gebhart/patrepeval huggingface dataset:
Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition (2008)

We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2-p53 interaction. MI-219 binds to human MDM2 with a K(i) value of 5 nM and is 10,000-fold selective for MDM2 over MDMX. It disrupts the MDM2-p53 interaction and activates the p53 pathway in cells with wild-type p53, which leads to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activates p53 in normal tissues with minimal p53 accumulation and is not toxic to animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.
The 100th Economic Roundup (2006)

Over the course of 100 issues the Economic Roundup has evolved from mainly discussing recent economic statistics and reprinting budget statements to being a vehicle for placing Treasury research and policy analysis before the wider community. To keep improving the Economic Roundup, and assess the ongoing demand for paper copies when the full contents are freely available on Treasury's website, a survey is included with the paper copies of this issue.
Optimization of Multivalent Bispecific Antibodies and Immunocytokines with Improved in Vivo Properties (2012)

Multifunctional antibody-based biologics, such as bispecific antibodies and immunocytokines, can be difficult to produce with sufficient yield and stability, and often exhibit inferior pharmacokinetics. Dock-and-Lock (DNL) is a modular method that combines recombinant engineering with site-specific conjugation, allowing the construction of various complex, yet defined, biostructures with multivalency and multispecificity. The technology platform exploits the natural interaction between two interactive human protein binding domains that are modified to provide covalent fusion. We explored the potential application of a new class of IgG-based DNL modules with an anchor domain fused at the C-terminal end of the kappa light chain (C(k)), instead of the C-terminal end of the Fc. Two C(k)-derived prototypes, an anti-CD22/CD20 bispecific hexavalent antibody, comprising epratuzumab (anti-CD22) and four Fabs of veltuzumab (anti-CD20), and a CD20-targeting immunocytokine, comprising veltuzumab and four molecules of interferon-α2b, were compared to their Fc-derived counterparts. The Ck-based conjugates exhibited superior Fc-effector functions in vitro, as well as improved pharmacokinetics, stability, and anti-lymphoma activity in vivo. These results favor the selection of DNL conjugates with the C(k)-design for future clinical development.
Generation of novel human MHC class II mutant B-cell lines by integrating YAC DNA into a cell line homozygously deleted for the MHC class II region (1997)

The human B lymphoblastoid cell line (LCL) 721.174 sustains a large homozygous deletion in the major histocompatibility complex (MHC) class II region that results in an absence of DQ and DR molecules as well as a deficiency in the assembly and transport of class I molecules to the cell surface. The deleted genes include the transporters associated with antigen processing TAP1 and TAP2, DMA and DMB which are involved in editing class II bound peptides, and four genes whose roles in antigen processing are unclear; the low mass polypeptide genes LMP2 and LMP7, and DNA and DOB. To study this region we have integrated into 721.174 two overlapping yeast artificial chromosome (YAC) clones which cover the interval LMP2-DRA inclusive. Three clones (11.2A1.1, 4D1D10.1 and 4D1D10.2), containing complete copies of the transfected YAC, produced varying levels of mRNA from the LMP, TAP, DQ and DR genes and corresponding levels of LMP and TAP protein. Class I cell surface expression was restored in 11.2A1.1 and 4D1D10.1, as was DR expression in both 4D1D10 transfectants. These studies demonstrate the feasibility of introducing large groups of functional genes back into human lymphoblastoid cells sustaining deletions, with full restoration of biological function. The procedure could be exploited in order to restore all but one gene covered by the deletion, effectively producing a single gene defect. This could be used to introduce copies of genes engineered to contain mutations and to study cis regulatory elements at some distance from the chosen loci.
[Effect of inhibitor HNP1 transfection on tumor growth of human nasopharyngeal carcinoma cell line HNE-1]. (2008)

HNP1 transfection can inhibit the proliferation of HNE1 cells, as well as tumor growth.
Ferrofluids: magnetically controllable liquids (2002)

