gebhart/patrepeval huggingface dataset:
Best Practices of Computer-Aided Drug Discovery: Lessons Learned from the Development of a Preclinical Candidate for Prostate Cancer with a New Mechanism of Action (2017)

Small-molecule drug design is a complex and iterative decision-making process relying on pre-existing knowledge and driven by experimental data. Low-molecular-weight chemicals represent an attractive therapeutic option, as they are readily accessible to organic synthesis and can easily be characterized.1 Their potency as well as pharmacokinetic and pharmacodynamic properties can be systematically and rationally investigated and ultimately optimized via expert science behind medicinal chemistry and methods of computer-aided drug design (CADD). In recent years, significant advances in molecular modeling techniques have afforded a variety of tools to effectively identify potential binding pockets on prospective targets, to map key interactions between ligands and their binding sites, to construct and assess energetics of the resulting complexes, to predict ADMET properties of candidate compounds, and to systematically analyze experimental and computational data to derive meaningful structure-activity relationships leading to the creation of a drug candidate. This Perspective describes a real case of a drug discovery campaign accomplished in a relatively short time with limited resources. The study integrated an arsenal of available molecular modeling techniques with an array of experimental tools to successfully develop a novel class of potent and selective androgen receptor inhibitors with a novel mode of action. It resulted in the largest academic licensing deal in Canadian history, totaling $142M. This project exemplifies the importance of team science, an integrative approach to drug discovery, and the use of best practices in CADD. We posit that the lessons learned and best practices for executing an effective CADD project can be applied, with similar success, to many drug discovery projects in both academia and industry.
Discovering discriminative action parts from mid-level video representations (2012)

We describe a mid-level approach for action recognition. From an input video, we extract salient spatio-temporal structures by forming clusters of trajectories that serve as candidates for the parts of an action. The assembly of these clusters into an action class is governed by a graphical model that incorporates appearance and motion constraints for the individual parts and pairwise constraints for the spatio-temporal dependencies among them. During training, we estimate the model parameters discriminatively. During classification, we efficiently match the model to a video using discrete optimization. We validate the model's classification ability in standard benchmark datasets and illustrate its potential to support a fine-grained analysis that not only gives a label to a video, but also identifies and localizes its constituent parts.
Spatially controlled crystal regrowth of ion-implanted silicon by laser irradiation (1978)

We demonstrate the unique capability of a repetitively pulsed laser to ’’write’’ a monocrystalline pattern in ion-implanted amorphous silicon layers. Ion-channeling data, from the samples scanned with a focused beam of a Q-switched Nd : YAG laser, show a continuity of the single-crystal layer produced with spatially overlapping laser pulses, at 60–80 MW cm−2. Scattering yields indicate very high substitutionality of the implanted ions and an interdependence between the laser power density and the depth redistribution of the implants. Finally, similar recrystallization was obtained with a CO2 laser at 10.6 μm.
MFI: A Case Study of Zeolite Synthesis (2003)

Zeolite synthesis occurs by a hydrothermal process with reagents being a silica source, an alumina source, a mineralizing agent such as OH− or F−, and, for higher Si/Al ratio zeolites, organic molecules as structure-directing agents. The role of inorganic metal cations, such as Na+ or K+, is quite profound. A schematic of the zeolite growth process is shown in Fig. 1(1). The complexity of the process, including the presence of numerous soluble species, an amorphous phase, polymerization and depolymerization reactions, makes the synthesis susceptible to physical effects such as stirring, aging, and order of reagent addition (2). Several independent processes are occurring in the medium, including nucleation of various structures, crystallization as well as dissolution of metastable phases. It is commonly observed that the conversion of the composition (gel or solution) to crystals is quite rapid once the crystallization process gets started. This suggests that nucleation is the rate-limiting step and is consistent with studies that report addition of seed crystals decrease the induction time (2). Tezak suggested several decades ago that rather than viewing the synthesis process as nucleation and crystallization, at least four subsystems be considered: (a) formation of simple and polymericaluminosilicates, (b) aggregation of these complexes to form embryo, (c) nucleation as aggregate formation with a well ordered core and micelle formation (primary particles), and (d) aggregation of primary particles via oriented aggregation (3). Flanigen has elaborated on these concepts further (4).
Physiological and Functional Imaging with CT: Techniques and Applications (2008)

Rapid advances in molecular biology in the past two decades have uncovered many genetic and molecular alterations in cancer. Based on the newly acquired knowledge, a number of molecularly targeted cancer treatment drugs have been developed that prolong survival, induce remission of tumor, and provide better quality of life for cancer patients. The product of permeability and blood concentration of a solute gives the unidirectional diffusional flux from blood to interstitial space per unit surface area of capillary endothelium. PS is the product of permeability and the total surface area of capillary endothelium in a mass of tissue (usually 100 g of tissue) and hence is the total diffusional flux across all capillaries in that mass. The structural and functional abnormalities of tumor vessels result in regions that are poorly perfused, hypoxic and high in interstitial pH (50). These characteristics of the tumor microenvironment limit the efficacy of many nonsurgical cancer treatments.
Bilateral pudendal afferent stimulation improves bladder emptying in rats with urinary retention (2011)

The results of the present study are consistent with an essential role for pudendal sensory feedback in efficient bladder emptying, and unilateral and bilateral electrical activation of pudendal nerve afferents are equally efficient in improving bladder emptying in an animal model of urinary retention. This could provide an approach to improve bladder emptying in patients with non-obstructive urinary retention.
Diagnostic Ultrasound Detection of Changes in Femoral Muscle Mass Recovery after Tibial Plateau Levelling Osteotomy in Dogs (2019)

The proximal femoral location, measured from the lateral aspect, appears to be the most suitable US measurement for detecting increases in femoral muscle mass in dogs recovering from TPLO. The provided pilot data suggest that further research evaluating this outcome measure is indicated.
Characterizing novel olfactory receptors expressed in the murine renal cortex (2019)

The kidney uses specialized G protein-coupled receptors, including olfactory receptors (ORs), to act as sensors of molecules and metabolites. In the present study, we cloned and studied seven renal ORs, which we previously found to be expressed in the murine renal cortex. As most ORs are orphan receptors, our goal was to identify ligands for these ORs in the hope that this will guide future research into their functional roles. We identified novel ligands for two ORs: Olfr558 and Olfr90. For Olfr558, we confirmed activation by previously reported ligands and identified 16 additional carboxylic acids that activated this OR. The strongest activation of Olfr558 was produced by butyric, cyclobutanecarboxylic, isovaleric, 2-methylvaleric, 3-methylvaleric, 4-methylvaleric, and valeric acids. The primary in vivo source of both butyric and isovaleric acids is gut microbial metabolism. We also identified 14 novel ligands that activated Olfr90, the strongest of which were 2-methyl-4-propyl-1,3-oxathiane, 1-octen-3-ol, 2-octanol, and 3-octanol. Interestingly, 8 of these 14 ligands are of fungal origin. We also investigated the tissue distribution of these receptors and found that they are each found in a subset of "nonsensory" tissues. Finally, we examined the putative human orthologs of Olfr558 and Olfr90 and found that the human ortholog of Olfr558 (OR51E1) has a similar ligand profile, indicating that the role of this OR is likely evolutionarily conserved. In summary, we examined seven novel renal ORs and identified new ligands for Olfr558 and Olfr90, which imply that both of these receptors serve to detect metabolites produced by microorganisms.
Global landscape of the host response to SARS-CoV-2 variants reveals viral evolutionary trajectories (2022)

ABSTRACT A series of SARS-CoV-2 variants of concern (VOCs) have evolved in humans during the COVID-19 pandemic—Alpha, Beta, Gamma, Delta, and Omicron. Here, we used global proteomic and genomic analyses during infection to understand the molecular responses driving VOC evolution. We discovered VOC-specific differences in viral RNA and protein expression levels, including for N, Orf6, and Orf9b, and pinpointed several viral mutations responsible. An analysis of the host response to VOC infection and comprehensive interrogation of altered virus-host protein-protein interactions revealed conserved and divergent regulation of biological pathways. For example, regulation of host translation was highly conserved, consistent with suppression of VOC replication in mice using the translation inhibitor plitidepsin. Conversely, modulation of the host inflammatory response was most divergent, where we found Alpha and Beta, but not Omicron BA.1, antagonized interferon stimulated genes (ISGs), a phenotype that correlated with differing levels of Orf6. Additionally, Delta more strongly upregulated proinflammatory genes compared to other VOCs. Systematic comparison of Omicron subvariants revealed BA.5 to have evolved enhanced ISG and proinflammatory gene suppression that similarly correlated with Orf6 expression, effects not seen in BA.4 due to a mutation that disrupts the Orf6-nuclear pore interaction. Our findings describe how VOCs have evolved to fine-tune viral protein expression and protein-protein interactions to evade both innate and adaptive immune responses, offering a likely explanation for increased transmission in humans. One sentence summary Systematic proteomic and genomic analyses of SARS-CoV-2 variants of concern reveal how variant-specific mutations alter viral gene expression, virus-host protein complexes, and the host response to infection with applications to therapy and future pandemic preparedness.
Structured Sparse Fully-Connected Layers in the CNNs and Its GPU Acceleration (2019)

Convolutional Neural Networks (CNNs) have become one of the most important and popular artificial intelligent techniques recently. While capabilities of CNNs have improved dramatically, enlargement of the network has become a problem. Thus far, several studies about network model compression for CNNs have been devoted. However, most of the compressed networks are unsuitable for parallel computing platforms since the compressed networks are unstructured. To address this problem, we propose a new sparse network architecture for CNNs. We compress the fully-connected layers (FLs) in the CNNs that occupying most of the weights. By considering the characteristic of the output of convolutional layers, we can highly compress the network structurally with almost the same accuracy. In addition, using the structure of the compressed network, we propose an efficient implementation of the inference computation on the GPU. We have applied the proposed approach to AlexNet for the classification problem for ILSVRC-2012 dataset. The experimental results show that the number of weights in FLs is reduced from 58.6 million to 6.8 million with 0.68% and 0.19% loss of top-1 and top-5 accuracy, respectively. Also, the GPU implementation for the compressed FLs can run 5.86 times faster than that for non-compressed FLs.
Dynamics of all-optical single-shot switching of magnetization in Tb/Co multilayers (2023)

The spatial and temporal dynamics of laser-induced single-shot magnetization switching are studied for various compositions of Tb/Co multilayers to understand the underlying mechanism. This is shown to be drastically different from the ones in Tb-Co alloys as well as in the previously studied toggle-switching Gd-containing ferrimagnets.
Discovery of a novel proteasome inhibitor selective for cancer cells over non-transformed cells (2009)

Numerous proteins controlling cell cycle progression, apoptosis and angiogenesis are degraded by the ubiquitin/proteasome system, which has become the subject for intense investigations for cancer therapeutics. Therefore, we used in silico and experimental approaches to screen compounds from the NCI chemical libraries for inhibitors against the chymotrypsin-like (CT-L) activity of the proteasome and discovered PI-083. Molecular docking indicates that PI-083 interacts with the Thr21, Gly47 and Ala49 residues of the beta5 subunit and Asp114 of the beta6 subunit of the proteasome. PI-083 inhibits CT-L activity and cell proliferation and induces apoptosis selectively in cancer cells (ovarian T80-Hras, pancreatic C7-Kras and breast MCF-7) as compared to their normal/immortalized counterparts (T80, C7 and MCF-10A, respectively). In contrast, Bortezomib, the only proteasome inhibitor approved by the Food and Drug Administration (FDA), did not exhibit this selectivity for cancer over non-transformed cells. In addition, in all cancer cells tested, including Multiple Myeloma (MM), breast, pancreatic, ovarian, lung, prostate cancer cell lines as well as fresh MM cells from patients, PI-083 required less time than Bortezomib to induce its antitumor effects. Furthermore, in nude mouse xenografts in vivo, PI-083, but not Bortezomib, suppressed the growth of human breast and lung tumors. Finally, following in vivo treatment of mice, PI-083 inhibited tumor, but not hepatic liver CT-L activity, whereas Bortezomib inhibited both tumor and liver CT-L activities. These results suggest that PI-083 is more selective for cancer cells and may have broader antitumor activity and therefore warrants further advanced preclinical studies.
Weighted mechanical models for residual stress determination using x-ray diffraction (2013)

Determining the mechanical response of thin films by diffraction-based methods requires appropriate elastic models. Weighting factors associated with the linear combination of Reuss and Voigt x-ray elastic constants are compared to the experimental values determined through linear, least-squares regression of diffraction data collected from multiple reflections of several materials. It is found that the optimal weighting factors, x*, determined by the experimental data of Cu, Ni, and Ti thin films vary significantly from those calculated under the Kröner and Neerfeld limits. The discrepancies may be due to plastic effects on the mechanical models that assume linear elastic behavior. The corresponding residual stress values under these limits exhibit a closer correspondence, where the relative variation among the mechanical models scales with the elastic anisotropy of the material.
PREVENTION OF SYNGENEIC GRAFT-VERSUS-HOST DISEASE BY RECOVERY OF THYMIC MICROENVIRONMENT AFTER CYCLOSPORINE (1991)

Following a course of cyclosporine, syngeneic rat radiation chimeras consistently develop a GVHD-like syndrome. Correlation of the thymic immunopathology with conditions leading to syngeneic graft-versus-host disease (sGVHD) suggested the hypothesis that reconstitution of the normal thymic microenvironment after CsA is necessary for self-tolerance. When thymic regeneration is impaired, as in rats receiving previous mediastinal irradiation, then self-reactive effector cells are not regulated and proceed to damage the target tissues. Alternately, it could be argued that the observed thymic abnormalities are irrelevant to sGVHD. To test the primary hypothesis, post-CsA thymic reconstitution was prevented by total thymectomy in unirradiated rats. These rats consistently developed acute type sGVHD seen at 7 and 21 days post-CsA while rats from the CsA-treated sham thymectomy control group failed to develop sGVHD. Because thymectomy prior to CsA blocks sGVHD, most likely the peripheral effector cells in the post-CsA thymectomy group were derived from the CsA-altered thymus. The absence of sGVHD in the sham group indicates that the thymus led to active regulation of these cells after stopping CsA. If regeneration of the thymus restored only negative selection, then the sham thymectomy group should have also developed sGVHD. Flow cytometry and morphology of the spleen and lymph nodes demonstrated that the thymectomized rats, like CsA-treated radiation chimeras, experienced a significant delay in maturation of T cells following CsA. In contrast to the usual model in radiation chimeras, however, the post-CsA thymectomized rats did not convert to chronic type sGVHD. The importance of an abnormal thymus for this transition was confirmed in syngeneic radiation chimeras. Thymectomy after CsA in these rats also blocked the rapid transition to chronic sGVHD.
Advances in Frequency Response Techniques for Diagnosing Inter-Turn Faults in Salient Poles (2023)

Frequency Response Analysis (FRA) technique has been widely used for many years to diagnose winding transformers. However, more recently, there has been a concerted effort to apply this technique to other types of windings, including large salient poles. This paper presents two new FRA diagnostic techniques that have been specifically developed and proven to work effectively on large salient poles. These two techniques - the FRA ungrounded test and the fault diagram method - are combined to provide a novel approach for predictive and corrective diagnosis of inter-turn faults on large salient poles. The fault diagram is constructed using the ungrounded technique test results, and an analysis is carried out to identify new properties and enhance the diagnostic sensitivity. The laboratory tests are described in detail, and a comparison with on-site tests is provided to validate the effectiveness of the new techniques.This paper presents a new and innovative approach to diagnose inter-turn faults on large salient poles using FRA techniques. The FRA ungrounded test and the fault diagram method have been specifically developed for this purpose and provide a reliable and cost-effective diagnosis compared to traditional methods. The comprehensive laboratory tests and comparison with on-site tests demonstrate the effectiveness and practicality of the proposed techniques.
Electromagnetic interference shielding with 2D transition metal carbides (MXenes) (2016)

Materials with good flexibility and high conductivity that can provide electromagnetic interference (EMI) shielding with minimal thickness are highly desirable, especially if they can be easily processed into films. Two-dimensional metal carbides and nitrides, known as MXenes, combine metallic conductivity and hydrophilic surfaces. Here, we demonstrate the potential of several MXenes and their polymer composites for EMI shielding. A 45-micrometer-thick Ti3C2Tx film exhibited EMI shielding effectiveness of 92 decibels (>50 decibels for a 2.5-micrometer film), which is the highest among synthetic materials of comparable thickness produced to date. This performance originates from the excellent electrical conductivity of Ti3C2Tx films (4600 Siemens per centimeter) and multiple internal reflections from Ti3C2Tx flakes in free-standing films. The mechanical flexibility and easy coating capability offered by MXenes and their composites enable them to shield surfaces of any shape while providing high EMI shielding efficiency.
DNA Binding Polyamides and the Importance of DNA Recognition in their use as Gene-Specific and Antiviral Agents (2014)

There is a long history for the bioorganic and biomedical use of N-methyl-pyrrole-derived polyamides (PAs) that are higher homologs of natural products such as distamycin A and netropsin. This work has been pursued by many groups, with the Dervan and Sugiyama groups responsible for many breakthroughs. We have studied PAs since about 1999, partly in industry and partly in academia. Early in this program, we reported methods to control cellular uptake of polyamides in cancer cell lines and other cells likely to have multidrug resistance efflux pumps induced. We went on to discover antiviral polyamides active against HPV31, where SAR showed that a minimum binding size of about 10 bp of DNA was necessary for activity. Subsequently we discovered polyamides active against two additional high-risk HPVs, HPV16 and 18, a subset of which showed broad spectrum activity against HPV16, 18 and 31. Aspects of our results presented here are incompatible with reported DNA recognition rules. For example, molecules with the same cognate DNA recognition properties varied from active to inactive against HPVs. We have since pursued the mechanism of action of antiviral polyamides, and polyamides in general, with collaborators at NanoVir, the University of Missouri-St. Louis, and Georgia State University. We describe dramatic consequences of β-alanine positioning even in relatively small, 8-ring polyamides; these results contrast sharply with prior reports. This paper was originally presented by JKB as a Keynote Lecture in the 2<sup>nd</sup> International Conference on Medicinal Chemistry and Computer Aided Drug Design Conference in Las Vegas, NV, October 2013.
ChemInform Abstract: Synthesis of a Novel Spirocyclic Lactone in a Potential Route to Squalestatin 1. (1994)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Collapsed variational bayesian inference of the author-topic model: application to large-scale coordinate-based meta-analysis (2016)

The author-topic (AT) model has been recently used to discover the relationships between brain regions, cognitive components and behavioral tasks in the human brain. In this work, we propose a novel Collapsed Variational Bayesian (CVB) inference algorithm for the AT model. The proposed algorithm is compared with the Expectation-Maximization (EM) algorithm on the large-scale BrainMap database of brain activation coordinates and behavioral tasks. Experiments suggest that the proposed CVB algorithm produces parameter estimates with better generalization power than the EM algorithm.
Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS (2012)

Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.
Preparation for antiretroviral interruption by boosting the immune system (2008)

In the last 2 years several studies of therapeutic immunization showed that preparation of the immune system by boosting specific immune responses may help patients to contain viral replication following combined antiretroviral therapy discontinuation. Although some of these results are encouraging, further studies are needed to confirm these results and to identify patients who may benefit from this strategy.