gebhart/patrepeval huggingface dataset:
Pharmacological induction of CFTR function in patients with cystic fibrosis: mutation-specific therapy (2005)

CFTR mutations cause defects of CFTR protein production and function by different molecular mechanisms. Mutations can be classified according to the mechanisms by which they disrupt CFTR function. This understanding of the different molecular mechanisms of CFTR dysfunction provides the scientific basis for the development of targeted drugs for mutation-specific therapy of cystic fibrosis (CF). Class I mutations are nonsense mutations that result in the presence of a premature stop codon that leads to the production of unstable mRNA, or the release from the ribosome of a short, truncated protein that is not functional. Aminoglycoside antibiotics can suppress premature termination codons by disrupting translational fidelity and allowing the incorporation of an amino acid, thus permitting translation to continue to the normal termination of the transcript. Class II mutations cause impairment of CFTR processing and folding in the Golgi. As a result, the mutant CFTR is retained in the endoplasmic reticulum (ER) and eventually targeted for degradation by the quality control mechanisms. Chemical and molecular chaperones such as sodium-4-phenylbutyrate can stabilize protein structure, and allow it to escape from degradation in the ER and be transported to the cell membrane. Class III mutations disrupt the function of the regulatory domain. CFTR is resistant to phosphorylation or adenosine tri-phosphate (ATP) binding. CFTR activators such as alkylxanthines (CPX) and the flavonoid genistein can overcome affected ATP binding through direct binding to a nucleotide binding fold. In patients carrying class IV mutations, phosphorylation of CFTR results in reduced chloride transport. Increases in the overall cell surface content of these mutants might overcome the relative reduction in conductance. Alternatively, restoring native chloride pore characteristics pharmacologically might be effective. Activators of CFTR at the plasma membrane may function by promoting CFTR phosphorylation, by blocking CFTR dephosphorylation, by interacting directly with CFTR, and/or by modulation of CFTR protein-protein interactions. Class V mutations affect the splicing machinery and generate both aberrantly and correctly spliced transcripts, the levels of which vary among different patients and among different organs of the same patient. Splicing factors that promote exon inclusion or factors that promote exon skipping can promote increases of correctly spliced transcripts, depending on the molecular defect. Inconsistent results were reported regarding the required level of corrected or mutated CFTR that had to be reached in order to achieve normal function.
Initiation of nanoporous energetic silicon by optically-triggered, residual stress powered microactuators (2012)

The integration of energetic materials with chip-scale MEMS fabrication processes, and in particular the development of nanoporous energetic silicon (NES), is a promising path to provide significant quantities of energy for certain microscale applications. Here we demonstrate the low-power wireless initiation of an on-chip energetic reaction, by absorbing optical energy, transmitting mechanical energy, and releasing a large amount of chemical energy, without the use of any external wires or batteries. A novel actuator powered by residual thin film stress absorbed 25 W/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> of optical power from a 532 nm visible laser, heated, and released up to 22 nJ of mechanical energy. The mechanical energy was sufficient to initiate 6.7 mg of NES and release up to 66 J of chemical energy.
Monoclonal Antibodies against the Adeno-Associated Virus Type 2 (AAV-2) Capsid: Epitope Mapping and Identification of Capsid Domains Involved in AAV-2–Cell Interaction and Neutralization of AAV-2 Infection (2000)

