gebhart/patrepeval huggingface dataset:
Antisense-mediated exon skipping for Duchennemuscular dystrophy (2009)

Duchenne muscular dystrophy (DMD) is a severe,
progressive muscle wasting disease for which there
is currently no cure. The disease is caused by
mutations in the DMD gene that completely abolish
the function of the protein dystrophin.
This thesis focuses on the development of a
promising new therapy, so called antisense-mediated
exon skipping, that aims to restore the disrupted
dystrophin reading frame to allow generation of
internally deleted, but partly functional dystrophin
proteins, as found in the less severe Becker
muscular dystrophy.
The thesis describes the DMD gene, the dystrophin
protein, diseases associated with mutations in the
DMD gene and animal models. It provides an overview
of potential therapies for Duchenne muscular
dystrophy and describes how antisense-mediated
modulation of splicing can be used for other
therapeutic and research purposes. Finally it gives
a detailed overview of the rationale and the
development of the exon skipping therapy for
Duchenne muscular dystrophy.
Arabidopsis and the plant immune system (2010)

Understanding the fundamental mechanisms of plant disease resistance is of central importance to sustainable agriculture and human health. Use of the model plant Arabidopsis thaliana has resulted in an explosion of information regarding both disease resistance and susceptibility to pathogens. The last 20 years of research have demonstrated the commonalities between Arabidopsis and crop species. In this review, commemorating the 10th anniversary of the sequencing of the Arabidopsis genome, we will address some of the insights derived from the use of Arabidopsis as a model plant pathology system.
Crystal Structure and Mechanism of Activation of TANK-Binding Kinase 1 (2013)

Tank-binding kinase I (TBK1) plays a key role in the innate immune system by integrating signals from pattern-recognition receptors. Here, we report the X-ray crystal structures of inhibitor-bound inactive and active TBK1 determined to 2.6 Å and 4.0 Å resolution, respectively. The structures reveal a compact dimer made up of trimodular subunits containing an N-terminal kinase domain (KD), a ubiquitin-like domain (ULD), and an α-helical scaffold dimerization domain (SDD). Activation rearranges the KD into an active conformation while maintaining the overall dimer conformation. Low-resolution SAXS studies reveal that the missing C-terminal domain (CTD) extends away from the main body of the kinase dimer. Mutants that interfere with TBK1 dimerization show significantly reduced trans-autophosphorylation but retain the ability to bind adaptor proteins through the CTD. Our results provide detailed insights into the architecture of TBK1 and the molecular mechanism of activation.
The γ 1 heavy chain gene includes all of the cis-acting elements necessary for expression of properly regulated germ-line transcripts (1996)

The regulation of heavy chain switch recombination and the production of germ-line transcripts are highly correlated. IL-4 induces the production of murine gamma 1 germ-line transcripts, and much, if not all, of the regulation is transcriptional. We have investigated the cis-acting elements involved in the regulation of expression of germ-line transcripts by preparing transgenes with the gamma 1 locus. A construct that includes 5' flanking regions, I gamma 1, S gamma 1, and C gamma 1, is regulated like the endogenous gene. Deletion of either most of S gamma 1 or most of C gamma 1 does not alter the correctly regulated expression of the transgenes. An element common to these three different gamma 1 transgenes confers insertion-site independence and copy-number dependence on the transgenes. Finally, the absolute amount of gamma 1-line transcripts is regulated, as transgenic mice with more than 30 gamma 1 genes express no more germ-line transcripts than nontransgenic mice.
γ‐Zein secondary structure in solution by circular dichroism (2007)

The proline-rich N-terminal domain of gamma-zein has been reported in relevant processes, which include its ability to cross the cell membranes. Evidences indicate that synthetic hexapeptide (PPPVHL), naturally found in N-terminal portion of gamma-zein, can adopt the polyproline II (PPII) conformation in aqueous solution. The secondary structure of gamma-zein in maize protein bodies had been analyzed by solid state Fourier transform infrared and nuclear magnetic resonance spectroscopies. However, it was not possible to measure PPII content in physiological environment since the beta-sheet and PPII signals overlap in both solid state techniques. Here, the secondary structure of gamma-zein has been analyzed by circular dichroism in SDS aqueous solution with and without ditiothreitol (DTT), and in 60% of 2-propanol and water with DTT. The results show that gamma-zein has high helical content in all solutions. The PPII conformation was present at about 7% only in water/DTT solution.
Designing a fast and adaptive error correction scheme for increasing the lifetime of phase change memories (2011)