The make up, properties and applications of suspensions containing magnetic particles with a size of about 10 nm - usually called ferrofluids - will be discussed. The specific interest in these fluids bases on the fact that they show normal liquid behavior coupled with superparamagnetic properties. That means that it is possible to control the flow and the properties of ferrofluids by means of moderate magnetic fields in the order of about 50 mT. The magnetically controllable forces on ferrofluids open wide fields for basic research as well as for technical applications. Some of the applications of ferrofluids entered everyday live meanwhile and gained high commercial importance. Beside the discussion of the basic properties of these liquids, particular interest will be drawn to the change of their viscosity in the presence of magnetic fields. This effect usually called magnetoviscous effect is one of the most vivid fields of ferrofluid research at present.
The Mitogen-Activated Protein Kinase Pathway Mediates Estrogen Neuroprotection after Glutamate Toxicity in Primary Cortical Neurons (1999)

Pharmacological and biochemical approaches were used to elucidate the involvement of growth factor signaling pathways mediating estrogen neuroprotection in primary cortical neurons after glutamate excitotoxicity. We addressed the activation of mitogen-activated protein kinase (MAPK) signaling pathways, which are activated by growth factors such as nerve growth factor (NGF). Inhibition of MAPK signaling with the MAPK kinase inhibitor PD98059 blocks both NGF and estrogen neuroprotection in these neurons. These results correlate with a rapid and sustained increase in MAPK activity within 30 min of estrogen exposure. The involvement of signaling molecules upstream from MAPK was also examined to determine whether activation of MAPK by estrogen is mediated by tyrosine kinase activity. Estrogen produces a rapid, transient activation of src-family tyrosine kinases and tyrosine phosphorylation of p21(ras)-guanine nucleotide activating protein. Effects of estrogen on neuroprotection, as well as rapid activation of tyrosine kinase and MAPK activity, are blocked by the anti-estrogen ICI 182,780. This provides evidence that activation of the MAPK pathway by estrogen participates in mediating neuroprotection via an estrogen receptor. These results describe a novel mechanism by which cytoplasmic actions of the estrogen receptor may activate the MAPK pathway, thus broadening the understanding of effects of estrogen in neurons.
Therapeutic Uses of Gallium Nitrate (1999)

Injectable gallium (Ga) nitrate, approved in the United States for the treatment of hypercalcemia of malignancy, has been known for more than 2 decades to have immunosuppressive properties. At therapeutic doses, it has few adverse effects, although high-dose infusions may result in severe nephrotoxicity, particularly in patients who are not adequately hydrated, and severe anemia. In animal models, Ga has been shown to have efficacy in the treatment of adjuvant arthritis, type 1 diabetes, experimental autoimmune encephalomyelitis, experimental pulmonary inflammation, cardiac allograft rejection, experimental autoimmune uveitis, endotoxic shock, and systemic lupus erythematosus. Clinical trials have demonstrated efficacy in Paget's disease of bone and activity against some malignancies, including epithelial ovarian carcinoma, non-squamous cell carcinoma of the cervix, bladder cancer, and non-Hodgkin's lymphoma. Other clinical trials underway include studies of sarcoidosis and rheumatoid arthritis. Future studies should be conducted not only in other autoimmune diseases, such as multiple sclerosis, but also in graft-versus-host disease, leprosy, and acquired immunodeficiency syndrome (AIDS).
On the relationship between sub‐fossil and recent British Water voles (1975)

Abstract Sub‐fossil remains of Arvicola from cave deposits dating from the Upper Palaeolithic through to the Romano‐British have been analysed and compared with recent material. The results suggest that only one species of Arvicola has been present in Central England during the past 12,000 years and that, during this time span, there have been trends towards an increase in size and towards a decrease in pro‐odonty.
Cross-domain sentiment classification via spectral feature alignment (2010)