The previously characterized monoclonal antibodies (MAbs) A1, A69, B1, and A20 are directed against assembled or nonassembled adeno-associated virus type 2 (AAV-2) capsid proteins (A. Wistuba, A. Kern, S. Weger, D. Grimm, and J. A. Kleinschmidt, J. Virol. 71:1341-1352, 1997). Here we describe the linear epitopes of A1, A69, and B1 which reside in VP1, VP2, and VP3, respectively, using gene fragment phage display library, peptide scan, and peptide competition experiments. In addition, MAbs A20, C24-B, C37-B, and D3 directed against conformational epitopes on AAV-2 capsids were characterized. Epitope sequences on the capsid surface were identified by enzyme-linked immunoabsorbent assay using AAV-2 mutants and AAV serotypes, peptide scan, and peptide competition experiments. A20 neutralizes infection following receptor attachment by binding an epitope formed during AAV-2 capsid assembly. The newly isolated antibodies C24-B and C37-B inhibit AAV-2 binding to cells, probably by recognizing a loop region involved in binding of AAV-2 to the cellular receptor. In contrast, binding of D3 to a loop near the predicted threefold spike does not neutralize AAV-2 infection. The identified antigenic regions on the AAV-2 capsid surface are discussed with respect to their possible roles in different steps of the viral life cycle.
Di-cobalt(ii) catalysts for the copolymerisation of CO2 and cyclohexene oxide: support for a dinuclear mechanism? (2012)

The synthesis and characterisation of a series of di-cobalt(II) halide complexes, coordinated by a macrocyclic ancillary ligand, is reported. The new complexes show excellent activity as catalysts for the copolymerisation of cyclohexene oxide (CHO) and carbon dioxide, under just 1 atmosphere of pressure of CO2. The complexation of a series of co-ligands has been investigated, including nucleophiles of varying strength, (4-dimethylaminopyridine (DMAP), N-methylimidazole (MeIm) and pyridine), and the anionic donor (Cl) from bulky ammonium salts, ([HNEt3]Cl, [DBU-H]Cl and [MTBD-H]Cl). Structure–activity studies of the complexes, including X-ray crystallography data, in conjunction with mass spectrometry experiments, are used to support a proposed dinuclear mechanism. The initial rate of copolymerisation, determined using in situ attenuated total reflectance infrared (ATR-IR) spectroscopy, shows a first order dependence on both the catalyst concentration and the concentration of cyclohexene oxide. A dinuclear mechanism is proposed in which catalysis occurs on the convex face of the molecule, leading to chain growth from a single site.
Stimulation of tumors to synthesize tumor necrosis factor-alpha in situ using 5,6-dimethylxanthenone-4-acetic acid: a novel approach to cancer therapy. (1999)

The selective induction of tumor vascular collapse represents an exciting approach to cancer treatment. However, clinical evaluation of tumor necrosis factor-alpha (TNF), an agent that accomplishes this goal, has been limited by systemic toxicity, and clinical approaches using bacterial components to induce TNF production have also been disappointing. Our laboratory has developed synthetic low molecular weight inducers of TNF, including 5,6-dimethylxanthenone-4-acetic acid (DMXAA), as an alternative strategy. DMXAA induces rapid vascular collapse in transplantable murine tumors and induces TNF synthesis in vitro in both murine and human systems. We show here that the extent of DMXAA-induced TNF synthesis is greater in tumors than that in the spleen, liver, or serum. As shown by in situ hybridization studies of the murine Colon 38 tumor, DMXAA induced tumor as well as host cells to express TNF mRNA. The distribution of cells containing TNF mRNA in tumor tissues after DMXAA administration contrasted significantly with that obtained after lipopolysaccharide (LPS) treatment, although splenic and hepatic tissues showed a similar distribution of TNF mRNA-positive cells. In the Colon 38 tumor, the action of LPS was limited to host cells in the periphery of the vessels. DMXAA treatment induced 7-fold higher peak TNF levels in tumor than in serum. In contrast, LPS treatment induced 9-fold higher TNF levels in serum than in tumor. DMXAA induced 35-fold higher TNF activity in the Colon 38 tissue than did LPS. One ovarian, one squamous, and three melanoma human tumor xenografts implanted in athymic nude mice expressed TNF mRNA of human and murine origin in response to DMXAA, confirming that DMXAA can activate both host and tumor cells. The use of low molecular weight agents to induce TNF synthesis in situ in the tumor represents a novel approach to TNF-mediated therapy of cancers.
The State of Sparsity in Deep Neural Networks (2019)

