gebhart/patrepeval huggingface dataset:
Glucocorticoids induce a near-total suppression of hyaluronan synthase mRNA in dermal fibroblasts and in osteoblasts: a molecular mechanism contributing to organ atrophy (2000)

Glucocorticoid (GC) administration induces atrophy of skin, bone, and other organs, partly by reducing tissue content of glycosaminoglycans, particularly hyaluronic acid (HA). We took advantage of the recent cloning of the three human hyaluronan synthase (HAS) enzymes (HAS1, HAS2 and HAS3), to explore the molecular mechanisms of this side effect. Northern and slot blots performed on RNA extracted from cultured dermal fibroblasts and the MG-63 osteoblast-like osteosarcoma cell line indicated that HAS2 is the predominant HAS mRNA in these cells. Incubation of both cell types for 24 h in the presence of 10-6 M dexamethasone (DEX) resulted in a striking 97-98% suppression of HAS2 mRNA levels. Time-course studies in fibroblasts demonstrated suppression of HAS2 mRNA to 28% of control by 1 h, and to 1.2% of control by 2 h, after addition of DEX. Dose-response studies in fibroblasts indicated that the majority of the suppressive effect required concentrations characteristic of cell-surface GC receptors, a point confirmed by persistent DEX-induced suppression in the presence of RU486, an antagonist of classic cytosolic steroid hormone receptors. Nuclear run-off experiments showed a 70% suppression of HAS2 gene transcription in nuclei from DEX-treated fibroblasts, which is unlikely to fully explain the rapid 50-80-fold reduction in message levels. Experiments with actinomycin D (AMD) demonstrated that the message half-life was 25 min in cells without DEX, whereas the combination of AMD with DEX dramatically increased the half-life of HAS2 mRNA, suggesting that DEX acts by inducing a short-lived destabilizer of the HAS2 message. Direct assessment of HAS2 mRNA stability by wash-out of incorporated uridine label established a half-life of 31 min in cells without DEX, which substantially shortened in the presence of DEX. In conclusion, GCs induce a rapid and sustained, near-total suppression of HAS2 message levels, mediated through substantial decreases in both gene transcription and message stability. These effects may contribute to the loss of HA in GC-treated organs.
Novel therapy for COPD (2000)

The incidence of chronic obstructive pulmonary disease (COPD) is increasing throughout the world. Much less is known about the pathogenesis of COPD than that of asthma and there is little response to current therapy. Most patients with COPD have acquired their lung disease through smoking cigarettes, and the major step in management is to minimise further damage by stopping this habit. A number of therapies are being developed for the treatment of COPD; including new bronchodilators such as tiotropium bromide, agents to block inflammation induced by neutrophils and macrophages, as well as strategies to combat proteases and oxidants. The long-term goal is to provide therapy that retards the accelerated loss of lung function occurring in COPD. Development of novel therapies for COPD requires reliable Phase II decision making before entering large scale Phase III studies. The patient with COPD is often overlooked compared to their asthmatic counterpart, who benefit from an urgent need to identify novel targets and better therapy.
Lack of mitochondrial topoisomerase I ( TOP1mt ) impairs liver regeneration (2015)

The liver has an exceptional replicative capacity following partial hepatectomy or chemical injuries. Cellular proliferation requires increased production of energy and essential metabolites, which critically depend on the mitochondria. To determine whether Top1mt, the vertebrate mitochondrial topoisomerase, is involved in this process, we studied liver regeneration after carbon tetrachloride (CCl4) administration. TOP1mt knockout (KO) mice showed a marked reduction in regeneration and hepatocyte proliferation. The hepatic mitochondrial DNA (mtDNA) failed to increase during recovery from CCl4 exposure. Reduced glutathione was also depleted, indicating increased reactive oxygen species (ROS). Steady-state levels of ATP, O2 consumption, mtDNA, and mitochondrial mass were also reduced in primary hepatocytes from CCl4-treated KO mice. To further test whether Top1mt acted by enabling mtDNA regeneration, we tested TOP1mt KO fibroblasts and human colon carcinoma HCT116 cells and measured mtDNA after 3-d treatment with ethidium bromide. Both types of TOP1mt knockout cells showed defective mtDNA regeneration following mtDNA depletion. Our study demonstrates that Top1mt is required for normal mtDNA homeostasis and for linking mtDNA expansion with hepatocyte proliferation.
GPipe: Efficient Training of Giant Neural Networks using Pipeline Parallelism (2018)

