gebhart/patrepeval huggingface dataset:
Water-soluble Aβ(N-40, N-42) Oligomers in Normal and Alzheimer Disease Brains (1996)

Ultracentrifugation and graded molecular sieving, as well as a sensitive sandwich enzyme-linked immunosorbent assay were used to isolate and quantitate the amounts of water-soluble oligomers of beta amyloid (Abeta) peptides N-40 and N-42 in cerebral cortex of normal and Alzheimer disease (AD) brains. AD brains contained 6-fold more water-soluble Abeta (wsAbeta) than control brains. The majority of water-soluble peptides in most AD cases was A beta N-42, representing 12 times the amount found in control brains. The wsAbeta was present in the form of monomers and oligomers ranging from less than 10 kDa to greater than 100 kDa. The amount of wsAbeta N-42 in AD brains is about 50 times greater than the level of soluble Abeta N-42 found in the CSF of AD patients. This disparity may be due to the rapid association of wsAbeta N-42 into fibrillar deposits and/or to the integrity of the anatomical barriers which separate the two extracellular spaces. In this paper, we consider soluble any form of Abeta which has not yet polymerized into its insoluble, filamentous form. This includes both the newly synthesized forms of Abeta and those peptides which may be loosely attached to insoluble filaments but which can, nevertheless, still be considered soluble. It has been previously shown that, once it has aggregated into its filamentous form, the Abeta peptides are resistant to disaggregation and degradation by a number of denaturing agents and aqueous buffers containing proteolytic enzymes. Therefore, it is likely that the water-soluble Abeta peptides we quantified are precursors to its insoluble, filamentous form. Consequently, reducing the levels of soluble Abeta in AD brains could have profound effects on AD pathophysiology.
Sequence analysis of T-cell repertoires in health and disease (2013)

T-cell antigen receptor (TCR) variability enables the cellular immune system to discriminate between self and non-self. High-throughput TCR sequencing (TCR-seq) involves the use of next generation sequencing platforms to generate large numbers of short DNA sequences covering key regions of the TCR coding sequence, which enables quantification of T-cell diversity at unprecedented resolution. TCR-seq studies have provided new insights into the healthy human T-cell repertoire, such as revised estimates of repertoire size and the understanding that TCR specificities are shared among individuals more frequently than previously anticipated. In the context of disease, TCR-seq has been instrumental in characterizing the recovery of the immune repertoire after hematopoietic stem cell transplantation, and the method has been used to develop biomarkers and diagnostics for various infectious and neoplastic diseases. However, T-cell repertoire sequencing is still in its infancy. It is expected that maturation of the field will involve the introduction of improved, standardized tools for data handling, deposition and statistical analysis, as well as the emergence of new and equivalently large-scale technologies for T-cell functional analysis and antigen discovery. In this review, we introduce this nascent field and TCR-seq methodology, we discuss recent insights into healthy and diseased TCR repertoires, and we examine the applications and challenges for TCR-seq in the clinic.
Expression of aurora kinase A is associated with metastasis-free survival in node-negative breast cancer patients (2012)

AURKA is associated with worse prognosis in estrogen receptor positive breast carcinomas. Patients with the highest AURKA expression (>75% percentile) have a particularly bad prognosis and may profit from therapy with AURKA inhibitors.
Structure of the MUR1 GDP-Mannose 4,6-Dehydratase from Arabidopsis thaliana:  Implications for Ligand Binding and Specificity (2002)

GDP-D-mannose 4,6-dehydratase catalyzes the first step in the de novo synthesis of GDP-L-fucose, the activated form of L-fucose, which is a component of glycoconjugates in plants known to be important to the development and strength of stem tissues. We have determined the three-dimensional structure of the MUR1 dehydratase isoform from Arabidopsis thaliana complexed with its NADPH cofactor as well as with the ligands GDP and GDP-D-rhamnose. MUR1 is a member of the nucleoside-diphosphosugar modifying subclass of the short-chain dehydrogenase/reductase enzyme family, having homologous structures and a conserved catalytic triad of Lys, Tyr, and Ser/Thr residues. MUR1 is the first member of this subfamily to be observed as a tetramer, the interface of which reveals a close and intimate overlap of neighboring NADP(+)-binding sites. The GDP moiety of the substrate also binds in an unusual syn conformation. The protein-ligand interactions around the hexose moiety of the substrate support the importance of the conserved triad residues and an additional Glu side chain serving as a general base for catalysis. Phe and Arg side chains close to the hexose ring may serve to confer substrate specificity at the O2 position. In the MUR1/GDP-D-rhamnose complex, a single unique monomer within the protein tetramer that has an unoccupied substrate site highlights the conformational changes that accompany substrate binding and may suggest the existence of negative cooperativity in MUR1 function.
Crystal Structure of Human AKT1 with an Allosteric Inhibitor Reveals a New Mode of Kinase Inhibition (2010)