We rigorously evaluate three state-of-the-art techniques for inducing sparsity in deep neural networks on two large-scale learning tasks: Transformer trained on WMT 2014 English-to-German, and ResNet-50 trained on ImageNet. Across thousands of experiments, we demonstrate that complex techniques (Molchanov et al., 2017; Louizos et al., 2017b) shown to yield high compression rates on smaller datasets perform inconsistently, and that simple magnitude pruning approaches achieve comparable or better results. Additionally, we replicate the experiments performed by (Frankle &amp; Carbin, 2018) and (Liu et al., 2018) at scale and show that unstructured sparse architectures learned through pruning cannot be trained from scratch to the same test set performance as a model trained with joint sparsification and optimization. Together, these results highlight the need for large-scale benchmarks in the field of model compression. We open-source our code, top performing model checkpoints, and results of all hyperparameter configurations to establish rigorous baselines for future work on compression and sparsification.
Comparing methods to combine functional loss and mortality in clinical trials for amyotrophic lateral sclerosis (2018)

Objective: Amyotrophic lateral sclerosis (ALS) clinical trials based on single end points only partially capture the full treatment effect when both function and mortality are affected, and may falsely dismiss efficacious drugs as futile. We aimed to investigate the statistical properties of several strategies for the simultaneous analysis of function and mortality in ALS clinical trials. Methods: Based on the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we simulated longitudinal patterns of functional decline, defined by the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and conditional survival time. Different treatment scenarios with varying effect sizes were simulated with follow-up ranging from 12 to 18 months. We considered the following analytical strategies: 1) Cox model; 2) linear mixed effects (LME) model; 3) omnibus test based on Cox and LME models; 4) composite time-to-6-point decrease or death; 5) combined assessment of function and survival (CAFS); and 6) test based on joint modeling framework. For each analytical strategy, we calculated the empirical power and sample size. Results: Both Cox and LME models have increased false-negative rates when treatment exclusively affects either function or survival. The joint model has superior power compared to other strategies. The composite end point increases false-negative rates among all treatment scenarios. To detect a 15% reduction in ALSFRS-R decline and 34% decline in hazard with 80% power after 18 months, the Cox model requires 524 patients, the LME model 794 patients, the omnibus test 526 patients, the composite end point 1,274 patients, the CAFS 576 patients and the joint model 464 patients. Conclusion: Joint models have superior statistical power to analyze simultaneous effects on survival and function and may circumvent pitfalls encountered by other end points. Optimizing trial end points is essential, as selecting suboptimal outcomes may disguise important treatment clues. Keywords: joint models, CAFS, clinical trials, amyotrophic lateral sclerosis
Persistent Dopants and Phase Segregation in Organolead Mixed-Halide Perovskites (2016)

Organolead mixed-halide perovskites such as CH3NH3PbX3–aX′a (X, X′ = I, Br, Cl) are interesting semiconductors because of their low cost, high photovoltaic power conversion efficiencies, enhanced moisture stability, and band gap tunability. Using a combination of optical absorption spectroscopy, powder X-ray diffraction (XRD), and, for the first time, 207Pb solid state nuclear magnetic resonance (ssNMR), we probe the extent of alloying and phase segregation in these materials. Because 207Pb ssNMR chemical shifts are highly sensitive to local coordination and electronic structure, and vary linearly with halogen electronegativity and band gap, this technique can provide the true chemical speciation and composition of organolead mixed-halide perovskites. We specifically investigate samples made by three different preparative methods: solution phase synthesis, thermal annealing, and solid phase synthesis. 207Pb ssNMR reveals that nonstoichiometric dopants and semicrystalline phases are prevalent in samples made by solution phase synthesis. We show that these nanodomains are persistent after thermal annealing up to 200 °C. Further, a novel solid phase synthesis that starts from the parent, single-halide perovskites can suppress phase segregation but not the formation of dopants. Our observations are consistent with the presence of miscibility gaps and spontaneous spinodal decomposition of the mixed-halide perovskites at room temperature. This underscores how strongly different synthetic procedures impact the nanostructuring and composition of organolead halide perovskites. Better optoelectronic properties and improved device stability and performance may be achieved through careful manipulation of the different phases and nanodomains present in these materials.
Electrical Interconnect Design Optimization for Fully Embedded Board-level Optical Interconnects (2008)

