gebhart/patrepeval huggingface dataset:
Deep Brain Stimulation for Obesity Control: Analyzing Stimulation Parameters to Modulate Energy Expenditure (2005)

Obesity, with 300,000 deaths and a $75 billion economic burden per year is the second leading cause of death after tobacco in the United States. Obesity arises from an imbalance in the energy homeostasis system. Among several hypothalamic regions that control this homeostatic system, the ventrolmedial hypothalamic nucleus (VMH) stands out as a target for the development of a new clinical application in which deep brain stimulation (DBS) could be used to treat obesity. We have assembled a system capable of following in real-time the resting energy expenditure (REE) in response to DBS in the VMH. In this manuscript, we discuss a preliminary analysis of the DBS parameters needed to efficiently modulate energy expenditure. Our findings show that DBS in the VMH can increases the REE without affecting the mechanical energy expenditure (MEE) in a manner that appears to be frequency dependent. Our overall objective is to analyze the stimulation parameters of DBS in the VMH so that the feasibility of a clinical application for morbid obesity can be assessed
In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain (2000)

The development of an in vivo procedure for the induction of massive proliferation, directed migration, and neurodifferentiation (PMD) in the damaged adult central nervous system would hold promise for the treatment of human neurodegenerative disorders such as Parkinson's disease. We investigated the in vivo induction of PMD in the forebrain of the adult rat by using a combination of 6-hydroxydopamine lesion of the substantia nigra dopaminergic neurons and infusions of transforming growth factor alpha (TGFalpha) into forebrain structures. Only in animals with both lesion and infusion of TGFalpha was there a rapid proliferation of forebrain stem cells followed by a timed migration of a ridge of neuronal and glial progenitors directed toward the region of the TGFalpha infusion site. Subsequently, increasing numbers of differentiated neurons were observed in the striatum. In behavioral experiments, there was a significant reduction of apomorphine-induced rotations in animals receiving the TGFalpha infusions. These results show that the brain contains stem cells capable of PMD in response to an exogenously administered growth factor. This finding has significant implications with respect to the development of treatments for both acute neural trauma and neurodegenerative diseases.
Solid phase DNA amplification: characterisation of primer attachment and amplification mechanisms (2000)

Different chemical methods used to attach oligonucleotides by their 5'-end on a glass surface were tested in the framework of solid phase PCR where surface-bound instead of freely-diffusing primers are used to amplify DNA. Each method was first evaluated for its capacity to provide a high surface coverage of oligonucleotides essentially attached via a 5'-specific linkage that satisfyingly withstands PCR conditions and leaves the 3'-ends available for DNA polymerase activity. The best results were obtained with 5'-thiol-modified oligonucleotides attached to amino-silanised glass slides using a heterobifunctional cross-linker reagent. It was then demonstrated that the primers bound to the glass surface using the optimal chemistry can be involved in attaching and amplifying DNA molecules present in the reaction mix in the absence of freely-diffusing primers. Two distinct amplification processes called interfacial and surface amplification have been observed and characterised. The newly synthesised DNA can be detected and quantified by radioactive and fluorescent hybridisation assays. These new surface amplification processes are seen as an interesting approach for attachment of DNA molecules by their 5'-end on a solid support and can be used as an alternative route for producing DNA chips for genomic studies.
Site-directed gene repair of the dystrophin gene mediated by PNA–ssODNs (2010)

Permanent correction of gene defects is an appealing approach to the treatment of genetic disorders. The use of single-stranded oligodeoxynucleotides (ssODNs) has been demonstrated to induce single-point mutations in the dystrophin gene and to restore dystrophin expression in the skeletal muscle of models of Duchenne muscular dystrophy (DMD). Here we show that ssODNs made of peptide nucleic acids (PNA-ssODNs) can achieve gene repair frequencies more than 10-fold higher than those obtained using an older generation of targeting oligonucleotides. Correction was demonstrated in muscles cells isolated from mdx(5cv) mice and was stably inherited over time. Direct intramuscular injection of PNA-ssODNs targeting the mdx(5cv) mutation resulted in a significant increase in dystrophin-positive fibers when compared with muscles that received the ssODNs designed to correct the dystrophin gene but made of unmodified bases. Correction was demonstrated at both the mRNA and the DNA levels using quantitative PCR and was confirmed by direct sequencing of amplification products. Analysis at the protein level demonstrated expression of full-length dystrophin in vitro as well as in vivo. These results demonstrate that oligonucleotides promoting strand invasion in the DNA double helix can significantly enhance gene repair frequencies of the dystrophin gene. The use of PNA-ssODNs has important implications in terms of both efficacy and duration of the repair process in muscles and may have a role in advancing the treatment of DMD.
IMMUNOLOGIC AND BIOLOGICAL PROPERTIES AND CLINICAL SIGNIFICANCE OF PLACENTAL PROTEINS PP5 AND PP12a (1983)

