gebhart/patrepeval huggingface dataset:
Targeting Ion Channels in Cancer: A Novel Frontier in Antineoplastic Therapy (2008)

Targeted therapy is considerably changing the treatment and prognosis of cancer. Progressive understanding of the molecular mechanisms that regulate the establishment and progression of different tumors is leading to ever more specific and efficacious pharmacological approaches. In this picture, ion channels represent an unexpected, but very promising, player. The expression and activity of different channel types mark and regulate specific stages of cancer progression. Their contribution to the neoplastic phenotype ranges from control of cell proliferation and apoptosis, to regulation of invasiveness and metastatic spread. As is being increasingly recognized, some of these roles can be attributed to signaling mechanisms independent of ion flow. Evidence is particularly extensive for K(+) channels. Their expression is altered in many primary human cancers, especially in early stages, and they frequently exert pleiotropic effects on the neoplastic cell physiology. For instance, by regulating membrane potential they can control Ca(2+) fluxes and thus the cell cycle machinery. Their effects on mitosis can also depend on regulation of cell volume, usually in cooperation with chloride channels. However, ion channels are also implicated in late neoplastic stages, by stimulating angiogenesis, mediating the cell-matrix interaction and regulating cell motility. Not surprisingly, the mechanisms of these effects are manifold. For example, intracellular signaling cascades can be triggered when ion channels form protein complexes with other membrane proteins such as integrins or growth factor receptors. Altered channel expression can be exploited for diagnostic purposes or for addressing traceable or cytotoxic compounds to specific neoplastic tissue. What is more, recent evidence indicates that blocking channel activity impairs the growth of some tumors, both in vitro and in vivo. This opens a new field for medicinal chemistry studies, which can avail of the many available tools, such as blocking antibodies, antisense oligonucleotides, small interfering RNAs, peptide toxins and a large variety of small organic compounds. The major drawback of this approach is that some ion channel blockers produce serious side effects, such as cardiac arrhythmias. Therefore, drug developing efforts aimed at producing less harmful compounds are needed and we discuss possible approaches toward this goal. Finally, we propose that a novel therapeutic tactic could be developed by unlocking ion channels from multiprotein membrane signaling complexes.
In vitro and in vivo activity of LY 146032, a new cyclic lipopeptide antibiotic (1986)

The in vitro activity of LY 146032, a cyclic lipopeptide antibiotic belonging to the class of agents designated A21978C, was compared with those of vancomycin, cefpirome, cefotaxime, and clindamycin against selected gram-positive bacteria. The new drug inhibited all staphylococcal isolates, including methicillin-resistant strains, at concentrations of less than or equal to 1.0 microgram/ml. The activity of LY 146032 was comparable to that of vancomycin against most streptococci, but the latter demonstrated greater potency against Streptococcus faecium and penicillin-resistant strains of pneumococci and viridans group streptococci. LY 146032 was markedly less active than vancomycin against Listeria monocytogenes (MICs for 90% of strains tested, 16 and 1.0 microgram/ml, respectively). The activity of LY 146032 was enhanced as the concentration of calcium in the test medium was increased. MBCs were within eightfold of the MIC for each of 12 strains tested. In a rat model of enterococcal endocarditis, the administration of LY 146032 resulted in increased survival and a reduction in the bacterial titer within cardiac vegetations compared with untreated control animals.
Comparative motility of X and Y chromosome-bearing bovine sperm separated on the basis of DNA content by flow sorting (1998)