This paper proposes an adaptive multi-bit error correcting code for phase change memories that provides a manifold increase in the lifetime of phase change memories thereby making them a more viable alternative for DRAM main memory. A novel aspect of the proposed approach is that the error correction code (ECC) is adapted over time as the number of failed cells in the phase change memory accumulates. The operating system (OS) monitors the number of errors corrected on a memory line, and when the number of errors on a line begins to exceed the strength of the ECC present, the ECC strength is adaptively increased. As this happens, the performance of the memory system gracefully degrades because more storage is taken up by check bits rather than data bits thereby reducing the effective size of a cache line since less data can be brought to the cache on each read operation to the PCM main memory. Experimental results show that the lifetime of a phase change memory can be significantly extended while keeping the fraction of data to check bits as high as possible at each stage in the lifetime of the phase change memory.
Inhibition of p-STAT3 Enhances IFN-α Efficacy against Metastatic Melanoma in a Murine Model (2010)

The immune modulatory effects of STAT3 blockade can enhance the therapeutic efficacy of IFN-alpha immunotherapy by enhancing both innate and adaptive cytotoxic T-cell activities. This combination therapy has the potential in the treatment of metastatic melanoma that is typically refractory to this type of immune therapeutic approach.
Method for the lysis of Gram-positive, asporogenous bacteria with lysozyme (1980)

A method developed for the lysis of oral streptococci that employed the action of lysozyme suspended in dilute tris(hydroxymethyl)aminomethane-hydrochloride buffer containing polyethylene glycol has been adapted for use with lactobacilli, actinomycetes, propionibacteria, and pediococci. Most of the cellular deoxyribonucleic acid was liberated from many strains of bacteria usually thought to be lysozyme resistant. The major observations were as follows: (i) supplementation of the growth medium with L-threonine, L-lysine, or both frequently produced cells that were more susceptible to lysis by lysozyme; (ii) glucose-containing media produced cells that were more easily lysed than those from cultures grown on other substrates; (iii) polyethylene glycol not only served as an osmotic stabilizer, it also enhanced the extent of lysis; and (iv) dilute tris(hydroxymethyl)aminomethane buffer was superior to the buffer systems most commonly employed in published muramidase-based lysis techniques. Stationary-phase cells of Lactobacillus casei and Streptococcus mutans were more easily lysed than those isolated from log-phase cultures. The method as detailed in this report should be generally applicable for the lysis of gram-positive, asporogenous bacteria.
Plasma Concentration of Interleukin-6 and the Risk of Future Myocardial Infarction Among Apparently Healthy Men (2000)

In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future MI. These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis.
Catch and release microwave mediated synthesis of cyanine dyes (2009)

Unsymmetrical functionalised cyanine dyes, covering the whole colour range, were readily synthesised (in 100 mg amounts) by a combination of microwave and solid-phase methodologies.
Basal Cell Carcinoma Identification and Treatment of the High-Risk Patient (1996)

For basal cell carcinomas with this high risk profile, complete excision by margin control or total destruction should be considered.
An Attention Mechanism for Answer Selection Using a Combined Global and Local View (2017)

We propose a new attention mechanism for neural based question answering, which depends on varying granularities of the input. Previous work focused on augmenting recurrent neural networks with simple attention mechanisms which are a function of the similarity between a question embedding and an answer embeddings across time. We extend this by making the attention mechanism dependent on a global embedding of the answer attained using a separate network. We evaluate our system on InsuranceQA, a large question answering dataset. Our model outperforms current state-of-the-art results on InsuranceQA. Further, we visualize which sections of text our attention mechanism focuses on, and explore its performance across different parameter settings.
Digital optical switch (1987)

We propose and demonstrate a novel polarization- and wavelength-independent digital electro-optic switch in Ti:LiNbO3. This four-port integrated optics switch is characterized by a steplike response to the applied voltage. Switching is achieved through adiabatic eigenmode transformation in an asymmetric waveguide junction. We demonstrate switching of both polarization components at two wavelengths (1.32 and 1.52 μm) with a crosstalk of −20 dB.
One-step generation of complete gene knockout mice and monkeys by CRISPR/Cas9-mediated gene editing with multiple sgRNAs (2017)

The CRISPR/Cas9 system is an efficient gene-editing method, but the majority of gene-edited animals showed mosaicism, with editing occurring only in a portion of cells. Here we show that single gene or multiple genes can be completely knocked out in mouse and monkey embryos by zygotic injection of Cas9 mRNA and multiple adjacent single-guide RNAs (spaced 10-200 bp apart) that target only a single key exon of each gene. Phenotypic analysis of F0 mice following targeted deletion of eight genes on the Y chromosome individually demonstrated the robustness of this approach in generating knockout mice. Importantly, this approach delivers complete gene knockout at high efficiencies (100% on Arntl and 91% on Prrt2) in monkey embryos. Finally, we could generate a complete Prrt2 knockout monkey in a single step, demonstrating the usefulness of this approach in rapidly establishing gene-edited monkey models.
Stimulation of stop codon readthrough: frequent presence of an extended 3′ RNA structural element (2011)

