cancer of unknown primary (CUP) represents a common and important clinical problem. There is evidence that most CUPs are metastases of carcinomas whose primary site cannot be recognized. Driven by the hypothesis that the knowledge of primary cancer could improve patient's prognosis, we investigated microRNA expression profiling as a tool for identifying the tissue of origin of metastases. We assessed microRNA expression from 101 formalin-fixed, paraffin-embedded (FFPE) samples from primary cancers and metastasis samples by using a microarray platform. Forty samples representing ten different cancer types were used for defining a cancer-type-specific microRNA signature, which was used for predicting primary sites of metastatic cancers. A 47-miRNA signature was identified and used to estimate tissue-of-origin probabilities for each sample. Overall, accuracy reached 100% for primary cancers and 78% for metastases in our cohort of samples. When the signature was applied to an independent published dataset of 170 samples, accuracy remained high: correct prediction was found within the first two options in 86% of the metastasis cases (first prediction was correct in 68% of cases). This signature was also applied to predict 16 CUPs. In this group, first predictions exhibited probabilities higher than 90% in most of the cases. These results establish that FFPE samples can be used to reveal the tissue of origin of metastatic cancers by using microRNA expression profiling and suggest that the approach, if applied, could provide strong indications for CUPs, whose correct diagnosis is presently undefined.
Quantum Computing and the Design of the Ultimate Accelerator (2021)

Quantum computers are domain-specific accelerators that can solve commercially important problems that are beyond the capability of conventional computers. Quantum computing is at an inflection point where small systems with a few dozen qubits have been demonstrated and the number of qubits is expected to increase to several hundred over the coming years. However, the qubit quality is likely to remain quite low making it difficult to execute programs reliably. Furthermore, scaling the designs to a large number of qubits would require specialized hardware that operates at cryogenic conditions. This article describes the compiler and hardware support for enabling reliable and scalable quantum computers.