gebhart/patrepeval huggingface dataset:
Various MRS Application Tools for Alzheimer Disease and Mild Cognitive Impairment (2014)

MR spectroscopy is a noninvasive technique that allows the detection of several naturally occurring compounds (metabolites) from well-defined regions of interest within the human brain. Alzheimer disease, a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. During the past 20 years, multiple studies have been performed on MR spectroscopy in patients with both mild cognitive impairment and Alzheimer disease. Generally, MR spectroscopy studies have found decreased N-acetylaspartate and increased myo-inositol in both patients with mild cognitive impairment and Alzheimer disease, with greater changes in Alzheimer disease than in mild cognitive impairment. This review summarizes the information content of proton brain MR spectroscopy and its related technical aspects, as well as applications of MR spectroscopy to mild cognitive impairment and Alzheimer disease. While MR spectroscopy may have some value in the differential diagnosis of dementias and assessing prognosis, more likely its role in the near future will be predominantly as a tool for monitoring disease response or progression in treatment trials. More work is needed to evaluate the role of MR spectroscopy as a biomarker in Alzheimer disease and its relationship to other imaging modalities.
Distribution and stability of antisense phosphorothioate oligonucleotides in rodent brain following direct intraparenchymal controlled-rate infusion (1997)

High-flow microinfusion is a novel technique for delivery of compounds directly into the brain parenchyma, bypassing the blood-brain barrier. The feasibility of this technique has been demonstrated with low-molecular-weight compounds, macromolecular dyes, and proteins. Delivery of antisense oligonucleotides into the brain parenchyma represents an additional potential application of this technique not previously described. In this report, the authors examined the distribution and disposition of phosphorothioate oligodeoxynucleotide (PS-ODN) infused for this reason. An 18-mer (35)S-PS-ODN (molecular weight approximately 6000) was infused over 1 hour into the caudate putamen of Fischer 344 rats. At 1, 6, 12, 24, and 48 hours after beginning the infusion, the brains were extracted and analyzed using quantitative autoradiographic techniques. Cerebrospinal fluid (CSF) was also aspirated from the cisterna magna and analyzed for radioactivity and stability of the (35)S-PS-ODN. At 1 hour, the infused ODN was uniformly distributed in brain tissue, with a maximum average concentration of 4806.5 +/- 210.5 nCi/g. This represents a tissue concentration of 19.2 +/- 0.84 microM. Extensive spread into surrounding parenchyma was observed over the ensuing 47 hours. The (35)S-PS-ODN radioactivity peaked in the CSF at the end of the 1-hour infusion, containing 10% (50 +/- 20 nCi) of the infused radioactivity. Activity then decayed exponentially over 11 hours, stabilizing at a lower CSF content of 0.2% (1 +/- 0.1 nCi). The volume of distribution (V(d)) was 105 +/- 7.9 mm3 at 1 hour, representing a ratio of V(d)/V(i) (volume of infusion) of 5.2. The V(d) increased to 443.4 +/- 62.3 mm(3) at the end of 48 hours, whereas the average minimum tissue concentration decreased from 15.2 to 3.2 microM. Undegraded 18-mer was seen throughout the 48-hour period using 20% polyacrylamide/7M urea gel electrophoresis. The animals tolerated the infusion without evidence of toxicity, and minimal structural changes in tissue were observed on histological examination. Thus, PS-ODN can be safely delivered in high concentrations to wide areas of the rat brain by using high-flow microinfusion, and the concentrations remain stable even after 48 hours in situ.
Reconstruction and Function of Ancestral Center-of-Tree Human Immunodeficiency Virus Type 1 Proteins (2007)

