gebhart/patrepeval huggingface dataset:
Tissue-specificity, functional characterization and subcellular localization of a rat ubiquitin-specific processing protease, UBP109, whose mRNA expression is developmentally regulated (2000)

A cDNA encoding an ubiquitin-specific processing protease, UBP109, in rat skeletal muscle was cloned and its product was characterized. Northern analysis revealed that UBP109 mRNA is highly expressed in testis and spleen, compared with other tissues. Furthermore, in situ hybridization showed that the level of UBP109 mRNA in liver, spinal cord and brain dramatically changed during embryonic development, indicating that the expression of UBP109 mRNA is developmentally regulated. UBP109 was expressed in Escherichia coli and purified to apparent homogeneity using a 125I-labelled ubiquitin-peptide fusion as a substrate. The purified enzyme cleaved at the C-terminus of the ubiquitin moiety in natural and engineered fusions irrespective of their sizes. UBP109 also released free ubiquitin from poly-His-tagged penta-ubiquitin. Moreover, it released free ubiquitin from poly-ubiquitinated protein conjugates of rabbit reticulocytes. In addition, UBP109 localized to both the cytoplasm and the nucleus and, among three putative nuclear localization sequences, only the one located near the C-terminus is responsible for nuclear localization. These results suggest that UBP109 may play an important role in generation of free ubiquitin from its precursors and its recycling from poly-ubiquitinated protein conjugates, and hence in regulation of ubiquitin-mediated cellular processes, particularly related to embryonic development.
Outcome measures in amyotrophic lateral sclerosis clinical trials (2014)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an average survival of 3-5 years. While therapies for ALS remain limited, basic and translational ALS research has been host to numerous influential discoveries in recent years. These discoveries have led to a large pipeline of potential therapies that await testing in clinical trials. Until recently, ALS clinical trials have relied on a limited cadre of 'traditional' outcome measures, including survival and measures of function. These measures have proven useful, although imperfect, in Phase III ALS trials. However, their utility in early-phase ALS trials is limited. For these early trials, outcome measures focused on target engagement or biological pathway analysis might improve trial outcomes and better support the drug development process.
Failure to achieve remyelination of demyelinated rat axons following transplantation of glial cells obtained from the adult human brain (1996)

The ability of transplanted glial cells to myelinate axons in experimental animals offers the prospect that it may be possible to achieve remyelination in human demyelinating disease by the implantation of oligodendrocyte lineage cells. Autologous normal white matter could represent a potential source of cells whose use would avoid tissue rejection and overcome ethical and practical constraints associated with the use of fetal tissue. To determine the remyelinating potential of cells isolated from adult human CNS, a cell preparation prepared from adult human white matter which contained 56% oligodendrocytes, 3% preoligodendrocytes and 1% precursor cells was transplanted into non-repairing demyelinating lesions in immunosuppressed rats created by the injection of ethidium bromide into x-irradiated spinal cord white matter. The extent of remyelination was examined 3 and 5 weeks after transplantation. Although the transplanted oligodendrocytes survived in the area of demyelination, associated with demyelinated axons and produced myelin membranes, no myelin sheaths were produced and there was no evidence of cell migration or division. The failure of human oligodendrocytes to form myelin sheaths may reflect the poor remyelinating potential of post mitotic oligodendrocytes, and the failure of the small number of co-transplanted bipotential oligodendrocyte progenitor cells to differentiate and myelinate axons may be a consequence of lack of appropriate environmental factors within the rat lesion required for expansion and differentiation of these cells.
Abstract B043: Systems pharmacology modeling of anti-CD20/CD3 T-cell dependent bispecific antibody and its application to clinical trial design (2016)