Among the number of newly isolated placental proteins, PP5 and PP12 share some common characteristics: Both are present in the syncytiotrophoblast of normal placenta and hydatidiform mole, but less frequently, if at all, in choriocarcinoma. The levels in heparinized plasma of both proteins are lower than those in serum, and both are heat-labile. The function of PP12 is completely unknown, whereas PP5 appears to be related to the blood coagulation and fibrinolytic systems at the placental site through its antiplasmin activity. Many exciting avenues of research have been opened to uncover the biological role of these proteins in fetal development and cancer. We are pursuing this research with the immediate goal of assessing the role of PP12 in the blood coagulation system and of studying the expression of both proteins in various forms of cancer.
Oncolytic Adenovirus: Preclinical and Clinical Studies in Patients with Human Malignant Gliomas (2009)

Oncolytic adenoviruses are emerging as a promising alternative therapy for glioma patients and are currently being tested in clinic. In this review, we summarize our experience with gene-based therapy targeting RB pathway in gliomas. Our study has evolved from the development of RB-expressing adenoviral vectors to the characterization of the oncolytic effects on gliomas of the replication competent adenoviruses Delta-24, Delta-24-RGD and ICOVIR. We also review the successful combination of the viruses with chemotherapies that are routinely used in glioma patients, the efficacy of Delta-24-RGD against brain tumor stem cells, the newly described adenovirus-induced autophagy and the potential for the systemic delivery of the oncolytic viruses with human mesenchymal stem cells. Finally, we comment on the preclinical and clinical studies of p53 expressing adenoviral vector and the lessons learned from the experience of Onyx-015, the first oncolytic adenovirus tested in clinical setting.
The molecular basis of virulence of the encephalitogenic flaviviruses. (1997)

Summary: Studies of flavivirus virulence have focussed on variants with differing neurovirulence or neuroinvasiveness in animal models, with the majority based on determining the contribution of viral structural proteins, in particular the envelope glycoprotein. Specific virulence determinants on protein E have recently been identified by the application of several experimental techniques such as selection and characterization of neutralization escape variants in the presence of anti-E protein MAbs or by site-directed mutagenesis of the E gene of infectious cDNA clones (see Fig. 2, Tables 2 And 3). However, the association of particular amino acid substitutions in protein E with loss of neurovirulence and/or neuroinvasiveness appears to be dependent on the virus system under study and thus the mechanism by which protein E controls these two virulence phenotypes is unclear. Existing data show that neurovirulence and neuroinvasiveness determinants map to identical regions of protein E, including the lateral surface of domain III (the putative receptor binding site) and the base of domain II (thought to be involved in pH-dependent fusion activity). Attenuation of some domain II and III variants is associated with changes in binding to cell membrane proteins or in pH-dependent fusion activity, suggesting that defects in the early events of virus replication are responsible for virulence attenuation. A small number of amino acid changes in domain I are associated with attenuation of virulence, including mutations in the protein E glycosylation site which result in significant reductions in viral glycoprotein expression. The mechanism of attenuation associated with other mutations in domain I is unknown. Several studies have identified putative neurovirulence determinants within other regions of the genome (e.g. non-structural protein genes, 3′ UTR), and in one example the mutation attenuates neurovirulence without alteration in neuroinvasiveness. Further work is necessary to map neurovirulence determinants within these regions. It is likely that significant advances in this field will come from the application of infectious cDNA clone technology.
Intraocular Lens Power Calculations After Laser In Situ Keratomileusis (2002)