A combination of flow cytometric sperm sorting of X and Y chromosome–bearing sperm (X and Y sperm) and computer-assisted sperm analysis (CASA) for measuring sperm motility allows assessment of motion parameters in the two populations. Bull sperm were separated into X and Y populations by flow cytometry following staining with the DNA-binding dye Hoechst 33342. The motion parameters differed depending on sperm concentration. Decreasing sperm concentration resulted in higher velocities and straighter trajectories. The concentrations of control (stained-unsorted and unstained-unsorted) and flow-sorted sperm were therefore adjusted to similar numbers (5 × 106 sperm per milliliter). Samples of sorted X and Y sperm and control sperm were transferred to prewarmed slides on a heated stage (37°C) and their motion video recorded for 2 min using a magnification of ×100 and a high-resolution camera. The sperm analysis was carried out on a Hobson Sperm Tracker (HST) using HST 7 software. The following motion parameters were measured: curvilinear, straight-line, and average path velocity; mean angular displacement (MAD); beat cross-frequency; amplitude of lateral head displacement; linearity (LIN); and straightness of path (STR). Sperm movement was unaffected by staining with Hoechst 33342, excitation by ultraviolet (UV) light, or the physical process of cell sorting. Significant differences were seen between X and Y sperm for MAD, LIN, and STR. No difference was observed for the other parameters. The results indicate that in a simple salts solution, Y bull sperm do not swim faster than X sperm but may be distinguished from X sperm on the basis of LIN and STR. Mol. Reprod. Dev. 50:323–327, 1998. Published 1998 Wiley-Liss, Inc.
Geometric control of vascular networks to enhance engineered tissue integration and function (2013)

Tissue vascularization and integration with host circulation remains a key barrier to the translation of engineered tissues into clinically relevant therapies. Here, we used a microtissue molding approach to demonstrate that constructs containing highly aligned "cords" of endothelial cells triggered the formation of new capillaries along the length of the patterned cords. These vessels became perfused with host blood as early as 3 d post implantation and became progressively more mature through 28 d. Immunohistochemical analysis showed that the neovessels were composed of human and mouse endothelial cells and exhibited a mature phenotype, as indicated by the presence of alpha-smooth muscle actin-positive pericytes. Implantation of cords with a prescribed geometry demonstrated that they provided a template that defined the neovascular architecture in vivo. To explore the utility of this geometric control, we implanted primary rat and human hepatocyte constructs containing randomly organized endothelial networks vs. ordered cords. We found substantially enhanced hepatic survival and function in the constructs containing ordered cords following transplantation in mice. These findings demonstrate the importance of multicellular architecture in tissue integration and function, and our approach provides a unique strategy to engineer vascular architecture.
Structural similarity between lung surfactant protein D and conglutinin (1993)

Preparations of bovine lung surfactant D (SP-D) and conglutinin were examined by electron microscopy, gel-filtration and SDS/PAGE. SP-D is composed of non-covalently linked subunits, of 160 kDa, which each contain three, disulphide-linked, 44-kDa polypeptide chains. In the electron microscope a single 160-kDa subunit of SP-D appears as a 45.8 +/- 3-nm-long rod connected to a small globular 'head'. Particles were also seen which correspond to non-covalently linked dimers, trimers and tetramers of the 160-kDa monomer subunit of SP-D. The tetramer structure contains 12 polypeptide chains and is very similar to the electron microscopy images and model reported by Strang et al. [Strang, C. J., Slayter, US., Lachmann, P. J. and Davis, A. E. (1986) Biochem. J. 236, 3811-389] for bovine conglutinin in which four 160-kDa subunits are disulphide-linked to give a molecule of expected molecular mass of 528 kDa. This study confirmed the findings by Strang et al. in the above paper for intact conglutinin and also emphasised that the rod-like structures, of length 37.6 +/- 3.7 nm, seen in the conglutinin subunits were significantly shorter than those in SP-D despite the close similarity in amino acid sequence (79% identify) and chain length between the two proteins. In addition, a truncated form of conglutinin was found in the conglutinin preparations, due to limited proteolysis of the Arg-Ala bond at position 54 in the 44-kDa chains. These truncated conglutinin chains yield a subunit composed of three shortened, non-disulphide-linked, chains and this subunit appears as a monomer with a rod length of 34.2 +/- 2.8 nm in the electron microscope. On gel-filtration, a proportion of the SP-D preparation behaved, as expected, as a molecule with an apparent molecular mass of 600 kDa. The remainder of the SP-D preparation behaved as aggregated material with a molecular mass greater than 900 kDa which yielded no distinct structures in the electron microscope. Intact conglutinin was eluted at a position greater than 900 kDa but yet provided clear electron microscopy images of the tetramer structure described above.(ABSTRACT TRUNCATED AT 400 WORDS)
Identification of a Universal Group B Streptococcus Vaccine by Multiple Genome Screen (2005)

