gebhart/patrepeval huggingface dataset:
Biomarkers in T cell therapy clinical trials (2011)

T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity. This review will focus on biomarker studies as they relate to T cell therapy trials, and more specifically: i. An overview and description of categories and classes of biomarkers that are specifically relevant to T cell therapy trials, and ii. Insights into future directions and challenges for the appropriate development of biomarkers to evaluate both product bioactivity and treatment efficacy of T cell therapy trials.
Stereochemical Effects in an Insect Repellent (2001)

Racemic 1-[3-cyclohexen-1-ylcarbonyl]-2-methylpiperidine repels blood-feeding arthropods such as mosquitoes, chiggers, and ticks. The compound contains two asymmetric carbon atoms and the racemate consists of four stereoisomers. Quantitative mosquito bioassays using Aedes aegypti (L.) showed that (1S,2'S) and (1R,2'S) configurations were 2.8-3.1 and 1.6-1.8 times more effective, respectively, than the other two stereoisomers in reducing mosquito bites. (1S,2'S) was 2.5 more repellent than the racemate. Biological data show that an interaction of the (2'S)-2-methylpiperidine configuration with a repellent receptor system in A. aegypti is apparently important to repellent activity. Nuclear magnetic resonance spectra and molecular mechanics calculations for the stereoisomers provided insight into the conformation of the (2'S)-group. Results indicate that enhanced repellent effects can be realized through formulation of the most active stereoisomers of the compound.
The Risk of the Hemolytic–Uremic Syndrome after Antibiotic Treatment ofEscherichia coliO157:H7 Infections (2000)

Children with gastrointestinal infections caused by Escherichia coli O157:H7 are at risk for the hemolytic–uremic syndrome. Whether antibiotics alter this risk is unknown.
Effects of 3‐D microwell culture on initial fate specification in human embryonic stem cells (2014)

Several studies have demonstrated that 3D culture systems influence human embryonic stem cell (hESC) phenotypes and fate choices. However, the effect that these microenvironmental changes have on signaling pathways governing hESC behaviors is not well understood. Here, we have used a 3D microwell array to investigate differences in activation of developmental pathways between 2D and 3D cultures of both undifferentiated hESCs and hESCs undergoing initial differentiation in embryoid bodies (EBs). We observed increased induction into mesoderm and endoderm and differences in expression of genes from multiple signaling pathways that regulate development, including Wnt/β-catenin, TGF-β superfamily, Notch and FGF during EB-mediated differentiation, in 3D microwells as compared with the 2D substrates. In undifferentiated hESCs, we also observed differences in epithelial-mesenchymal transition phenotypes and the TGFβ/BMP pathway between cultures in 3D and 2D. These results illustrate that 3D culture influences multiple pathways that may regulate the differentiation trajectories of hESCs.
Acute ACE Inhibition Causes Plasma Extravasation in Mice That is Mediated by Bradykinin and Substance P (1998)

The use of angiotensin-converting enzyme (ACE) has been associated with the occurrence of adverse effects, including cough and angioneurotic edema. Accumulation of kinins has been suggested to play a major role in these adverse effects of ACE inhibitor, although conclusive evidence for such a role is lacking. We investigated whether ACE inhibition increases plasma extravasation in mice (Swiss, C57Bl/6J, and J129Sv/Ev strains) via inhibition of bradykinin metabolism and stimulation of neurogenic inflammatory mechanisms. Intravenous captopril and enalapril increased the extravasation of Evans blue dye in all tissues examined (trachea, stomach, duodenum, and pancreas). This effect was evident 15 minutes after drug administration. The particulate dye Monastral blue identified the sites of captopril-induced leakage in the microvasculature. Pretreatment with the bradykinin B2 receptor antagonist Hoe 140 or with the tachykinin NK1 receptor antagonist SR 140333 inhibited captopril-evoked increase in plasma extravasation. In mice in which the gene encoding the bradykinin B2 receptor was disrupted by gene targeting, neither bradykinin nor captopril increased plasma extravasation. Pretreatment with Hoe 140 did not reduce the hypotensive response induced by captopril. The present findings suggest that ACE inhibition increases kinin levels in tissues and/or plasma. These increased kinin levels increase microvascular leakage in mouse airways and digestive tract via the release of tachykinins from terminals of primary sensory neurons. Exaggerated kinin production and the subsequent stimulation of peptide release from sensory nerves may be involved in adverse effects of ACE inhibitors.
JUNCTIONAL COMPLEXES IN VARIOUS EPITHELIA (1963)

