gebhart/patrepeval huggingface dataset:
Preclinical PK and PD Studies on 2′-O-Methyl-phosphorothioate RNA Antisense Oligonucleotides in the mdx Mouse Model (2010)

Antisense oligonucleotides (AONs) are being developed as RNA therapeutic molecules for Duchenne muscular dystrophy. For oligonucleotides with the 2'-O-methyl-phosphorothioate (2OMePS) RNA chemistry, proof of concept has been obtained in patient-specific muscle cell cultures, the mouse and dog disease models, and recently by local administration in Duchenne patients. To further explore the pharmacokinetic (PK)/pharmacodynamic (PD) properties of this chemical class of oligonucleotides, we performed a series of preclinical studies in mice. The results demonstrate that the levels of oligonucleotides in dystrophin-deficient muscle fibers are much higher than in healthy fibers, leading to higher exon-skipping levels. Oligonucleotide levels and half-life differed for specific muscle groups, with heart muscle showing the lowest levels but longest half-life (approximately 46 days). Intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) delivery methods were directly compared. For each method, exon-skipping and novel dystrophin expression were observed in all muscles, including arrector pili smooth muscle in skin biopsies. After i.v. administration, the oligonucleotide peak levels in plasma, liver, and kidney were higher than after s.c. or i.p. injections. However, as the bioavailability was similar, and the levels of oligonucleotide, exon-skipping, and dystrophin steadily accumulated overtime after s.c. administration, we selected this patient-convenient delivery method for future clinical study protocols.
Structural Basis for Herbicidal Inhibitor Selectivity Revealed by Comparison of Crystal Structures of Plant and Mammalian 4-Hydroxyphenylpyruvate Dioxygenases (2004)

A high degree of selectivity toward the target site of the pest organism is a desirable attribute for new safer agrochemicals. To assist in the design of novel herbicides, we determined the crystal structures of the herbicidal target enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD; EC 1.13.11.27) from the plant Arabidopsis thaliana with and without an herbicidal benzoylpyrazole inhibitor that potently inhibits both plant and mammalian HPPDs. We also determined the structure of a mammalian (rat) HPPD in complex with the same nonselective inhibitor. From a screening campaign of over 1000 HPPD inhibitors, six highly plant-selective inhibitors were found. One of these had remarkable (>1600-fold) selectivity toward the plant enzyme and was cocrystallized with Arabidopsis HPPD. Detailed comparisons of the plant and mammalian HPPD-ligand structures suggest a structural basis for the high degree of plant selectivity of certain HPPD inhibitors and point to design strategies to obtain potent and selective inhibitors of plant HPPD as agrochemical leads.
Discovering Sequence Motifs with Arbitrary Insertions and Deletions (2008)

BIOLOGY IS ENCODED IN MOLECULAR SEQUENCES: deciphering this encoding remains a grand scientific challenge. Functional regions of DNA, RNA, and protein sequences often exhibit characteristic but subtle motifs; thus, computational discovery of motifs in sequences is a fundamental and much-studied problem. However, most current algorithms do not allow for insertions or deletions (indels) within motifs, and the few that do have other limitations. We present a method, GLAM2 (Gapped Local Alignment of Motifs), for discovering motifs allowing indels in a fully general manner, and a companion method GLAM2SCAN for searching sequence databases using such motifs. glam2 is a generalization of the gapless Gibbs sampling algorithm. It re-discovers variable-width protein motifs from the PROSITE database significantly more accurately than the alternative methods PRATT and SAM-T2K. Furthermore, it usefully refines protein motifs from the ELM database: in some cases, the refined motifs make orders of magnitude fewer overpredictions than the original ELM regular expressions. GLAM2 performs respectably on the BAliBASE multiple alignment benchmark, and may be superior to leading multiple alignment methods for "motif-like" alignments with N- and C-terminal extensions. Finally, we demonstrate the use of GLAM2 to discover protein kinase substrate motifs and a gapped DNA motif for the LIM-only transcriptional regulatory complex: using GLAM2SCAN, we identify promising targets for the latter. GLAM2 is especially promising for short protein motifs, and it should improve our ability to identify the protein cleavage sites, interaction sites, post-translational modification attachment sites, etc., that underlie much of biology. It may be equally useful for arbitrarily gapped motifs in DNA and RNA, although fewer examples of such motifs are known at present. GLAM2 is public domain software, available for download at http://bioinformatics.org.au/glam2.
Expression of MaTu‐MN protein in human tumor cultures and in clinical specimens (1993)