Group B Streptococcus (GBS) is a multiserotype bacterial pathogen representing a major cause of life-threatening infections in newborns. To develop a broadly protective vaccine, we analyzed the genome sequences of eight GBS isolates and cloned and tested 312 surface proteins as vaccines. Four proteins elicited protection in mice, and their combination proved highly protective against a large panel of strains, including all circulating serotypes. Protection also correlated with antigen accessibility on the bacterial surface and with the induction of opsonophagocytic antibodies. Multigenome analysis and screening described here represent a powerful strategy for identifying potential vaccine candidates against highly variable pathogens.
Detoxification of lipopolysaccharide (LPS) by egg white lysozyme (1994)

Recent studies carried out by our group suggest that lysozyme binds to bacterial lipopolysaccharide with a high affinity to produce a complex, and inhibits various biological activities of lipopolysaccharide. Although the basic structure of lipopolysaccharide is independent of the species and strains of Gram-negative bacteria, many structural factors such as O-antigenic polysaccharide, lipid A, substituted groups, and associated molecules, affect the biological activities of lipopolysaccharide. In this study, we prepared lysozyme/lipopolysaccharide complexes using various structures of lipopolysaccharide and compared the activity and physicochemical properties. Native and dansylated lysozyme were found to bind to all tested lipopolysaccharides. The mitogenic activity and TNF production by all tested lipopolysaccharides were significantly reduced by complex formation in vitro. Administration of the complex prepared by various lipopolysaccharides produced significantly less quantities of TNF in the septic shock model. These results suggested that binding of lysozyme to lipopolysaccharide is important for the host both in pathophysiological responses to lipopolysaccharides and in the modification of lipopolysaccharide biological activity.
Recombinant Adenovirus Induces Maturation of Dendritic Cells via an NF-κB-Dependent Pathway (2000)

Recombinant adenovirus (rAd) infection is one of the most effective and frequently employed methods to transduce dendritic cells (DC). Contradictory results have been reported recently concerning the influence of rAd on the differentiation and activation of DC. In this report, we show that, as a result of rAd infection, mouse bone marrow-derived immature DC upregulate expression of major histocompatibility complex class I and II antigens, costimulatory molecules (CD40, CD80, and CD86), and the adhesion molecule CD54 (ICAM-1). rAd-transduced DC exhibited increased allostimulatory capacity and levels of interleukin-6 (IL-6), IL-12p40, IL-15, gamma interferon, and tumor necrosis factor alpha mRNAs, without effects on other immunoregulatory cytokine transcripts such as IL-10 or IL-12p35. These effects were not related to specific transgenic sequences or to rAd genome transcription. The rAd effect correlated with a rapid increase (1 h) in the NF-kappaB-DNA binding activity detected by electrophoretic mobility shift assays. rAd-induced DC maturation was blocked by the proteasome inhibitor Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) or by infection with rAd-IkappaB, an rAd-encoding the dominant-negative form of IkappaB. In vivo studies showed that after intravenous administration, rAds were rapidly entrapped in the spleen by marginal zone DC that mobilized to T-cell areas, a phenomenon suggesting that rAd also induced DC differentiation in vivo. These findings may explain the immunogenicity of rAd and the difficulties in inducing long-term antigen-specific T-cell hyporesponsiveness with rAd-transduced DC.
Fiberless Recombinant Adenoviruses: Virus Maturation and Infectivity in the Absence of Fiber (1999)

In vivo targeting of therapeutic genes to specific tissues has become a major issue in gene therapy, in particular when recombinant adenovirus vectors are used. Restriction of the viral tropism to selected cell types requires the abrogation of the interaction between the viral fiber and its natural cellular receptors and the introduction of a new binding specificity into the virion. In this context, fiberless adenoviruses are attractive vectors, since they may be used as substrates for the insertion of a new ligand in other capsid proteins. In this study, we confirm by using cloned full-length adenovirus genomes with the fiber gene deleted that efficient virus particle formation can occur in the absence of fiber. As expected, the infectivity of such fiberless viruses was severely reduced, but it could be only partially restored when the viruses were produced in cells stably providing the fiber in trans. Although incorporation of penton base into the fiberless particles was normal and binding of the particles to the cellular integrins was functional, several pieces of experimental evidence suggest that later steps in the cell entry process are impaired in correlation with an incorrect maturation of several structural proteins of the fiberless particles. These observations support the hypothesis that the fiber protein may have additional biological functions besides its role in cell binding. Together with the fiber complementation cells, such fiberless vectors constitute unique tools to investigate the role of the fiber in virus assembly, maturation, and cell entry and to explore the possibility of deriving gene transfer vectors with novel target specificities.
Synthesis of Iso-C-nucleoside Analogues from 1-(Methyl 2-O-benzyl-4,6- O-benzylidene-3-deoxy-α-D-altropyranosid-3-yl)but-3-yn-2-ones (2005)