The epithelia of a number of glands and cavitary organs of the rat and guinea pig have been surveyed, and in all cases investigated, a characteristic tripartite junctional complex has been found between adjacent cells. Although the complex differs in precise arrangement from one organ to another, it has been regularly encountered in the mucosal epithelia of the stomach, intestine, gall bladder, uterus, and oviduct; in the glandular epithelia of the liver, pancreas, parotid, stomach, and thyroid; in the epithelia of pancreatic, hepatic, and salivary ducts; and finally, between the epithelial cells of the nephron (proximal and distal convolution, collecting ducts). The elements of the complex, identified as zonula occludens (tight junction), zonula adhaerens (intermediary junction), and macula adhaerens (desmosome), occupy a juxtaluminal position and succeed each other in the order given in an apical-basal direction. The zonula occludens (tight junction) is characterized by fusion of the adjacent cell membranes resulting in obliteration of the intercellular space over variable distances. Within the obliterated zone, the dense outer leaflets of the adjoining cell membranes converge to form a single intermediate line. A diffuse band of dense cytoplasmic material is often associated with this junction, but its development varies from one epithelium to another. The zonula adhaerens (intermediate junction) is characterized by the presence of an intercellular space ( approximately 200 A) occupied by homogeneous, apparently amorphous material of low density; by strict parallelism of the adjoining cell membranes over distances of 0.2 to 0.5 micro; and by conspicuous bands of dense material located in the subjacent cytoplasmic matrix. The desmosome or macula adhaerens is also characterized by the presence of an intercellular space ( approximately 240 A) which, in this case, contains a central disc of dense material; by discrete cytoplasmic plaques disposed parallel to the inner leaflet of each cell membrane; and by the presence of bundles of cytoplasmic fibrils converging on the plaques. The zonula occludens appears to form a continuous belt-like attachment, whereas the desmosome is a discontinuous, button-like structure. The zomula adhaerens is continuous in most epithelia but discontinuous in some. Observations made during experimental hemoglobinuria in rats showed that the hemoglobin, which undergoes enough concentration in the nephron lumina to act as an electron-opaque mass tracer, does not penetrate the intercellular spaces beyond the zonula occludens. Similar observations were made in pancreatic acini and ducts where discharged zymogen served as a mass tracer. Hence the tight junction is impervious to concentrated protein solutions and appears to function as a diffusion barrier or "seal." The desmosome and probably also the zonula adhaerens may represent intercellular attachment devices.
Increasing IgG Concentration Modulates the Conformational Heterogeneity and Bonding Network that Influence Solution Properties (2009)

Multiple molecular driving forces mediate protein stability, association, and recognition in concentrated solutions. Here we investigate the interactions that modulate the nonideal solution behavior of two immunoglobulins (IgG1s) in highly concentrated solutions using two-dimensional vibrational correlation spectroscopy (2D-COS) and principal components analysis (PCA). A specific sequence of changes is observed in the concentration-dependent vibrational spectra of the highly viscous IgG solution that deviates from ideality, whereas that sequence is reversed for all other conditions examined. The asynchronous spectra reveal variation in beta-sheet and turn regions occur before intensity variations in disordered and alpha-helical regions as the concentration is increased for the highly viscous regime. This is in contrast to the sequence observed for all other conditions studied and to the idea that beta-sheet regions are resistant to concentration-dependent affects. Finally, we show that increased hydrogen bonding and electrostatics primarily modulate the intermolecular association and nonideal behavior. Specifically, 2D-COS and PCA analysis of the amide II region suggests that Glu and Asp residues trigger the change resulting in increased viscosity and association of one IgG.
A finite-element model of the mechanical effects of implantable microelectrodes in the cerebral cortex (2005)

The viability of chronic neural microelectrodes for electrophysiological recording and stimulation depends on several factors, including the encapsulation of the implant by a reactive tissue response. We postulate that mechanical strains induced around the implant site may be one of the leading factors responsible for the sustained tissue response in chronic implants. The objectives of this study were to develop a finite-element model of the probe-brain tissue interface and analyze the effects of tethering forces, probe-tissue adhesion and stiffness of the probe substrate on the interfacial strains induced around the implant site. A 3D finite-element model of the probe-brain tissue microenvironment was developed and used to simulate interfacial strains created by 'micromotion' of chronically implanted microelectrodes. Three candidate substrates were considered: (a) silicon, (b) polyimide and (c) a hypothetical 'soft' material. Simulated tethering forces resulted in elevated strains both at the tip and at the sharp edges of the probe track in the tissue. The strain fields induced by a simulated silicon probe were similar to those induced by a simulated polyimide probe, albeit at higher absolute values for radial tethering forces. Simulations of poor probe-tissue adhesion resulted in elevated strains at the tip and delamination of the tissue from the probe. A tangential tethering force results in 94% reduction in the strain value at the tip of the polyimide probe track in the tissue, whereas the simulated 'soft' probe induced two orders of magnitude smaller values of strain compared to a simulated silicon probe. The model results indicate that softer substrates reduce the strain at the probe-tissue interface and thus may also reduce tissue response in chronic implants.
Realization of highly reproducible ZnO nanowire field effect transistors with n-channel depletion and enhancement modes (2007)

The authors demonstrate the highly reproducible fabrication of n-channel depletion-mode (D-mode) and enhancement-mode (E-mode) field effect transistors (FETs) created from ZnO nanowires (NWs). ZnO NWs were grown by the vapor transport method on two different types of substrates. It was determined that the FETs created from ZnO NWs grown on an Au-coated sapphire substrate exhibited an n-channel D mode, whereas the FETs of ZnO NWs grown on an Au-catalyst-free ZnO film exhibited an n-channel E mode. This controlled fabrication of the two operation modes of ZnO NW-FETs is important for the wide application of NW-FETs in logic circuits.
Exact and approximate unitary 2-designs and their application to fidelity estimation (2009)

We develop the concept of a unitary $t$-design as a means of expressing operationally useful subsets of the stochastic properties of the uniform (Haar) measure on the unitary group $U({2}^{n})$ on $n$ qubits. In particular, sets of unitaries forming 2-designs have wide applicability to quantum information protocols. We devise an $O(n)$-size in-place circuit construction for an approximate unitary 2-design. We then show that this can be used to construct an efficient protocol for experimentally characterizing the fidelity of a quantum process on $n$ qubits with quantum circuits of size $O(n)$ without requiring any ancilla qubits, thereby improving upon previous approaches.
Vesicular acetylcholine transporter (VAChT) protein: A novel and unique marker for cholinergic neurons in the central and peripheral nervous systems (1997)

Acetylcholine (ACh) is synthesized in nerve terminals from choline and acetyl coenzyme A by the cytoplasmic enzyme choline acetyltransferase (ChAT). The neurotransmitter is thereafter transported into synaptic vesicles, where it is stored until release. cDNA clones encoding a vesicular ACh transporter (VAChT) were recently isolated. In this paper, we report on the generation of highly specific goat polyclonal antisera to the rat VAChT protein by using a synthetic carboxy-terminal 20-amino-acid peptide sequence as an immunogen. Characterization of the antisera revealed recognition of VAChT, but not vesicular monoamine transporter (VMAT) protein, in transfected CV-1 cells. VAChT immunoreactivity was also detected in cells that endogenously express the protein, such as in PC12 cells and in primary cultures of spinal motoneurons. Absorption controls showed that the VAChT antisera could be completely blocked at the 10(-5) M concentration by cognate peptide used for immunization. The antisera cross-reacted with the VAChT protein in rat and mouse but not in guinea pig, rabbit, or cat. Immunohistochemistry and confocal laser microscopy, using the goat VAChT antisera, showed strong immunoreactivity in discrete fibers and neuronal cell bodies of the central and peripheral nervous systems. Within cell bodies and axonal nerve terminals, as well as in dendrites, the staining appeared granular, presumably representing labeling of synaptic vesicles containing ACh. In the rat central nervous system, VAChT-positive cell bodies were demonstrated in the cerebral cortex, striatum, septum, nucleus basalis, medial habenula, mesopontine complex, cranial, and autonomic and spinal motor nuclei and in the intermediomedial region near the central canal. High densities of VAChT-immunoreactive axonal fibers were encountered in areas such as the olfactory bulb, cerebral cortex, striatum, basal forebrain, amygdala, thalamus, hypothalamus including median eminence, hippocampal formation, superior colliculus, interpeduncular nucleus, and pedunculopontine and laterodorsal tegmental nuclei. In cranial and spinal motor nuclei, particularly large varicosities were seen in close proximity to the motoneuron cell somata and their proximal dendrites. In the peripheral nervous system, VAChT immunoreactivity was also detected in motor endplates of skeletal muscle as well as in fibers of sympathetic and parasympathetic abdominal ganglia, heart atrium, respiratory tract, gastrointestinal tract, pancreas, adrenal medulla, male genitourinary tract, and salivary and lacrimal glands. Direct double labeling revealed colocalization of VAChT and ChAT immunoreactivity in neurons. The results show that VAChT antisera represent novel and unique tools for the study of cholinergic neurons in the central and peripheral nervous systems.
Molecular heterogeneity of tumor rejection antigen/heat shock protein GP96 (1995)

Glycoproteins of 96 kDa (gp96) have been shown to mediate tumor-specific immunogenicity of a number of murine sarcomas. The purity of gp96 preparations used in these studies was originally demonstrated by their homogeneity on silver-stained gels and the observation that a single amino acid terminus was detected by micro-sequencing. Results reported here show that gp96 preparations consist of 3-4 closely spaced bands. However, each of the bands is recognized by well-characterized monoclonal or monospecific antibodies to gp96. We have obtained purified preparations of a slowly migrating 110-kDa and a faster migrating 96-kDa band of the gp96 cluster from the Meth A sarcoma and have observed both species to be immunogenic in a dose-restricted manner. In addition to the size-based heterogeneity, purified 96-kDa molecules are found to contain 2 major populations, which share the same amino and carboxy termini but differ in the region recognized by an anti-grp94 monoclonal antibody (MAb). The heterogeneity in gp96 preparations does not result from differences in glycosylation but may result from differential phosphorylation, conformation or the antigenic peptides associated with gp96. It has been suggested that the tumor-specific immunogenicity of gp96 preparations does not derive from gp96 but from a 110-kDa protein which co-purifies with gp96 and is distinct from it. Our observations show instead that the presence of a number of bands in purified gp96 preparations is due to heterogeneity within gp96 molecules rather than to contamination with unrelated proteins.
[Principles of morphogenesis of the visceral innervation during different stages of human postnatal development]. (2004)

