gebhart/patrepeval huggingface dataset:
Defining a Smaller RNA Substrate for Elongation Factor Tu (1995)

A nuclease protection assay was used to obtain equilibrium dissociation constants of Thermus thermophilus EF-Tu with two well-characterized internal deletions of Escherichia coli Ala-tRNA(Ala) and yeast Phe-tRNA(Phe). Aminoacylated tRNAs with the anticodon hairpin substituted by a tetranucleotide bind to EF-Tu as well as the corresponding full-sized tRNAs. However, the Ala minihelix, where residue A7 is joined directly to A49, binds to EF-Tu less well than the full-sized Ala-tRNA(Ala). Similar data were obtained for Escherichia coli EF-Tu. An in vitro selection strategy was used to isolate a substrate for EF-Tu from an RNA library where nine random nucleotides inserted between A7 and A49 in the Ala minihelix. After six rounds of enrichment, two groups of RNA were obtained that bound T. thermophilus EF-Tu as well as Ala-tRNA(Ala). Group I molecules have the consensus sequence UNDUGACUY (N = U, C, A, G; D = U, G; Y = U, C) in the randomized region, and Group II molecules generally have 5'-terminal GUG, but are more variable in the remaining six nucleotides. The selected RNAs bind EF-Tu better than the minihelix either because they provide additional function groups for protein binding or because they have a structure more similar to the aminoacyl acceptor branch of tRNA.
Systemic and Biophase Bioavailability and Pharmacokinetics of Nanoparticulate Drug Delivery Systems (2013)

The development of the vectorized delivery systems combining advantages of the colloidal carriers, with active targeting to the receptors sites suggests that nanoparticles have a considerable potential for treatment after biophase internalization and pharmacokinetics, as for example gene therapy. Two major mechanisms can be distinguished for addressing the desired sites for drug release: (i) passive and (ii) active targeting. Examples of passive targeting were presented: organ targeting by the Enhanced Permeability and Retention (EPR) effect; targeting the mononuclear phagocitic system; organ targeting by chemoembolization or local (organ) administration;sterical stabilization of nanoparticles (PEGylation). A strategy that could allow active targeting involves the surface functionalization of drug carriers with ligands that are selectively recognized by receptors on the surface of the cells of interest. The source for biophase bioavailability can be the systemic bioavailability following common routes of administration (generally for systemic delivery of medicines), or directly the site specific biophase bioavailability for the formulations capable of cellular or nuclear drug internalization where the drug release only will take place (for nanoparticulate drug delivery systems, DDS). Once the pharmaceutical nanosystem was internalized, begins the release of the active moiety by different mechanisms, as for example the escape from endosome, or biodegradation of the polymer carrier or liberation of the active peptide or gene from a biological construct in the nucleus, etc. The presentation will discusses the pharmacokinetics of drugs after systemic administration but especially the biophase bioavailability and pharmacokinetics after the administration of biotechnology origin of therapeutic proteins like monoclonal antibodies, gene transfer products, plasmid DNAs, nucleotides, antisense oligonucleotides (AODNs) or small interfering RNAs (siRNA).
Immunogenotype Changes Prevail in Relapses of Young Children with TEL-AML1-Positive Acute Lymphoblastic Leukemia and Derive Mainly from Clonal Selection (2005)

These findings imply that the clonal heterogeneity in younger children most likely reflects an ongoing high recombinatorial activity in the preleukemic/leukemic cells, whereas the more uniform repertoire observed in older children mirrors end-stage rearrangement patterns of selected cell clones that evolved during the prolonged latency period.
Direct femtosecond laser surface nano/microstructuring and its applications (2012)

Abstract This paper reviews a new field of direct femtosecond laser surface nano/microstructuring and its applications. Over the past few years, direct femtosecond laser surface processing has distinguished itself from other conventional laser ablation methods and become one of the best ways to create surface structures at nano‐ and micro‐scales on metals and semiconductors due to its flexibility, simplicity, and controllability in creating various types of nano/microstructures that are suitable for a wide range of applications. Significant advancements were made recently in applying this technique to altering optical properties of metals and semiconductors. As a result, highly absorptive metals and semiconductors were created, dubbed as the “black metals” and “black silicon”. Furthermore, various colors other than black have been created through structural coloring on metals. Direct femtosecond laser processing is also capable of producing novel materials with wetting properties ranging from superhydrophilic to superhydrophobic. In the extreme case, superwicking materials were created that can make liquids run vertically uphill against the gravity over an extended surface area. Though impressive scientific achievements have been made so far, direct femtosecond laser processing is still a young research field and many exciting findings are expected to emerge on its horizon.
Head and Velocity Covariances Under Quasi‐Steady State flow and their Effects on Advective Transport (1996)

Most stochastic models of solute transport assume flow to be at steady state. However, even locally uniform gradients tend to show seasonal fluctuations in magnitude and direction. Such transients affect the prediction of flow and plume migration and spread. The question is how and to what extent. We address this question by developing low‐order approximations for autocovariances and cross covariances of velocity, head, and log hydraulic conductivity under quasi‐steady state flow, then using a first‐order Lagrangian approach to examine their effect on advective transport. Our results show that whereas periodic temporal fluctuations in the magnitude of the mean velocity may either enhance or reduce dispersion, similar fluctuations in its direction always cause longitudinal dispersion to decrease and transverse dispersion to increase.
Notch ligands Delta1 and Jagged1 transmit distinct signals to T-cell precursors (2004)

Signaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow-derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and gamma delta T-cell lineages.
Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity (1998)

The transit of immature to mature sIgM+ B cells, the life span, maturation kinetics and response to polyclonal activators have been analyzed with the help of a new mAb (493), that distinguishes immature, 493+ from mature, 493 B cells in a variety of mouse strains tested. Analysis of the turnover of immature 493+ B cells by bromodeoxyuridine (BrdU) labeling kinetics indicate that only 10-20 % of the cells reach the spleen as immature 493+ cells. The life span of 493+ B cells in bone marrow and spleen is around 4 days. BrdU chase experiments show that most of the immature cells in spleen enter the pool of mature, 493+ B cells where they gain a longer life span of 15-20 weeks. Immature and mature B cells respond equally well to LPS stimulation; anti-CD40, however, stimulates mature B cells better than immature B cells. IgM cross-linking of mature B cells results in proliferation, while it induces apoptosis in immature B cells. This apoptosis of immature cells can be inhibited by costimulation with anti-CD40 or by overexpression of bcl-2. We speculate that Ig receptor ligand-mediated apoptosis (negative selection) plays a major role in the transit of immature B cells from bone marrow to spleen, but only a minor role in the transit from immature B cells to mature B cells in the spleen.
Calcitonin Gene-Related Peptide (CGRP): A New Target for Migraine (2014)

Migraine is a neurological disorder that manifests as a debilitating headache associated with altered sensory perception. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. Clinical trials carried out during the past decade have proved that CGRP receptor antagonists are effective for treating migraine, and antibodies to the receptor and CGRP are currently under investigation. Despite this progress in the clinical arena, the mechanisms by which CGRP triggers migraine remain uncertain. This review discusses mechanisms whereby CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Future studies on epistatic and epigenetic regulators of CGRP actions are expected to shed further light on CGRP actions in migraine. In conclusion, targeting CGRP represents an approachable therapeutic strategy for migraine.
Antigen Recognition and the Immune Response: the Capacity of L-Tyrosine-Azobenzenearsonate to Serve as a Carrier for a Macromolecular Hapten (1971)

Abstract The low molecular weight compound l-tyrosine-azobenzenearsonate (RAT) induced immunity in guinea pigs, as evidenced by delayed cutaneous hypersensitivity and stimulation of DNA synthesis by lymphoid cells in culture. Two different conjugates of RAT and a poly-γ-D-glutamic acid hapten of m.w. 35,000 were prepared. In one, an average of nine molecules of RAT were linked directly to the PGA backbone [PGA-(RAT)9]. In the other, RAT was joined to PGA by means of 6-aminocaproyl (SAC) hydrocarbon chains that extended the RAT groups out from the PGA backbone by a maximum of 10 Å [PGA-(SAC-RAT)12]. Immunization with the two conjugates gave rise to anti-PGA antibody, PGA-(SAC-RAT)12 being somewhat more effective in that regard, and all animals developed delayed hypersensitivity to RAT but not to PGA. Lymphoid cells from animals sensitized to PGA-RAT conjugates demonstrated specificity for the homologous conjugates, assessed by the rate of incorporation of 14C-thymidine into DNA. Prior immunization with RAT potentiated the response to PGA following administration of the conjugates. Thus, it appears that a molecule with an m.w. of about 400 was recognized by antigenreactive cells and could serve as a carrier for a hapten with an m.w. of 35,000.
Focused ultrasound therapy combined with pembrolizumab in metastatic breast cancer. (2018)

TPS19 Background: Focused ultrasound (FUS) is an ablative therapy which can heat tumors rapidly to cell damaging temperatures and simultaneously perturb the microenvironment, the microvasculature, and the lymphatics. At typical energy levels, FUS can induce controlled apoptotic cell death rather than liquefactive necrosis. FUS does not involve radiation. FUS is a partially ablative therapy using high energy ultrasound waves to induce heat shock proteins, cytokine release and cellular mediated mechanisms resulting in T cell activation and recognition of tumor antigens. FUS has been demonstrated to be an effective method for inducing tumor antigen exposure and presentation to dendritic cells, thus acting as an auto-vaccine. Pembrolizumab (PBZ) is a PD-1 targeted antibody used in multiple solid tumors to augment T cell activation. It is hypothesized that the combination of these two modalities will result in T cell infiltration into breast tumors as well as systemic immune responses. Methods: In this pilot study, we will examine PBZ therapy in combination with FUS to assess for immune stimulation and antitumor effects at local ablation sites, distant non-treated sites and in the blood. Biopsy before and after treatments will examine the tissue in the peripheral zone of ablation as well as at distant metastatic sites for CD8 and CD4 T cells, MDSC’s, T-regulatory cells and cytokine responses. Twelve patients will be randomized to receive either PBZ 14 days before or 7 days after a single time FUS partial tumor ablation on day 15. Biopsies will be on days 1, 22 and 64 and tumor imaging will be every 12 weeks. Patients must have metastatic or unresectable breast cancer, adequate organ function, and prior therapy in the metastatic setting. They must also have a tumor in the breast or axilla amenable to FUS and biopsy. Clinical trial information: NCT03237572.
Induction of IgG antibodies directed to a M(r) 31,000 melanoma antigen in patients immunized with vaccinia virus melanoma oncolysates. (1994)

Pre- and postimmunization sera from eight tumor-free melanoma patients undergoing vaccinia melanoma oncolysate (VMO) therapy were used to investigate the humoral response to antigens from infected and uninfected melanoma cells and from vaccinia virus. Immunodetection on Western blots showed that all patients, in addition to reacting to several other proteins, developed IgG antibodies to a M(r) 31,000 protein antigen within 1 month of immunization. This M(r) 31,000 antigen is expressed both on VMO and on melanoma metastases in situ, disappears in primary cultures of these metastases, and is absent in extracts from vaccinia virus, from human melanoma cell lines, and from normal melanocytes, suggesting that this M(r) 31,000 protein is reexpressed following vaccinia virus infection of human melanoma cells. Periodate treatment of the blotted antigens abolished reactivity of patients' postimmunization sera with the M(r) 31,000 antigen, thus showing that this antigen is a glycoprotein and that the relevant epitope is likely to reside on its carbohydrate moiety. These anti-M(r) 31,000 IgG antibodies were absent in the sera of VMO-treated patients before immunization, absent in the serum of a normal donor hyperimmunized with vaccinia virus, and absent in normal human sera. In addition, these anti-M(r) 31,000 antibodies appeared 1 week after the first VMO injection, remained stable during the treatment, and decreased when the treatment was stopped. Such antibodies can also be demonstrated in sera of melanoma patients bearing metastases but disappeared following resection of their metastases. Thus, in melanoma patients, immunization with VMO induces an antibody response directed against a M(r) 31,000 glycoprotein likely to represent a new melanoma antigen. Further identification of this antigen could be of utmost interest for the further development of melanoma vaccines.
A 90 GHz Hybrid Switching Pulsed-Transmitter for Medical Imaging (2010)

This paper reports a fully integrated 90 GHz-carrier pulsed transmitter in 0.13 μm SiGe BiCMOS process for imaging applications. To obtain ultra-short programmable pulses, the transmitter employs a number of novel techniques including hybrid switching and Antentronics. The transmit path includes a quadrature VCO, PA driver, PA and the on-chip folded slot antenna. High speed ECL circuits generate and provide the short pulses in several operating modes. The transmitter achieves a record pulsewidth of 26 ps in the hybrid mode and 33 ps in the independent mode. This translates to >30 GHz of RF BW in the transmitter.
Purification of the tetrodotoxin-binding component associated with the voltage-sensitive sodium channel from Electrophorus electricus electroplax membranes. (1978)

The tetrodotoxin-binding component associated with the voltage-sensitive sodium channel from electroplax membranes of Electrophorus electricus has been purified. The toxin-binding site could be efficiently solubilized with Lubrol-PX, resulting in an extract of high initial specific activity. Purification was facilitated by the development of a rapid, quantitative binding assay. The binding component was stabilized during purification by the use of mixed lipid/detergent micelles of defined composition, and by the saturation of the site with tetrodotoxin. The purification was achieved by means of a highly selective adsorption of the toxin-binding component to DEASE-Sephadex A-25, followed by desorption at high ionic strength and chromatography over Sepharose 6B. Final peak specific activities were at least 50% of the specific activity expected for a pure, undenatured toxin-binding componenet of 230,000 molecular weight. The purified material exhibited a sedimentation coefficient of approximately 8 S and an unusual Stokes radius of 95 A. Purified material showed a relatively simple pattern on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, being comprised of only three polypeptides.
Characterization of C4-2 as a tumor-suppressor gene in human brain tumors (1997)

We conclude that C4-2 may function as a potential tumor-suppressor gene.
Conformational Changes in the Rod Domain of Human Keratin 8 following Heterotypic Association with Keratin 18 and Its Implication for Filament Stability (2004)

Keratin intermediate filaments are heteropolymers of type I and type II polypeptides that constitute the bulk of the epithelial cytoskeleton. We microinjected seven keratin monoclonal antibodies into human epithelial cells, and two of them, only A45-B/B3 and LP3K, caused the formation of keratin aggregates. The keratin filaments in human epithelial cells were also disrupted by a monovalent A45-B/B3 Fab fragment, suggesting that the binding of the antibody, rather than cross-linking, collapses the filaments. Immunoblotting and ELISA experiments suggested that the antibody reacted weakly with recombinant K8 but did not react with recombinant K18 at all. However, the antibody reactivity increased substantially when a mixture of the two keratin polypeptides, either recombinant or derived from MCF-7, was used. The epitopes of 15 monoclonal antibodies recognizing human K8 were characterized by their reactivity with recombinant fragments of K8. Reactivity of antibody A45-B/B3 with fragments of K8 in the presence of K18 revealed that the antibody recognizes an epitope in the rod domain of K8, between residues 313 and 332, on the amino-terminal side of the stutter in helix 2B, which is involved in heterotypic association. The data suggest that this region of K8 undergoes a conformational change following interaction with the complementary K18 either to expose the epitope or to increase its affinity for the antibody. Taken together, the data highlight the role of this epitope in heterotypic association and in filament stabilization.
Microanatomical Correlates of Cognitive Ability and Decline: Normal Ageing, MCI, and Alzheimer's Disease (2011)

Few microanatomical measures have been reliably correlated with cognitive measures in aging and Alzheimer's disease (AD), particularly in the early stages of degeneration, such as mild cognitive impairment (MCI). However, cortical minicolumn organization has been shown to correlate with cognitive ability in aging monkeys, and the present study extends this finding to humans. We have previously reported that minicolumn spacing of cells in human association cortex is selectively reduced in normal aging (minicolumn thinning). The present study found that such measures detected early disease changes in MCI as well as further minicolumn thinning and disruption in AD. Plaques, tangles, and minicolumns were quantified, postmortem, for 20 controls, 10 MCI, and 20 AD subjects. Minicolumn changes were correlated with premortem cognitive scores (mini-mental state examination and verbal fluency). Two regions were studied from each brain: association cortex in the planum temporale (BA22) and primary auditory cortex (BA41). The relationship between minicolumns and cognitive function was strongest in association cortex, whereas in primary auditory cortex, it appeared to be an epiphenomenon of overall brain atrophy. Microanatomical changes reflecting selective regional vulnerability to AD pathology and differential involvement in the cognitive deficit of AD are therefore detectable in the early stage of MCI.
Magneto-optic magnetic field sensor with 1.4 pT/√(Hz) minimum detectable field at 1 kHz (1993)

The Letter demonstrates that the sensitivity of magneto-optic magnetic field sensors employing iron garnets can be increased by approximately two orders of magnitude by applying flux concentration. A minimum detectable field of 1.4 pT/√(Hz) was measured when a cylindrical gallium-substituted yttrium iron garnet crystal was combined with two conically tapered nickel–zinc ferrite cylinders.
Design of a Targeted Peptide Nucleic Acid Prodrug To Inhibit Hepatic Human Microsomal Triglyceride Transfer Protein Expression in Hepatocytes (2002)

In this study, we present the design and synthesis of an antisense peptide nucleic acid (asPNA) prodrug, which displays an improved biodistribution profile and an equally improved capacity to reduce the levels of target mRNA. The prodrug, K(GalNAc)(2)-asPNA, comprised of a 14-mer sequence complementary to the human microsomal triglyceride transfer protein (huMTP) gene, conjugated to a high-affinity tag for the hepatic asialoglycoprotein receptor (K(GalNAc)(2)). The prodrug was avidly bound and rapidly internalized by HepG2s. After iv injection into mice, K(GalNAc)(2)-asPNA accumulated in the parenchymal liver cells to a much greater extent than nonconjugated PNA (46% +/- 1% vs 3.1% +/- 0.5% of the injected dose, respectively). The prodrug was able to reduce MTP mRNA levels in HepG2 cells by 35-40% (P < 0.02) at 100 nM in an asialoglycoprotein receptor- and sequence-dependent fashion. In conclusion, hepatocyte-targeted PNA prodrugs combine a greatly improved tropism with an enhanced local intracellular availability and activity, making them attractive therapeutics to lower the expression level of hepatic target genes such as MTP.
Specific Binding and Mineralization of Calcified Surfaces by Small Peptides (2009)

Several small (<25aa) peptides have been designed based on the sequence of the dentin phosphoprotein, one of the major noncollagenous proteins thought to be involved in the mineralization of the dentin extracellular matrix during tooth development. These peptides, consisting of multiple repeats of the tripeptide aspartate-serine-serine (DSS), bind with high affinity to calcium phosphate compounds and, when immobilized, can recruit calcium phosphate to peptide-derivatized polystyrene beads or to demineralized human dentin surfaces. The affinity of binding to hydroxyapatite surfaces increases with the number of (DSS)(n) repeats, and though similar repeated sequences-(NTT)(n), (DTT)(n), (ETT)(n), (NSS)(n), (ESS)(n), (DAA)(n), (ASS)(n), and (NAA)(n)-also showed HA binding activity, it was generally not at the same level as the natural sequence. Binding of the (DSS)(n) peptides to sectioned human teeth was shown to be tissue-specific, with high levels of binding to the mantle dentin, lower levels of binding to the circumpulpal dentin, and little or no binding to healthy enamel. Phosphorylation of the serines of these peptides was found to affect the avidity, but not the affinity, of binding. The potential utility of these peptides in the detection of carious lesions, the delivery of therapeutic compounds to mineralized tissues, and the modulation of remineralization is discussed.