AKT1 (NP_005154.2) is a member of the serine/threonine AGC protein kinase family involved in cellular metabolism, growth, proliferation and survival. The three human AKT isozymes are highly homologous multi-domain proteins with both overlapping and distinct cellular functions. Dysregulation of the AKT pathway has been identified in multiple human cancers. Several clinical trials are in progress to test the efficacy of AKT pathway inhibitors in treating cancer. Recently, a series of AKT isozyme-selective allosteric inhibitors have been reported. They require the presence of both the pleckstrin-homology (PH) and kinase domains of AKT, but their binding mode has not yet been elucidated. We present here a 2.7 Å resolution co-crystal structure of human AKT1 containing both the PH and kinase domains with a selective allosteric inhibitor bound in the interface. The structure reveals the interactions between the PH and kinase domains, as well as the critical amino residues that mediate binding of the inhibitor to AKT1. Our work also reveals an intricate balance in the enzymatic regulation of AKT, where the PH domain appears to lock the kinase in an inactive conformation and the kinase domain disrupts the phospholipid binding site of the PH domain. This information advances our knowledge in AKT1 structure and regulation, thereby providing a structural foundation for interpreting the effects of different classes of AKT inhibitors and designing selective ones.
Try to Development of an Instrument to Measure the Cognitive Appraisal for Preoperative Surgical Patient in the Adulthood (1999)

本研究は成人期の術前患者の認知的評価尺度開発への試みとして初期段階での尺度の信頼性と妥当性を検討することを目的とした.はじめに,尺度原案はLazarusら (1984/1991) の理論を概念枠組みとし, また面接を通じて得たデータを基に3下位尺度70項目で構成された.次に尺度の信頼性と妥当性を内容妥当性, 表面妥当性, 構成概念妥当性, 内的整合性の視点から検討した. 内容妥当性は外科系実践看護婦6名と成人看護学領域の研究者21名の計27名を被検者に, 表面妥当性はがん疾患で術前1週間以内の患者17名を被検者に検討した. この時点で4下位尺度55項目となった. 構成概念妥当性と内的整合性 (信頼性) は同条件の患者70名を被検者に検討した. 因子分析 (主因子法・バリマックス回転) の結果7因子を抽出し, 最終的には手術との出会いにおける (1) 抑うつ的見積もり,(2) 消極的対処選択への見積もり,(3) 好機的見積もり,(4)防衛的見積もり,(5) 挑戦的見積もり,(6) 回避的見積もり,(7) 楽観的対処選択への見積もり, の7下位尺度47項目で構成された. また内的整合性は全体でCronbach's α 係数0.83, 下位尺度ごとでCronbach's α 係数0.62～0.86の値を示し, 尺度開発への試みの段階としてはある程度の信頼性と妥当性を得ることができた.
Anti-tumor activity of stability-engineered IgG-like bispecific antibodies targeting TRAIL-R2 and LTβR (2009)