MaTu is a novel agent which may be of relevance in human oncogenesis, and has 2 components. One of them, the exogenous MX (coding for protein p58X), is transmissible to human fibroblasts, to HeLa and to HeLa x fibroblast (H/F) hybrids. The other component, MN, is a cellular gene. Its product, the protein p54/58N, is inducible by infecting HeLa cells with MX or by growing them in dense cultures. This p54/58N appears to be a tumor-associated antigen: it is expressed in HeLa and in tumorigenic cells (H/F-T), but not in fibroblasts or in nontumorigenic hybrid cells (H/F-N). Proteins related to p54/58N were also found on immunoblots prepared from human carcinomas of ovary, endometrium and uterine cervix, but not from normal tissues from corresponding organs or from placenta. Using genetically engineered MN protein, we developed a radioimmunoassay for MN-specific antibodies, and for quantitative determination of MN proteins in cell extracts. In HeLa cells infected with MX we observed conspicuous ultrastructural alterations: formation of abundant filaments on the cell surface and amplification of mitochondria. Using immunogold-staining, we visualized the p54/58N on the surface microvilli and in the nucleus, particularly in nucleoli.
Structural Basis of Mos1 Transposase Inhibition by the Anti-retroviral Drug Raltegravir (2014)

DNA transposases catalyze the movement of transposons around genomes by a cut-and-paste mechanism related to retroviral integration. Transposases and retroviral integrases share a common RNaseH-like domain with a catalytic DDE/D triad that coordinates the divalent cations required for DNA cleavage and integration. The anti-retroviral drugs Raltegravir and Elvitegravir inhibit integrases by displacing viral DNA ends from the catalytic metal ions. We demonstrate that Raltegravir, but not Elvitegravir, binds to Mos1 transposase in the presence of Mg(2+) or Mn(2+), without the requirement for transposon DNA, and inhibits transposon cleavage and DNA integration in biochemical assays. Crystal structures at 1.7 Å resolution show Raltegravir, in common with integrases, coordinating two Mg(2+) or Mn(2+) ions in the Mos1 active site. However, in the absence of transposon ends, the drug adopts an unusual, compact binding mode distinct from that observed in the active site of the prototype foamy virus integrase.
Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: Implications in atherosclerosis (2002)

We previously reported that testosterone attenuated atherogenesis in LDLR(-/-) male mice, and that this effect of testosterone was most likely caused by its conversion to estradiol. Estradiol inhibits vascular cell adhesion molecule-1 (VCAM-1) expression, and expression of VCAM-1 is one of the early events in atherogenesis. We assessed the cellular mechanism(s) involved by which testosterone attenuates atherogenesis. We evaluated whether testosterone inhibited TNFalpha-induced VCAM-1 expression via its conversion to estradiol by the enzyme aromatase in human umbilical vein endothelial cells (HUVEC). Aromatase mRNA was dedected by reverse transcription-PCR in these cells. Testosterone (30 nM-1 microM) attenuated VCAM-1 mRNA expression in a concentration-dependent manner. The non aromatizable androgen, dihydrotestosterone, had no effect on VCAM-1 mRNA expression. Testosterone was less effective in attenuating VCAM-1 expression in the presence of anastrozole, an inhibitor of aromatase, indicating that testosterone inhibited VCAM-1 via conversion to estradiol. Estradiol also attenuated VCAM-1 mRNA expression, but this action was not abolished in the presence of anastrozole, indicating that anastrozole itself did not modulate VCAM-1 mRNA expression. The effect of testosterone on VCAM-1 mRNA expression was inhibited in the presence of the estrogen receptor antagonist, ICI-182780. Testosterone also attenuated TNFalpha-induced VCAM-1 protein expression, and this attenuation was abolished in the presence of anastrozole. In conclusion, testosterone inhibited VCAM-1 mRNA and protein expression in HUVEC by its conversion to estradiol via the enzyme aromatase present in the endothelial cells. Results from our study may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system.
The Respectability Trap: Gender Conventions in 20th Century Movements for Social Change (2013)

