gebhart/patrepeval huggingface dataset:
Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward (2007)

Opioids remain the most effective analgesics despite their potential adverse effects such as tolerance and addiction. Mechanisms underlying these opiate-mediated processes remain the subject of much debate. Here we describe opioid-induced behaviors of Lmx1b conditional knockout mice (Lmx1bf/f/p), which lack central serotonergic neurons, and we report that opioid analgesia is differentially dependent on the central serotonergic system. Analgesia induced by a kappa opioid receptor agonist administered at the supraspinal level was abolished in Lmx1bf/f/p mice compared with their wild-type littermates. Furthermore, compared with their wild-type littermates Lmx1bf/f/p mice exhibited significantly reduced analgesic effects of mu and delta opioid receptor agonists at both spinal and supraspinal sites. In contrast to the attenuation in opioid analgesia, Lmx1bf/f/p mice developed tolerance to morphine analgesia and displayed normal morphine reward behavior as measured by conditioned place preference. Our results provide genetic evidence supporting the view that the central serotonergic system is a key component of supraspinal pain modulatory circuitry mediating opioid analgesia. Furthermore, our data suggest that the mechanisms of morphine tolerance and morphine reward are independent of the central serotonergic system.
Ligand-induced activation of A431 cell epidermal growth factor receptors occurs primarily by an autocrine pathway that acts upon receptors on the surface rather than intracellularly. (1991)

A431 cells express high numbers of epidermal growth factor (EGF) receptors and produce a ligand for these receptors, transforming growth factor-alpha (TGF-alpha). We have obtained evidence that the EGF receptors on these cells may be activated through an "autocrine" pathway by ligand and have investigated whether activation of phosphorylation of the receptor by the endogenously produced TGF-alpha occurs intracellularly or at the cell surface. When A431 cells were cultured under serum-free conditions, in the absence of exogenous ligand, EGF receptors were found to have a basal level of phosphorylation. When cells were labeled by culturing with 32Pi in the continuous presence of monoclonal antibodies that block binding of TGF-alpha to the EGF receptor, phosphorylation decreased to 30 +/- 10% of the basal level. This reduction could not be accounted for by the decrease in receptor content attributable to down-regulation and catabolism of EGF receptors that resulted from the binding of anti-receptor monoclonal antibodies. The reduction in receptor phosphorylation mediated by antibody was accompanied by the accumulation of increased levels of secreted TGF-alpha species in the culture medium. We also pulse-labeled A431 cells for 15 min with [35S]cysteine and immunoprecipitated the cell lysate with anti-phosphotyrosine antibody after various chase periods. Tyrosine-phosphorylated EGF receptor became detectable after 40 min of chase and reached a maximum after 4-6 h; these times are in agreement with the intervals required for EGF receptors to reach the cell surface after synthesis and then to achieve maximal expression. In addition, only the 170-kDa, mature EGF receptor species, and not the 160-kDa intracellular precursor, was immunoprecipitated with the anti-phosphotyrosine antibody. The results of these pulse-chase experiments and the finding that anti-receptor monoclonal antibody can block receptor phosphorylation suggest that activation of EGF receptors can result from the binding of an endogenous ligand (presumably TGF-alpha), which occurs at the cell surface and not during receptor biosynthesis and intracellular processing.
Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor (2010)

Primary human keratinocytes are useful for studying the pathogenesis of many different diseases of the cutaneous and mucosal epithelia. In addition, they can form organotypic tissue equivalents in culture that can be used as epidermal autografts for wound repair as well as for the delivery of gene therapy. However, primary keratinocytes have a finite lifespan in culture that limits their proliferative capacity and clinical use. Here, we report that treatment of primary keratinocytes (originating from 3 different anatomical sites) with Y-27632, a Rho kinase inhibitor, greatly increased their proliferative capacity and resulted in efficient immortalization without detectable cell crisis. More importantly, the immortalized cells displayed characteristics typical of primary keratinocytes; they had a normal karyotype and an intact DNA damage response and were able to differentiate into a stratified epithelium. This is the first example to our knowledge of a defined chemical compound mediating efficient cell immortalization, and this finding could have wide-ranging and profound investigational and medical applications.
Polarization sensitive optical coherence tomography in the human eye (2011)

Optical coherence tomography (OCT) has become a well established imaging tool in ophthalmology. The unprecedented depth resolution that is provided by this technique yields valuable information on different ocular tissues ranging from the anterior to the posterior eye segment. Polarization sensitive OCT (PS-OCT) extends the concept of OCT and utilizes the information that is carried by polarized light to obtain additional information on the tissue. Several structures in the eye (e.g. cornea, retinal nerve fiber layer, retinal pigment epithelium) alter the polarization state of the light and show therefore a tissue specific contrast in PS-OCT images. First this review outlines the basic concepts of polarization changing light-tissue interactions and gives a short introduction in PS-OCT instruments for ophthalmic imaging. In a second part a variety of different applications of this technique are presented in ocular imaging that are ranging from the anterior to the posterior eye segment. Finally the benefits of the method for imaging different diseases as, e.g., age related macula degeneration (AMD) or glaucoma is demonstrated.
Cloning and Mutagenesis of the Murine Gammaherpesvirus 68 Genome as an Infectious Bacterial Artificial Chromosome (2000)

Gammaherpesviruses cause important infections of humans, in particular in immunocompromised patients. Recently, murine gammaherpesvirus 68 (MHV-68) infection of mice has been developed as a small animal model of gammaherpesvirus pathogenesis. Efficient generation of mutants of MHV-68 would significantly contribute to the understanding of viral gene functions in virus-host interaction, thereby further enhancing the potential of this model. To this end, we cloned the MHV-68 genome as a bacterial artificial chromosome (BAC) in Escherichia coli. During propagation in E. coli, spontaneous recombination events within the internal and terminal repeats of the cloned MHV-68 genome, affecting the copy number of the repeats, were occasionally observed. The gene for the green fluorescent protein was incorporated into the cloned BAC for identification of infected cells. BAC vector sequences were flanked by loxP sites to allow the excision of these sequences using recombinase Cre and to allow the generation of recombinant viruses with wild-type genome properties. Infectious virus was reconstituted from the BAC-cloned MHV-68. Growth of the BAC-derived virus in cell culture was indistinguishable from that of wild-type MHV-68. To assess the feasibility of mutagenesis of the cloned MHV-68 genome, a mutant virus with a deletion of open reading frame 4 was generated. Genetically modified MHV-68 can now be analyzed in functionally modified mouse strains to assess the role of gammaherpesvirus genes in virus-host interaction and pathogenesis.
Molybdenum and Tungsten Imido Alkylidene Complexes as Efficient Olefin‐Metathesis Catalysts (2003)

Catalytic olefin metathesis has quickly emerged as one of the most often-used transformations in modern chemical synthesis. One class of catalysts that has led the way to this significant development are the high-oxidation-state alkylidene complexes of molybdenum. In this review key observations that resulted in the discovery and development of molybdenum- and tungsten-based metathesis catalysts are outlined. An account of the utility of molybdenum catalysts in the synthesis of biologically significant molecules is provided as well. Another focus of the review is the use of chiral molybdenum complexes for enantioselective synthesis. These highly efficient catalysts provide unique access to materials of exceptional enantiomeric purity and often without generating solvent waste.
2016년 상법총칙, 상행위법 주요판례의 분석 (2017)

이 글은 2016년에 공간된 주요 상법총칙, 상행위법 판례 6건을 차례로 살펴본 것이다. 구체적으로 ① 영업양도에 대한 채권자 취소권 행사(2013다84162), ② 영업임차인에 대한 상호속용자 책임(2014다9212), ③ 상호 부정사용(2013다 76635), ④ 개업준비행위와 상사시효(2014다37552), ⑤ 공동수급체 구성원의 지분환급청구권과 상법상 연대책임(2015다233098), ⑥ 손해배상액 예정과 상사법정이율(2014다200763, 200770)이 각 판례의 주된 쟁점들이었다. 이 글에서는 가급적 일반론에 대한 논의를 줄이고 구체적인 쟁점에 초점을 맞추어 사안들을 분석하였다. 위 여섯 건에 관한 대부분의 대법원 판단은 합리적인 범위 내에서 이루어진 것으로 보인다. 다만 아래에서 보듯이 ⑥ 판결에서 손해배상액 예정액에 관하여 과실상계를 허용하지 않은 것은 비판의 소지가 있다. 판결들의 주요 판시사항 및 시사점을 구체적으로 살펴보면 다음과 같다. ① 영업양도에 대하여도 채권자 취소권을 행사할 수 있도록 함이 타당하다. 다만 향후 분할 등 조직법적 행위에 관하여도 채권자 취소권이 행사가능한지에 관하여는 아직 논란의 소지가 남아있다. ② 영업임차인에게 영업양도시 상호속용 양수인의 책임을 유추적용할 수는 없다. 상법 제42조 제1항은 “채권이 잔존함에도 불구하고 영업양수도 과정에서 병존적으로 인수된 것으로 오인한 채권자”를 보호하기 위한 것일 뿐 이를 영업임대차에까지 확장할 수는 없다. ③ 설사 창업주 때부터 실질적으로 함께 사용해 오던 영업표지라고 하더라도, 일부 계열사가 먼저 이를 이용해 상호 등기한 이후 다른 계열사가 유사한 상호를 사용한 경우, 후자의 사용에 오인가능성과 부정목적이 객관적으로 인정된다면 상호폐지청구권의 대상이다. ④ 개업준비행위과정에서 이루어진 자금대여인 경우 일정 요건하에 상사시효가 적용될 수 있는바, 주채무와 연대채무는 독립성을 갖기 때문에 각기 다른 시효가 적용될 여지도 있다. ⑤ 공동이행방식의 공동수급체는 민법상 조합이라고 할 것인바, 그 중 일부 조합원이 탈퇴하는 경우 잔존조합원들이 부담하는 지분환급의무는 상법 제57조 제1항에 따른 연대채무관계에 있다. 이렇듯 ① 내지 ⑤의 판시사항은 나름의 합리성을 갖는다. 반면 ⑥ 판결(2016.6. 10. 선고 2014다200763, 200770 판결)에서 대법원은 손해배상 예정시 과실상계는 허용되지 않는다고 판단하였으나, 의문이 있다. 손해배상 예정액 자체의 감액사유와 과실상계사유가 구분될 뿐 아니라, 채권자 자신의 과실에 대하여 배상할 필요가 없다는 과실상계의 일반적 논거는 손해배상 일반에 타당한 것으로 보아야 하기 때문이다.
Biomorphic Cellular Ceramics (2000)

Biotemplating—a new concept for preparation of ceramic composite materials with biomorphic microstructures will be described. Biological carbon preforms (CB-templates) were derived from different wood structures by high-temperature pyrolysis at temperatures between 800 and 1800 °C and used as templates for infiltration with gaseous or liquid Si to form SiC- and SiSiC-ceramics. During high-temperature processing, the microstructural details of the bioorganic preforms were retained. Cellular ceramic composites with unidirectional porous morphologies and anisotrophic mechanical properties were obtained. The cellular composites show low density, but high specific strength and excellent high temperature stability.
Pericentrin in cellular function and disease (2009)