Optical interconnect on printed circuit board are promising for backplane and motherboard applications due to their low propagation loss and high data-transfer density as an alternative to electrical interconnections which fail to meet the increasing data rate equipment. The advantages of embedded polymer waveguide as optical interconnects is the potential compatibility with the current PCB manufacturing process facilitating a smooth technological transfer from electrical to optical interconnects on PCB. In this manuscript, we report on the electrical design, design constraints, layout optimization and challenges in realizing a polymer waveguide embedded in a multi layer printed circuit board (PCB) for high speed applications.
Online Tracking of Migrating and Proliferating Cells Imaged with Phase-Contrast Microscopy (2006)

Automated visual-tracking of cell population in vitro using phase-contrast time-lapse microscopy is vital for the quantitative and systematic study of cell behaviors, including spatiotemporal quantification of migration, proliferation, and apoptosis. The low image quality, high and varying density of the cell culture, and the complexity of cell behaviors pose many challenges to existing tracking techniques. This paper presents a fully-automated multitarget tracking system that can simultaneously track hundreds of cells and efficiently cope with these challenges. The approach exploits a fast topology-constrained level-set method in conjunction with a stochastic motion filter, with a careful formulation that makes it suitable for real-time tracking during acquisition. Our methodology was applied to human tissue cell tracking in vitro under various imaging conditions and yielded a 88.4% tracking accuracy.
Bromodomain inhibitors and cancer therapy: From structures to applications (2016)

Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are "writers," "erasers," or "readers" of histone modification marks are common. Bromodomains are "readers" that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. In recent years, there has been increasing interest in developing small molecules that can target specific bromodomains. First, this has helped clarify biological functions of bromodomain-containing proteins. Secondly, it opens a new front for combatting cancer. In this review we will describe the structures and mechanisms associated with Bromodomain and Extra-Terminal motif (BET) inhibitors and non-BET inhibitors, their current status of development, and their promising role as anti-cancer agents.
Defective viral DNA ameliorates symptoms of geminivirus infection in transgenic plants. (1990)

Nicotiana benthamiana was transformed with a single copy of a tandem repeat of subgenomic DNA B isolated from plants infected with a Kenyan isolate of the bipartite geminivirus African cassava mosaic virus. Symptoms in transformed plants were less severe than in nontransformed controls when challenged with virus or cloned DNA of Kenyan or Nigerian isolates. Symptom amelioration was associated with the mobilization and amplification of the subgenomic DNA, producing a comparable reduction in the amount of DNA specific to each genomic component. The disproportionate reduction in the levels of full-length components (DNA A, 20%; DNA B, 70%) indicates that the episomally replicating subgenomic DNA has been amplified at the expense of full-length DNA B to three times the level of the latter. Serial infection of transformants resulted in a further decrease in symptom severity and viral DNA levels. No differences were observed in the severity of symptoms or levels of viral DNA when transformants and controls were challenged with the related geminiviruses beet curly top virus and tomato golden mosaic virus, demonstrating the specific nature of the interaction. Analysis of infected tissue showed that tomato golden mosaic virus was unable to amplify the subgenomic DNA. However, since the production of subgenomic DNA is possibly a common feature of the bipartite geminiviruses, this approach might contribute to the production of plants showing increased tolerance to a number of economically important viral diseases.
Plasmid rolling circle replication and its control (1995)

This review summarises current information on rolling circle replicating plasmids originally isolated from Gram-positive bacteria with a low guanine and cytosine content in their DNA. It focuses on the peculiar biological features of these small, high copy number plasmids that replicate via an asymmetric RC mechanism. The regulation of plasmid copy number is also discussed.
Pseudorabies virus latency and reactivation in vaccinated swine (1990)