1-(Methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-α-D-altropyranosid-3-yl)but-3-yn-2-one (3a) reacted with 3-amino-1H-1,2,4-triazole and 5-aminopyrazole-4-carboxylic acid derivatives in the presence of base to furnish the triazolo[1,5-a]pyrimidine (5) and the pyrazolo[1,5- a]pyrimidines (8a - d), respectively. Treatment of 1-(methyl 2-O-benzyl-4,6-O-benzylidene-3- deoxy-α-D-altropyranosid-3-yl)-4-phenyl-but-3-yn-2-one (3b) with cyanacetamide, 2-cyano-N- (4-methoxyphenyl)acetamide und N-aryl-3-oxo-butyramides afforded the substituted nicotinonitriles (11a - d). Furthermore, reaction of 3b with 2-benzimidazolyl-acetonitrile yielded the benz[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (13). Deprotection of 8d in two steps afforded the 2-amino-N-benzyl-5-(methyl 3-deoxy-α-D-altropyranosid-3-yl-methyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide (10). Compounds 5 and 11d were treated with AcOH/H 2 O to furnish the 5-(methyl 2-O-benzyl-3-deoxy-α-D-altropyranosid-3-yl-methyl)[1,2,4]triazolo[1,5-a]pyrimidine (6) and the 3-acetyl-1,2-dihydro-1-(4-methoxyphenyl)-6-(methyl 2-O-benzyl-3-deoxy-α-D-altropyranosid-3-ylmethyl)- 4-phenylpyridin-2-one (12), respectively.
Design and Implementation of a Compact 6-Port Antenna (2009)

A pair of half-wavelength slot and narrow patch antennas stacked closely together to form a set of nearly colocated antennas for achieving polarization diversity is described. A reduced-size version is then proposed by utilizing a quarter-wavelength slot and planar inverted-F antenna (PIFA) pair, respectively. When three sets of these antennas are placed on each orthogonal axis, a compact 6-port antenna is constructed. Key characteristics of the antennas are found through electromagnetic simulation and physical measurements.
Virtual computing and the Virtual Computer (2002)

Virtual computing is an entirely new form of supercomputing that allows an algorithm to be implemented in hardware. Based on the Xilinx FPGA and ICube's FPID the Virtual Computer is completely reconfigurable in every respect. Computing machines based on reconfigurable logic are hyper-scalable meaning they scale up better than 1-1.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Non-uniform signal constellation for iteratively decoded bit interleaved coded modulation (BICM-ID) with convolution and LDPC codes (2011)

Bit interleaved coded modulation with iterative demapping and decoding (BICM-ID) is an effective technique to achieve high spectral efficiency with performance close to capacity limits. However, the use of non-uniform signal constellation following a Gaussian distribution instead of conventional equiprobable signaling provides a further improvement, i.e. shaping gain. In this paper, we investigate the effect of nonuniform constellation on the performance of BICM-ID systems with different forward error correction (FEC) coding schemes such as convolution code and low-density parity-check (LDPC) code as outer code. Simulation results show that the non-uniform constellations can offer a shaping gain up to 0.21 dB.
Synthesis and Pharmacology of Site Specific Cocaine Abuse Treatment Agents:  8-Substituted Isotropane (3-Azabicyclo[3.2.1]octane) Dopamine Uptake Inhibitors (2003)