The extensive diversity of human immunodeficiency virus type 1 (HIV-1) and its capacity to mutate and escape host immune responses are major challenges for AIDS vaccine development. Ancestral sequences, which minimize the genetic distance to circulating strains, provide an opportunity to design immunogens with the potential to elicit broad recognition of HIV epitopes. We developed a phylogenetics-informed algorithm to reconstruct ancestral HIV sequences, called Center of Tree (COT). COT sequences have potentially significant benefits over isolate-based strategies, as they minimize the evolutionary distances to circulating strains. COT sequences are designed to surmount the potential pitfalls stemming from sampling bias with the consensus method and outlier bias with the most-recent-common-ancestor approach. We computationally derived COT sequences from circulating HIV-1 subtype B sequences for the genes encoding the major viral structural protein (Gag) and two regulatory proteins, Tat and Nef. COT genes were synthesized de novo and expressed in mammalian cells, and the proteins were characterized. COT Gag was shown to generate virus-like particles, while COT Tat transactivated gene expression from the HIV-1 long terminal repeat and COT Nef mediated downregulation of cell surface major histocompatibility complex class I. Thus, retrodicted ancestral COT proteins can retain the biological functions of extant HIV-1 proteins. Additionally, COT proteins were immunogenic, as they elicited antigen-specific cytotoxic T-lymphocyte responses in mice. These data support the utility of the COT approach to create novel and biologically active ancestral proteins as a starting point for studies of the structure, function, and biological fitness of highly variable genes, as well as for the rational design of globally relevant vaccine candidates.
Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways † (2007)

Autism is a heterogeneous condition that is likely to result from the combined effects of multiple genetic factors interacting with environmental factors. Given its complexity, the study of autism associated with Mendelian single gene disorders or known chromosomal etiologies provides an important perspective. We used microarray analysis to compare the mRNA expression profile in lymphoblastoid cells from males with autism due to a fragile X mutation (FMR1-FM), or a 15q11-q13 duplication (dup(15q)), and non-autistic controls. Gene expression profiles clearly distinguished autism from controls and separated individuals with autism based on their genetic etiology. We identified 68 genes that were dysregulated in common between autism with FMR1-FM and dup(15q). We also identified a potential molecular link between FMR1-FM and dup(15q), the cytoplasmic FMR1 interacting protein 1 (CYFIP1), which was up-regulated in dup(15q) patients. We were able to confirm this link in vitro by showing common regulation of two other dysregulated genes, JAKMIP1 and GPR155, downstream of FMR1 or CYFIP1. We also confirmed the reduction of the Jakmip1 protein in Fmr1 knock-out mice, demonstrating in vivo relevance. Finally, we showed independent confirmation of roles for JAKMIP1 and GPR155 in autism spectrum disorders (ASDs) by showing their differential expression in male sib pairs discordant for idiopathic ASD. These results provide evidence that blood derived lymphoblastoid cells gene expression is likely to be useful for identifying etiological subsets of autism and exploring its pathophysiology.
Analysis of FOXP3+ Regulatory T Cells That Display Apparent Viral Antigen Specificity during Chronic Hepatitis C Virus Infection (2009)

We reported previously that a proportion of natural CD25(+) cells isolated from the PBMC of HCV patients can further upregulate CD25 expression in response to HCV peptide stimulation in vitro, and proposed that virus-specific regulatory T cells (Treg) were primed and expanded during the disease. Here we describe epigenetic analysis of the FOXP3 locus in HCV-responsive natural CD25(+) cells and show that these cells are not activated conventional T cells expressing FOXP3, but hard-wired Treg with a stable FOXP3 phenotype and function. Of approximately 46,000 genes analyzed in genome wide transcription profiling, about 1% were differentially expressed between HCV-responsive Treg, HCV-non-responsive natural CD25(+) cells and conventional T cells. Expression profiles, including cell death, activation, proliferation and transcriptional regulation, suggest a survival advantage of HCV-responsive Treg over the other cell populations. Since no Treg-specific activation marker is known, we tested 97 NS3-derived peptides for their ability to elicit CD25 response (assuming it is a surrogate marker), accompanied by high resolution HLA typing of the patients. Some reactive peptides overlapped with previously described effector T cell epitopes. Our data offers new insights into HCV immune evasion and tolerance, and highlights the non-self specific nature of Treg during infection.
Mechanism for discrimination between viral and host mRNA in interferon-treated cells. (1979)

In extracts of interferon-treated HeLa cells, RNA covalently linked to double-stranded RNA (dsRNA) is preferentially degraded compared with mRNA not linked in dsRNA. This was established by following the degradation of poly(A)-containing mRNA annealed with poly(U), of poly(C)-containing encephalomyocarditis virus RNA annealed with poly(I), and of the replicative intermediate of the virus isolated from infected cells. In extracts of interferon-treated cells, dsRNA promotes the synthesis of a series of oligonucleotides, designated (2'-5')oligo(A), which in turn activate an endonuclease. Several lines of evidence suggest that the (2'-5')oligo(A) polymerase/endonuclease system is involved in the preferential degradation of mRNA linked to dsRNA. Conditions that prevent synthesis of (2'-5')oligo(A) prevent this preferential degradation, whereas addition of (2'-5')oligo(A) or conditions that favor its synthesis result in degradation of mRNA both linked and not linked to dsRNA. These results are best explained by a localized activation of the endonuclease near the dsRNA region of our model substrates. We propose that in infected cells activation of the endonuclease takes place near the replicative intermediates of RNA viruses. The replicative intermediates of encephalomyocarditis virus promote synthesis of (2'-5')-oligo(A) in extracts of interferon-treated cells and are degraded to a 20S "core" resistant to digestion with RNase A. This mechanism may be responsible for discrimination between viral and cellular mRNA in interferon-treated cells.
A low switching voltage organic-on-inorganic heterojunction memory element utilizing a conductive polymer fuse on a doped silicon substrate (2004)

We present a simple, nonvolatile, write-once-read-many-times (WORM) memory device utilizing an organic-on-inorganic heterojunction (OI–HJ) diode with a conductive polymer fuse consisting of polyethylene dioxythiophene:polysterene sulfonic acid (PEDOT:PSS) forming one side of the rectifying junction. Current transients are used to change the fuse from a conducting to a nonconducting state to record a logical “1” or “0”, while the nonlinearity of the OI–HJ allows for passive matrix memory addressing. The device switches at 2 and 4 V for 50 nm thick PEDOT:PSS films on p-type Si and n-type Si, respectively. This is significantly lower than the switching voltage used in PEDOT:PSS/p-i-n Si memory elements [J. Appl Phys. 94, 7811 (2003)]. The switching results in a permanent reduction of forward-bias current by approximately five orders of magnitude. These results suggest that the OI–HJ structure has potential for use in low-cost passive matrix WORM memories for archival storage applications.
Bone Morphogenesis in Implants of Insoluble Bone Gelatin (1973)

Insoluble bone gelatin with inclusions of insoluble noncollagenous protein produces new bone when implanted in muscle in allogeneic rats. The implanted residue provides the milieu for expression of bone morphogenetic potential of migratory mesenchymal cells. Neutral buffer solutions activate endogenous enzymes that degrade components essential for cell interactions and differentiation of bone. Chloroform-methanol either denatures or extracts constituents responsible for degradation. Insoluble bone gelatin produces new bone after extraction at 2 degrees with neutral salts, 0.5 M EDTA, 0.1 M Tris.HCl, 4 M urea, 0.5 M hydroxylamine, and 10 M KCNS, as well as after limited digestion with pepsin or collagenase, but not after extraction with 5 M guanidine, 7 M urea, water saturated with phenol, or after alkali hydrolysis with 0.1 N NaOH. The specific activity of cell populations interacting with insoluble bone gelatin suggests that a chemical bond between collagen and a noncollagenous protein or part of a protein, cleaved by a neutral proteinase, controls the bone morphogenetic reaction.
Distortion-rate bounds for fixed- and variable-rate multiresolution source codes (1999)

The source coding theorem for stationary sources describes the optimal performance theoretically achievable by fixed- and variable-rate block quantizers. The source coding theorem may be generalized by considering the problem of multiresolution or successive refinement source coding, which is the topic of this work. Given a distortion vector (D/sub 1/,...,D/sub L/), this work describes the family of achievable rate vectors (R/sub 1/,...,R/sub L/) for describing a stationary source at L resolutions, where the description at the first resolution is given at rate R/sub 1/ and achieves an expected distortion no greater than D/sub 1/, the description at the second resolution includes both the first description and a refining description of rate R/sub 2/ and achieves expected distortion no greater than D/sub 2/, and so on. The work includes performance bounds for both fixed- and variable-rate source codes on discrete-time stationary ergodic sources and discrete-time stationary nonergodic sources for any integer number of resolutions L/spl ges/1. For L=1, the source coding theorems for stationary sources result. For L>1, the results extend previous theorems for discrete-alphabet memoryless sources.
Functional characterization of the NCC27 nuclear protein in stable transfected CHO‐K1 cells (2000)

NCC27 belongs to a family of small, highly conserved, organellar ion channel proteins. It is constitutively expressed by native CHO-K1 and dominantly localized to the nucleus and nuclear membrane. When CHO-K1 cells are transfected with NCC27-expressing constructs, synthesized proteins spill over into the cytoplasm and ion channel activity can then be detected on the plasma as well as nuclear membrane. This provided a unique opportunity to directly compare electrophysiological characteristics of the one cloned channel, both on the nuclear and cytoplasmic membranes. At the same time, as NCC27 is unusually small for an ion channel protein, we wished to directly determine whether it is a membrane-resident channel in its own right. In CHO-K1 cells transfected with epitope-tagged NCC27 constructs, we have demonstrated that the NCC27 conductance is chloride dependent and that the electrophysiological characteristics of the channels are essentially identical whether expressed on plasma or nuclear membranes. In addition, we show that a monoclonal antibody directed at an epitope tag added to NCC27 rapidly inhibits the ability of the expressed protein to conduct chloride, but only when the antibody has access to the tag epitope. By selectively tagging either the amino or carboxyl terminus of NCC27 and varying the side of the membrane from which we record channel activity, we have demonstrated conclusively that NCC27 is a transmembrane protein that directly forms part of the ion channel and, further, that the amino terminus projects outward and the carboxyl terminus inward. We conclude that despite its relatively small size, NCC27 must form an integral part of an ion channel complex.
Radiation-Mediated Control of Drug Delivery (2001)

Clinical trials of radiotherapy to control drug delivery were initiated in 1999 at Vanderbilt University. The initial studies exploited the findings that platelets are activated in tumor blood vessels after high-dose irradiation as used in radiosurgery and high-dose-rate brachytherapy. Platelets labeled with 111In showed binding in tumor blood vessels. However, the platelet labeling process caused platelets to also accumulate in the spleen. That clinical trial was closed, and subsequent clinical trials targeted protein activation in irradiated tumor blood vessels. Preclinical studies showed that peptide libraries that bind within irradiated tumor blood vessels contained the peptide sequence Arg-Gln-Asp (RGD). RGD binds to integrin receptors (e.g., receptors for fibrinogen, fibronectin, and vitronectin). We found that the fibrinogen receptor (GPIIb/IIIa, alpha2bbeta3) is activated within irradiated tumor blood vessels. RGD peptidemimetics currently in clinical trials include GPIIb/IIIa antagonists and the platelet-imaging agent biapcitide. Biapcitide is an RGD mimetic that is labeled with 99Tc to allow gamma camera imaging of the biodistribution of the GPIIb/IIIa receptor in neoplasms of patients treated with radiosurgery. This study has shown that the schedule of administration of the RGD mimetic is crucial. The peptide mimetic must be administered immediately before irradiation, whereas the natural ligands to the receptor compete for biapcitide binding if biapcitide is administered after irradiation. The authors currently are conducting a dose deescalation study to determine the threshold dosage required for RGD mimetic binding to radiation activated receptor. Radiation-guided clinical trials have been initiated by use of high-dose-rate brachytherapy. In a separate trial, the pharmacokinetics of radiation-inducible gene therapy are being investigated. In this trial, the radiation-activated promoter Egr-1 regulates expression of the tumor necrosis factor alpha gene, which is administered by use of the attenuated adenovirus vector. The Ad.Egr-TNF (ADGV) gene is administered by intratumoral injection of vector followed by irradiation in patients with soft-tissue sarcomas. This review highlights recent findings in these phase I pharmacokinetic studies of radiation-controlled drug delivery systems.
An experimental study on the site for ventricular pacing of a dog heart with special reference to biventricular pacing. (1987)

