gebhart/patrepeval huggingface dataset:
MicroRNA-regulated viral vectors for gene therapy (2016)

Safe and effective gene therapy approaches require targeted tissue-specific transfer of a therapeutic transgene. Besides traditional approaches, such as transcriptional and transductional targeting, microRNA-dependent post-transcriptional suppression of transgene expression has been emerging as powerful new technology to increase the specificity of vector-mediated transgene expression. MicroRNAs are small non-coding RNAs and often expressed in a tissue-, lineage-, activation- or differentiation-specific pattern. They typically regulate gene expression by binding to imperfectly complementary sequences in the 3' untranslated region (UTR) of the mRNA. To control exogenous transgene expression, tandem repeats of artificial microRNA target sites are usually incorporated into the 3' UTR of the transgene expression cassette, leading to subsequent degradation of transgene mRNA in cells expressing the corresponding microRNA. This targeting strategy, first shown for lentiviral vectors in antigen presenting cells, has now been used for tissue-specific expression of vector-encoded therapeutic transgenes, to reduce immune response against the transgene, to control virus tropism for oncolytic virotherapy, to increase safety of live attenuated virus vaccines and to identify and select cell subsets for pluripotent stem cell therapies, respectively. This review provides an introduction into the technical mechanism underlying microRNA-regulation, highlights new developments in this field and gives an overview of applications of microRNA-regulated viral vectors for cardiac, suicide gene cancer and hematopoietic stem cell therapy, as well as for treatment of neurological and eye diseases.
Endothelium-Independent Relaxation and Hyperpolarization to C-Type Natriuretic Peptide in Porcine Coronary Arteries (1998)

Endothelial cells produce C-type natriuretic peptide (CNP), which has been proposed as an endothelium-derived hyperpolarizing factor. In porcine coronary arteries, we investigated the vasodilatory effects of CNP and compared them with endothelium-dependent relaxations and hyperpolarizations to bradykinin. Isolated epicardial porcine coronary arteries were studied in organ chambers, and concentration-response curves to CNP and bradykinin were obtained. Membrane potential was measured in endothelial cells and smooth muscle of intact porcine coronary arteries during stimulation with CNP or bradykinin. In precontracted porcine coronary arteries with or without endothelium, CNP (10[-10]-10[-6] M) evoked relaxations (maximum, 42 +/- 4%) smaller than those evoked by bradykinin (100 +/- 1%), blunted in preparations contracted by KCl instead of U46619 (9,11-dideoxy-11a,9a-epoxymethano-prostaglandin F2alpha; p < 0.05) and unaffected by inhibition of NO synthase (NS). CNP evoked hyperpolarization of vascular smooth muscle of similar magnitude in endothelium-intact (-4.4 +/- 1 mV) and endothelium-denuded (-4.6 +/- 1 mV) porcine coronary arteries. Bradykinin (10[-10]-10[-6] M) evoked concentration-dependent relaxations in preparations with endothelium only. Although atrial natriuretic peptide-receptor antagonist HS-142-1 (25 microM) slightly reduced the sensitivity to bradykinin (log shift at IC50, twofold; p < 0.05), it had no effect on the maximal response to bradykinin. Inhibition of NO synthase partially attenuated, whereas high potassium chloride (30 mM) markedly inhibited relaxations to bradykinin (p < 0.05). Hyperpolarization to bradykinin was much more pronounced than that to CNP (-17 +/- 3 mV; p < 0.05 vs. CNP) and was observed in endothelium-intact preparations only and unaffected by HS-142-1. In conclusion, in contrast to bradykinin, CNP induces endothelium-independent and weaker relaxation and hyperpolarization of coronary artery vascular smooth muscle, suggesting that CNP is an unlikely mediator of endothelium-dependent hyperpolarization of porcine coronary arteries.
Evolution of the RAG1-RAG2 locus: both proteins came from the same transposon (2015)

