gebhart/patrepeval huggingface dataset:
Short Antisense Oligonucleotides with Novel 2′−4′ Conformationaly Restricted Nucleoside Analogues Show Improved Potency without Increased Toxicity in Animals (2008)

The potency of second generation antisense oligonucleotides (ASOs) in animals was increased 3- to 5 -fold (ED(50) approximately 2-5 mg/kg) without producing hepatotoxicity, by reducing ASO length (20-mer to 14-mer) and by employing novel nucleoside modifications that combine structural elements of 2'-O-methoxyethyl residues and locked nucleic acid. The ability to achieve this level of potency without any formulation agents is remarkable and likely to have a significant impact on the future design of ASOs as therapeutic agents.
Directed evolution of formate dehydrogenase from Candida boidinii for improved stability during entrapment in polyacrylamide (2006)

In two cycles of an error-prone PCR process, variants of formate dehydrogenase from Candida boidinii were created which revealed an up to 4.4-fold (440%) higher residual activity after entrapment in polyacrylamide gels than the wild-type enzyme. These were identified in an assay using single precursor molecules of polyacrylamide instead of the complete gel for selection. The stabilization resulted from an exchange of distinct lysine, glutamic acid, and cysteine residues remote from the active site, which did not affect the kinetics of the catalyzed reaction. Thermal stability increased at the exchange of lysine and glutamic acid, but decreased due the exchange of cysteine. Overall, the variants reveal very suitable properties for application in a technical synthetic process, enabling use of entrapment in polyacrylamide as an economic and versatile immobilization method.
Dexmedetomidine‐Associated Bradycardia Progressing to Pulseless Electrical Activity: Case Report and Review of the Literature (2009)

Dexmedetomidine is an alpha(2)-agonist indicated for sedation in critically ill patients and procedural sedation in nonintubated patients. It is a distinctive sedative because it does not cause respiratory depression, but it may cause hypotension and bradycardia. We describe a 74-year-old man who was receiving dexmedetomidine for agitation and experienced progressive bradycardia. The patient experienced a postoperative myocardial infarction 3 days after repair of an abdominal aortic aneurysm. A dexmedetomidine infusion was started at 0.11 microg/kg/hour, without a loading dose, for agitation; the patient's heart rate was 123 beats/minute and blood pressure was 147/70 mm Hg, both within normal limits. Over the next 6 hours, the dexmedetomidine infusion rate was increased to a maximum of 0.7 microg/kg/hour; the patient's heart rate progressively decreased to 21 beats/minute, followed by pulseless electrical activity. After 2 minutes of chest compressions and an intravenous bolus of atropine 0.4 mg, the patient regained a pulse. Dexmedetomidine was discontinued, and the patient's heart rate and blood pressure returned to within normal limits. The patient was discharged home 7 days later without any cardiac or neurologic sequelae. Clinicians need to be educated about the potential for dexmedetomidine to cause bradycardia progressing to pulseless electrical activity, and patients need to be closely monitored. Patients who receive dexmedetomidine and develop a greater than 30% decrease in heart rate may be at high risk for severe bradycardia leading to pulseless electrical activity. We urge caution when using dexmedetomidine, especially in patients with significant cardiac disease.
Lupus neutrophils (2012)

NETs are a potent stimulus for IFNα release by plasmacytoid dendritic cells, and, as such, may play an important role in propagation of the lupus phenotype. NETs can also directly damage tissues - including the endothelium - with implications for lupus nephritis and accelerated atherosclerosis. Whether aberrant NETosis is sufficient to trigger systemic lupus erythematosus, and whether inhibition of NETosis can ameliorate clinical manifestations of lupus, are open questions, and will be exciting topics of future research.
The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status (2005)