Scaling up deep neural network capacity has been known as an effective approach to improving model quality for several different machine learning tasks. In many cases, increasing model capacity beyond the memory limit of a single accelerator has required developing special algorithms or infrastructure. These solutions are often architecture-specific and do not transfer to other tasks. To address the need for efficient and task-independent model parallelism, we introduce GPipe, a pipeline parallelism library that allows scaling any network that can be expressed as a sequence of layers. By pipelining different sub-sequences of layers on separate accelerators, GPipe provides the flexibility of scaling a variety of different networks to gigantic sizes efficiently. Moreover, GPipe utilizes a novel batch-splitting pipelining algorithm, resulting in almost linear speedup when a model is partitioned across multiple accelerators. We demonstrate the advantages of GPipe by training large-scale neural networks on two different tasks with distinct network architectures: (i) Image Classification: We train a 557-million-parameter AmoebaNet model and attain a top-1 accuracy of 84.4% on ImageNet-2012, (ii) Multilingual Neural Machine Translation: We train a single 6-billion-parameter, 128-layer Transformer model on a corpus spanning over 100 languages and achieve better quality than all bilingual models.
Phytochromes B, D, and E Act Redundantly to Control Multiple Physiological Responses in Arabidopsis (2003)

Phytochrome-mediated perception of the ratio of red to far-red wavelengths in the ambient light environment is fundamental to plant growth and development. Such monitoring enables plants to detect neighboring vegetation and initiate avoidance responses, thus conferring considerable selective advantage. The shade avoidance syndrome in plants is characterized by elongation growth and early flowering, responses that are fully induced by end-of-day far-red light treatments. Elucidating the roles of individual phytochromes in mediating responses to red to far-red has however always been confounded by synergistic and mutually antagonistic coactions between family members. The creation of triple and quadruple mutants in Arabidopsis, deficient in multiple phytochromes, has revealed functional redundancy between phyB, D, and E in controlling flowering time, leaf development, and regulation of the homeobox gene, ATHB-2. In addition, mutant analysis suggests a possible novel role for phyC in suppressing ATHB-2 transcription in the light.
Resonance transmittance through a metal film with subwavelength holes (2002)

An analytical theory for extraordinary light transmittance through an optically thick metal film with subwavelength holes is developed. It is shown that the film transmittance has sharp peaks that are due to the Maxwell-Garnet resonances in the holes. There are localized electric and magnetic resonances resulting in, respectively, dramatically enhanced electric and magnetic fields in the holes. A simple analytical expression for the resonance transmittance is derived that holds for arbitrary hole distribution. It is also shown that there are other types of transmittance resonances, when the holes are arranged into a regular lattice. These resonances occur because of the excitation of surface plasmon polaritons propagating over the film surface. A combination of the two kinds of resonances results in a rich spectral behavior in the extraordinary optical transmittance.
Activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine against human cytomegalovirus when administered as single-bolus dose and continuous infusion in in vitro cell culture perfusion system (1994)

HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] is a potent inhibitor of human cytomegalovirus (HCMV) replication as determined by conventional tissue culture methods in which the drug concentration remains constant over time. Previous studies have shown HPMPC to have a long intracellular half-life. Despite its relatively short extracellular half-life, HPMPC might provide significant anti-HCMV activity long after the elimination of the drug by first-order kinetics. We addressed this hypothesis by measuring the activity of HPMPC in a novel cell culture perfusion system. This system allows us to compare the activity of HPMPC when given as a continuous infusion with its activity when given as a single-bolus dose followed by elimination that simulates the drug's in vivo pharmacokinetics. We show that continuous infusions maintaining maximum concentrations (Cmaxs) of 0.05, 0.10, 0.31, and 1.0 micrograms/ml and achieving areas under the drug concentration-time curves (AUCs) of 8.4, 17, 50, and 162 micrograms.h/ml, respectively, result in 27, 56, 63, and 88% inhibition of viral DNA accumulation, respectively, compared with an untreated control. Single-bolus doses achieving Cmaxs of 0.10, 1.25, 3.0, and 7.7 micrograms/ml with an elimination half-life of 20 h achieved AUCs of 2.4, 32, 78, and 138 micrograms.h/ml and resulted in 0, 48, 69, and 87% inhibition of HCMV DNA accumulation. Single-bolus doses achieving Cmaxs of 3.9 and 12 micrograms/ml with an elimination half-life of 6.5 h achieved AUCs of 34 and 105 micrograms.h/ml, respectively, resulting in 15 and 76% inhibition of viral DNA accumulation. Comparison of Cmax-versus-effect curves for these three regimens suggests that maximum concentration is not the only important pharmacokinetic determinant of HPMPC's antiviral activity. Similar comparisons of AUC-versus-effect curves for continuous and bolus dosing suggest that the AUC is an important determinant of antiviral activity for AUCs greater than 100 micrograms . h/ml. We conclude that single-bolus doses of HPMPC potently inhibit HCMV DNA accumulation but that this activity is more heavily influenced by the AUC than the Cmax at the upper end of the AUC range tested. At lower AUCs, some other parameter may be the primary determinant of antiviral activity. Our cell culture perfusion system provides a novel, efficient, and convenient method for addressing questions relating the effects of constantly changing drug concentrations to antiviral effects.
Lipoxygenase H1 Gene Silencing Reveals a Specific Role in Supplying Fatty Acid Hydroperoxides for Aliphatic Aldehyde Production (2002)

Lipoxygenases catalyze the formation of fatty acid hydroperoxide precursors of an array of compounds involved in the regulation of plant development and responses to stress. To elucidate the function of the potato 13-lipoxygenase H1 (LOX H1), we have generated transgenic potato plants with reduced expression of the LOX H1 gene as a consequence of co-suppression-mediated gene silencing. Three independent LOX H1-silenced transgenic lines were obtained, having less than 1% of the LOX H1 protein present in wild-type plants. This depletion of LOX H1 has no effect on the basal or wound-induced levels of jasmonates derived from 13-hydroperoxylinolenic acid. However, LOX H1 depletion results in a marked reduction in the production of volatile aliphatic C6 aldehydes. These compounds are involved in plant defense responses, acting as either signaling molecules for wound-induced gene expression or as antimicrobial substances. LOX H1 protein was localized to the chloroplast and the protein, expressed in Escherichia coli, showed activity toward unesterified linoleic and linolenic acids and plastidic phosphatidylglycerol. The results demonstrate that LOX H1 is a specific isoform involved in the generation of volatile defense and signaling compounds through the HPL branch of the octadecanoid pathway.
cis - and trans -Acting Elements in Flavivirus RNA Replication (2000)

Most of the seven flavivirus nonstructural proteins (NS1 to NS5) encoded in the distal two-thirds of the RNA positive-sense genome are believed to be essential components of RNA replication complexes. To explore the functional relationships of these components in RNA replication, we used trans-complementation analysis of full-length infectious RNAs of Kunjin (KUN) virus with a range of lethal in-frame deletions in the nonstructural coding region, using as helper a repBHK cell line stably producing functional replication complexes from KUN replicon RNA. Recently we showed that replication of KUN RNAs with large carboxy-terminal deletions including the entire RNA polymerase region in the NS5 gene, representing 34 to 75% of the NS5 coding content, could be complemented after transfection into repBHK cells. In this study we have demonstrated that KUN RNAs with deletions of 84 to 97% of the NS1 gene, or of 13 to 63% of the NS3 gene including the entire helicase region, were also complemented in repBHK cells with variable efficiencies. In contrast, KUN RNAs with deletions in any of the other four nonstructural genes NS2A, NS2B, NS4A, and NS4B were not complemented. We have also demonstrated successful trans complementation of KUN RNAs containing either combined double deletions in the NS1 and NS5 genes or triple deletions in the NS1, NS3, and NS5 genes comprising as much as 38% of the entire nonstructural coding content. Based on these and our previous complementation results, we have generated a map of cis- and trans-acting elements in RNA replication for the nonstructural coding region of the flavivirus genome. These results are discussed in the context of our model on formation and composition of the flavivirus replication complex, and we suggest molecular mechanisms by which functions of some defective components of the replication complex can be complemented by their wild-type counterparts expressed from another (helper) RNA molecule.
Microchemical systems for continuous-flow synthesis (2009)