The present study was undertaken to compare hemodynamic status during ventricular pacing at different sites. Ten mongrel dogs were used. By epicardial mapping the point of an early breakthrough was determined on each of the body surface areas corresponding to the left and right ventricles place with bipolar pacing electrodes. Then measurements of hemodynamic parameters and epicardial mapping were done during left ventricular pacing, during right ventricular pacing and during biventricular pacing . The pattern of epicardial mapping varied with different pacing sites and was invariably different from that of the sinus rhythm. The time required for spread of epicardial excitation was remarkably longer during ventricular pacing than during the sinus rhythm and did not become noticeably shorter during the biventricular pacing than during the left ventricular pacing. As for hemodynamic parameters, a significantly higher max dp/dt value for the left ventricule was obtained during the left ventricular pacing than during the right ventricular pacing, with differences between the pacing sites being noticeably significantt in this respect. In terms of hemodynamics, the left ventricular pacing was found to be better than the right ventricular pacing and virtually equivalent to biventricular pacing.
A distributed multiple media network architecture (2003)

The Media Resource Controller (MRC) project was initiated to develop an advanced development model (ADM) testbed to be used in the evaluation of reconstitutable network control techniques using multiple-media point-to-point radio links. The planned operational application of this technology is to the 21st century tactical air control system. The ADM MRC was required to integrate three distinct point-to-point radios (two specific VHF and EHF radios and a generic X.25 interface for future definition), a vocoder port for voice capability, and an X.25 interface for host traffic. Also included in the testbed development were an operator interface for the system control and evaluation, a host simulator to generate user datagram and virtual circuit traffic in the absence of an actual host connection, and a network simulator that can emulate the presence and operation of up to 20 pseudonodes. The authors present a functional description of the MRC architecture and describe the distributed algorithms used for network monitoring and control.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Low-magnification unstable resonators used with ruby and alexandrite lasers (1986)

Low-magnification unstable resonators that utilize radially birefringent elements and that have been shown to be suitable for use with ruby and alexandrite lasers are described. From these resonators, 400 mJ of energy in a Q-switched pulse with ~2.5x diffraction-limited output has been obtained from alexandrite, and 250-mJ Q-switched output that is near diffraction limited has been obtained from ruby.
Differential regulatory signals delivered by antibody binding to the CD28 (Tp44) molecule during the activation of human T lymphocytes. (1988)

Molecule CD28 (Tp44) is expressed on the surface of majority of human T cells and has been implicated to play an active role in the regulation of T cell growth. The present study examines the effect of antibody binding to the CD28 molecule during T cell activation. Anti-CD28 but not isotype-matched anti-CD5 mAb consistently augmented anti-CD3-induced and IL-2-induced T cell proliferation and subsequent release of soluble CD25 molecule. When added together, mAb anti-CD28 and anti-CD5 acted synergistically to cause 2- to 7-fold enhancement of T cell activation induced by anti-CD3 mAb or IL-2 with no effect on the development of non-MHC-restricted IL-2-activated killer T cells. In contrast, alloantigen-induced T cell proliferation, soluble CD25 release, and the subsequent development of CTL were all inhibited by anti-CD28 mAb. Moreover, alloantigen-induced proliferative response of both CD4+ and CD8+ T cells was inhibited by anti-CD28 without affecting the cytolytic effect of CTL. Because valency of anti-CD28 binding has been implicated as an important factor in signal transduction, this was explored in the allogeneic MLR by using Fab and F(ab')2 fragments of anti-CD28 mAb and anti-mouse kappa mAb. The inhibitory effect of anti-CD28 mAb in the MLR was reversed by cross-linking of anti-CD28 mAb with anti-mouse kappa mAb. In addition, cross-linking of the CD28 molecule on alloactivated T lymphoblasts but not that on resting T cells with anti-CD28 and anti-mouse kappa induced their proliferation in the absence of the priming alloantigen. These results indicate that stimulatory or inhibitory signals delivered through the CD28 molecule are determined by the degree of cross-linking of this molecule. In addition, these results also suggest that Ag-induced CD3-TCR-mediated T cell responses are more dependent on signals delivered through the CD28 molecule than those induced with anti-CD3, and thus these results have implications for potential use of anti-CD28 in sustained propagation of Ag-specific T cells.