Mantle-cell lymphoma (MCL) is a mature B-cell lymphoma with an aggressive course and generally poor prognosis. Conventional chemotherapy has little efficacy. Bortezomib is a novel, reversible, and highly specific proteasome inhibitor that appears as a new hope for MCL treatment. We have analyzed the in vitro sensitivity to bortezomib in 4 MCL cell lines and in primary tumor cells from 10 MCL patients. Bortezomib induced phosphatidylserine exposure, mitochondrial depolarization, ROS generation, Bax and Bak conformational changes, and caspase activation. In addition, ROS scavengers, but not pancaspase inhibitors, blocked all apoptosis hallmarks. Protein and mRNA-expression analysis, revealed marked up-regulation of the BH3-only protein Noxa, between 4 to 6 hours after bortezomib addition, independent of p53 status. However, this up-regulation was faster and higher in cells with functional p53. Noxa RNA interference markedly decreased sensitivity to bortezomib, pointing to this protein as a key mediator between proteasome inhibition and mitochondrial depolarization in MCL cells. Noxa interacts with the antiapoptotic protein Mcl-1 and promotes Bak release from Mcl-1, suggesting that up-regulation of Noxa might counteract Mcl-1 accumulation after bortezomib treatment. These findings should be useful to extend the therapeutic strategies in MCL patients and to improve their prognosis.
Four IgG anti-islet human monoclonal antibodies isolated from a type 1 diabetes patient recognize distinct epitopes of glutamic acid decarboxylase 65 and are somatically mutated (1996)

The selective destruction by an autoimmune process of the beta cells in the pancreas is the hallmark of the type 1 insulin-dependent diabetes mellitus. What triggers islet cell-specific autoreactive T and B cells, however, remains unclear. Identification of the targets of the anti-islet cell autoantibodies frequently found in insulin-dependent diabetes mellitus patients and analysis of their sequences should provide some insights into the nature of this disease. We have combined EBV transformation with CD40 activation of peripheral B cells from one patient with insulin-dependent diabetes mellitus to isolate four B cell clones that secrete islet cell-specific autoantibodies, These four human monoclonal autoantibodies are of the IgG1 isotype, and they each recognize a different epitope of the glutamic acid decarboxylase enzyme. Analysis of their variable gene sequences shows that, while clonally unrelated, three of the four human monoclonal autoantibodies use a member of the VH4 family, and two have rearranged the same delta light chain variable gene. The IgG1 isotype of the four autoantibodies as well as the presence of somatic mutations in both heavy and light chain genes provide concrete evidence for their derivation by a T cell-dependent immune response.
Effects of a Velocity-Dependent Collision Frequency on Wave-Plasma Interactions (1966)

Two parameters, an effective collision frequency and an effective plasma frequency, are introduced to describe the effects of the velocity dependence of the collision frequency on wave-plasma interactions. Although mathematically related to other parameters previously used, this particular choice has the decided advantage of providing physical insight into the effect of the collision frequency variation. These parameters are calculated from actual cross section data for He, Ne, A, and N2. A discussion is also given of the effect of the velocity dependence of the collision frequency on the electron cyclotron line shape in magnetoplasmas. The introduction of these effective parameters provides a means for understanding the non-Lorentzian line shapes obtained from exact calculations of the absorption coefficients.
Compression for full-parallax light field displays (2014)

Full-parallax light field displays utilize a large volume of data and demand efficient real-time compression algorithms to be viable. Many compression techniques have been proposed. However, such solutions are impractical in bandwidth, processing or power requirements for a real-time implementation. Our method exploits the spatio angular redundancy in a full parallax light field to compress the light field image, while reducing the total computational load with minimal perceptual degradation. Objective analysis shows that depending on content, bandwidth reduction from two to four orders of magnitude is possible. Subjective analysis shows that the compression technique produces images with acceptable quality, and the system can successfully reproduce the 3D light field, providing natural binocular and full motion parallax.
Site-selective and stepwise complexation of two M(cod)+ (M = Rh, Ir) fragments with calix[4]areneElectronic supplementary information (ESI) available: experimental section. Fig. S1: structure of one of the independent molecules of 4. See http://www.rsc.org/suppdata/cc/b2/b201992m/ (2002)