An analysis of how a variety of women in 19th and 20th century movements for social change in the United States negotiated normative gender expectations in both their activism and their personal lives. While challenging norms or using traditional norms as a part of a movement tactic are both common in social movements, women leaders still sometimes found themselves in a ‘respectability trap’ when they reflexively applied the dictates of respectable behavior. In these moments, the often invisible privileges attached to the social recognition of a woman’s respectability – and implied morality – become visible. Women who eschewed traditional norms of public behavior and presentation risked having themselves and their movements dismissed out of hand. Seen in this light, leaders who fell into ingrained conventional social norms should not been seen as weak or incompletely radicalized, rather their experiences point to the complexities for women inherent in negotiating social expectations.
Synthesis and Characterization of Chitosan-Based Diazeniumdiolates (2008)

diethylenetriamine(DETA) and propionic aldehyde(PA) were employed individually to modify the primary amine groups on chitosan.Two diazeniumdiolates(chitosan/NO adducts) were prepared by suspending the chitosan derivatives in sodium methoxide-methanol solution at 6 atm for seven days,and their chemical structures were identified by FT-IR,UV and 1H-NMR and 13C-NMR.The NO release profiles for chitosans derivatives in PBS solution(pH 7.4,37 ℃) were investigated by the Griess assay.The results show that the increase of nucleophilic sites on DETA modified chitosan results in high loadings of NO,the maximum NO release of CS/DETA/NO and CS/PA/NO is 1945 nmol/mg and 1156 nmol/mg respectively.
Emulating the Electrical Activity of the Neuron Using a Silicon Oxide RRAM Cell (2016)

In recent years, formidable effort has been devoted to exploring the potential of Resistive RAM (RRAM) devices to model key features of biological synapses. This is done to strengthen the link between neuro-computing architectures and neuroscience, bearing in mind the extremely low power consumption and immense parallelism of biological systems. Here we demonstrate the feasibility of using the RRAM cell to go further and to model aspects of the electrical activity of the neuron. We focus on the specific operational procedures required for the generation of controlled voltage transients, which resemble spike-like responses. Further, we demonstrate that RRAM devices are capable of integrating input current pulses over time to produce thresholded voltage transients. We show that the frequency of the output transients can be controlled by the input signal, and we relate recent models of the redox-based nanoionic resistive memory cell to two common neuronal models, the Hodgkin-Huxley (HH) conductance model and the leaky integrate-and-fire model. We employ a simplified circuit model to phenomenologically describe voltage transient generation.
Mechanism and stereochemical course at phosphorus of the reaction catalyzed by a bacterial phosphotriesterase (1988)

The reaction mechanism for the phosphotriesterase from Pseudomonas diminuta has been examined. When paraoxon (diethyl 4-nitrophenyl phosphate) is hydrolyzed by this enzyme in oxygen-18-labeled water, the oxygen-18 label is found exclusively in the diethyl phosphate product. The absolute configurations for the (+) and (-) enantiomers of O-ethyl phenylphosphonothioic acid have been determined by X-ray diffraction structural determination of the individual crystalline 1-phenylethylamine salts. The (+) enantiomer of the free acid corresponds to the RP configuration. The RP enantiomer of O-ethyl phenylphosphonothioic acid has been converted to the SP enantiomer of EPN [O-ethyl O-(4-nitrophenyl) phenylphosphonothioate]. (SP)-EPN is hydrolyzed by the phosphotriesterase to the SP enantiomer of O-ethyl phenylphosphonothioic acid. The enzymatic reaction therefore proceeds with inversion of configuration. These results have been interpreted as an indication of a single in-line displacement by an activated water molecule directly at the phosphorus center of the phosphotriester substrate. (RP)-EPN is not hydrolyzed by the enzyme at an appreciable rate.
microRNA in erythrocytes (2010)