Sentiment classification aims to automatically predict sentiment polarity (e.g., positive or negative) of users publishing sentiment data (e.g., reviews, blogs). Although traditional classification algorithms can be used to train sentiment classifiers from manually labeled text data, the labeling work can be time-consuming and expensive. Meanwhile, users often use some different words when they express sentiment in different domains. If we directly apply a classifier trained in one domain to other domains, the performance will be very low due to the differences between these domains. In this work, we develop a general solution to sentiment classification when we do not have any labels in a target domain but have some labeled data in a different domain, regarded as source domain. In this cross-domain sentiment classification setting, to bridge the gap between the domains, we propose a spectral feature alignment (SFA) algorithm to align domain-specific words from different domains into unified clusters, with the help of domain-independent words as a bridge. In this way, the clusters can be used to reduce the gap between domain-specific words of the two domains, which can be used to train sentiment classifiers in the target domain accurately. Compared to previous approaches, SFA can discover a robust representation for cross-domain data by fully exploiting the relationship between the domain-specific and domain-independent words via simultaneously co-clustering them in a common latent space. We perform extensive experiments on two real world datasets, and demonstrate that SFA significantly outperforms previous approaches to cross-domain sentiment classification.
Phenotypic characterization of 10 methanol oxidation mutant classes in Methylobacterium sp. strain AM1 (1986)

Twenty-five methanol oxidation mutants of the facultative methylotroph Methylobacterium sp. strain AM1 have been characterized by complementation analysis and assigned to 10 complementation groups, Mox A1, A2, A3, and B through H (D. N. Nunn and M. E. Lidstrom, J. Bacteriol. 166:582-591, 1986). In this study we have characterized each of the mutants belonging to the 10 Mox complementation groups for the following criteria: phenazine methosulfate-dichlorophenolindophenol dye-linked methanol dehydrogenase activity; methanol-dependent whole-cell oxygen consumption; the presence or absence of methanol dehydrogenase protein by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting; the absorption spectra of purified mutant methanol dehydrogenase proteins; and the presence or absence of the soluble cytochrome c proteins of Methylobacterium sp. strain AM1, as determined by reduced-oxidized difference spectra and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. With this information, we have proposed functions for each of the genes deficient in the mutants of the 10 Mox complementation groups. These proposed gene functions include two linked genes that encode the methanol dehydrogenase structural protein and the soluble cytochrome cL, a gene encoding a secretion function essential for the synthesis and export of methanol dehydrogenase and cytochrome cL, three gene functions responsible for the proper association of the pyrrolo-quinoline quinone prosthetic group with the methanol dehydrogenase apoprotein, and four positive regulatory gene functions controlling the expression of the ability to oxidize methanol.
Single Dose Pharmacokinetics of Oral Tenofovir in Plasma, Peripheral Blood Mononuclear Cells, Colonic Tissue, and Vaginal Tissue (2013)

HIV seroconversion outcomes in preexposure prophylaxis (PrEP) trials of oral tenofovir (TFV)-containing regimens are highly sensitive to drug concentration, yet less-than-daily dosing regimens are under study. Description of TFV and its active moiety, TFV diphosphate (TFV-DP), in blood, vaginal tissue, and colon tissue may guide the design and interpretation of PrEP clinical trials. Six healthy women were administered a single oral dose of 300 mg tenofovir disoproxil fumarate (TDF) and 4.3 mg (12.31 MBq, 333 μCi) (14)C-TDF slurry. Blood was collected every 4 h for the first 24 h, then at 4, 8, 11, and 15 days postdosing. Colonic and vaginal samples (tissue, total and CD4(+) cells, luminal fluid and cells) were collected 1, 8 and 15 days postdose. Samples were analyzed for TFV and TFV-DP. Plasma TFV demonstrated triphasic decay with terminal elimination half-life median [interquartile range (IQR)] 69 h (58-77). Peripheral blood mononuclear cell (PBMC) TFV-DP demonstrated biphasic peaks (median 12 h and 96 h) followed by a terminal 48 h (38-76) half-life; Cmax was 20 fmol/million cells (2-63). One day postdose, the TFV-DP paired colon:vaginal tissue concentration ratio was 1 or greater in all subjects' tissue homogenates, median 124 (range 1-281), but was not sustained. The ratio was lower and more variable in cells extracted from tissue. Among all sample types, TFV and TFV-DP half-life ranged from 23 to 139 h. PBMC TFV-DP rose slowly in the hours after dosing indicating that success with exposure-driven dosing regimens may be sensitive to timing of the dose prior to exposure. Colonic tissue homogenate TFV-DP concentrations were greater than in vaginal homogenate at 24 h, but not in cells extracted from tissue. These and the other pharmacokinetic findings will guide the interpretation and design of future PrEP trials.
In Situ Hybridization and Detection Using Nonisotopic Probes (2007)