The reaction of [(cod)M(mu-OMe)]2 (M = Rh, Ir; cod = cycloocta-1,5-diene) with calix[4]arenes (LH4) in the molar ratio of 0.5-0.6:1 gave the rhodium and iridium pi-arene complexes [(cod)M(eta 6-LH3)], while that in the molar ratio of 1.1-1.5:1 (M = Rh) led to the selective formation of the dinuclear complexes [((cod)Rh)2(eta 6:eta 2-LH2)] in which one of the Rh(cod)+ fragments is coordinated by an eta 6-aryl group and the other by two phenolic oxygen atoms; the stepwise synthesis of the Rh-Ir heterobimetallic analogue of the latter complex was further achieved.
The Yeast Forkhead Transcription Factors Fkh1 and Fkh2 Regulate Lifespan and Stress Response Together with the Anaphase-Promoting Complex (2012)

Forkhead box O (FOXO) transcription factors have a conserved function in regulating metazoan lifespan. A key function in this process involves the regulation of the cell cycle and stress responses including free radical scavenging. We employed yeast chronological and replicative lifespan assays, as well as oxidative stress assays, to explore the potential evolutionary conservation of function between the FOXOs and the yeast forkhead box transcription factors FKH1 and FKH2. We report that the deletion of both FKH genes impedes normal lifespan and stress resistance, particularly in stationary phase cells, which are non-responsive to caloric restriction. Conversely, increased expression of the FKHs leads to extended lifespan and improved stress response. Here we show the Anaphase-Promoting Complex (APC) genetically interacts with the Fkh pathway, likely working in a linear pathway under normal conditions, as fkh1Δ fkh2Δ post-mitotic survival is epistatic to that observed in apc5(CA) mutants. However, under stress conditions, post-mitotic survival is dramatically impaired in apc5(CA) fkh1Δ fkh2Δ, while increased expression of either FKH rescues APC mutant growth defects. This study establishes the FKHs role as evolutionarily conserved regulators of lifespan in yeast and identifies the APC as a novel component of this mechanism under certain conditions, likely through combined regulation of stress response, genomic stability, and cell cycle regulation.
NXY-059 for Acute Ischemic Stroke (2006)

The administration of NXY-059 within six hours after the onset of acute ischemic stroke significantly improved the primary outcome (reduced disability at 90 days), but it did not significantly improve other outcome measures, including neurologic functioning as measured by the NIHSS score. Additional research is needed to confirm whether NXY-059 is beneficial in ischemic stroke. (ClinicalTrials.gov number, NCT00119626.).
Effective hardware-based data prefetching for high-performance processors (1995)

Memory latency and bandwidth are progressing at a much slower pace than processor performance. In this paper, we describe and evaluate the performance of three variations of a hardware function unit whose goal is to assist a data cache in prefetching data accesses so that memory latency is hidden as often as possible. The basic idea of the prefetching scheme is to keep track of data access patterns in a reference prediction table (RPT) organized as an instruction cache. The three designs differ mostly on the timing of the prefetching. In the simplest scheme (basic), prefetches can be generated one iteration ahead of actual use. The lookahead variation takes advantage of a lookahead program counter that ideally stays one memory latency time ahead of the real program counter and that is used as the control mechanism to generate the prefetches. Finally the correlated scheme uses a more sophisticated design to detect patterns across loop levels. These designs are evaluated by simulating the ten SPEC benchmarks on a cycle-by-cycle basis. The results show that 1) the three hardware prefetching schemes all yield significant reductions in the data access penalty when compared with regular caches, 2) the benefits are greater when the hardware assist augments small on-chip caches, and 3) the lookahead scheme is the preferred one cost-performance wise.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
View Scalable Multiview Video Coding Using 3-D Warping With Depth Map (2007)

Multiview video coding demands high compression rates as well as view scalability, which enables the video to be displayed on a multitude of different terminals. In order to achieve view scalability, it is necessary to limit the inter-view prediction structure. In this paper, we propose a new multiview video coding scheme that can improve the compression efficiency under such a limited inter-view prediction structure. All views are divided into two groups in the proposed scheme: base view and enhancement views. The proposed scheme first estimates a view-dependent geometry of the base view. It then uses a video encoder to encode the video of base view. The view-dependent geometry is also encoded by the video encoder. The scheme then generates prediction images of enhancement views from the decoded video and the view-dependent geometry by using image-based rendering techniques, and it makes residual signals for each enhancement view. Finally, it encodes residual signals by the conventional video encoder as if they were regular video signals. We implement one encoder that employs this scheme by using a depth map as the view-dependent geometry and 3-D warping as the view generation method. In order to increase the coding efficiency, we adopt the following three modifications: (1) object-based interpolation on 3-D warping; (2) depth estimation with consideration of rate-distortion costs; and (3) quarter-pel accuracy depth representation. Experiments show that the proposed scheme offers about 30% higher compression efficiency than the conventional scheme, even though one depth map video is added to the original multiview video.
A role for jasmonate in pathogen defense of Arabidopsis (1998)