Significant refractive errors occurred with each of the methods investigated for determining IOL power after LASIK. RH, CL, or AVG 2 provided the most accurate results.
IL-15 Is Required for Sustained Lymphopenia-Driven Proliferation and Accumulation of CD8 T Cells (2007)

Naive T cells undergo slow homeostatic proliferation in response to T cell lymphopenia, which is also called lymphopenia-induced proliferation (LIP). IL-7 is critically required for this process, but previous studies suggested IL-15 was expendable for LIP of naive CD8 T cells. In contrast, we show that IL-15 is important for sustained CD8 T cell proliferation and accumulation in a lymphopenic setting, as revealed by truncated LIP in IL-15(-/-) hosts. At the same time, we find that IL-12 enhances LIP by acting directly on the CD8 T cells and independently of IL-15, suggesting distinct pathways by which cytokines can regulate homeostatic proliferation. Interestingly, the memory-phenotype CD8 T cell generated by LIP in IL-15(-/-) hosts are phenotypically distinct from the rare endogenous memory-phenotype cells found in IL-15(-/-) animals, suggesting these cells are generated by different means. These findings demonstrate that cytokine requirements for LIP change during the process itself, illustrating the need to identify factors that regulate successive stages of lymphopenia-driven proliferation.
In vivo Colocalization of Antigen and CpG within Dendritic Cells Is Associated with the Efficacy of Cancer Immunotherapy (2008)

Immunostimulatory cytidyl guanosyl (CpG) motifs are of great interest as cancer vaccine adjuvants. They act as potent inducers of Th1 responses, including the activation of cytotoxic CD8(+) T lymphocytes (CTL). Whereas animal models have provided clear evidence that CpG enhances antitumor immunity, clinical trials in humans have thus far been less successful. Applying cryosurgery as an instant in situ tumor destruction technique, we now show that timing of CpG administration crucially affects colocalization of antigen and CpG within EEA-1(+) and LAMP-1(+) compartments within dendritic cells in vivo. Moreover, antigen/CpG colocalization is directly correlated with antigen cross-presentation, the presence of CTL, and protective antitumor immunity. Thus, failure or success of CpG as a vaccine adjuvant may depend on colocalization of antigen/CpG inside DCs and hence on the timing of CpG administration. These data might aid in the design of future immunotherapeutic strategies for cancer patients.
Identification of Functional Domains of Bordetella Dermonecrotizing Toxin (1999)

Bordetella dermonecrotizing toxin (DNT) stimulates the assembly of actin stress fibers and focal adhesions by deamidating Gln63 of the small GTPase Rho. To clarify the functional and structural organization of DNT, we cloned and sequenced the DNT gene and examined the functions of various DNT mutants. Our analyses of the nucleotide and amino acid sequences revealed that the start codon of the DNT gene is a GTG triplet located 39 bp upstream of the reported putative initiation ATG codon; consequently, DNT contains an additional 13 amino acids at its N-terminal end. All of the N-terminally truncated mutants were found to modify Rho. The shortest fragment of DNT possessing the Rho modification activity consists of amino acids from Ile1176 to the C-terminal end. This fragment overlaps the region homologous to Escherichia coli cytotoxic necrotizing factors (CNFs), which show activity similar to that of DNT. The introduction of a mutation at Cys1305 located in the highly conserved region between CNFs and DNT eliminated the activity, indicating that this domain is the catalytic center of DNT. The N-terminal fragment (1 to 531) of DNT failed to modify Rho but reduced the DNT-induced polynucleation in MC3T3-E1 cells when simultaneously added with the holotoxin, suggesting competitive inhibition in the receptor-binding or internalizing step. Our finding that DNT consists of an N-terminal receptor-binding and/or internalizing domain and a C-terminal catalytically active domain may facilitate analysis of the overall action of the toxin on the mammalian target cells.
Modulation of P-glycoprotein-mediated drug transport by alterations in lipid fluidity of rat liver canalicular membrane vesicles. (1992)