Abstract Objectives: To develop and apply a quantitative systems pharmacology (QSP) model to support clinical trial design for anti-CD20/CD3 T-cell dependent bispecific antibody in non-Hodgkin lymphoma (NHL). Methods: We developed a mechanistic model to describe the dynamics of B- and T-lymphocytes and their interactions in multiple physiological compartments (peripheral blood, tumor, and lymphoid tissues including the spleen, lymph nodes, and bone marrow) in the presence of an anti-CD20/CD3 T-cell dependent bispecific antibody (CD20-TDB) and the CD19-targeting bispecifc T-cell engager blinatumomab (a molecule with a similar mechanism of action, approved for ALL). The model is based on physiological, mechanistic, pharmacokinetic, and pharmacodynamic data and includes: 1) multiple activation states of CD8+ T-cells; 2) CD19+CD20- (pro-B), and CD19+CD20+ (pre- to mature-B) B-lymphocytes; and 3) the pharmacokinetics of CD20-TDB and blinatumomab and their mechanistic effects (activation of CD8+ T-lymphocytes and consequent killing of CD20+ and CD19+ B-lymphocytes, respectively). Results: The model was calibrated using in vitro potency data and circulating cell measurements in cynomolgous monkeys treated with CD20-TDB [1]. Preclinical and translational validation was performed using additional CD20-TDB preclinical data and blinatumomab clinical data [2, 3]. The model replicated the effects of CD20-TDB on cell dynamics in circulation, and predicted CD20-TDB preclinical data at lower doses and in tissues, and blinatumomab clinical data in patients with ALL and NHL. The model will be used to evaluate and propose dosing strategies for CD20-TDB in patients with NHL and to inform other clinical development considerations. Conclusions: The mechanism-based systems model accurately captures and predicts the pharmacodynamics of CD20-TDB in cynomolgous monkeys and in patients with ALL and NHL. The model provides a novel approach for evaluation of clinical dosing strategies for CD20-TDB and can be extended to related molecules and/or other B cell malignancies. References: [1] Sun LL, et al. Sci Transl Med. 2015; 7(287): 1-10. [2] Klinger M, et al. Blood. 2012;119(26):6226-3. [3] Hijazi Y, et al. Abstract: 3051. ASCO; May 31-June 4, 2013. Citation Format: Iraj Hosseini, Kapil Gadkar, Eric Stefanich, Chi-Chung Li, Laura Sun, Yu-Waye Chu, Saroja Ramanujan. Systems pharmacology modeling of anti-CD20/CD3 T-cell dependent bispecific antibody and its application to clinical trial design [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B043.
Homeodomain Leucine Zipper Class I Genes in Arabidopsis. Expression Patterns and Phylogenetic Relationships (2005)

Members of the homeodomain leucine zipper (HDZip) family of transcription factors are present in a wide range of plants, from mosses to higher plants, but not in other eukaryotes. The HDZip genes act in developmental processes, including vascular tissue and trichome development, and several of them have been suggested to be involved in the mediation of external signals to regulate plant growth. The Arabidopsis (Arabidopsis thaliana) genome contains 47 HDZip genes, which, based on sequence criteria, have been grouped into four different classes: HDZip I to IV. In this article, we present an overview of the class I HDZip genes in Arabidopsis. We describe their expression patterns, transcriptional regulation properties, duplication history, and phylogeny. The phylogeny of HDZip class I genes is supported by data on the duplication history of the genes, as well as the intron/exon patterning of the HDZip-encoding motifs. The HDZip class I genes were found to be widely expressed and partly to have overlapping expression patterns at the organ level. Further, abscisic acid or water deficit treatments and different light conditions affected the transcript levels of a majority of the HDZip I genes. Within the gene family, our data show examples of closely related HDZip genes with similarities in the function of the gene product, but a divergence in expression pattern. In addition, six HDZip class I proteins tested were found to be activators of gene expression. In conclusion, several HDZip I genes appear to regulate similar cellular processes, although in different organs or tissues and in response to different environmental signals.
Cellular Mechanisms Which Distinguish between Hormone‐ and Antihormone‐Activated Estrogen Receptor (1995)

