gebhart/patrepeval huggingface dataset:
Deep Learning Applications for Predicting Pharmacological Properties of Drugs and Drug Repurposing Using Transcriptomic Data (2016)

Deep learning is rapidly advancing many areas of science and technology with multiple success stories in image, text, voice and video recognition, robotics, and autonomous driving. In this paper we demonstrate how deep neural networks (DNN) trained on large transcriptional response data sets can classify various drugs to therapeutic categories solely based on their transcriptional profiles. We used the perturbation samples of 678 drugs across A549, MCF-7, and PC-3 cell lines from the LINCS Project and linked those to 12 therapeutic use categories derived from MeSH. To train the DNN, we utilized both gene level transcriptomic data and transcriptomic data processed using a pathway activation scoring algorithm, for a pooled data set of samples perturbed with different concentrations of the drug for 6 and 24 hours. In both pathway and gene level classification, DNN achieved high classification accuracy and convincingly outperformed the support vector machine (SVM) model on every multiclass classification problem, however, models based on pathway level data performed significantly better. For the first time we demonstrate a deep learning neural net trained on transcriptomic data to recognize pharmacological properties of multiple drugs across different biological systems and conditions. We also propose using deep neural net confusion matrices for drug repositioning. This work is a proof of principle for applying deep learning to drug discovery and development.
Design and Modeling of the Structural Integrity of a Universal Toolbar for a Two Wheeled Power Tiller (2009)

This project is concerned with the design and analysis of a universal toolbar for a two wheeled tractor. In order to estimate the forces that the toolbar may encounter, tractive force is predicted. Analysis of key components of the toolbar is then carried out using the Finite Element Method. It is found that the current design of the toolbar has significant strength reserve. Areas of high stress are identified. Modifications to the current design are also suggested.
Pembrolizumab in cervical cancer: latest evidence and clinical usefulness (2017)

Cervical cancer is the fourth most common cause of cancer-related deaths in women worldwide. With the development of detection of precancerous lesions and preventive human papillomavirus (HPV) vaccination program, a survival improvement has been observed in these patients in developed countries, although disparities in accessibility to treatments exist across countries. While early-stage cervical cancer can be curable with surgery, prognosis of patients who recur remains poor, with limited treatment options. In this latter setting, recently, bevacizumab, an antiangiogenic monoclonal antibody targeting vascular endothelial growth factor (VEGF), has been shown to improve overall survival in combination with chemotherapy as compared with chemotherapy alone. No standard treatments exist beyond this treatment regimen. New effective treatments are therefore much needed in this setting. Immunotherapy has represented a breakthrough in recent years in oncology, with antitumor activity reported with immune-checkpoint inhibitors in a variety of tumor types. We discuss here the latest evidence and clinical usefulness of pembrolizumab, anti-PD-1 checkpoint inhibitor, in the treatment of advanced cervical cancer.
Double indexing overcomes inaccuracies in multiplex sequencing on the Illumina platform (2011)

Due to the increasing throughput of current DNA sequencing instruments, sample multiplexing is necessary for making economical use of available sequencing capacities. A widely used multiplexing strategy for the Illumina Genome Analyzer utilizes sample-specific indexes, which are embedded in one of the library adapters. However, this and similar multiplex approaches come with a risk of sample misidentification. By introducing indexes into both library adapters (double indexing), we have developed a method that reveals the rate of sample misidentification within current multiplex sequencing experiments. With ~0.3% these rates are orders of magnitude higher than expected and may severely confound applications in cancer genomics and other fields requiring accurate detection of rare variants. We identified the occurrence of mixed clusters on the flow as the predominant source of error. The accuracy of sample identification is further impaired if indexed oligonucleotides are cross-contaminated or if indexed libraries are amplified in bulk. Double-indexing eliminates these problems and increases both the scope and accuracy of multiplex sequencing on the Illumina platform.
Invited Review: Cell localization, physiology, and nongenomic actions of estrogen receptors (2001)

The existence of binding proteins for the female sex steroid, 17β-estradiol, has been known for almost 50 years. Presently, two estrogen receptors (ERs), ER-α and ER-β, have been cloned in mammals, and they are expressed in many cell types of metazoans. ERs act primarily as nuclear transcription factors, and this effect is enhanced by ligand binding. Emerging data have identified a separate pool of receptors for this steroid in the plasma membrane, but the mechanisms of action and cellular functions of these proteins are just beginning to be defined. In this review, the known details of the nuclear and plasma membrane ER functions will be discussed. A particular focus will be to define the signaling pathways from the membrane that lead to important cell physiology effects of estrogen. The potential interactions of membrane ER with other local proteins will also be discussed, and the unique but often complementary roles of the receptor pools will be highlighted. These details may be of additional relevance to other steroid receptors, since there is evidence of their existence in the cell membrane.
Transplantation of cultured small bowel enterocytes. (1993)

Development of successful primary culture techniques for mammalian cells, have permitted the study of basic molecular mechanisms governing physiological and patho-
An interactive numerical model of diode-pumped, Q-switched/cavity-dumped lasers (1995)

We have developed an interactive numerical model, which describes the operational characteristics of multiple diode-pumped laser systems that are Q-switched or Q-switched/cavity-dumped. These are the first computer-generated results obtained using rate equations that incorporate the 'inversion reduction parameter' gamma . The quantity gamma can partially take into account effects of relaxation and thermally driven transfer, which occurs between laser level multiplets. A value of gamma near unity is found for the Nd:YAG lasers, implying considerable thermal relaxation of the lower lasing level, and it may also imply some thermal refreshing of the upper lasing level. A value of gamma =2 is found to fit the Ti:sapphire results, indicating that the lower lasing level is not relaxed during laser pulse development. The interactive nature of the model allows for variation of all the significant parameters required to generate a Q-switched or cavity-dumped pulse. Input information is expressed in terms of standard variables such as stored energy, optical and dissipative losses and stimulated emission and pump absorption cross sections. The effects of additional parameters, including the Gaussian beam profile of the cavity, the induced losses associated with the rise and fall times of the Q-switch and cavity-dump Pockels cell, and the induced thermal lensing effects produced by the pump rate in the gain medium are taken into account. The width and energy of the cavity-dumped laser pulse can also be studied in the model by varying the cavity-dump voltage switch transition time.
GATA-1 and NF-Y cooperate to mediate erythroid-specific transcription of Gfi-1B gene (2004)

Expression of Gfi (growth factor-independence)-1B, a Gfi-1-related transcriptional repressor, is restricted to erythroid lineage cells and is essential for erythropoiesis. We have determined the transcription start site of the human Gfi-1B gene and located its first non-coding exon approximately 7.82 kb upstream of the first coding exon. The genomic sequence preceding this first non-coding exon has been identified to be its erythroid-specific promoter region in K562 cells. Using gel-shift and chromatin immunoprecipitation (ChIP) assays, we have demonstrated that NF-Y and GATA-1 directly participate in transcriptional activation of the Gfi-1B gene in K562 cells. Ectopic expression of GATA-1 markedly stimulates the activity of the Gfi-1B promoter in a non-erythroid cell line U937. Interestingly, our results have indicated that this GATA-1-mediated trans-activation is dependent on NF-Y binding to the CCAAT site. Here we conclude that functional cooperation between GATA-1 and NF-Y contributes to erythroid-specific transcriptional activation of Gfi-1B promoter.
Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency (2018)

In patients with aromatic l-amino acid decarboxylase (AADC) deficiency, a decrease in catecholamines and serotonin levels in the brain leads to developmental delay and movement disorders. The beneficial effects of gene therapy in patients from 1 to 8 years of age with homogeneous severity of disease have been reported from Taiwan. We conducted an open-label phase 1/2 study of population including adolescent patients with different degrees of severity. Six patients were enrolled: four males (ages 4, 10, 15 and 19 years) and one female (age 12 years) with a severe phenotype who were not capable of voluntary movement or speech, and one female (age 5 years) with a moderate phenotype who could walk with support. The patients received a total of 2 × 1011 vector genomes of adeno-associated virus vector harbouring DDC via bilateral intraputaminal infusions. At up to 2 years after gene therapy, the motor function was remarkably improved in all patients. Three patients with the severe phenotype were able to stand with support, and one patient could walk with a walker, while the patient with the moderate phenotype could run and ride a bicycle. This moderate-phenotype patient also showed improvement in her mental function, being able to converse fluently and perform simple arithmetic. Dystonia disappeared and oculogyric crisis was markedly decreased in all patients. The patients exhibited transient choreic dyskinesia for a couple of months, but no adverse events caused by vector were observed. PET with 6-[18F]fluoro-l-m-tyrosine, a specific tracer for AADC, showed a persistently increased uptake in the broad areas of the putamen. In our study, older patients (>8 years of age) also showed improvement, although treatment was more effective in younger patients. The genetic background of our patients was heterogeneous, and some patients suspected of having remnant enzyme activity showed better improvement than the Taiwanese patients. In addition to the alleviation of motor symptoms, the cognitive and verbal functions were improved in a patient with the moderate phenotype. The restoration of dopamine synthesis in the putamen via gene transfer provides transformative medical benefit across all patient ages, genotypes, and disease severities included in this study, with the most pronounced improvements noted in moderate patients.10.1093/brain/awy331_video1awy331media15991361892001.
Monodispersed InP Quantum Dots Prepared by Colloidal Chemistry in a Noncoordinating Solvent (2005)

III−V semiconductor quantum dots are of considerable interest as their applications cover a broad spectrum, from optoelectronic to biomedical technology. For them to be of practical value, there is a need for a method that provides rapid and scalable production of highly monodispersed nanoparticles. This paper reports an efficient and rapid method of producing highly monodispersed InP quantum dots using a novel precursor-based colloidal synthesis in a noncoordinating solvent. The method also allows judicious control over the size of the quantum dots and can also be extended to produce other III−V quantum dots. In this paper, the synthesis and characterization of highly monodispersed InP quantum dots from newly prepared indium(III) carboxylate complexes in octadecene are detailed. When using indium(III) carboxylate as the indium precursor, no surfactant or coordinating solvents are required to prepare high-quality InP quantum dots in octadecene. The in situ formation of a surfactant upon injection of the phosphine precursor [P(SiMe3)3] helps control the growth of the resulting quantum dots. Structural and optical studies (continuous wave and time-resolved) have been performed on the as-prepared InP quantum dots. In addition, time-resolved photoluminescence has been conducted on etched InP quantum dots. The effects of the carboxylate chain length in indium(III) carboxylate and injection temperature on the growth and properties of quantum dots have been studied.
Series connected soft switched IGBTs for high power, high voltage drives applications: experimental results (2002)

An inverter phase made of two series connected IGBTs has been operated in a quasi resonant zero voltage switching mode. Commutation losses, achievable switching frequencies, output voltage gradient and performances both in normal and fault condition are discussed and compared to hard switching equivalent topology.
Concerted Evolution in an Egg Receptor for a Rapidly Evolving Abalone Sperm Protein (1998)

Gamete interactions during fertilization exhibit species specificity. In abalone, the sperm protein lysin species-specifically creates a hole in the egg envelope. Lysin evolves rapidly by positive Darwinian selection. Evolution of the egg receptor for lysin provides the selective pressure for lysin's divergence. The egg receptor for lysin is a tandemly repeated sequence that evolves by concerted evolution. Concerted evolution in the egg receptor could explain the rapid, adaptive evolution in sperm lysin and may provide an underlying molecular mechanism that gives rise to species-specific fertilization.
Depolymerization of β-1,6-N-Acetyl-d-Glucosamine Disrupts the Integrity of Diverse Bacterial Biofilms (2004)

Polymeric beta-1,6-N-acetyl-D-glucosamine (poly-beta-1,6-GlcNAc) has been implicated as an Escherichia coli and Staphylococcus epidermidis biofilm adhesin, the formation of which requires the pgaABCD and icaABCD loci, respectively. Enzymatic hydrolysis of poly-beta-1,6-GlcNAc, demonstrated for the first time by chromatography and mass spectrometry, disrupts biofilm formation by these species and by Yersinia pestis and Pseudomonas fluorescens, which possess pgaABCD homologues.
Thrombopoietin primes human platelet aggregation induced by shear stress and by multiple agonists (1996)