The RAG1 and RAG2 proteins are essential subunits of the V(D)J recombinase that is required for the generation of the enormous variability of antibodies and T-cell receptors in jawed vertebrates. It was demonstrated previously that the 600-aa catalytic core of RAG1 evolved from the transposase of the Transib superfamily transposons. However, although homologs of RAG1 and RAG2 genes are adjacent in the purple sea urchin genome, a transposon encoding both proteins so far has not been reported. Here we describe such transposons in the genomes of green sea urchin, a starfish and an oyster. Comparison of the domain architectures of the RAG1 homologs in these transposons, denoted TransibSU, and other Transib superfamily transposases provides for reconstruction of the structure of the hypothetical TransibVDJ transposon that gave rise to the VDJ recombinases at the onset of vertebrate evolution some 500 million years ago.
Prolonged Survival of a Patient Affected by Pancreatic Adenocarcinoma with Massive Lymphocyte and Dendritic Cell Infiltration after Interleukin-2 Immunotherapy. Report of a Case (2008)

Several studies have shown that there is a paucity of immune cells within the stroma of pancreatic adenocarcinoma, a very aggressive cancer with a median survival of about 18 months. A 65-year-old man presented with jaundice. Abdominal ultrasound revealed intra- and extrahepatic bile duct dilatation and a 45-mm diameter hypoechoic solid mass within the pancreatic head; a computed tomography scan excluded vascular infiltration and metastatic lesions. The patient received immunotherapy consisting of 6,000,000 IU human recombinant interleukin-2 administered subcutaneously twice a day for 3 consecutive days. Thirty-six hours after the last dose, he underwent a pylorus-preserving pancreatoduodenectomy. Because of the presence of high-grade dysplasia detected by intraoperative histological examination of a distal section, a spleen preserving total pancreatectomy was performed. The postoperative course was uneventful. The patient died 32 months after surgery because of local recurrence. Histopathology showed G3 pancreatic ductal adenocarcinoma infiltrating the anterior and posterior peripancreatic tissue, duodenal wall and intrapancreatic common bile duct, with sarcoma-like foci and a component of intraductal tumor involving the common bile duct. In the distal pancreas, widespread foci of pancreatic intraepithelial neoplasia (PanI2-3) were found. The Ki-67 proliferation index was 16%. TNM staging was pT3 pN1 R1. Sections were immunostained for the T-lymphocyte marker CD3 and for the dendritic cell marker CD1a. Intratumoral infiltration was high for CD1a+ cells and mild for CD3+ cells. Preoperative immunotherapy with interleukin-2 may contribute to massive stromal infiltration of immune cells in pancreatic adenocarcinoma. This may prolong the survival even in the presence of negative prognostic factors (age >65 years, tumor diameter >20 mm, R1, tumor grade G3).
Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer (2012)

Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).
A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood (2016)

Heterochronic parabiosis rejuvenates the performance of old tissue stem cells at some expense to the young, but whether this is through shared circulation or shared organs is unclear. Here we show that heterochronic blood exchange between young and old mice without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis. Investigating muscle, liver and brain hippocampus, in the presence or absence of muscle injury, we find that, in many cases, the inhibitory effects of old blood are more pronounced than the benefits of young, and that peripheral tissue injury compounds the negative effects. We also explore mechanistic explanations, including the role of B2M and TGF-beta. We conclude that, compared with heterochronic parabiosis, heterochronic blood exchange in small animals is less invasive and enables better-controlled studies with more immediate translation to therapies for humans.
Myocardial Changes Associated with Cardiogenic Shock (1971)

The amount of left ventricular myocardium destroyed by recent and old infarcts in patients with acute myocardial infarction with and without cardiogenic shock was compared in hearts obtained at autopsy. All 20 patients with, and only one of 14 without, shock had lost 40 per cent or more of the left ventricle. The remainder lost 35 per cent or less. These results indicate that cardiogenic shock is associated with extensive loss of left ventricular myocardium due to new and frequently old infarcts as well. In five cases the new infarct was small as compared to the total amount of myocardial destruction. Patients with cardiogenic shock consistently showed marginal extension of the recent infarct (unlike those not in shock) and focal areas of necrosis throughout both left and right ventricles. Similar focal lesions were encountered in a third series of 20 patients with shock from other causes. A sharp reduction in coronary perfusion pressure could explain this combination of findings, which indicate that cardiogenic shock is a continuous, self-perpetuating, vicious circle leading to progressive, irreversible myocardial dysfunction.
Faster R-CNN: Towards Real-Time Object Detection with Region Proposal Networks (2015)