Mammalian erythrocytes are generally thought to lack RNA and therefore to be unable to translate new proteins in response to internal or external signals. Support for this long-standing view has accumulated from diverse studies, most of which have focused on the total content of RNA or the overall level of translation. However, more recent work on specific types of RNA has shown the presence in human erythrocytes of both Y RNA and microRNA. The latter seem particularly incongruous given that their normal role is to attenuate the translation of mRNA. Y RNA binds the Ro autoantigen which may have a role in cellular RNA quality control. Therefore the presence of both of these non-coding RNAs indicates the possible existence of other cryptic RNAs in erythrocytes. It also suggests either the existence of low levels of translation or new uncharacterized processes involving microRNA in these cells.
Advanced services management via intelligent access peripherals (2002)

The new reality of worldwide telecommunications deregulation is forcing service providers to quickly adapt networks for delivery of new value added services. This paper proposes a new paradigm of network technology deployment for value added services delivery. The proposal demonstrates that an intelligent access peripheral (IAP), based on the advanced intelligent network (AIN) standards, is the catalyst for service providers (SPs) to efficiently and effectively provide value added services. Although researchers focus on "residential broadband" and other futuristic technologies, most SPs are asking the following question. What services can be installed today that will increase the network's efficiency and profitability? One can always increase the "utility" value of a network by supplying more bandwidth, since faster speeds generally mean lower delays and fewer packet losses. However, one can also increase the network value by keeping the bandwidth fixed and delivering a wider variety of services than just a single class of best effort service. We show, by way of example, that IAPs are an ideal vehicle for delivering a wider variety of services.
농어촌 독거노인의 생활실태 및 복지욕구 조사 - 전라남도를 중심으로 - (2011)

본 연구는 전남 지역 농·어촌 독거노인의 삶의 질을 향상시키고 정책 수립의 기초자료로 사용하고자 292명의 독거노인을 대상으로 생활실태와 복지서비스 요구를 설문조사하였다. 그 결과 독거노인의 고령화와 여성화 경향이 크게 나타났고 경제적으로는 공적 부조에 의존하고 있으며 건강 상태는 대부분 좋지 못한 것으로 나타났다. 대부분 재래식 단독주택에 거주하였으나 현재 주거에 만족하였으며, 여가생활은 T.V시청과 라디오 청취가 대부분이었다. 생활만족도는 생활에 활기나 보람이 없다고 응답한 비율이 높았다. 가장 많이 이용하는 사회복지 서비스는 무료 급식이었고, 가장 이용하고 싶어 하는 것은 방문요양서비스, 가장 필요로 하는 것은 소득보장과 일자리 지원이었다. 이런 결과로 볼 때 농어촌 노인의 삶의 질을 높이기 위해서는 자신의 집에서 자립해서 생활할 수 있도록 농어촌 지역 특성을 살려 일자리를 창출하고 가정 간호, 가사 지원, 주거 개선, 교통 환경 개선 등의 재가복지를 위한 서비스를 제공하는 것이 바람직하다고 볼 수 있다.
Mutations in the Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews (2004)

Our results suggest that heterozygosity for a GBA mutation may predispose Ashkenazi Jews to Parkinson's disease.
Protease Inhibitors as Anticarcinogens<xref ref-type="fn" rid="FN3">3</xref> (1984)

editorials as a means of transmitting to investigators in cancer
Classifying trending topics (2011)

Twitter summarizes the great deal of messages posted by users in the form of trending topics that reflect the top conversations being discussed at a given moment. These trending topics tend to be connected to current affairs. Different happenings can give rise to the emergence of these trending topics. For instance, a sports event broadcasted on TV, or a viral meme introduced by a community of users. Detecting the type of origin can facilitate information filtering, enhance real-time data processing, and improve user experience. In this paper, we introduce a typology to categorize the triggers that leverage trending topics: news, current events, memes, and commemoratives. We define a set of straightforward language-independent features that rely on the social spread of the trends to discriminate among those types of trending topics. Our method provides an efficient way to immediately and accurately categorize trending topics without need of external data, outperforming a content-based approach.
Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cellsin vitroin a TLR4-independent manner (2012)

Myeloid cells play a key role in the outcome of anti-tumor immunity and response to anti-cancer therapy, since in the tumor microenvironment they may exert both stimulatory and inhibitory pressures on the proliferative, angiogenic, metastatic, and immunomodulating potential of tumor cells. Therefore, understanding the mechanisms of myeloid regulatory cell differentiation is critical for developing strategies for the therapeutic reversal of myeloid derived suppressor cell (MDSC) accumulation in the tumor-bearing hosts. Here, using an in vitro model system, several potential mechanisms of the direct effect of paclitaxel on MDSC were tested, which might be responsible for the anti-tumor potential of low-dose paclitaxel therapy in mice. It was hypothesized that a decreased level of MDSC in vivo after paclitaxel administration might be due to (i) the blockage of MDSC generation, (ii) an induction of MDSC apoptosis, or (iii) the stimulation of MDSC differentiation. The results revealed that paclitaxel in ultra-low concentrations neither increased MDSC apoptosis nor blocked MDSC generation, but stimulated MDSC differentiation towards dendritic cells. This effect of paclitaxel was TLR4-independent since it was not diminished in cell cultures originated from TLR4-/- mice. These results support a new concept that certain chemotherapeutic agents in ultra-low non-cytotoxic doses may suppress tumor progression by targeting several cell populations in the tumor microenvironment, including MDSC.
Multi‐Way Analysis with Applications in the Chemical Sciences (2004)

This book is an introduction to the field of multi-way analysis for chemists and chemometricians. Its emphasis is on the ideas behind the method and its pratical applications. Sufficient mathematical background is given to provide a solid understanding of the ideas behind the method. There are currently no other books on the market which deal with this method from the viewpoint of its applications in chemistry. Applicable in many areas of chemistry. No comparable volume currently available. The field is becoming increasingly important.
ERG Cooperates with Androgen Receptor in Regulating Trefoil Factor 3 in Prostate Cancer Disease Progression (2010)

To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.
The light field stereoscope (2015)

Over the last few years, virtual reality (VR) has re-emerged as a technology that is now feasible at low cost via inexpensive cellphone components. In particular, advances of high-resolution micro displays, low-latency orientation trackers, and modern GPUs facilitate immersive experiences at low cost. One of the remaining challenges to further improve visual comfort in VR experiences is the vergence-accommodation conflict inherent to all stereoscopic displays. Accurate reproduction of all depth cues is crucial for visual comfort. By combining well-known stereoscopic display principles with emerging factored light field technology, we present the first wearable VR display supporting high image resolution as well as focus cues. A light field is presented to each eye, which provides more natural viewing experiences than conventional near-eye displays. Since the eye box is just slightly larger than the pupil size, rank-1 light field factorizations are sufficient to produce correct or nearly-correct focus cues; no time-multiplexed image display or gaze tracking is required. We analyze lens distortions in 4D light field space and correct them using the afforded high-dimensional image formation. We also demonstrate significant improvements in resolution and retinal blur quality over related near-eye displays. Finally, we analyze diffraction limits of these types of displays.
Role of Nitric Oxide in the Visible Light-Induced Rapid Increase of Human Skin Microcirculation at the Local and Systemic Level: I. Diabetic Patients (2008)

Both types of irradiation stimulated microcirculation at the local and systemic levels through a mechanism of enhancement of endothelium-dependent and endothelium-independent vasodilation, in which nitric oxide plays a major role.
PARALOGOUS HOX GENES: Function and Regulation (1996)

The Hox homeobox gene family plays a pivotal role in regulating patterning and axial morphogenesis in vertebrates. Molecular characterization of the four Hox clusters has shown that they are evolutionarily related with respect to sequence, organization, and expression, suggesting they arose by duplication and divergence. Transgenic analysis has clearly demonstrated the functional roles of individual genes in a broad range of embryonic tissues, and in compound mutants has addressed the issues of cooperativity and redundancy. There is an emerging picture of the cis-regulatory elements underlying Hox expression, and for the 3' members of the clusters there is a considerable degree of conservation between paralogous genes with respect to their functional roles and regulatory control.