This atricle presents the results of the studies of the neurovascular complexes in intestinal arteries, spleen, ovary, testis, thyroid gland, liver, kidney, heart, brain, common carotid, femoral and humeral arteries and great saphenous vein, obtained from neonates, mature and old humans. Within each age group, the normative parameters of adventitial plexuses are established according to the number of macro-microscopic and microscopic nerve bundles and their absolute and relative content of thin, intermediate and thick myelinated nerve fibers (MNFs) (Weigert-Pal's staining), relative density of acetylcholinesterase-positive fibers in nerve plexuses (Koelle-Gomori's and Karnovsky-Ruts methods), presence of destructive changes in MNFs (Bielschowsky-Gross's method). Comparison of adventitial plexuses construction in different arteries suggests the regularity in the development of nervous connections of visceral organs in human postnatal ontogenesis according to the following periods: productive, stabilization and involution. Productive period is characterized by the increase in the number of nerves and their MNF content, formation of heterogeneous population of MNFs belonging to different morpho-functional classes. In the period of relative stabilization no changes were found in the number of nerves and their MNF content, while after the age of 60 massive MNF destruction was detected. Organ specificity and an individual status of the nervous connections of the organs studied during postnatal human life was demonstrated.
Solution Structure of a Recombinant Type I Sculpin Antifreeze Protein, (2005)

We have determined the solution structure of rSS3, a recombinant form of the type I shorthorn sculpin antifreeze protein (AFP), at 278 and 268 K. This AFP contains an unusual sequence of N-terminal residues, together with two of the 11-residue repeats that are characteristic of the type I winter flounder AFP. The solution conformation of the N-terminal region of the sculpin AFP has been assumed to be the critical factor that results in recognition of different ice planes by the sculpin and flounder AFPs. At 278 K, the two repeats units (residues 11-20 and 21-32) in rSS3 form a continuous alpha-helix, with the residues 30-33 in the second repeat somewhat less well defined. Within the N-terminal region, residues 2-6 are well defined and helical and linked to the main helix by a more flexible region comprising residues A7-T11. At 268 K the AFP is overall more helical but retains the apparent hinge region. The helical conformation of the two repeats units is almost identical to the corresponding repeats in the type I winter flounder AFP. We also show that while tetracetylated rSS3 has antifreeze activity comparable to the natural AFP, its overall structure is the same as that of the unacetylated peptide. These data provide some insight into the structural determinants of antifreeze activity and should assist in the development of models that explain the recognition of different ice interfaces by the sculpin and flounder type I AFPs.
Neuroprosthetics : Theory and Practice (2004)

Neuroprosthetics is an area of intense scientific and clinical interest and rapid progress. Since the introduction of the cardiac pacemaker in 1932, we have seen developments that include cochlear prostheses, techniques for bladder and bowel control, deep brain stimulation, and restoration of mobility and respiration to paralyzed individuals. The chapters in this book have been contributed by authors who are recognized internationally in their fields. The result is a comprehensive and up-to-date review that will be invaluable to graduate students, clinicians and researchers in neuroprosthetics. It is broadly divided into three sections: Section 1 provides a core of knowledge that forms a foundation for the rest of the book, and covers the basics of neuroanatomy and neurophysiology, biomaterials and biocompatibility, stimulation and recording techniques; Section 2 describes current clinical applications of neuroprosthetics; Section 3 looks at future developments in the field
Direct Observation of the Rotation of ε Subunit in F1-ATPase (1998)

Rotation of the epsilon subunit in F1-ATPase from thermophilic Bacillus strain PS3 (TF1) was observed under a fluorescence microscope by the method used for observation of the gamma subunit rotation (Noji, H., Yasuda, R., Yoshida, M., and Kinosita, K., Jr. (1997) Nature 386, 299-302). The alpha3 beta3 gamma epsilon complex of TF1 was fixed to a solid surface, and fluorescently labeled actin filament was attached to the epsilon subunit through biotin-streptavidin. In the presence of ATP, the filament attached to epsilon subunit rotated in a unidirection. The direction of the rotation was the same as that observed for the gamma subunit. The rotational velocity was slightly slower than the filament attached to the gamma subunit, probably due to the experimental setup used. Thus, as suggested from biochemical studies (Aggeler, R., Ogilvie, I. , and Capaldi, R. A. (1997) J. Biol. Chem. 272, 19621-19624), the epsilon subunit rotates with the gamma subunit in F1-ATPase during catalysis.