State-of-the-art object detection networks depend on region proposal algorithms to hypothesize object locations. Advances like SPPnet and Fast R-CNN have reduced the running time of these detection networks, exposing region proposal computation as a bottleneck. In this work, we introduce a Region Proposal Network (RPN) that shares full-image convolutional features with the detection network, thus enabling nearly cost-free region proposals. An RPN is a fully convolutional network that simultaneously predicts object bounds and objectness scores at each position. The RPN is trained end-to-end to generate high-quality region proposals, which are used by Fast R-CNN for detection. We further merge RPN and Fast R-CNN into a single network by sharing their convolutional features---using the recently popular terminology of neural networks with 'attention' mechanisms, the RPN component tells the unified network where to look. For the very deep VGG-16 model, our detection system has a frame rate of 5fps (including all steps) on a GPU, while achieving state-of-the-art object detection accuracy on PASCAL VOC 2007, 2012, and MS COCO datasets with only 300 proposals per image. In ILSVRC and COCO 2015 competitions, Faster R-CNN and RPN are the foundations of the 1st-place winning entries in several tracks. Code has been made publicly available.
Discovery of Multiple-Level Association Rules from Large Databases (1995)

Discovery of association rules from large databases has been a focused topic recently in the research into database mining. Previous studies discover association rules at a single concept level, however, mining association rules at multiple concept levels may lead to finding more informative and refined knowledge from data. In this paper, we study efficient methods for mining multiple-level association rules from large transaction databases. A top-down progressive deepening method is proposed by extension of some existing (single-level) association rule mining algorithms. In particular, a group of algorithms for mining multiple-level association rules are developed and their relative performance are tested on different kinds of transaction data. Relaxation of the rule conditions for finding flexible multiple-level association rules is also discussed. Our study shows that efficient algorithms can be developed for the discovery of interesting and strong multiple-level association rules f...
An NMR study of the covalent and noncovalent interactions of CC-1065 and DNA (1990)

The binding of the antitumor drug CC-1065 has been studied with nuclear magnetic resonance (NMR) spectroscopy. This study involves two parts, the elucidation of the covalent binding site of the drug to DNA and a detailed investigation of the noncovalent interactions of CC-1065 with a DNA fragment through analysis of 2D NOE (NOESY) experiments. A CC-1065-DNA adduct was prepared, and an adenine adduct was released upon heating. NMR (1H and 13C) analysis of the adduct shows that the drug binds to N3 of adenine by reaction of its cyclopropyl group. The reaction pathway and product formed were determined by analysis of the 13C DEPT spectra. An octamer duplex, d(CGATTAGC.GCTAATCG), was synthesized and used in the interaction study of CC-1065 and the oligomer. The duplex and the drug-octamer complex were both analyzed by 2D spectroscopy (COSY, NOESY). The relative intensity of the NOEs observed between the drug (CC-1065) and the octamer duplex shows conclusively that the drug is located in the minor groove, covalently attached to N3 of adenine 6 and positioned from the 3'----5' end in relation to strand A [d(CGATTA6GC)]. A mechanism for drug binding and stabilization can be inferred from the NOE data and model-building studies.
Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. (2001)

Certain refractory neoplasms, such as glioblastoma multiforme (GBM) and melanoma, demonstrate a resistant tumor phenotype in vivo. We observed that these refractory tumor models (GBM and melanoma) contain blood vessels that are relatively resistant to radiotherapy. To determine whether the vascular endothelial growth factor receptor-2 (Flk-1/KDR) may be a therapeutic target to improve the effects of radiotherapy, we used the soluble extracellular component of Flk-1 (ExFlk), which blocks vascular endothelial growth factor binding to Flk-1 receptor expressed on the tumor endothelium. Both sFlk-1 and the Flk-1-specifc inhibitor SU5416 eliminated the resistance phenotype in GBM and melanoma microvasculature as determined by both the vascular window and Doppler blood flow methods. Human microendothelial cells and human umbilical vein endothelial cells showed minimal radiation-induced apoptosis. The Flk-1 antagonists sFlk-1 and SU5416 reverted these cell models to apoptosis-prone phenotype. Flk-1 antagonists also reverted GBM and melanoma tumor models to radiation-sensitive phenotype after treatment with 3 Gy. These findings demonstrate that the tumor microenvironment including the survival of tumor-associated endothelial cells contributes to tumor blood vessel resistance to therapy.
Respiratory syncytial virus fusion glycoprotein: nucleotide sequence of mRNA, identification of cleavage activation site and amino acid sequence of N-terminus of F1subunit (1985)

The amino acid sequence of respiratory syncytial virus fusion protein (Fo) was deduced from the sequence of a partial cDNA clone of mRNA and from the 5' mRNA sequence obtained by primer extension and dideoxysequencing. The encoded protein of 574 amino acids is extremely hydrophobic and has a molecular weight of 63371 daltons. The site of proteolytic cleavage within this protein was accurately mapped by determining a partial amino acid sequence of the N-terminus of the larger subunit (F1) purified by radioimmunoprecipitation using monoclonal antibodies. Alignment of the N-terminus of the F1 subunit within the deduced amino acid sequence of Fo permitted us to identify a sequence of lys-lys-arg-lys-arg-arg at the C-terminus of the smaller N-terminal F2 subunit that appears to represent the cleavage/activation domain. Five potential sites of glycosylation, four within the F2 subunit, were also identified. Three extremely hydrophobic domains are present in the protein; a) the N-terminal signal sequence, b) the N-terminus of the F1 subunit that is analogous to the N-terminus of the paramyxovirus F1 subunit and the HA2 subunit of influenza virus hemagglutinin, and c) the putative membrane anchorage domain near the C-terminus of F1.
Trehalose Lipid and α-Branched-β-hydroxy Fatty Acid Formed by Bacteria Grown on n-Alkanes (1969)

A bacterium isolated in our laboratory, Arthrobacter paraffineus KY 4303. when grown on n-paraffin as the sole source of carbon, produced anthrone-positive lipid in the emulsion layer (holding bacterial cells, lipids and n-paraffin remained) of the culture medium. This was isolated and identified as α-branched-β-hydroxy fatty acid trehalose ester. The addition of penicillin to the growing culture caused a significant suppression of trehalose lipid formation and led consequently to the accumulation of both the precursors, α, α-trehalose and α-branched-β-hydroxy fatty acid, in the culture medium. The formation of trehalose lipid was also observed in other bacteria which can utilize n-paraffin as the sole source of carbon. In addition, a possible role of this trehalose lipid in the utilization of n-paraffin by these bacteria was discussed.
Cellular senescence as a therapeutic target to improve renal transplantation outcome (2018)

Kidney transplants from aged donors are more vulnerable to ischemic injury, suffer more from delayed graft function and have a lower graft survival compared to kidneys from younger donors. On a cellular level, aging results in an increase in cells that are in a permanent cell cycle arrest, termed senescence, which secrete a range of pro-inflammatory cytokines and growth factors. Consequently, these senescent cells negatively influence the local milieu by causing inflammaging, and by reducing the regenerative capacity of the kidney. Moreover, the oxidative damage that is inflicted by ischemia-reperfusion injury during transplantation can induce senescence and accelerate aging. In this review, we describe recent developments in the understanding of the biology of aging that have led to the development of a new class of therapeutic agents aimed at eliminating senescent cells. These compounds have already shown to be able to restore tissue homeostasis in old mice, improve kidney function and general health- and lifespan. Use of these anti-senescence compounds holds great promise to improve the quality of marginal donor kidneys as well as to remove senescent cells induced by ischemia-reperfusion injury. Altogether, senescent cell removal may increase the donor pool, relieving the growing organ shortage and improve long-term transplantation outcome.
A New Approach To Utilize PCR–Single-Strand-Conformation Polymorphism for 16S rRNA Gene-Based Microbial Community Analysis (1998)