Microchemical systems have evolved rapidly over the last decade with extensive chemistry applications. Such systems enable discovery and development of synthetic routes while simultaneously providing increased understanding of underlying pathways and kinetics. We review basic trends and aspects of microsystems as they relate to continuous-flow microchemical synthesis. Key literature reviews are summarized and principles governing different microchemical operations discussed. Current trends and limitations of microfabrication, micromixing, chemical synthesis in microreactors, continuous-flow separations, multi-step synthesis, and integration of analytics are delineated. We conclude by summarizing the major challenges and outlook related to these topics.
Changes and Regulation of the C5a Receptor on Neutrophils during Septic Shock in Humans (2013)

During experimental sepsis, excessive generation of the anaphylatoxin C5a results in reduction of the C5a receptor (C5aR) on neutrophils. These events have been shown to result in impaired innate immunity. However, the regulation and fate of C5aR on neutrophils during sepsis are largely unknown. In contrast to 30 healthy volunteers, 60 patients in septic shock presented evidence of complement activation with significantly increased serum levels of C3a, C5a, and C5b-9. In the septic shock group, the corresponding decrease in complement hemolytic activity distinguished survivors from nonsurvivors. Neutrophils from patients in septic shock exhibited decreased C5aR expression, which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome. In vitro exposure of normal neutrophils to native pentameric CRP led to a dose- and time-dependent loss of C5aR expression on neutrophils, whereas the monomeric form of CRP, as well as various other inflammatory mediators, failed to significantly alter C5aR levels on neutrophils. A circulating form of C5aR (cC5aR) was detected in serum by immunoblotting and a flow-based capture assay, suggestive of an intact C5aR molecule. Levels of cC5aR were significantly enhanced during septic shock, with serum levels directly correlating with lethality. The data suggest that septic shock in humans is associated with extensive complement activation, CRP-dependent loss of C5aR on neutrophils, and appearance of cC5aR in serum, which correlated with a poor outcome. Therefore, cC5aR may represent a new sepsis marker to be considered in tailoring individualized immune-modulating therapy.
Internalization of the thrombopoietin receptor is regulated by 2 cytoplasmic motifs (2003)

Receptor-mediated internalization appears to be the primary mean of regulating the plasma level of thrombopoietin (TPO). However, the processes that regulate Mpl internalization have not previously been described. Using the cytokine-dependent cell line BaF3, we have identified 2 distinct motifs within the cytoplasmic domain of Mpl that underlie ligand-dependent internalization. Removal of the fourth cytoplasmic tyrosine residue by deletion or truncation results in a significant decrease in maximal internalization. The remaining receptor internalization is abrogated by deletion of cytoplasmic residues 54-69, which include the core box2 region (L54L55E56I57L58) and the only dileucine motifs (L54L55 and I57L58) within the cytoplasmic domain of Mpl. Receptor internalization mediated by this latter subdomain does not require Jak2 activation. Furthermore, TPO-stimulated cellular proliferation appears to be directly correlated with receptor internalization, indicating that internalization of the TPO/Mpl complex may be essential for normal signal transduction. Finally, we have demonstrated that upon removal of TPO from the supernatant, Mpl promptly reappears on the cell surface, suggesting that a pool of intracellular Mpl can be rapidly recycled to the cell surface. These data help identify the receptor motifs involved in TPO-induced internalization of Mpl and suggest that Mpl translocation may be necessary for normal cellular proliferation.
Intraoperative localization of neuroendocrine tumors with 125I-TYR(3)-octreotide and a hand-held gamma-detecting probe. (1993)

Tumor-specific peptide-receptor binding can be detected in situ with 125J-TYR(3)-octreotide and a hand-held gamma-detecting probe. This technique may facilitate neuroendocrine tumor localization and operative cytoreduction.
[Effectiveness of various alfuzosin schedules in patients with benign prostatic hyperplasia (BPH)]. (2001)