P-glycoprotein (P-gp) is believed to function as an ATP-dependent efflux pump for natural product anti-cancer drugs in multidrug-resistant (MDR) tumor cells and in certain normal tissues. P-gp has been localized to the apical plasma membrane of the bile canaliculus where it has been shown to transport [3H]daunomycin. In this study, we investigated whether alterations in membrane lipid fluidity of canalicular membrane vesicles (CMV) could modulate the P-gp-mediated accumulation of [3H]daunomycin and [3H]vinblastine. Accumulation of both cytotoxic agents was stimulated by ATP, exhibited temperature dependence and osmotic sensitivity, and followed Michaelis-Menten kinetics. Alterations in CMV lipid fluidity were induced by the known fluidizers, 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A2C) and benzyl alcohol, and were assessed by fluorescence polarization techniques using the fluorescent probe, 1,6-diphenyl-1,3,5-hexatriene (DPH). Both A2C (2.5-5.0 microM) and benzyl alcohol (10-20 mM) produced a dose-dependent increase in CMV lipid fluidity. Moreover, both fluidizers, at the above doses, significantly inhibited (p < 0.05) the ATP-dependent accumulation of [3H]daunomycin. [3H]Vinblastine accumulation was also inhibited by A2C (p < 0.05). Lower doses of A2C (0.6 microM) and benzyl alcohol (1 mM) failed to influence either lipid fluidity or P-gp-mediated drug accumulation. Kinetic analysis revealed that A2C (5.0 microM) noncompetitively inhibited [3H]daunomycin accumulation and uncompetitively inhibited [3H]vinblastine accumulation with apparent Ki values of approximately 1.5 and approximately 1.2 microM, respectively. Verapamil competitively inhibited P-gp-mediated accumulation of [3H]daunomycin but failed to alter the fluidity of CMV. Taken together, the present results demonstrate that while increases in membrane fluidity of CMV are not necessarily required to inhibit P-gp-mediated drug accumulation, they can inhibit these processes, at least in CMV. Alterations in the physical state of CMV, therefore, appear to be at least one important modulator of P-gp function.
Biochemical characterization of baculovirus-expressed rap1A/Krev-1 and its regulation by GTPase-activating proteins. (1990)

Normal human rap1A and 35A rap1A (which encodes a protein with a Thr-35----Ala mutation) were cloned into a baculovirus transfer vector and expressed in Sf9 insect cells. The resulting proteins were purified, and their nucleotide binding, GTPase activities, and responsiveness to GTPase-activating proteins (GAPs) were characterized and compared with those of Rap1 purified from human neutrophils. Recombinant wild-type Rap1A bound GTP gamma S, GTP, and GDP with affinities similar to those observed for neutrophil Rap1 protein. The rate of exchange of GTP by Rap1 without Mg2+ was much slower than that by Ras. The basal GTPase activities by both recombinant proteins were lower than that observed with the neutrophil Rap1, but the GTPase activity of the neutrophil and wild-type recombinant Rap1 proteins could be stimulated to similar levels by Rap-GAP activity in neutrophil cytosol. In contrast to wild-type Rap1A, the GTPase activity of 35A Rap was unresponsive to Rap-GAP stimulation. Neither recombinant Rap1A nor neutrophil Rap1 protein GTPase activity could be stimulated by recombinant Ras-GAP at a concentration 25-fold higher than that required to hydrolyze 50% of H-Ras-bound GTP under similar conditions. These results suggest that the putative effector domains (amino acids 32 to 40) shared between Rap1 and Ras are functionally similar and interact with their respective GAPs. However, although Rap1 and Ras are identical in this region, secondary structure or additional regions must confer the ability to respond to GAPs.
Differentiation of axon-related Schwann cells in vitro: II. Control of myelin formation by basal lamina (1989)