Nonisotopic in situ hybridization can be used to determine the cellular location and relative levels of expression for specific transcripts within cells and tissues. RNA in specimen preparations is hybridized with a biotin- or digoxigenin-labeled probe, which is generally detected by fluorescence or enzymatic methods. Fluorescence in situ hybridization (FISH), probably the most widely used method, is described here, along with amplification of weak FISH signals. Nonisotopic probes can also be detected by enzymatic reactions using horseradish peroxidase or alkaline phosphatase, as described here.
Low-Molecular-Weight Peptidic and Cyclic Antagonists of the Receptor for the Complement Factor C5a (1999)

Activation of the human complement system of plasma proteins during immunological host defense can result in overproduction of potent proinflammatory peptides such as the anaphylatoxin C5a. Excessive levels of C5a are associated with numerous immunoinflammatory diseases, but there is as yet no clinically available antagonist to regulate the effects of C5a. We now describe a series of small molecules derived from the C-terminus of C5a, some of which are the most potent low-molecular-weight C5a receptor antagonists reported to date for the human polymorphonuclear leukocyte (PMN) C5a receptor. 1H NMR spectroscopy was used to determine solution structures for two cyclic antagonists and to indicate that antagonism is related to a turn conformation, which can be stabilized in cyclic molecules that are preorganized for receptor binding. While several cyclic derivatives were of similar antagonistic potency, the most potent antagonist was a hexapeptide-derived macrocycle AcF[OPdChaWR] with an IC50 = 20 nM against a maximal concentration of C5a (100 nM) on intact human PMNs. Such potent C5a antagonists may be useful probes to investigate the role of C5a in host defenses and to develop therapeutic agents for the treatment of many currently intractable inflammatory conditions.
De Novo Protein Design: Fully Automated Sequence Selection (1997)

The first fully automated design and experimental validation of a novel sequence for an entire protein is described. A computational design algorithm based on physical chemical potential functions and stereochemical constraints was used to screen a combinatorial library of 1.9 x 10(27) possible amino acid sequences for compatibility with the design target, a betabetaalpha protein motif based on the polypeptide backbone structure of a zinc finger domain. A BLAST search shows that the designed sequence, full sequence design 1 (FSD-1), has very low identity to any known protein sequence. The solution structure of FSD-1 was solved by nuclear magnetic resonance spectroscopy and indicates that FSD-1 forms a compact well-ordered structure, which is in excellent agreement with the design target structure. This result demonstrates that computational methods can perform the immense combinatorial search required for protein design, and it suggests that an unbiased and quantitative algorithm can be used in various structural contexts.
Sequence memory for prediction, inference and behaviour (2009)

In this paper, we propose a mechanism which the neocortex may use to store sequences of patterns. Storing and recalling sequences are necessary for making predictions, recognizing time-based patterns and generating behaviour. Since these tasks are major functions of the neocortex, the ability to store and recall time-based sequences is probably a key attribute of many, if not all, cortical areas. Previously, we have proposed that the neocortex can be modelled as a hierarchy of memory regions, each of which learns and recalls sequences. This paper proposes how each region of neocortex might learn the sequences necessary for this theory. The basis of the proposal is that all the cells in a cortical column share bottom-up receptive field properties, but individual cells in a column learn to represent unique incidences of the bottom-up receptive field property within different sequences. We discuss the proposal, the biological constraints that led to it and some results modelling it.
Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. (1995)