Bispecific antibodies (BsAbs) represent an emerging class of biologics that achieve dual targeting with a single agent. Recombinant DNA technologies have facilitated a variety of creative bispecific designs with many promising therapeutic applications; however, practical methods for producing high quality BsAbs that have good product stability, long serum half-life, straightforward purification, and scalable production have largely been limiting. Here we describe a protein-engineering approach for producing stable, scalable tetravalent IgG-like BsAbs. The stability-engineered IgG-like BsAb was envisioned to target and crosslink two TNF family member receptors, TRAIL-R2 (TNF-Related Apoptosis Inducing Ligand Receptor-2) and LTbetaR (Lymphotoxin-beta Receptor), expressed on the surface of epithelial tumor cells with the goal of triggering an enhanced anti-tumor effect. Our IgG-like BsAbs consists of a stability-engineered anti-LTbetaR single chain Fv (scFv) genetically fused to either the N- or C-terminus of the heavy chain of a fulllength anti-TRAIL-R2 IgG1 monoclonal antibody. Both N- or C-terminal BsAbs were active in inhibiting tumor cell growth in vitro, and with some cell lines demonstrated enhanced activity relative to the combination of parental Abs. Pharmacokinetic studies in mice revealed long serum half-lives for the BsAbs. In murine tumor xenograft models, therapeutic treatment with the BsAbs resulted in reduction in tumor volume either comparable to or greater than the combination of parental antibodies, indicating that simultaneously targeting and cross-linking receptor pairs is an effective strategy for treating tumor cells. These studies support that stability-engineering is an enabling step for producing scalable IgG-like BsAbs with properties desirable for biopharmaceutical development.
Severity of mucosal inflammation as a predictor for alterations of visceral sensory function in a rat model (2006)

Transient inflammation is known to alter visceral sensory function and frequently precede the onset of symptoms in a subgroup of patients with irritable bowel syndrome (IBS). Duration and severity of the initial inflammatory stimulus appear to be risk factors for the manifestation of symptoms. Therefore, we aimed to characterize dose-dependent effects of trinitrobenzenesulfonic acid (TNBS)/ethanol on: (1) colonic mucosa, (2) cytokine release and (3) visceral sensory function in a rat model. Acute inflammation was induced in male Lewis rats by single administration of various doses of TNBS/ethanol (total of 0.8, 0.4 or 0.2 ml) in test animals or saline in controls. Assessment of visceromotor response (VMR) to colorectal distensions, histological evaluation of severity of inflammation, and measurement of pro-inflammatory cytokine levels (IL-2, IL-6) using enzyme-linked immunosorbent assay (ELISA) were performed 2h and 3, 14, 28, 31 and 42 days after induction. Increased serum IL-2 and IL-6 levels were evident prior to mucosal lesions 2h after induction of colitis and persist up to 14 days (p<0.05 vs. saline), although no histological signs of inflammation were detected at 14 days. In the acute phase, VMR was only significantly increased after 0.8 ml and 0.4 ml TNBS/ethanol (p<0.05 vs. saline). After 28 days, distension-evoked responses were persistently elevated (p<0.05 vs. saline) in 0.8 and 0.4 ml TNBS/ethanol-treated rats. In 0.2 ml TNBS/ethanol group, VMR was only enhanced after repeated visceral stimulation. Visceral hyperalgesia occurs after a transient colitis. However, even a mild acute but asymptomatic colitis can induce long-lasting visceral hyperalgesia in the presence of additional stimuli.
Expression of Cre recombinase during transient phage infection permits efficient marker removal in Streptomyces (2006)

We report a system for the efficient removal of a marker flanked by two loxP sites in Streptomyces coelicolor, using a derivative of the temperate phage phiC31 that expresses Cre recombinase during a transient infection. As the test case for this recombinant phage (called Cre-phage), we present the construction of an in-frame deletion of a gene, pglW, required for phage growth limitation or Pgl in S.coelicolor. Cre-phage was also used for marker deletion in other strains of S.coelicolor.
Therapeutic effects of two antidepressant agents in the treatment of posttraumatic stress disorder (PTSD) (2003)

Posttraumatic stress disorder (PTSD) is a psychiatric disorder characterised by an acute emotional response to a traumatic event or situation involving severe environmental stress (natural disasters, wars, epidemics, rape, assaults, physical torture, catastrophic illness or accident), which may be identified in cognitive, affective or sensory motor activities. The objective was to perform a pilot clinical trial designed to compare the effects of older (tricyclic) and newer "second-generation" (selective inhibitors of serotonin uptake) antidepressants in the treatment of PTSD. A total of 20 hospitalised chronic military combat Bosnian veterans with PTSD symptoms were randomly assigned into two groups of 10 patients each. One group was treated with amitriptyline hydrochloride (AMYZOL) 75 mg/day as a representative of older antidepressants and the other with fluoxetine hydrochloride 60 mg/day (OXETIN) as a representative of newer antidepressants. Those drugs were administered by mouth two or three times-a-day in equally divided doses for at least 8 weeks. Favourable response was achieved in 70% of patients treated with amitriptyline hydrochloride and 60% of patients treated with fluoxetine hydrochloride. Amitriptyline hydrochloride was more effective in the treatment of acute PTSD symptoms (emotional numbing, startle reaction, nightmares, flashbacks, intrusive thoughts, vulnerability, poor impulse control or irritability and explosiveness). Fluoxetine hydrochloride showed a greater efficacy in the treatment of chronic PTSD symptoms (avoidance and numbing symptoms, hyperarousal, nightmares and a feeling of guilt).
Effect of Histone Deacetylase Inhibitors on HIV Production in Latently Infected, Resting CD4+ T Cells From Infected Individuals Receiving Effective Antiretroviral Therapy (2012)