238 patients with initial BPH (mean age 64.07 years) were treated with alfusosine in a standard dose 5 mg twice a day for 6 months. After that 117 patients continued the above scheme while 121 patients continued to receive alfusosine in the same dose each other day. The results assessed by IPSS, QOL, maximal urine flow rate, levels of prostate-specific antigen in the serum appeared identical in both groups. Thus, the split course of alfusosine after 6-month standard therapy is perspective as it is more cost effective than the standard scheme being equally beneficial.
Palmitate Impairs and Eicosapentaenoate Restores Insulin Secretion Through Regulation of SREBP-1c in Pancreatic Islets (2008)

SREBP-1c plays a dominant role in palmitate-mediated insulin secretion defect, and EPA prevents it through SREBP-1c inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity.
A Big Gene Linked to Small Eyes Encodes Multiple Mitf Isoforms: Many Promoters Make Light Work (1998)

Among more than 80 different loci related to mouse coat color, microphthalmia-associated transcription factor (Mitf) encoded at the mouse microphthalmia locus is one of the most exciting molecules that regulates the development and survival of many cell types, including melanocyte, retinal pigment epithelium (RPE), and mast cells. Mitf and its human homolog MITF consist of at least three isoforms, referred to as Mitf-A/MITF-A, the heart-type Mitf-H/MITF-H, and the melanocyte lineage-specific Mitf-M/MITF-M, respectively. These isoforms differ in the amino-terminal domains but share a transactivation domain and a basic helix-loop-helix and leucine-zipper structure that is required for DNA binding and dimerization. MITF-M is exclusively expressed in melanocytes and melanoma cells, but not in other cell types, including RPE cells. In contrast, MITF-A mRNA is widely expressed in many cell types. These three isoform mRNAs are possibly generated by differential usage of the gene promoters and by alternative splicing. We predict that the entire MITF gene spans about 200 kb of DNA. Like MITF-M, MITF-A is able to activate the two melanogenesis gene promoters, tyrosinase and tyrosinase-related protein 1. These results suggest that melanogenesis may be regulated by different MITF isoforms in melanocyte and RPE. Possible implications of the multiplicity in Mitf/MITF isoforms are discussed.
Complications of Smallpox Vaccination, 1968: Results of Ten Statewide Surveys (1970)

Complications of Smallpox Vaccination, 1968: Results of Ten Statewide Surveys Get access J. Michael Lane, J. Michael Lane Search for other works by this author on: Oxford Academic PubMed Google Scholar Frederick L. Ruben, Frederick L. Ruben Search for other works by this author on: Oxford Academic PubMed Google Scholar John M. Neff, John M. Neff Search for other works by this author on: Oxford Academic PubMed Google Scholar J. D. Millar J. D. Millar Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 122, Issue 4, October 1970, Pages 303–309, https://doi.org/10.1093/infdis/122.4.303 Published: 01 October 1970 Article history Received: 03 April 1970 Revision received: 26 June 1970 Published: 01 October 1970
An Efficient Four-Parameter Affine Motion Model for Video Coding (2017)

In this paper, we study a simplified affine motion model-based coding framework to overcome the limitation of a translational motion model and maintain low-computational complexity. The proposed framework mainly has three key contributions. First, we propose to reduce the number of affine motion parameters from 6 to 4. The proposed four-parameter affine motion model can not only handle most of the complex motions in natural videos, but also save the bits for two parameters. Second, to efficiently encode the affine motion parameters, we propose two motion prediction modes, i.e., an advanced affine motion vector prediction scheme combined with a gradient-based fast affine motion estimation algorithm and an affine model merge scheme, where the latter attempts to reuse the affine motion parameters (instead of the motion vectors) of neighboring blocks. Third, we propose two fast affine motion compensation algorithms. One is the one-step sub-pixel interpolation that reduces the computations of each interpolation. The other is the interpolation-precision-based adaptive block size motion compensation that performs motion compensation at the block level rather than the pixel level to reduce the number of interpolation. Our proposed techniques have been implemented based on the state-of-the-art high-efficiency video coding standard, and the experimental results show that the proposed techniques altogether achieve, on average, 11.1% and 19.3% bits saving for random access and low-delay configurations, respectively, on typical video sequences that have rich rotation or zooming motions. Meanwhile, the computational complexity increases of both the encoder and the decoder are within an acceptable range.