Recombinant thrombopoietin has been reported to stimulate megakaryocytopoiesis and thrombopoiesis and it may be quite useful to treat patients with low platelet counts after chemotherapy. As little is known regarding the possible activation of platelets by thrombopoietin, we examined the effects of thrombopoietin on platelet aggregation induced by shear stress and various agonists in native plasma. Using hirudin as an anticoagulant, thrombopoietin (1 to 100 ng/mL) enhanced platelet aggregation induced by 2 micromol/L adenosine-diphosphate (ADP) in a dose dependent fashion. The enhancement was not affected by treatment of platelets with 1 mmol/L aspirin plus SQ-29548 (a thromboxane antagonist, 1 micromol/L) but was inhibited by a soluble form of the thrombopoietin receptor, suggesting that the enhancement was mediated by the specific receptors and does not require thromboxane production. Epinephrine (1 micromol/L), which does not induce platelet aggregation in hirudin platelet rich plasma (PRP), did so in the presence of thrombopoietin (10 ng/mL). Thrombopoietin (10 ng/mL) also enhanced or primed platelet aggregation induced by collagen (0.5 micron.mL),. thrombin, serotonin, and vasopressin. Thrombopoietin does not induce any rise in cytosolic ionized calcium concentration nor activation of protein kinase C, as estimated by phosphorylation of preckstrin, indicating that the priming effects of thrombopoietin does not require those processes. The ADP- or thrombin-induced rise in cytosolic ionized calcium concentration was not enhanced by thrombopoietin (100 ng/mL). Further, shear (ca. 90 dyn/cm2)-induced platelet aggregation was also potentiated by thrombopoietin. The priming effect on epinephrine-induced platelet aggregation in hirudin PRP was unique to thrombopoietin, with no effects seen using interleukin-6 (IL-6), IL-11, IL-3, erythropoietin, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, or c-kit ligand. These data indicate that monitoring of platelet functions may be necessary in the clinical trials of thrombopoietin.
Hierarchical or Not? Effect of the Length Scale and Hierarchy of the Surface Roughness on Omniphobicity of Lubricant-Infused Substrates (2013)

Lubricant-infused textured solid substrates are gaining remarkable interest as a new class of omni-repellent nonfouling materials and surface coatings. We investigated the effect of the length scale and hierarchy of the surface topography of the underlying substrates on their ability to retain the lubricant under high shear conditions, which is important for maintaining nonwetting properties under application-relevant conditions. By comparing the lubricant loss, contact angle hysteresis, and sliding angles for water and ethanol droplets on flat, microscale, nanoscale, and hierarchically textured surfaces subjected to various spinning rates (from 100 to 10,000 rpm), we show that lubricant-infused textured surfaces with uniform nanofeatures provide the most shear-tolerant liquid-repellent behavior, unlike lotus leaf-inspired superhydrophobic surfaces, which generally favor hierarchical structures for improved pressure stability and low contact angle hysteresis. On the basis of these findings, we present generalized, low-cost, and scalable methods to manufacture uniform or regionally patterned nanotextured coatings on arbitrary materials and complex shapes. After functionalization and lubrication, these coatings show robust, shear-tolerant omniphobic behavior, transparency, and nonfouling properties against highly contaminating media.
Sensitivity of the Eye to Spectral Radiation at Scotopic and Mesopic Intensity Levels (1955)

Spectral sensitivity curves were established for three intensity levels above scotopic threshold with a two-degree field placed ten degrees from fixation against a dark surround. These curves were compared with the minimum scotopic luminosity curve determined for the same retinal position for each observer. The results showed that (1) there is a range of intensities over which relative spectral sensitivity does not change appreciably from the scotopic luminosity function, (2) there are irregularities in these mesopic curves which may be attributed to cone activity, and (3) the first change in spectral sensitivity with increased intensity is found in the long-wavelength half of the spectrum.
PyNN: a common interface for neuronal network simulators (2008)

Computational neuroscience has produced a diversity of software for simulations of networks of spiking neurons, with both negative and positive consequences. On the one hand, each simulator uses its own programming or configuration language, leading to considerable difficulty in porting models from one simulator to another. This impedes communication between investigators and makes it harder to reproduce and build on the work of others. On the other hand, simulation results can be cross-checked between different simulators, giving greater confidence in their correctness, and each simulator has different optimizations, so the most appropriate simulator can be chosen for a given modelling task. A common programming interface to multiple simulators would reduce or eliminate the problems of simulator diversity while retaining the benefits. PyNN is such an interface, making it possible to write a simulation script once, using the Python programming language, and run it without modification on any supported simulator (currently NEURON, NEST, PCSIM, Brian and the Heidelberg VLSI neuromorphic hardware). PyNN increases the productivity of neuronal network modelling by providing high-level abstraction, by promoting code sharing and reuse, and by providing a foundation for simulator-agnostic analysis, visualization and data-management tools. PyNN increases the reliability of modelling studies by making it much easier to check results on multiple simulators. PyNN is open-source software and is available from http://neuralensemble.org/PyNN.
Molecular analysis of the A322D mutation in the GABAA receptor α1‐subunit causing juvenile myoclonic epilepsy (2005)

Juvenile myoclonic epilepsy (JME) belongs to the most common forms of hereditary epilepsy, the idiopathic generalized epilepsies. Although the mode of inheritance is usually complex, mutations in single genes have been shown to cause the disease in some families with autosomal dominant inheritance. The first mutation in a multigeneration JME family has been recently found in the alpha1-subunit of the GABAA receptor (GABRA1), predicting the single amino acid substitution A322D. We further characterized the functional consequences of this mutation by coexpressing alpha1-, beta2- and gamma2-subunits in human embryonic kidney (HEK293) cells. By using an ultrafast application system, mutant receptors have shown reduced macroscopic current amplitudes at saturating GABA concentrations and a highly reduced affinity to GABA compared to the wild-type (WT). Dose-response curves for current amplitudes, activation kinetics, and GABA-dependent desensitization parameters showed a parallel shift towards 30- to 40-fold higher GABA concentrations. Both deactivation and resensitization kinetics were considerably accelerated in mutant channels. In addition, mutant receptors labelled with enhanced green fluorescent protein (EGFP) were not integrated in the cell membrane, in contrast to WT receptors. Therefore, the A322D mutation leads to a severe loss-of-function of the human GABAA receptor by several mechanisms, including reduced surface expression, reduced GABA-sensitivity, and accelerated deactivation. These molecular defects could decrease and shorten the resulting inhibitory postsynaptic currents (IPSCs) in vivo, which can induce a hyperexcitability of the postsynaptic membrane and explain the occurrence of epileptic seizures.
Light and electron microscopy studies on homograft and heterograft heart valves (1975)

Light and electron microscopical changes were studied in 23 valvular homografts and six pig aortic heterografts, which had been inserted into patients for lengths of time varying from three days to 54 months. Prior to insertion, eleven of the homografts had been sterilised by beta-propriolactone and freeze-dried, the other twelve had been sterilised by gamma-radiation. The morphological changes in the freeze-dried group were characterised by moderate to severe structural changes including gross vacuolation, fibrinoid degeneration and calcification in the absence of any significant cellular events. It is concluded that the structural changes were due to physico-chemical degradation of the collagen due to improper preservation of the graft, prior to insertion. The morphological changes in the homografts treated with gamma-radiation were fewer and less severe in that there was less vacuolation of the matrix, less fibrinoid degeneration and no examples of calcification. Clear-cut examples of graft regeneration were never observed in either group, but the significance of minor cellular infiltrates in two of the gamma-irradiated grafts is discussed in terms of abortive regeneration. The heterografts showed moderate to intense cellularity, predominantly of macrophages. It is postulated that graft rejection phenomena are responsible for the graft failure in this group.