The growth, differentiation, and development of an organism is orchestrated by the choreographed expression of a wide array of genes. The switching "on" and "off" of gene expression is the province of transcription factors, which operate singly or in association with other proteins. Usually transcription factors form families, whereas individual members perform specific, distinct, or similar tasks. One such family includes the R ~~/ N F -K B proteins (NF-KB), which have the unique property of being sequestered in the cytoplasm in association with inhibitory proteins called IKB.
tRNA biology charges to the front (2010)

tRNA biology has come of age, revealing an unprecedented level of understanding and many unexpected discoveries along the way. This review highlights new findings on the diverse pathways of tRNA maturation, and on the formation and function of a number of modifications. Topics of special focus include the regulation of tRNA biosynthesis, quality control tRNA turnover mechanisms, widespread tRNA cleavage pathways activated in response to stress and other growth conditions, emerging evidence of signaling pathways involving tRNA and cleavage fragments, and the sophisticated intracellular tRNA trafficking that occurs during and after biosynthesis.
Redistribution of Rydberg states by intense picosecond pulses (1992)

Starting with Ba atoms in one Rydberg state we have observed the population of adjacent Rydberg states when the atom is exposed to an intense 1.5-ps laser pulse. The initial Rydberg state population is redistributed by a Raman-like two-photon process, rather than simply being photoionized. This population trapping, which is associated with stabilization against ionization, is described in terms of Rydberg antiwave packets.
Embedded Carbon‐Nanotube‐Stiffened Polymer Surfaces (2005)

Multiwalled-carbon-nanotube (MWNT)-reinforced polymer surfaces were prepared by infiltration and in situ polymerization of excess monomer into aligned MWNT arrays (see SEM image; scale bar=1 μm). The electrical and mechanical properties of the MWNT-reinforced surface were compared with those of the pure polymer surface. The reinforced polymer films show large enhancements in surface stiffness and electrical conductivity compared to the soft and insulating pure polymer.
Repair of gaps opposite lesions by homologous recombination in mammalian cells (2009)

Damages in the DNA template inhibit the progression of replication, which may cause single-stranded gaps. Such situations can be tolerated by translesion DNA synthesis (TLS), or by homology-dependent repair (HDR), which is based on transfer or copying of the missing information from the replicated sister chromatid. Whereas it is well established that TLS plays an important role in DNA damage tolerance in mammalian cells, it is unknown whether HDR operates in this process. Using a newly developed plasmid-based assay that distinguishes between the three mechanisms of DNA damage tolerance, we found that mammalian cells can efficiently utilize HDR to repair DNA gaps opposite an abasic site or benzo[a]pyrene adduct. The majority of these events occurred by a physical strand transfer (homologous recombination repair; HRR), rather than a template switch mechanism. Furthermore, cells deficient in either the human RAD51 recombination protein or NBS1, but not Rad18, exhibited decreased gap repair through HDR, indicating a role for these proteins in DNA damage tolerance. To our knowledge, this is the first direct evidence of gap-lesion repair via HDR in mammalian cells, providing further molecular insight into the potential activity of HDR in overcoming replication obstacles and maintaining genome stability.
Chlamydial vaccine development (2003)

Microbiology Society journals contain high-quality research papers and topical review articles. We are a not-for-profit publisher and we support and invest in the microbiology community, to the benefit of everyone. This supports our principal goal to develop, expand and strengthen the networks available to our members so that they can generate new knowledge about microbes and ensure that it is shared with other communities.
A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity (2008)

Airway hypersensitive reaction (AHR) is an animal model for asthma, which is caused or enhanced by environmental factors such as allergen exposure. However, the precise mechanisms that drive AHR remain unclear. We identified a novel subset of natural killer T (NKT) cells that expresses the interleukin 17 receptor B (IL-17RB) for IL-25 (also known as IL-17E) and is essential for the induction of AHR. IL-17RB is preferentially expressed on a fraction of CD4(+) NKT cells but not on other splenic leukocyte populations tested. IL-17RB(+) CD4(+) NKT cells produce predominantly IL-13 and Th2 chemokines upon stimulation with IL-25 in vitro. IL-17RB(+) NKT cells were detected in the lung, and depletion of IL-17RB(+) NKT cells by IL-17RB-specific monoclonal antibodies or NKT cell-deficient Jalpha18(-/-) mice failed to develop IL-25-dependent AHR. Cell transfer of IL-17RB(+) but not IL-17RB(-) NKT cells into Jalpha18(-/-) mice also successfully reconstituted AHR induction. These results strongly suggest that IL-17RB(+) CD4(+) NKT cells play a crucial role in the pathogenesis of asthma.