To investigate the role of jasmonate in the defense of plants against fungal pathogens, we have studied a mutant of Arabidopsis, fad3-2 fad7-2 fad8, that cannot accumulate jasmonate. Mutant plants were extremely susceptible to root rot caused by the fungal root pathogen Pythium mastophorum (Drechs.), even though neighboring wild-type plants were largely unaffected by this fungus. Application of exogenous methyl jasmonate substantially protected mutant plants, reducing the incidence of disease to a level close to that of wild-type controls. A similar treatment with methyl jasmonate did not protect the jasmonate-insensitive mutant coi1 from infection, showing that protective action of applied jasmonate against P. mastophorum was mediated by the induction of plant defense mechanisms rather than by a direct antifungal action. Transcripts of three jasmonate-responsive defense genes are induced by Pythium challenge in the wild-type but not in the jasmonate-deficient mutant. Pythium species are ubiquitous in soil and root habitats world-wide, but most (including P. mastophorum) are considered to be minor pathogens. Our results indicate that jasmonate is essential for plant defense against Pythium and, because of the high exposure of plant roots to Pythium inoculum in soil, may well be fundamental to survival of plants in nature. Our results further indicate that the fad3-2 fad7-2 fad8 mutant is an appropriate genetic model for studying the role of this important signaling molecule in pathogen defense.
Using pharmacodynamic and pharmacokinetic surrogate markers in clinical practice: optimizing antimicrobial therapy in respiratory-tract infections (1999)

Pharmacodynamic and pharmacokinetic surrogate markers and their relationship to outcomes in respiratory-tract infections are reviewed. While several limitations affect the universal application of antimicrobial pharmacodynamic principles in clinical practice, recent studies have suggested that these principles may allow optimization of selected therapies. For the fluoroquinolones, the pharmacodynamic variable that has been correlated with antimicrobial efficacy is the ratio of the area under the serum concentration-time curve to the minimum inhibitory concentration. On the basis of their pharmacodynamic profiles, the newer fluoroquinolones, including such investigational agents as gatifloxacin, should produce satisfactory clinical and microbiological outcomes against pathogens commonly associated with community-acquired respiratory-tract infections. An assessment of the individual agent's pharmacodynamic profile will assist in choosing the best fluoroquinolone regimen; however, consideration should also be given to the agent's adverse-event potential.
Galectin-1 Upregulates CXCR4 to Promote Tumor Progression and Poor Outcome in Kidney Cancer (2014)

Galectin-1, a β-galactoside-binding lectin, is involved in many physiologic and pathologic processes, including cell adhesion, differentiation, angiogenesis, and tumor progression. However, the role of galectin-1 in kidney cancer remains elusive. This study evaluated the role of galectin-1 in the progression and clinical prognosis of renal cell carcinoma. We found significant overexpression of galectin-1 in both kidney cancer cell lines and metastatic tissue specimens from patients with renal cell carcinoma. Knockdown of galectin-1 gene expression in renal cancer cell lines reduced cell invasion, clonogenic ability, and epithelial-mesenchymal transition in vitro; reduced tumor outgrowth in vivo; and inhibited the angiogenesis-inducing activity of these cells in vitro and in vivo. Galectin-1 knockdown decreased CXCR4 expression levels in kidney cancer cells, and restoration of CXCR4 expression in galectin-1-silenced cells rescued cell motility and clonogenic ability. Additional studies suggested that galectin-1 induced CXCR4 expression through activation of nuclear factor-κB (NF-κB). Analysis of patient specimens confirmed the clinical significance and positive correlation between galectin-1 and CXCR4 expression levels and revealed concomitant overexpression of galectin-1 and CXCR4 associated adversely with overall and disease-free survival. Our findings suggest that galectin-1 promotes tumor progression through upregulation of CXCR4 via NF-κB. The coordinated upregulation of galectin-1 and CXCR4 may be a novel prognostic factor for survival in patients with renal cell carcinoma and the galectin-1-CXCR4 axis may serve as a therapeutic target in this disease.
A Mini-Review for Cancer Immunotherapy: Molecular Understanding of PD-1/PD-L1 Pathway & Translational Blockade of Immune Checkpoints (2016)