Latency and reactivation of pseudorabies virus in swine was studied. Thirty-one pigs were assigned to 5 groups and were given 1 of 4 vaccines; 10 remained unvaccinated controls. All pigs were then challenge exposed with a sublethal dose of virulent pseudorabies virus. One hundred one days after challenge exposure, all pigs were treated with dexamethasone to reactivate the virus. Virus-positive tonsil and nasal mucus isolates were recovered from 29 of the 31 pigs over a 12-day period. Frequency and duration of virus-positivity were significantly (P less than 0.05) and consistently lower among vaccinated pigs than among the unvaccinated controls. It was concluded that vaccination before challenge exposure had little or no effect on the rate of establishment of virus latency, but that vaccination reduced shedding after subsequent reactivation of the virus.
Characterization of New Fluorogenic Substrates for the Rapid and Sensitive Assay of Cathepsin E and Cathepsin D (1999)

Cathepsin E and cathepsin D are two major intracellular aspartic proteinases implicated in the physiological and pathological degradation of intra- and extracellular proteins. In this study, we designed and constructed highly sensitive synthetic decapeptide substrates for assays of cathepsins E and D based on the known sequence specificities of their cleavage sites. These substrates contain a highly fluorescent (7-methoxycoumarin-4-yl)acetyl (MOCAc) moiety and a quenching 2,4-dinitrophenyl (Dnp) group. When the Phe-Phe bond is cleaved, the fluorescence at an excitation wavelength of 328 nm and emission wavelength of 393 increases due to diminished quenching resulting from the separation of the fluorescent and quenching moieties. The first substrate, MOCAc-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Le u-Lys(Dnp)gamma-NH2, in which the Lys-Pro combination at positions P5 and P4 was designed for specific interaction with cathepsin E, is hydrolyzed equally well by cathepsins E and D (kcat/Km = 10.9 microM(-1) x s(-1) for cathepsin E and 15.6 microM(-1) x s(-1) for cathepsin D). A very acidic pH optimum o was obtained for both enzymes. The second substrate, MOCAc-Gly-Lys-Pro-Ile-Ile-Phe-Phe-Arg-Le u-Lys(Dnp)gamma-NH2, in which the isoleucine residue at position P2 was meant to increase the specificity for cathepsin E, is also hydrolyzed equally by both enzymes (kcat/Km = 12.2 microM(-1) x s(-1) for cathepsin E and 16.3 microM(-1) x s(-1) for cathepsin D). The kcat/Km values for both substrates are greater than those for the best substrates for cathepsins E and D described so far. Unfortunately, each substrate shows little discrimination between cathepsin E and cathepsin D, suggesting that amino acids at positions far from the cleavage site are important for discrimination between the two enzymes. However, in combination with aspartic proteinase inhibitors, such as pepstatin A and Ascaris pepsin inhibitor, these substrates enable a rapid and sensitive determination of the precise levels of cathepsins E and D in crude cell extracts of various tissues and cells. Thus these substrates represent a potentially valuable tool for routine assays and for mechanistic studies on cathepsins E and D.
Integration of self-assembled diblock copolymers for semiconductor capacitor fabrication (2001)

We combine a self-organizing diblock copolymer system with semiconductor processing to produce silicon capacitors with increased charge storage capacity over planar structures. Our process uses a diblock copolymer thin film as a mask for dry etching to roughen a silicon surface on a 30 nm length scale, which is well below photolithographic resolution limits. Electron microscopy correlates measured capacitance values with silicon etch depth, and the data agree well with a geometric estimate. This block copolymer nanotemplating process is compatible with standard semiconductor processing techniques and is scalable to large wafer dimensions.
Alpha-interferon therapy for lymphoproliferative disorders developing in two children following bone marrow transplants. (1989)

Two children developed lymphoproliferative processes following marrow transplantation. One of the two lymphoproliferative processes was documented to be Epstein-Barr virus (EBV)-associated. Both children received an extended course of alpha-interferon and gammaglobulin and responded with the disappearance of the lymphoproliferative process. Side effects from the alpha-interferon were minimal. Previous experience with EBV-associated lymphoproliferative processes following marrow transplantation have been usually fatal. This report further substantiates that alpha-interferon has a role in the treatment of EBV-associated lymphoproliferative processes following marrow transplantation.