In Sindbis, Venezuelan equine encephalitis and related alphaviruses, the polymerase is translated as a fusion with other non-structural proteins via readthrough of a UGA stop codon. Surprisingly, earlier work reported that the signal for efficient readthrough comprises a single cytidine residue 3'-adjacent to the UGA. However, analysis of variability at synonymous sites revealed strikingly enhanced conservation within the ∼ 150 nt 3'-adjacent to the UGA, and RNA folding algorithms revealed the potential for a phylogenetically conserved stem-loop structure in the same region. Mutational analysis of the predicted structure demonstrated that the stem-loop increases readthrough by up to 10-fold. The same computational analysis indicated that similar RNA structures are likely to be relevant to readthrough in certain plant virus genera, notably Furovirus, Pomovirus, Tobravirus, Pecluvirus and Benyvirus, as well as the Drosophilia gene kelch. These results suggest that 3' RNA stimulatory structures feature in a much larger proportion of readthrough cases than previously anticipated, and provide a new criterion for assessing the large number of cellular readthrough candidates that are currently being revealed by comparative sequence analysis.
Six distinct nuclear factors interact with the 75-base-pair repeat of the Moloney murine leukemia virus enhancer. (1987)

Binding sites for six distinct nuclear factors on the 75-base-pair repeat of the Moloney murine leukemia virus enhancer have been identified by an electrophoretic mobility shift assay combined with methylation interference. Three of these factors, found in WEHI 231 nuclear extracts, which we have named LVa, LVb, and LVc (for leukemia virus factors a, b, and c) have not been previously identified. Nuclear factors that bind to the conserved simian virus 40 corelike motif, the NF-1 motif, and the glucocorticoid response element were also detected. Testing of multiple cell lines showed that most factors appeared ubiquitous, except that the NF-1 binding factor was found neither in nuclear extracts from MEL cells nor in the embryonal carcinoma cell lines PCC4 and F9, and core-binding factor was relatively depleted from MEL and F9 nuclear extracts.
A family of high-swing CMOS operational amplifiers (1989)

A family of high-swing CMOS operational amplifiers has been developed to maximize the available dynamic range with low supply voltages. Complementary differential pairs are used to achieve an almost rail-to-rail input common-mode voltage range. High linearity is obtained by summing currents so that the small-signal differential-mode voltage gain is constant over the entire input common-mode range. With a 5.0-V power supply, the total harmonic distortion is typically only 1% in a unity-gain configuration with a 4.5-V/sub p-p/ signal. The measured DC offset voltages versus input common-mode range track between the conventional and high-swing versions. These measurements suggest that the commonly feared crossover distortion may not be a problem when the current summation high-swing topology is used. The measured step response characteristics were excellent and exhibited no signs of phase mismatch crossover distortion for high-frequency signals.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Direct Association of STAT3 with the IFNAR-1 Chain of the Human Type I Interferon Receptor (1996)

Based on the reports of the activation of the transcription factor known as STAT3 (for signal transducers and activators of transcription) or APRF (for acute phase response factor) by various cytokines, we investigated the possible role of STAT3 in type I interferon (IFN) receptor signaling. We show that STAT3 undergoes IFNalpha-dependent tyrosine phosphorylation and IFNalpha treatment induces protein-DNA complexes that contain STAT3. In addition, STAT3 associates with the IFNAR-1 chain of the type I receptor in a tyrosine phosphorylation-dependent manner upon IFNalpha addition. The binding of STAT3 to the IFNAR-1 chain occurs through a direct interaction between the SH2 domain-containing portion of STAT3 and the tyrosine-phosphorylated IFNAR-1 chain. Furthermore, tyrosine-phosphorylated STAT3 bound to the IFNAR-1 chain also undergoes a secondary modification involving serine phosphorylation. This phosphorylation event is apparently mediated by protein kinase C, since it was blocked by low concentrations of the protein kinase inhibitor H-7. The biological relevance of IFN activation of STAT3 is further illustrated by the finding that STAT3 is not activated by IFN in a cell line resistant to the antiviral and antiproliferative actions of IFN alpha but in which other components of the JAK-STAT pathway are activated by IFNalpha.
Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease (2014)