Several recent observations suggest that Schwann cell (SC) differentiation, including myelin formation, is dependent upon the development of basal lamina which characteristically surrounds each axon-SC unit in peripheral nerve. This dependence can be tested in a neuron-SC culture system developed in our laboratory in which SC differentiation, including basal lamina formation and myelination, is faithfully reproduced. The use of serum-free, defined medium (DM) with this culture system allows axon-driven SC proliferation but not basal lamina formation or myelination. We previously demonstrated that ascorbic acid, in the presence of a nondialyzable serum factor(s), stimulates basal lamina assembly and myelin formation with similar dose-response relationships (Eldridge et al., 1987). We hypothesized that ascorbic acid acts to promote SC myelination indirectly, by enabling the assembly of basal lamina. We now provide support for this hypothesis by demonstrating the following. (1) Pepsin-resistant triple-helical collagen molecules were produced only by SCs grown in the presence of ascorbic acid, suggesting that triple-helical type IV collagen may mediate the effect of ascorbic acid on basal lamina formation. (2) The formation of myelin by oligodendrocytes, which myelinate axons in the CNS without the concomitant deposition of basal lamina, was little affected by ascorbic acid, suggesting that the biosynthesis and assembly of myelin per se does not require ascorbic acid. (3) The provision of exogenous basal lamina matrix to SCs grown with neurons in DM without ascorbic acid promoted control levels of myelination (and basal lamina formation); the provision of exogenous fibrillar collagen matrix did not. (4) Purified laminin promoted control levels of myelination in the absence of ascorbic acid, but purified type IV collagen and heparan sulfate proteoglycan (HSPG) did not. Laminin caused SCs to assemble basal lamina-like structures that contained not only laminin but also HSPG and non-triple-helical type IV collagen. Thus, several types of experiments demonstrate that SC myelin formation can be controlled by regulating the ability of the SC to assemble basal lamina, illustrating that acquisition of basal lamina is a crucial prefatory step for further SC differentiation.
A General Method for the Synthesis of Unsymmetrically Substituted Ureas via Palladium-Catalyzed Amidation (2009)

A general and practical method for the preparation of unsymmetrically substituted ureas has been developed utilizing palladium-catalyzed amidation. Both aryl bromides and chlorides, as well as heteroaryl chlorides, have been coupled to aryl, benzyl, and aliphatic ureas by using a novel nonproprietary bipyrazole ligand (bippyphos).
Design and applications of silica-based planar lightwave circuits (1999)

Planar lightwave circuits (PLCs) are waveguide devices that integrate fiber-matched optical waveguides on silicon or glass substrate to provide an efficient means of interaction for the guided-wave optical signals, PLCs provide various important and functional devices for optical wavelength-division multiplexing, time-division-multiplexing systems, and subscriber networks. This paper reviews the recent progress and future prospects of PLC technologies including arrayed-waveguide grating multiplexers, optical add-drop multiplexers and hybrid optoelectronics integration technologies.
Polymer-Free Fracturing Fluid Exhibits Improved Cleanup for Unconventional Natural Gas Well Applications (2004)

Abstract Hydraulic fracturing treatments in unconventional (coalbed and carboniferous shale) natural gas wells have been successful in stimulating gas production. However, the wells often do not perform up to potential following the treatments for various reasons. Some of the factors that can contribute to the relatively poor performance include low coal or shale permeability, complex cleating and natural fracture networks, gas content and adsorption characteristics, water content, and fracturing fluid interaction with formation surfaces. Fracturing fluid damage in coal formations has been shown to cause significant reductions in permeability, and whole gel leakoff into the cleat networks can further impair production. The same damage mechanisms can impair the production of carboniferous shale formations. To avoid the damage associated with polymer-based fluids, a coal/carboniferous shale-compatible solids-free (CCSF) fluid was developed for unconventional natural gas well applications. The CCSF fluid is a nitrogen-foamed fluid that was designed to be environmentally friendly to minimize risk to ground water that could be contacted during fracturing treatments. This study investigates the effects of various hydraulic fracturing fluids including conventional polymer-based fluids, water containing friction reducers, and a coal/carboniferous shale-compatible solids-free fluid on coal and shale pack cleanup. Laboratory coal pack cleanup tests demonstrate a significant reduction in retained permeability with polymer-based fluids. In addition, a high cleanup factor (a parameter introduced to provide a measure of the pressure and time required for cleanup) is required to establish only marginal flow conditions with brine injected in the production direction. Even water containing low concentrations of friction reducer may result in less than 50% retained permeability. The CCSF fluid provides 70 to 100% retained permeability and a low cleanup factor for effective coal pack cleanup with coal samples from seven coal basins in North America. Similar improvements were observed with carboniferous shale pack cleanup tests. Field case histories in coal and carboniferous shale formations are consistent with laboratory observations and demonstrate a dependence of fracture cleanup on retained permeability and the cleanup factor measured in the laboratory. Production results demonstrate a 30 to 60% increase in production with the CCSF fluid compared to conventional fracturing fluids in coal and carboniferous shale basins in the United States.