Pericentrin is an integral component of the centrosome that serves as a multifunctional scaffold for anchoring numerous proteins and protein complexes. Through these interactions, pericentrin contributes to a diversity of fundamental cellular processes. Recent studies link pericentrin to a growing list of human disorders. Studies on pericentrin at the cellular, molecular, and, more recently, organismal level, provide a platform for generating models to elucidate the etiology of these disorders. Although the complexity of phenotypes associated with pericentrin-mediated disorders is somewhat daunting, insights into the cellular basis of disease are beginning to come into focus. In this review, we focus on human conditions associated with loss or elevation of pericentrin and propose cellular and molecular models that might explain them.
A Novel Algorithm of Sparse Representations for Speech Compression/Enhancement and Its Application in Speaker Recognition System (2016)

This paper proposes sparse and redundancy representation spectral domain compression of the speech signal using novel sparsing algorithms to the problem of speech compression (SC)/enhancement (SE). In Automatic Speaker Recognition (ASR) sparsification can play a major role to resolve big data issues in speech compression and its storage in the database, where the speech signal can be uncompressed before applying to ASR system. The speech signal is converted to a spectral domain using Discrete Rajan Transform (DRT) and only first and mid spectrum component is retained forcing the remaining component to zero. The speech signal spectrum can be maximally compressed 8:1 ratio to the unique one. Spectrally compressed speech signal can be stored in the database and during training and testing time it can be synthesized using Inverse Discrete Rajan Transform (IDRT) in ASR. Sparsification and spectral compression up to 75% with Equal Error Rate (EER) of ASR is 3%. Percentage of Identification Accuracy (PIA) of ASR with sparsification and speech enhancement is 99.1% and without sparsification 98.8% for TIMIT database respectively.
Clinical recognition and management of patients exposed to biological warfare agents (1997)

Concern regarding the use of biological agents--bacteria, viruses, or toxins--as tools of warfare or terrorism has led to measures to deter their use or, failing that, to deal with the consequences. Unlike chemical agents, which typically lead to violent disease syndromes within minutes at the site of exposure, diseases resulting from biological agents have incubation periods of days. Therefore, rather than a paramedic, it will likely be a physician who is first faced with evidence of the results of a biological attack. We provide here a primer on 10 classic biological warfare agents to increase the likelihood of their being considered in a differential diagnosis. Although the resultant diseases are rarely seen in many countries today, accepted diagnostic and epidemiologic principles apply; if the cause is identified quickly, appropriate therapy can be initiated and the impact of a terrorist attack greatly reduced.
Suppression of spontaneous melanoma metastasis in scid mice with an antibody to the epidermal growth factor receptor. (1991)

The human melanoma cell line M24met metastasizes spontaneously from s.c. tumors to multiple distant sites in mice with severe combined immunodeficiency. Metastasis to lymph nodes and lungs is found in 100% of the animals. M24met has an undifferentiated phenotype and extra copies of the short arm of chromosome 7. This cell line expresses the epidermal growth factor receptor, and 425.3, a monoclonal antibody to the epidermal growth factor receptor, binds to 291,000 receptor molecules per M24met cell with a KD of 2.3 x 10(-10) M. This antibody has no effect on the proliferation of M24met cells under tissue culture conditions and does not mediate effector cell or complement-dependent cytotoxicity of these cells in vitro. However, treatment of established s.c. M24met tumors in mice with severe combined immunodeficiency with monoclonal antibody 425.3 specifically suppresses spontaneous metastasis of these tumors. Total doses of 4, 2, and 1 mg antibody per mouse decrease the number and size of melanoma metastases and prolong the life span of treated animals. Treatment with 4 mg of the F(ab')2 fragment of monoclonal antibody 425.3 does not influence M24met melanoma metastasis, implying a significant contribution of the Fc portion to the antimetastatic effect of this antibody.
Achieving cell penetration with distance-matching cysteine cross-linkers: a facile route to cell-permeable peptide dual inhibitors of Mdm2/Mdmx (2011)

We report the design of bisarylmethylene bromides as a new class of rigid, distance-matching cysteine cross-linkers. By cross-linking a peptide dual inhibitor of Mdm2/Mdmx containing cysteines at i,i+7 positions, dramatic enhancement in cell permeability was achieved, along with increased helicity and biological activity.
Minimize the Detection of False Positives by the Software Program DetectShift for 18O-Labeled Cross-Linked Peptide Analysis (2008)

In order to speed up the process of cross-linked peptide identification and characterization, we have previously reported the development of Pro-CrossLink, a suite of software tools consisting of three programs, DetectShift, IdentifyXLink and AssignXLink for mass spectrometric data analysis. Since its public disclosure, Pro-CrossLink has been downloaded by 101 research groups. Pro-CrossLink users have provided us with valuable feedback on the use of the DetectShift program. Here we assess some reasons for the generation of false positives by DetectShift. In addition, we provide users with suggestions on optimal parameter setting and efficient use of the software program.
Failure of Poly(ADP-Ribose) Polymerase Cleavage by Caspases Leads to Induction of Necrosis and Enhanced Apoptosis (1999)

Activation of poly(ADP-ribose) polymerase (PARP) by DNA breaks catalyzes poly(ADP-ribosyl)ation and results in depletion of NAD+ and ATP, which is thought to induce necrosis. Proteolytic cleavage of PARP by caspases is a hallmark of apoptosis. To investigate whether PARP cleavage plays a role in apoptosis and in the decision of cells to undergo apoptosis or necrosis, we introduced a point mutation into the cleavage site (DEVD) of PARP that renders the protein resistant to caspase cleavage in vitro and in vivo. Here, we show that after treatment with tumor necrosis factor alpha, fibroblasts expressing this caspase-resistant PARP exhibited an accelerated cell death. This enhanced cell death is attributable to the induction of necrosis and an increased apoptosis and was coupled with depletion of NAD+ and ATP that occurred only in cells expressing caspase-resistant PARP. The PARP inhibitor 3-aminobenzamide prevented the NAD+ drop and concomitantly inhibited necrosis and the elevated apoptosis. These data indicate that this accelerated cell death is due to NAD+ depletion, a mechanism known to kill various cell types, caused by activation of uncleaved PARP after DNA fragmentation. The present study demonstrates that PARP cleavage prevents induction of necrosis during apoptosis and ensures appropriate execution of caspase-mediated programmed cell death.
Integrated approach to designing growth factor delivery systems (2007)

Growth factors have been widely used in strategies to regenerate and repair diseased tissues, but current therapies that go directly from bench to bedside have had limited clinical success. We hypothesize that engineering successful therapies with recombinant proteins will often require specific quantitative information of the spatiotemporal role of the factors and the development of sophisticated delivery approaches that provide appropriate tissue exposures. This hypothesis was tested in the context of therapeutic angiogenesis. An in vitro model of angiogenesis was adapted to quantify the role of the concentration/gradient of vascular endothelial growth factor [VEGF(165)] on microvascular endothelial cells, and a delivery system was then designed, based on a mathematical model, to provide the desired profile in ischemic mice hindlimbs. This system significantly enhanced blood vessel formation, and perfusion and recovery from severe ischemia. This general approach may be broadly applicable to growth factor therapies.
Modelling and fabrication of optimum structure of novel interdigital sensors for food inspection (2011)

SUMMARY Modelling of an interdigital sensor‐based sensing system for the detection of dangerous contaminated marine biotoxin in seafood has been carried out. Three interdigital sensors having new electrode configurations have been analysed using COMSOL Multiphysics. All sensors were designed to have an equal number of electrodes with the same sensing area. Based on the maximum sensitivity, the best electrode configuration has been chosen. Experiments on raw seafood contaminated with domoic acid have been conducted using the new fabricated sensor and very good results were obtained. Copyright © 2011 John Wiley &amp; Sons, Ltd.
Oxidative Dimer Formation Is the Critical Rate-Limiting Step for Parkinson's Disease α-Synuclein Fibrillogenesis (2002)

Intraneuronal deposition of alpha-synuclein as fibrils and oxidative stress are both implicated in the pathogenesis of Parkinson's disease. We found that the critical rate-limiting step in nucleation of alpha-synuclein fibrils under physiological conditions is the oxidative formation and accumulation of a dimeric, dityrosine cross-linked prenucleus. Dimer formation is accelerated for the pathogenic A30P and A53T mutant alpha-synucleins, because of their greater propensity to self-interact, which is reflected in the smaller values of the osmotic second virial coefficient compared to that of wild-type synuclein. Our finding that oxidation is an essential step in alpha-synuclein aggregation supports a mechanism of Parkinson's disease pathogenesis in which the separately studied pathogenic factors of oxidative stress and alpha-synuclein aggregation converge at the critical step of alpha-synuclein dimer formation.
Characterization and growth mechanism of nonpolar and semipolar GaN layers grown on patterned sapphire substrates (2012)

Nonpolar and semipolar GaN layers with markedly improved crystalline quality can be obtained by selective-area growth from the sapphire sidewalls of patterned sapphire substrates (PSSs). In this paper, we review the crystalline qualities of GaN layers grown on PSSs and their growth mechanism. We grew semipolar {1 1 −2 2} and {1 0 −1 1} GaN layers on r- and n-PSSs. The crystalline qualities of the GaN layers grown on the PSSs were higher than those of GaN layers grown directly on heteroepitaxial substrates. To reveal the growth mechanism of GaN layers grown on PSSs, we also grew various nonpolar and semipolar GaN layers such as m-GaN on a-PSS, {1 1 −2 2} GaN on r-PSS, {1 0 − 1 1} GaN on n-PSS, m-GaN on c-PSS and a-GaN on m-PSS. It was found that the nucleation of GaN on the c-plane-like sapphire sidewall results in selective growth from the sapphire sidewall, and nonpolar or semipolar GaN can be obtained. Finally, we demonstrated a light-emitting diode fabricated on a {1 1 −2 2} GaN layer grown on an r-PSS.
Sorafenib Functions to Potently Suppress RET Tyrosine Kinase Activity by Direct Enzymatic Inhibition and Promoting RET Lysosomal Degradation Independent of Proteasomal Targeting (2007)

Germ line missense mutations in the RET (rearranged during transfection) oncogene are the cause of multiple endocrine neoplasia, type 2 (MEN2), but at present surgery is the only treatment available for MEN2 patients. In this study, the ability of Sorafenib (BAY 43-9006) to act as a RET inhibitor was investigated. Sorafenib inhibited the activity of purified recombinant kinase domain of wild type RET and RET(V804M) with IC(50) values of 5.9 and 7.9 nm, respectively. Interestingly, these values were 6-7-fold lower than the IC(50) for the inhibition of B-RAF(V600E). In cell-based assays, Sorafenib inhibited the kinase activity and signaling of wild type and oncogenic RET in MEN2 tumor and established cell lines at a concentration between 15 and 150 nm. In contrast, inhibition of oncogenic B-RAF- or epidermal growth factor-induced ERK1/2 phosphorylation required micromolar concentrations of Sorafenib demonstrating the high specificity of this drug in targeting RET. Moreover, prolonged exposure to Sorafenib resulted in inhibition of cell proliferation and RET protein degradation. Using lysosomal and proteasomal inhibitors, we demonstrate that Sorafenib induces RET lysosomal degradation independent of proteasomal targeting. Furthermore, we provide a structural model of the Sorafenib.RET complex in which Sorafenib binds to and induces the DFG(out) conformation of the RET kinase domain. These results strengthen the argument that Sorafenib may be effective in the treatment of MEN2 patients. In addition, because inhibition of RET is not impaired by mutation of the Val(804) gatekeeper residue, MEN2 tumors may be less susceptible to acquired Sorafenib resistance.