Background Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann–Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. Methods We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. Results With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P = 0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P = 0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). Conclusions Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.)
Dynamic Polarized Infrared Spectroscopy of Electric Field-Induced Molecular Reorientation in a Chiral Smectic-ALiquid Crystal (1995)

We report transient molecular orientation and conformation changes accompanying the electric field-induced soft mode molecular tilt in a chiral smectic- $A$ liquid crystal. We exhibit directly the loss of uniaxial molecular symmetry with field-induced tilt, showing that the molecular tails are less tilted with respect to the layer normal than the cores, and during switching reach their equilibrium orientation later than the cores. We also find evidence for a collective mode of rotation about the molecular long axis.
Viscosity Is Not a Parameter of Postdeglutitive Pharyngeal Residue: Quantification and Analysis with Scintigraphy (2007)

The aim of this study was to explore the influence of viscosity on pharyngeal residue in normal healthy volunteers. Scintigraphy was used to measure pharyngeal residue in 11 healthy volunteers after swallowing three different substances (age = 20.2-48.3 years). The first substance was a 10-ml solution of tap water with 0.5% xanthan with a viscosity of 4500 mPa s, comparable to a yogurt drink. The second and third substances were a 0.75% xanthan and a 1.00% xanthan solution, with viscosities of 10,500 and 21,000 mPa s, comparable to low-fat yogurt and 3% fat yogurt, respectively. Tap water was used as the control substance. Mean pharyngeal residue after swallowing tap water was 2.3% (SD = 1.2) of the initial volume in the oral cavity. Pharyngeal residue after swallowing 0.5% xanthan solution was 1.8% (SD = 0.8), after swallowing 0.75% xanthan solution 2.6% (SD = 2.2), and after swallowing 1.00% xanthan solution 2.8% (SD = 1.7). No significant correlation between increase of viscosity and pharyngeal residue was found. In healthy persons viscosity does not seem to be a significant parameter for pharyngeal residue for boluses with viscosities ranging from tap water to solutions having a viscosity comparable to 3% fat yogurt.
Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium (2008)

Our findings support a relationship between gene expression in extra- and intrathoracic airway epithelial cells and extend the concept of a smoking-induced field of injury to epithelial cells that line the mouth and nose. This relationship could potentially be utilized to develop a non-invasive biomarker for tobacco exposure as well as a non-invasive screening or diagnostic tool providing information about individual susceptibility to smoking-induced lung diseases.
RNA aptamers and their therapeutic and diagnostic applications. (2013)

RNA Aptamers refer to RNA oligonulceotides that are capable of binding to specific targets with high affinity and specificity. Through a process called Systematic Evolution of Ligands by EXponential enrichment (SELEX), a number of RNA aptamers have been identified against various targets including organic compounds, nucleotides, proteins and even whole cells and organisms. RNA aptamers have proven to be of high therapeutic and diagnostic value with recent FDA approval of the first aptamer drug and additional ones in the clinical pipelines. It has also been found to be a particularly useful tool for cell-type specific delivery of other RNA therapeutics like siRNA. All these establish RNA aptamers as one of the pivotal tools of the emerging RNA nanotechnology field in the fight against human diseases including cancer, viral infections and other diseases. This article summarizes the current advancement in the identification of RNA aptamers and also provides some examples of their therapeutic and diagnostic applications.
Differential Effects of Stable Prostacyclin Analogs on Smooth Muscle Proliferation and Cyclic AMP Generation in Human Pulmonary Artery (2002)

Primary pulmonary hypertension is characterized by increased pulmonary vascular resistance and smooth muscle proliferation. Stable analogs are increasingly being used to treat this disease, although no data exists comparing their effects on proliferation. We therefore investigated the antiproliferative activity of several prostacyclin (PGI(2)) analogs on human pulmonary arterial smooth muscle cells, including UT-15 and iloprost, analogs that have recently completed successful clinical trials. Serum-induced proliferation, as assessed by [(3)H]thymidine incorporation (30 h) or cell number (48 h), was significantly inhibited with a 10-fold difference in potency, ranking in effectiveness UT-15 > iloprost > cicaprost > beraprost. Effects were reversed by the adenylyl cyclase inhibitor, 2,5'dideoxyadenosine (DDA) but not SQ22536. Intracellular cyclic AMP (cAMP) was elevated by all analogs and inhibited by DDA, although SQ22536 was a highly variable inhibitor, suggesting that different pathways might mediate cAMP generation. UT-15 produced a significantly larger and more sustained increase in cAMP compared with other analogs, with iloprost being the weakest elevator. Thus, PGI(2) analogs potently inhibit proliferation of human pulmonary artery, probably via a cAMP-dependent pathway, although cAMP elevation in itself is not a good predictor of antiproliferative potency.