Persistence of the latent viral reservoir has been recognized as a major obstacle to eradicating human immunodeficiency virus (HIV) in infected individuals receiving antiretroviral therapy. It has been suggested that histone deacetylase inhibitors (HDACis) may purge HIV in the latent viral reservoir. However, the effect of HDACis on the degree and extent of HIV expression in the latent viral reservoir has not been fully delineated. Here we demonstrate that HDACis do not induce HIV production in the latent viral reservoir of aviremic individuals. Therefore, alternative therapeutic strategies may be necessary to eliminate HIV in the latent viral reservoir.
Pneumonic plague in monkeys. An electron microscopic study. (1969)

Abstract : The infection of monkey lungs by Pasteurella pestis was studied with the electron microscope. The disease was first apparent clinically at 60 to 70 hours and pathologically at 72 hours. At this time, the initial response seen with the light microscope was alveolar edema with massive proliferation of organisms. With the electron microscope, interstitial edema around veins and bronchi was the earliest observed response to the presence of numerous intra- alveolar bacilli. Early in the disease, before the onset of a leukocytic exudate, interstitial fluid also accumulated in the form of subepithelial blebs. No evidence of significant vascular damage was found to account for the marked increase in permeability, even with the aid of intravenous injections of colloidal carbon prior to sacrifice. Leukocytic and mast cell factors in the pathogenesis of the edema appear unlikely. Once the cellular component of the reaction developed, P. pestis resisted both phagocytosis by polymorphonuclear neutrophils and intracellular digestion by mononuclear phagocytes. Invasion of the tissues by the organism was observed only in the advanced stages of the pneumonia, when all components of the alveolar septa were undergoing necrosis.
Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patientswith human immunodeficiency virus: Inverse Gaussian density absorption and 2‐compartment disposition* (2002)

An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.
Oligodeoxynucleotides as inhibitors of gene expression: a review. (1988)

The past several years have seen an explosive growth in the application of antisense oligodeoxynucleotides as modulators of gene expression. In this review, we discuss the various classes of compounds currently receiving attention. These include unmodified oligodeoxynucleotides, methylphosphonates, phosphorothioates, and alpha-oligonucleotides. The relative advantages and disadvantages of each class with regard to parameters such as (a) duplex stability (b) nuclease resistance, and (c) effectiveness of specific gene inhibition are noted. Oligodeoxynucleotides covalently linked to intercalating and other reactive groups are also described, as are possible mechanisms of oligodeoxynucleotide action. Finally, we consider potential future directions for this field and note that it holds the promise for specific gene therapy.
Chromosomal bar codes produced by multicolor fluorescence in situ hybridization with multiple YAC clones and whole chromosome painting probes (1993)

Colored chromosome staining patterns, termed chromosomal 'bar codes' (CBCs), were obtained on human chromosomes by fluorescence in situ hybridization (FISH) with pools of Alu-PCR products from YAC clones containing human DNA inserts ranging from 100 kbp to 1 Mbp. In contrast to conventional G- or R-bands, the chromosomal position, extent, individual color and relative signal intensity of each 'bar' could be modified depending on probe selection and labeling procedures. Alu-PCR amplification products were generated from 31 YAC clones which mapped to 37 different chromosome bands. For multiple color FISH, Alu-PCR amplification products from various clones were either biotinylated or labeled with digoxigenin. Probes from up to twenty YAC clones were used simultaneously to produce CBCs on selected human chromosomes. Evaluation using a cooled CCD camera and digital image analysis confirmed the high reproducibility of the bars from one metaphase spread to another. Combinatorial FISH with mixtures of whole chromosomes paint probes was applied to paint seven chromosomes simultaneously in different colors along with a set of YAC clones which map to these chromosomes. We discuss the potential to construct analytical chromosomal bar codes adapted to particular needs of cytogenetic investigations and automated image analysis.
Use of C57BL/6N mice on the variety of immunological researches (2017)