The use of reverse genetics has permitted a definition of the structural features within estrogen receptor required for its productive association with the transcription apparatus. These sequences, transactivation function 1 (TAF1) in the amino terminus and TAF2 at the carboxyl terminus, display distinct transcriptional functions. Using specific receptor mutations it has been shown that on some promoters both TAF1 and TAF2 are required for maximal transcriptional activity, whereas on others, additional factors bound to the target promoter can functionally substitute for TAF1 or TAF2. Estrogen functions as an ER agonist by promoting functional synergism between TAF1 and TAF2. Conversely, 4-OH-tamoxifen inhibits TAF2 activity and functions as an antagonist in cell contexts where TAF2 is required. Alternatively, if a 'TAF2 function' is supplied by another factor, 4-OH tamoxifen can manifest ER agonist activity. These data indicate that alterations in the cellular expression of proteins which mimic TAF1 or TAF2 activity can have a profound effect on the pharmacology of ER modulators. Thus the identification of the cellular proteins which interact with ER and its TAF regions will allow a definition of the mechanism used by the cell to distinguish between hormone- and antihormone-activated estrogen receptor.
TEL/PDGFβR Induces Hematologic Malignancies in Mice That Respond to a Specific Tyrosine Kinase Inhibitor (1999)

The TEL/PDGFβR fusion protein is expressed as the consequence of a recurring t(5;12) translocation associated with chronic myelomonocytic leukemia (CMML). Unlike other activated protein tyrosine kinases associated with hematopoietic malignancies, TEL/PDGFβR is invariably associated with a myeloid leukemia phenotype in humans. To test the transforming properties of TEL/PDGFβR in vivo, and to analyze the basis for myeloid lineage specificity in humans, we constructed transgenic mice with TEL/PDGFβR expression driven by a lymphoid-specific immunoglobulin enhancer-promoter cassette. These mice developed lymphoblastic lymphomas of both T and B lineage, demonstrating that TEL/PDGFβR is a transforming protein in vivo, and that the transforming ability of this fusion is not inherently restricted to the myeloid lineage. Treatment of TEL/PDGFβR transgenic animals with a protein tyrosine kinase inhibitor with in vitro activity against PDGFβR (CGP57148) resulted in suppression of disease and a prolongation of survival. A therapeutic benefit was apparent both in animals treated before the development of overt clonal disease and in animals transplanted with clonal tumor cells. These results suggest that small-molecule tyrosine kinase inhibitors may be effective treatment for activated tyrosine kinase–mediated malignancies both early in the course of disease and after the development of additional transforming mutations.
Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation (2005)

Systemic lupus erythematosus (SLE) is the most common disease associated with antiphospholipid syndrome (APS). We, therefore, evaluated 46 patients with refractory SLE treated by autologous hematopoietic stem cell transplantation (HSCT) for a history of APS prior to transplantation. The prevalence of SLE-related APS in our patient population was 61% (28 of 46 patients with refractory SLE). Nineteen of 28 patients with APS had lupus anticoagulant (LA) or high titers of anticardiolipin antibodies (ACLAs), either immunoglobulin (Ig)G or IgM, when evaluated at study entry. Six of 8 evaluable LA+ patients became and remained LA-; 5 of 7 initially ACLA IgG+ patients and 9 of 11 ACLA IgM+ patients demonstrated normalization of ACLA titers when followed after HSCT. Eighteen of 22 patients refractory to chronic anticoagulation discontinued anticoagulation therapy a median of 4 months after transplantation; 78% of them remained free of thrombotic events and in complete SLE remission for up to 78 months (median, 15 months) after HSCT. There was no treatment-related mortality. Autologous HSCT may be performed safely in patients with APS and appears to be effective therapy for eliminating ALPAs and preventing thrombotic complications in patients with SLE.
How Do Humans Control Physiological Strain during Strenuous Endurance Exercise? (2008)

The overall results suggest that athletes are actively regulating their relative physiologic strain during competition, although there is evidence of poor regulation in the case of competitive failures.
Improved Golgi-like Visualization in Retrogradely Projecting Neurons after EGFP-Adenovirus Infection in Adult Rat and Monkey (2005)

An adenovirus vector was generated using a neuron-specific promoter synapsin I and enhanced green fluorescent protein (EGFP) reporter (AdSynEGFP). In addition, two modifications were identified that resulted in robust and reliable retrograde transport and EGFP expression after injection of the virus into three different brain regions in adult rats (medial prefrontal cortex, posterior thalamic nuclear group, and CA1). These are postinjection survival times of 14 days and addition of high concentrations of NaCl (>or=600 mM) to the injection buffer. These modifications resulted in obvious improvement in the intensity of the EGFP signal and in the number of labeled cells. Use of anti-EGFP in immunofluorescence or immunoperoxidase processing further enhanced the signal so that Golgi-like filling of dendritic spines and axon collaterals was routinely achieved. Effectiveness of the AdSynEGFP for Golgi-like filling was confirmed in one rhesus monkey with injections in visual area V4. Because of the long-term viability of the infected neurons (at least up to 28 days in rats and 22 days in monkey), this AdSynEGFP is suitable for use in microcircuitry studies in combination with other fluorescently tagged elements, including anterogradely labeled extrinsic projections. The native EGFP signal (without antibody enhancement) may be sufficient for studies involving cultured cells or slices.
Novel Antigen Identification Method for Discovery of Protective Malaria Antigens by Rapid Testing of DNA Vaccines Encoding Exons from the Parasite Genome (2004)

We describe a novel approach for identifying target antigens for preerythrocytic malaria vaccines. Our strategy is to rapidly test hundreds of DNA vaccines encoding exons from the Plasmodium yoelii yoelii genomic sequence. In this antigen identification method, we measure reduction in parasite burden in the liver after sporozoite challenge in mice. Orthologs of protective P. y. yoelii genes can then be identified in the genomic databases of Plasmodium falciparum and Plasmodium vivax and investigated as candidate antigens for a human vaccine. A pilot study to develop the antigen identification method approach used 192 P. y. yoelii exons from genes expressed during the sporozoite stage of the life cycle. A total of 182 (94%) exons were successfully cloned into a DNA immunization vector with the Gateway cloning technology. To assess immunization strategies, mice were vaccinated with 19 of the new DNA plasmids in addition to the well-characterized protective plasmid encoding P. y. yoelii circumsporozoite protein. Single plasmid immunization by gene gun identified a novel vaccine target antigen which decreased liver parasite burden by 95% and which has orthologs in P. vivax and P. knowlesi but not P. falciparum. Intramuscular injection of DNA plasmids produced a different pattern of protective responses from those seen with gene gun immunization. Intramuscular immunization with plasmid pools could reduce liver parasite burden in mice despite the fact that none of the plasmids was protective when given individually. We conclude that high-throughput cloning of exons into DNA vaccines and their screening is feasible and can rapidly identify new malaria vaccine candidate antigens.
Structural basis for reversible photobleaching of a green fluorescent protein homologue (2007)

Fluorescent protein (FP) variants that can be reversibly converted between fluorescent and nonfluorescent states have proven to be a catalyst for innovation in the field of fluorescence microscopy. However, the structural basis of the process remains poorly understood. High-resolution structures of a FP derived from Clavularia in both the fluorescent and the light-induced nonfluorescent states reveal that the rapid and complete loss of fluorescence observed upon illumination with 450-nm light results from cis-trans isomerization of the chromophore. The photoinduced change in configuration from the well ordered cis isomer to the highly nonplanar and disordered trans isomer is accompanied by a dramatic rearrangement of internal side chains. Taken together, the structures provide an explanation for the loss of fluorescence upon illumination, the slow light-independent recovery, and the rapid light-induced recovery of fluorescence. The fundamental mechanism appears to be common to all of the photoactivatable and reversibly photoswitchable FPs reported to date.
Role of Complement Cascade in Abdominal Aortic Aneurysms (2011)

These results provide strong evidence that the complement cascade plays a role in human AAA. Based on our microarray studies, the pathway is activated in AAA, particularly via the lectin and classical pathways. The overrepresented binding sites of transcription factor STAT5A in the complement cascade gene promoters suggest a role for STAT5A in the coordinated regulation of complement cascade gene expression.
Broad-host-range IncP-4 plasmid R1162: effects of deletions and insertions on plasmid maintenance and host range (1982)

R1162 is an 8.7-kilobase (kb) broad-host-range replicon encoding resistance to streptomycin and sulfa drugs. In vitro deletion of 1.8-kb DNA between coordinates 3.0 and 5.3 kb did not affect plasmid maintenance, but a Tn1 insertion at coordinate 6.3 kb led to a recessive defect in plasmid maintenance. The only cis-acting region necessary for plasmid replication appears to lie between the Tn1 insertion at coordinate 6.3 kb and a second Tn1 insertion at coordinate 6.5 kb. All R1162 sequences between position 6.5 kb and the EcoRI site at coordinate 8.7/0 kb were dispensible for replication in Escherichia coli and Pseudomonas putida. Plasmids carrying insertions in a variety of restriction sites in an R1162::Tn1 derivative were unstable in P. putida but stable in E. coli. Tn5 insertions in R1162 showed a hot spot at coordinate 7.5 kb. A Tn5 insertion at coordinate 8.2 kb appeared to mark the 3' end of the streptomycin phosphotransferase coding sequence. All R1162::Tn5 derivatives showed specific instability in Pseudomonas strains but not in E. coli. The instability could be relieved by internal deletions of Tn5 sequences. In the haloaromatic-degrading Pseudomonas sp. strain B13, introduction of an unstable R1162::Tn5 plasmid led to loss of ability to utilize m-chlorobenzoate as a growth substrate. Our results showed that alteration of plasmid sequence organization in nonessential regions can result in restriction of plasmid host range.
Stress measurements in mice after transportation (1995)

Experiments were performed using physiological measures and behavioural parameters to find the acclimatization period in mice to common scientific procedures. Corticosterone levels were significantly elevated in mice killed immediately after being moved to an experimental room (P < 0.05) but levels returned to the normal in less than 1 day, despite mice being exposed to additional stressors such as novel environment, new cages, new bedding material, separation from their cage mates, regrouping, isolation in individually housed mice and a new handler. Behaviours such as rearing, climbing, grooming, feeding and sexual, changed significantly immediately after transportation of mice but most of these behaviours stabilized relatively quickly. In spite of the corticosterone levels, our behavioural observations suggest that even 4 days were not enough to allow the mice to acclimatize fully.
Object voxelization by filtering (2002)

The authors analyze different filters used for the voxelization of analytically described objects. They show that, when the voxel model is used for visualization, the filter design is related to the subsequent rendering phase, namely the gradient estimation technique. The theoretical and experimental analyses show that, in order to avoid a systematic error in normal estimation, the density profile near the surface should be linearly proportional to the distance from the surface. Optimal thickness of this transient region has been estimated to be about 3 voxel units. Based on these results, they propose a technique for voxelization of arbitrary parametric surfaces, using a hierarchical subdivision of the 2D surface domain.
Longer and Shorter Forms of Sendai Virus C Proteins Play Different Roles in Modulating the Cellular Antiviral Response (2001)

The Sendai virus (SeV) C gene codes for a nested set of four C proteins that carry out several functions, including the modulation of viral RNA synthesis and countering of the cellular antiviral response. Using mutant C genes (and in particular a C gene with a deletion of six amino acids present only in the larger pair of C proteins) and recombinant SeV carrying these mutant C genes, we find that the nested set of C proteins carry out a nested set of functions. All of the C proteins interdict interferon (IFN) signaling to IFN-stimulated genes (ISGs) and prevent pY701-Stat1 formation. However, only the larger C proteins can induce STAT1 instability, prevent IFN from inducing an antiviral state, or prevent programmed cell death. Remarkably, interdiction of IFN signaling to ISGs and the absence of pY701-Stat1 formation did not prevent IFN-alpha from inducing an anti-Vesicular stomatitis virus (VSV) state. It is possible that IFN-alpha signaling to induce an anti-VSV state can occur independently of the well-established Jak/Stat/ISGF3 pathway and that it is this parallel pathway that is targeted by the longer C proteins.