Interference of the binding of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has become a new inspiring immunotherapy for resisting cancers. To date, the FDA has approved two PD-1 monoclonal antibody drugs against cancer as well as a monoclonal antibody for PD-L1. More PD-1 and PD-L1 monoclonal antibody drugs are on their way in clinical trials. In this review, we focused on the mechanism of the PD-1/PD-L1 signaling pathway and the monoclonal antibodies (mAbs) against PD-1 and PD-L1, which were approved by the FDA or are still in clinical trials. And also presented is the prospect of the PD-1/PD-L1 immune checkpoint blockade in the next generation of immunotherapy.
The Development of Amyloid β Protein Deposits in the Aged Brain (2006)

The deposition of amyloid beta protein (Abeta) in the human brain and the generation of neurofibrillary tangles are the histopathological hallmarks of Alzheimer's disease. Accumulation of Abeta takes place in senile plaques and in cerebrovascular deposits as a result of an imbalance between Abeta production and clearance. This Review describes the different types of Abeta deposits, which can be distinguished by their morphology and by the hierarchical involvement of distinct areas of the brain in Abeta deposition. The role of intracellular Abeta in Abeta deposition and the mechanism of Abeta toxicity are also discussed.
2009 Biospecimen Research Network Symposium: Advancing Cancer Research through Biospecimen Science (2009)

This report details the proceedings of the 2009 Biospecimen Research Network (BRN) Symposium that took place on March 16 to 18, 2009, the second in a series of annual symposia sponsored by the National Cancer Institute Office of Biorepositories and Biospecimen Research. The BRN Symposium is a public forum addressing the relevance of biospecimen quality to progress in cancer research and the systematic investigation needed to understand how different methods of collection, processing, and storage of human biospecimens affect subsequent molecular research results. More than 300 participants from industry, academia, and government attended the symposium, which featured both formal presentations and a day of workshops aimed at addressing several key issues in biospecimen science. An additional 100 individuals participated via a live webcast (archived at http://brnsymposium.com). The BRN Symposium is part of a larger program designed as a networked, multidisciplinary research approach to increase the knowledge base for biospecimen science. Biospecimens are generally understood to represent an accurate representation of a patient's disease biology, but can instead reflect a combination of disease biology and the biospecimen's response to a wide range of biological stresses. The molecular signatures of disease can thus be confounded by the signatures of biospecimen biological stress, with the potential to affect clinical and research outcomes through incorrect diagnosis of disease, improper use of a given therapy, and irreproducible research results that can lead to misinterpretation of artifacts as biomarkers. Biospecimen research represents the kind of bricks-and-mortar research that provides a solid scientific foundation for future advances that will directly help patients.
The Primary Structure of Epidermal Growth Factor (1972)

The complete amino acid sequence of epidermal growth factor (EGF) has been established through the use of automated Edman degradation and standard enzymatic and chemical techniques. The location of the half-cystinyl residues was facilitated by the use of the S-[14C]aminoethyl derivative of EGF. The sequence is: [see PDF for sequence]. The calculated molecular weight of the 53-residue polypeptide is 6045, a value that is in agreement with the molecular weight of 6400 established by physical measurements. The peptide is acidic and the 6 half-cystines exist in disulfide linkage. Four arginine residues are located in the COOH-terminal portion of the molecule. The six COOH-terminal amino acids are not necessary for biological activity and EGF1–47 has activity identical with that of the 53-residue native molecule.