Inbred mice are an essential animal strain for research as they can improve the reproducibility and reliability of study results. The establishment of new inbred lines is continuing, and new inbred lines are being used in many research fields. C57BL/6 is a mouse laboratory animal that has been developed and used as an inbred strain since early stage of mouse strain development, and, in the 1950s, C57BL/6 was separated into substrains by the Jackson Laboratory (C57BL/6J) and the National Institutes of Health (C57BL/6N). C57BL/6 mice have been used in immunology and antitumor activity studies since the early strain development stage. After the mouse genome was fully described, C57BL/6 mice use in many areas of research has expanded. In particular, immunological characteristics such as those related to cell-mediated immunity and NK cell activity are relatively higher in C57BL/6 mice than in other mice. The C57BL/6NKorl is a stock of C57BL/6N established as part of a localization of experimental animal strategy of the Korean Food and Drug Administration. Based on analysis of single nucleotide polymorphisms (SNPs), C57BL/6NKorl is considered a genetically distinct inbred stock from other C57BL/6N. Various research efforts have been made to describe the characteristics and increase knowledge of the characteristics of C57BL/6Nkorl. The results obtained through these efforts are expected to increase the utilization of C57BL/6Nkorl as a domestic laboratory animal resource and to enhance the reliability of mouse based studies.
Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. (1991)

Intercellular adhesion molecule 1 (ICAM-1) is a glycoprotein expressed on the surface of both hemopoietic and nonhemopoietic cells that mediates, in part, the emigration of leukocytes out of the vasculature. Expression of ICAM-1 on the surface of human umbilical vein endothelial cells and a human lung carcinoma cell line (A549) was increased by interleukin-1 beta, tumor necrosis factor alpha, and interferon gamma in a concentration-dependent manner. Phosphorothioate antisense oligonucleotides designed to hybridize to 10 target sites on the human ICAM-1 mRNA were tested for inhibition of ICAM-1 expression in both cell lines by an ICAM-1 enzyme-linked immunosorbent assay. Based upon potency and unique mRNA target sites, two oligonucleotides were studied in greater detail: ISIS 1570, which targeted the AUG translation initiation codon, and ISIS 1939, which targeted specific sequences in the 3'-untranslated region of the mRNA. Both oligonucleotides specifically inhibit expression of ICAM-1 as analyzed by immunoprecipitation of 35S-labeled proteins. Treatment of cells with ISIS 1939 promoted a reduction in ICAM-1 mRNA, whereas ISIS 1570 did not change the level of ICAM-1 mRNA, suggesting that the two oligonucleotides may be inhibiting ICAM-1 expression by two different mechanisms. The activity of both oligonucleotides was blocked by hybridization of the oligonucleotide to its complementary sense strand prior to addition to the cells. Neither ISIS 1570 nor ISIS 1939 changed the transcriptional rate of the ICAM-1 gene, demonstrating that both oligonucleotides were working through a post-transcriptional mechanism. 2'-O-Methyl phosphorothioate analogs, which do not support RNase H-mediated cleavage of target mRNA, were used to determine if the active antisense oligonucleotides inhibited ICAM-1 expression by an RNase H-dependent mechanism. The 2'-O-methyl phosphorothioate analog of ISIS 1939 did not significantly reduce interleukin-1 beta-induced ICAM-1 expression, whereas the 2'-O-methyl phosphorothioate analog of ISIS 1570 did inhibit ICAM-1 expression, suggesting that the reduction of ICAM-1 mRNA following treatment with ISIS 1939 was due, in part, to RNase H-mediated hydrolysis. Adherence of HL-60 cells to human umbilical vein cell monolayers was inhibited by ISIS 1570 and ISIS 1939, demonstrating that the reduced levels of ICAM-1 impact on ICAM-1-associated function.
Humanized mice for immune system investigation: progress, promise and challenges (2020)

Significant advances in our understanding of the in vivo functions of human cells, tissues and immune systems have resulted from the development of mouse strains that are based on severely immunodeficient mice expressing mutations in the interleukin-2 (IL-2) receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analysis of human immune biology, development and functions. In this Review, we discuss recent advances in the development of humanized mice, the lessons learned, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology.