gebhart/patrepeval huggingface dataset:
Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex (2003)

Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.
A second-generation vaccine protects against the psychoactive effects of cocaine (2001)

The effects of immunization with the second-generation cocaine immunoconjugate GND-keyhole limpet hemocyanin (KLH) or with the anti-cocaine mAb GNC92H2 were assessed in a model of acute cocaine-induced locomotor activity. After i.p. administration of cocaine small middle dotHCl (15 mg/kg), rats were tested in photocell cages, and stereotypy was rated to determine preimmunization drug response (baseline). Experimental animals were subjected to an immunization protocol with GND-KLH or treated with the mAb GNC92H2. Rats were then challenged with systemic cocaine, and their locomotor responses were again measured. Active immunization with GND-KLH produced a 76% decrease in the ambulatory measure (crossovers) in the experimental group and a 12% increase in the control group compared with baseline values. Also, stereotypic behavior was significantly suppressed in the vaccinated animals. Decreases in both measures were seen in the experimental group on two subsequent challenges. The maximum effect was observed at the time of the second challenge with a dramatic 80% decrease in crossovers. Treatment with GNC92H2 resulted in a 69% decrease in crossovers compared with baseline. This effect persisted across two additional challenges over 11 days with decreases of 46--47%. In contrast, the control group showed increases of up to 28%. Significant differences between groups were observed in the stereotypic measure in all three challenges. The results indicate that these immunopharmacotherapeutic agents have significant cocaine-blockade potential and therefore may offer an effective strategy for the treatment of cocaine abuse.
Biodegradable polymers in controlled drug delivery. (1984)

Erosion mechanisms are divided into three types and drug release within each type is described. Type I erosion involves hydrolysis of hydrogels and these are useful in the controlled release of macromolecules entangled within their network structure. Type II erosion involves solubilization of water-insoluble polymers by reactions involving groups pendant from the polymer backbone. Of particular interest are polymers that solubilize by ionization of carboxylic acid groups, and the utilization of those systems is described. Type III erosion involves cleavage of hydrolytically labile bonds within the polymer backbone and four distinct polymer systems within this category are under development. One system involves the diffusion of drugs from a reservoir through a bioerodible membrane, another system utilizes microcapsules, a third system utilizes monolithic devices, and the fourth system utilizes drugs chemically bound to a bioerodible polymer.
Cationic Albumin–Conjugated Pegylated Nanoparticles Allow Gene Delivery into Brain Tumors via Intravenous Administration (2006)

Patients with malignant gliomas have a poor prognosis because these tumors do not respond well to conventional treatments. Studies of glioma xenografts suggest that they may be amenable to gene therapy with cytotoxic genes, such as the proapoptotic Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL). Gene therapy of gliomas ideally employs i.v. given vectors, thus excluding viral vectors as they cannot cross the brain microvascular endothelium or blood-brain barrier. Recently, we reported the synthesis of cationic albumin-conjugated pegylated nanoparticles (CBSA-NP) and showed their accumulation in mouse brain cells upon i.v. administration. In this study, plasmid pORF-hTRAIL (pDNA) was incorporated into CBSA-NP, and the resulting CBSA-NP-hTRAIL was evaluated as a nonviral vector for gene therapy of gliomas. Thirty minutes after transfection of C6 glioma cells, CBSA-NP-hTRAIL was internalized and mostly located in the cytoplasm, whereas NP-hTRAIL was entrapped in the endolysosomal compartment. At 6 and 48 hours after transfection, respectively, released pDNA was present in the nuclei and induced apoptosis. At 30 minutes after i.v. administration of CBSA-NP-hTRAIL to BALB/c mice bearing i.c. C6 gliomas, CBSA-NP-hTRAIL colocalized with glycoproteins in brain and tumor microvasculature and, via absorptive-mediated transcytosis, accumulated in tumor cells. At 24 and 48 hours after i.v. administration of CBSA-NP-hTRAIL, respectively, hTRAIL mRNA and protein were detected in normal brain and tumors. Furthermore, repeated i.v. injections of CBSA-NP-hTRAIL induced apoptosis in vivo and significantly delayed tumor growth. In summary, this study indicates that CBSA-NP-hTRAIL is a promising candidate for noninvasive gene therapy of malignant glioma.
A label‐free protein microfluidic array for parallel immunoassays (2006)

A label-free protein microfluidic array for immunoassays based on the combination of imaging ellipsometry and an integrated microfluidic system is presented. Proteins can be patterned homogeneously on substrate in array format by the microfluidic system simultaneously. After preparation, the protein array can be packed in the microfluidic system which is full of buffer so that proteins are not exposed to denaturing conditions. With simple microfluidic channel junction, the protein microfluidic array can be used in serial or parallel format to analyze single or multiple samples simultaneously. Imaging ellipsometry is used for the protein array reading with a label-free format. The biological and medical applications of the label-free protein microfluidic array are demonstrated by screening for antibody-antigen interactions, measuring the concentration of the protein solution and detecting five markers of hepatitis B.
Synthesis, Anti-HIV Activity, and Molecular Mechanism of Drug Resistance of l-2‘,3‘-Didehydro-2‘,3‘-dideoxy-2‘-fluoro-4‘-thionucleosides (2002)

beta-l-2',3'-Didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides (beta-l-2'-F-4'-S-d4Ns) have been synthesized and evaluated against HIV-1 in primary human lymphocytes. The key intermediate 8, which was prepared from 2,3-O-isopropylidene-l-glyceraldehyde 1 in 13 steps, was condensed with various pyrimidine and purine bases followed by elimination and deprotection to give the target compounds, beta-l-2'-F-4'-S-d4Ns (17-20 and 27-30). The antiviral activity of the newly synthesized compounds was evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which the cytosine 17, 5-fluorocytosine 18, and adenine 27 derivatives showed potent anti-HIV activities (EC(50) = 0.12, 0.15, and 1.74 microM, respectively) without significant cytotoxicity up to 100 microM in human PBM, CEM, and Vero cells. The cytosine derivative 17 (beta-l-2'-F-4'-S-d4C), however, showed cross-resistance to a 3TC-resistant variant (HIV-1(M184V)). Molecular modeling studies suggest that the pattern of antiviral activity, similar to that of beta-l-2'-F-d4N, stemmed from their conformational and structural similarities. The isosteric substitution of sulfur for 4'-oxygen was well tolerated in the catalytic site of HIV-1 reverse transcriptase in the wild-type virus. However, the steric hindrance between the sugar moiety of the unnatural l-nucleoside and the side chains of Val184 of M184V RT in 3TC-resistant mutant HIV strains destabilizes the RT-nucleoside triphosphate complex, which causes the cross-resistance to 3TC (M184V mutant).
Methods for Peptide and Protein Quantitation by Liquid Chromatography-Multiple Reaction Monitoring Mass Spectrometry (2011)

Liquid chromatography-multiple reaction monitoring mass spectrometry of peptides using stable isotope dilution (SID) provides a powerful tool for targeted protein quantitation. However, the high cost of labeled peptide standards for SID poses an obstacle to multiple reaction monitoring studies. We compared SID to a labeled reference peptide (LRP) method, which uses a single labeled peptide as a reference standard for all measured peptides, and a label-free (LF) approach, in which quantitation is based on analysis of un-normalized peak areas for detected MRM transitions. We analyzed peptides from the Escherichia coli proteins alkaline phosphatase and β-galactosidase spiked into lysates from human colon adenocarcinoma RKO cells. We also analyzed liquid chromatography-multiple reaction monitoring mass spectrometry data from a recently published interlaboratory study by the National Cancer Institute Clinical Proteomic Technology Assessment for Cancer network (Addona et al. (2009) Nat. Biotechnol. 27: 633-641), in which unlabeled and isotopically labeled synthetic peptides or their corresponding proteins were spiked into human plasma. SID displayed the highest correlation coefficients and lowest coefficient of variation in regression analyses of both peptide and protein spike studies. In protein spike experiments, median coefficient of variation values were about 10% for SID and 20-30% for LRP and LF methods. Power calculations indicated that differences in measurement error between the methods have much less impact on measured protein expression differences than biological variation. All three methods detected significant (p < 0.05) differential expression of three endogenous proteins in a test set of 10 pairs of human lung tumor and control tissues. Further, the LRP and LF methods both detected significant differences (p < 0.05) in levels of seven biomarker candidates between tumors and controls in the same set of lung tissue samples. The data indicate that the LRP and LF methods provide cost-effective alternatives to SID for many quantitative liquid chromatography-multiple reaction monitoring mass spectrometry applications.
Induction of nerve growth factor receptor in Schwann cells after axotomy. (1986)

We have discovered that axotomy of sciatic nerve induces Schwann cells distal to the lesion to express de novo, or at greatly increased levels, receptors for nerve growth factor (NGF). Surgical transection of sciatic nerve was performed on adult Sprague-Dawley rats, and, at various times after the operation, the following tissues were dissected for quantitation of NGF receptor: L4 and L5 dorsal root ganglia, sciatic nerve proximal to the transection, sciatic nerve distal to the transection, tibialis anterior muscle, and skin of the dorsum of the foot. The NGF receptor content of these samples was determined by labeling receptor molecules with radioiodinated NGF (125I-NGF) and then specifically immunoprecipitating the 125I-NGF-receptor complexes with 192-IgG, a monoclonal antibody directed against the rat NGF receptor. We observed a time-dependent increase in the amount of radioligand-labeled NGF receptor proteins found in the distal segment of transected sciatic nerve; by 7 days the density of receptor (crosslinked 125I-NGF molecules per mg of homogenate protein) had increased at least 50-fold. The number of receptor molecules in tibialis anterior muscle and dorsal foot skin, two structures denervated by the transection, also increased, with time courses parallel to that of distal sciatic nerve. There was little increase in the density of NGF receptors in the sciatic nerve proximal to the lesion and in the dorsal root ganglia. Immunohistochemical examination of the distal portion of transected sciatic nerve and of the muscle, with 192-IgG as the primary ligand, revealed prominent and exclusive staining of apparently all Schwann cells of the endoneurium, indicating that these peripheral neuroglial cells were expressing NGF receptors. These results show that axonal damage can induce the expression of NGF receptors in the population of sheath cells thought to promote neuronal regeneration. This dramatic increase in NGF receptors may be a mechanism to facilitate the regeneration of NGF-responsive neurons.
A New Paradigm for Diabetes and Obesity: the Hepatic Insulin Sensitizing Substance (HISS) Hypothesis (2004)

The glucose disposal effect of insulin after a meal is accounted for in approximately equal measure by the direct action of insulin and the action of HISS (hepatic insulin sensitizing substance) released from the liver and acting on skeletal muscle to stimulate glucose storage as glycogen. The ability of insulin to cause HISS release is determined by hepatic parasympathetic nerves. Eliminating the parasympathetic signal by surgical denervation of the liver or by blockade of hepatic muscarinic receptors, hepatic nitric oxide synthase, or hepatic cyclooxygenase results in insulin resistance that can be accounted for by the absence of HISS action and is referred to as HISS-dependent insulin resistance (HDIR). Animal models in which the insulin resistance has been shown to be HDIR includes the spontaneously hypertensive rat, sucrose fed rats, animals with liver disease, adult offspring of fetal alcohol exposure, acute stress, and ageing. We suggest that HDIR accounts for the major metabolic disturbances in type 2 diabetes, including the postprandial hyperglycemia that results in the majority of pathologies related to diabetes. The observation of meal-induced insulin sensitization (MIS) and the role of HISS allows for consideration of a new paradigm relating meal processing, diabetes, obesity, and insulin resistance. New diagnostic approaches and therapeutic targets are described.
Electrodes with High Power and High Capacity for Rechargeable Lithium Batteries (2006)

New applications such as hybrid electric vehicles and power backup require rechargeable batteries that combine high energy density with high charge and discharge rate capability. Using ab initio computational modeling, we identified useful strategies to design higher rate battery electrodes and tested them on lithium nickel manganese oxide [Li(Ni(0.5)Mn(0.5))O2], a safe, inexpensive material that has been thought to have poor intrinsic rate capability. By modifying its crystal structure, we obtained unexpectedly high rate-capability, considerably better than lithium cobalt oxide (LiCoO2), the current battery electrode material of choice.
Anti-Stokes photoluminescence in colloidal semiconductor quantum dots (1999)

We report anti-Stokes photoluminescence (photon energy up-conversion) from size-quantized CdSe and InP nanocrystalline colloids. The observed up-conversion is highly efficient and occurs at very low excitation intensities. With low temperatures the intensity of the up-converted photoluminescence decreases while that of the usual Stokes photoluminescence increases; the up-converted photoluminescence is also restricted to energies corresponding to the band gaps of the quantum dots that are present in the colloid ensemble. The anti-Stokes photoluminescence is explained by a model that involves surface states.
Smart pixel optoelectronic receiver based on a charge sensitive amplifier design (1996)

The application of charge sensitive amplifier techniques to the design of receivers within smart pixel optoelectronic systems is presented. An example optical input amplifier is given which should provide high sensitivity (/spl plusmn/0.3 /spl mu/A differential), low power consumption (0.6 mW) and small area usage (50 /spl mu/m/spl times/20 /spl mu/m) for operation at a conventional CMOS bit rate of 100 Mb/s. The minimum (simulated) optical switching energy is 6 fJ.
Comparison of IRES and F2A-Based Locus-Specific Multicistronic Expression in Stable Mouse Lines (2011)

Efficient and stoichiometric expression of genes concatenated by bi- or multi-cistronic vectors has become an invaluable tool not only in basic biology to track and visualize proteins in vivo, but also for vaccine development and in the clinics for gene therapy. To adequately compare, in vivo, the effectiveness of two of the currently popular co-expression strategies - the internal ribosome entry site (IRES) derived from the picornavirus and the 2A peptide from the foot-and-mouth disease virus (FDMV) (F2A), we analyzed two locus-specific knock-in mouse lines co-expressing SRY-box containing gene 9 (Sox9) and enhanced green fluorescent protein (EGFP) linked by the IRES (Sox9(IRES-EGFP)) or the F2A (Sox9(F2A-EGFP)) sequence. Both the constructs expressed Sox9 and EGFP proteins in the appropriate Sox9 expression domains, with the IRES construct expressing reduced levels of EGFP compared to that of the F2A. The latter, on the other hand, produced about 42.2% Sox9-EGFP fusion protein, reflecting an inefficient ribosome 'skipping' mechanism. To investigate if the discrepancy in the 'skipping' process was locus-dependent, we further analyzed the FLAG(3)-Bapx1(F2A-EGFP) mouse line and found similar levels of fusion protein being produced. To assess if EGFP was hindering the 'skipping' mechanism, we examined another mouse line co-expressing Bagpipe homeobox gene 1 homolog (Bapx1), Cre recombinase and EGFP (Bapx1(F2A-Cre-F2A-EGFP)). While the 'skipping' was highly efficient between Bapx1 and Cre, the 'skipping' between Cre and EGFP was highly inefficient. We have thus demonstrated in our comparison study that the efficient and close to equivalent expression of genes linked by F2A is achievable in stable mouse lines, but the EGFP reporter may cause undesirable inhibition of the 'skipping' at the F2A sequence. Hence, the use of other reporter genes should be explored when utilizing F2A peptides.
Neurocognitive Consequences of Sleep Deprivation (2005)

Deficits in daytime performance due to sleep loss are experienced universally and associated with a significant social, financial, and human cost. Microsleeps, sleep attacks, and lapses in cognition increase with sleep loss as a function of state instability. Sleep deprivation studies repeatedly show a variable (negative) impact on mood, cognitive performance, and motor function due to an increasing sleep propensity and destabilization of the wake state. Specific neurocognitive domains including executive attention, working memory, and divergent higher cognitive functions are particularly vulnerable to sleep loss. In humans, functional metabolic and neurophysiological studies demonstrate that neural systems involved in executive function (i.e., prefrontal cortex) are more susceptible to sleep deprivation in some individuals than others. Recent chronic partial sleep deprivation experiments, which more closely replicate sleep loss in society, demonstrate that profound neurocognitive deficits accumulate over time in the face of subjective adaptation to the sensation of sleepiness. Sleep deprivation associated with disease-related sleep fragmentation (i.e., sleep apnea and restless legs syndrome) also results in neurocognitive performance decrements similar to those seen in sleep restriction studies. Performance deficits associated with sleep disorders are often viewed as a simple function of disease severity; however, recent experiments suggest that individual vulnerability to sleep loss may play a more critical role than previously thought.
Supercritical fluid (SCF) treatment: Its effect on bending strength and stiffness of ponderosa pine sapwood (1993)

Adverse effects on mechanical properties from using a supercritical fluid (SCF) to increase preservative penetration of refractory woods were evaluated by treating small ponderosa pine sapwood specimens with supercritical carbon dioxide at 64 combinations of temperatures (35 to 80 C), pressure (1,000 to 4,000 psig), and time (0.5 to 2 h). Thereafter, the treated and identical untreated specimens were equilibrated to constant moisture content and tested for bending strength and stiffness. The SCZFtreated and untreated specimens were not significantly different in modulus of rupture (MOR) or modulus of elasticity (MOE). Temperature, pressure, and time had no significant effect on MOR, there were interacting effects of these variables on MOE, although these interactions had no meaningful patterns.
Molecular Interaction of Poly(acrylic acid) Gold Nanoparticles with Human Fibrinogen (2012)

The binding of fibrinogen to various nanoparticles can result in protein unfolding and exposure of cryptic epitopes that subsequently interact with cell surface receptors. This response is dependent on the size, charge, and concentration of the nanoparticle. Here we examine the binding kinetics of human fibrinogen to negatively charged poly(acrylic acid)-coated gold nanoparticles ranging in size from 7 to 22 nm. These particles have previously been shown to elicit an inflammatory response in human cells. The larger nanoparticles bound fibrinogen with increasing affinity and a slower dissociation rate. Each fibrinogen molecule could accommodate two 7 nm nanoparticles but only one when the diameter increased to 10 nm. Nanoparticles larger than 12 nm bound multiple fibrinogen molecules in a positively cooperative manner. However, in the presence of excess nanoparticle, fibrinogen induced aggregation of the larger particles that could bind more than one protein molecule. This is consistent with interparticle bridging by the fibrinogen. Taken together, these results demonstrate that subtle changes in nanoparticle size can influence protein binding both with the surface of the nanoparticle and within the protein corona.