A series of 8-substituted-3-azabicyclo[3.2.1]octanes (isotropanes) were synthesized and tested for inhibitor potency using [(3)H]WIN 35,428 binding at the dopamine (DA) transporter, [(3)H]citalopram binding at the serotonin (5-HT) transporter, and [(3)H]DA uptake assays. The synthesis started with a Mannich condensation of cyclopentanone, benzylamine, and fomaldehyde to afford N-benzyl-3-azabicyclo[3.2.1]octan-8-one (6). The 8-phenyl group was introduced by Grignard addition to ketone 6 or nucleophilic displacement via a triflate of the corresponding alcohol 7a. The 8beta-phenyl-8alpha-alcohols from Grignard addition generally have low affinity for the two transporters and do not effectively inhibit the uptake of [(3)H]DA. The 8beta-phenyl compound (14) without the hydroxyl group at C-8 was much more potent (22-fold) for [(3)H]WIN 35,428 binding inhibition than the corresponding 8beta-phenyl-8alpha-hydroxy compound (7a). The 8alpha-phenyl compound 8a was almost as potent as cocaine in binding to the DA transporter (IC(50) = 234 nM vs 159 nM for cocaine), whereas the C-8 epimer, compound 14, was somewhat less potent (IC(50) = 785 nM). The lower potency of 14 (beta-orientation of 8-phenyl group) as compared to 8a (alpha-orientation) was unexpected, based on modeling studies comparing the new compounds to WIN 35,065-2, an analogue of cocaine. The benzhydryl ethers at C-8 (17), analogous to the benztropines, had better selectivity than the corresponding phenyl compounds, 8a and 14, for the DA transporter as compared to the 5-HT transporter. The isotropane and benzisotropine analogues seem to bind in a manner that is more similar to that of the benztropine compounds 5 rather than those of cocaine and WIN 35,065-2.
Optimized Flow Cytometric Analysis of Central Nervous System Tissue Reveals Novel Functional Relationships Among Cells Expressing CD133, CD15, and CD24 (2007)

Although flow cytometry is useful for studying neural lineage relationships, the method of dissociation can potentially bias cell analysis. We compared dissociation methods on viability and antigen recognition of mouse central nervous system (CNS) tissue and human CNS tumor tissue. Although nonenzymatic dissociation yielded poor viability, papain, purified trypsin replacement (TrypLE), and two purified collagenase/neutral protease cocktails (Liberase-1 or Accutase) each efficiently dissociated fetal tissue and postnatal tissue. Mouse cells dissociated with Liberase-1 were titrated with antibodies identifying distinct CNS precursor subtypes, including CD133, CD15, CD24, A2B5, and PSA-NCAM. Of the enzymes tested, papain most aggressively reduced antigenicity for mouse and human CD24. On human CNS tumor cells, CD133 expression remained highest after Liberase-1 and was lowest after papain or Accutase treatment; Liberase-1 digestion allowed magnetic sorting for CD133 without the need for an antigen re-expression recovery period. We conclude that Liberase-1 and TrypLE provide the best balance of dissociation efficiency, viability, and antigen retention. One implication of this comparison was confirmed by dissociating E13.5 mouse cortical cells and performing prospective isolation and clonal analysis on the basis of CD133/CD24 or CD15/CD24 expression. Highest fetal expression of CD133 or CD15 occurred in a CD24(hi) population that was enriched in neuronal progenitors. Multipotent cells expressed CD133 and CD15 at lower levels than did these neuronal progenitors. We conclude that CD133 and CD15 can be used similarly as selectable markers, but CD24 coexpression helps to distinguish fetal mouse multipotent stem cells from neuronal progenitors and postmitotic neurons. This particular discrimination is not possible after papain treatment. Disclosure of potential conflicts of interest is found at the end of this article.
Large-scale recombinant adeno-associated virus production (2011)

Since recombinant adeno-associated virus (rAAV) was first described as a potential mammalian cell transducing system, frequent reports purportedly solving the problems of scalable production have appeared. Yet few of these processes have enabled the development of robust and economical rAAV production. Two production platforms have emerged that have gained broad support for producing both research and clinical grade vectors. These processes differ fundamentally in several aspects. One approach is based on adherent mammalian cells and uses optimized chemical transient transfection for introducing the essential genetic components into the cells. The other approach utilizes suspension cultures of invertebrate cells. Baculovirus expression vectors are used for introducing the AAV genes into the cells. In addition, the baculovirus provides the helper functions necessary for efficient AAV DNA replication. The use of suspension cell culture provides an intrinsically more scalable platform system than using adherent cells. The upstream processes for suspension cultures are amenable for automation and are easily monitored and regulated to maintain optimum conditions that produce consistent yields of rAAV. Issues relating to developing new and improving existing rAAV production methods are discussed.