Single-strand-conformation polymorphism (SSCP) of DNA, a method widely used in mutation analysis, was adapted to the analysis and differentiation of cultivated pure-culture soil microorganisms and noncultivated rhizosphere microbial communities. A fragment (approximately 400 bp) of the bacterial 16S rRNA gene (V-4 and V-5 regions) was amplified by PCR with universal primers, with one primer phosphorylated at the 5' end. The phosphorylated strands of the PCR products were selectively digested with lambda exonuclease, and the remaining strands were separated by electrophoresis with an MDE polyacrylamide gel, a matrix specifically optimized for SSCP purposes. By this means, reannealing and heteroduplex formation of DNA strands during electrophoresis could be excluded, and the number of bands per organism was reduced. PCR products from 10 of 11 different bacterial type strains tested could be differentiated from each other. With template mixtures consisting of pure-culture DNAs from 5 and 10 bacterial strains, most of the single strains could be detected from such model communities after PCR and SSCP analyses. Purified bands amplified from pure cultures and model communities extracted from gels could be reamplified by PCR, but by this process, additional products were also generated, as detected by further SSCP analysis. Profiles generated with DNAs of rhizosphere bacterial communities, directly extracted from two different plant species grown in the same field site, could be clearly distinguished. This study demonstrates the potential of the selected PCR-single-stranded DNA approach for microbial community analysis.
An RTOS API Translator for Model-Driven Embedded Software Development (2006)

In this paper, we present a model-driven approach to RTOS-based embedded software development and an automated tool that can produce RTOS-specific code. Our contributions are two fold. First, we defined generic RTOS APIs (application programming interfaces) that can capture most of typical RTOS services but are not bound to any specific RTOS. The generic RTOS APIs can be used as a means for describing application's RTOS-related behavior at an early design stage. We then developed an automated transformation tool that can generate functional code by transforming generic RTOS APIs into RTOS-specific APIs. Our tool, called TransPI, is able to produce 'C' code aimed at POSIX-compliant RTOSs, and is also configurable to target other RTOSs that do not conform to the POSIX standard
Ex vivo analysis of acinar and endocrine cell development in the human embryonic pancreas (2005)

In contrast to the considerable body of data on pancreas development in rodents, information on pancreas development in humans is scant. We previously described a model in which mature beta cells developed from human embryonic pancreas: human embryonic pancreas was grafted under the kidney capsule of scid mice, beta cells were then seen to develop in the graft. Here, we showed that not only beta cells, but also other endocrine cells, acinar cells and ducts develop in this model. We then used this model to probe the mechanisms underlying acinar and beta cell development in the human embryonic pancreas. BrdU pulse/chase experiments produced evidence of clonal acinar cell development: the first acinar cells to appear proliferated, thereby expanding the acinar cell population. In contrast, beta cell development was regulated by the proliferation of pancreatic progenitor cells, followed by beta-cell differentiation. We then showed that early progenitors expressing PDX1 proliferated, whereas late endocrine progenitors expressing Ngn3 did not. This proliferative capacity of early endocrine progenitor cells in embryonic human pancreas may hold promise for obtaining human beta-cell expansion.
Endoscopic treatment of vesico‐ureteric reflux and urinary incontinence: technical problems in the paediatric patient (1995)

Endoscopic treatment of VUR seems to be a valid alternative to open surgery, even though concerns remain about the long-term efficacy of collagen implantation. An important distinction should be made between early and late failure of the procedure. Early failure, which we define as persistence of reflux, is usually due to incorrect technique or technical difficulties. Late failure, or recurrence of reflux, which has previously been attributed to the biodegradability of collagen, seems to be due to the displacement of the injected collagen. Micturition itself or high bladder pressure (such as detrusor instability) could be responsible for the displacement of the injected collagen medially and distally, where it can no longer support the submucosal ureteric tunnel. In the treatment of urinary incontinence, both the implant technique and the choice of the site of injection seem to have a considerable effect on the results. In our experience, endoscopic collagen injection is effective in the treatment of both urinary incontinence and VUR in paediatric patients. Accurate selection of patients and technical adjustments and refinements are essential to obtain the best results.