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At least 1,261 records · Page 70Linked to original sources
PubMed2006

Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity.

Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203-treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro.

Animals↗
PubMed1993

New aspects of neurotransplantation.

We have examined the possibility of promoting axonal regeneration within lesioned neural tissue using grafted artificial gel matrices. Polymeric matrices which feature a three-dimensional crosslinked macromolecular network were implanted into preformed lesions of the central nervous system (CNS). The host response consisted of matrix invasion by glial elements and the deposition of newly synthesized extracellular molecules. This rearrangement of the brain scarring process into an organized cellular coating promoted axonal regeneration into the gels. Entrapment of embryonic neurons and embryonal carcinoma (EC)-derived neurons, within the gels, was performed to explore the possibility of using polymer brain implants as neural graft microcarriers. Our results suggest that this approach will be useful for the delivery of cells and the promotion of axonal elongation required for successful neurotransplantation.

Animals↗
PubMed1983

Ultracytochemical studies of vesicular and canalicular transport structures in the injured mammalian blood-brain barrier.

An ultracytochemical investigation was performed to study the origin of pinocytic vesicles and canalicular structures within endothelial cells (EC) of the injured mammalian blood-brain barrier (BBB). To accomplish this goal, two electron-dense tracers, native ferritin (NF) and horseradish peroxidase (HRP), were used in conjunction with the detection of alkaline phosphatase (AP) activity, a known marker of EC plasmalemma of brain micro-blood vessels. Brain ECs from (1) mice subjected to crude leptomeningeal damage for 1, 2, or 3 days and (2) cats subjected to cold lesion injury for 1, 4, or 24 h were evaluated for tracer transport and AP activity. Fine structural analysis of leaking segments of micro-blood vessels from damaged cerebral cortex or basal ganglia demonstrated pinocytic vesicles, deep invaginations of the luminal plasmalemma and elongated, tubular profiles, all containing tracer. Because we observed in ECs from both experimental models of brain injury a positive reaction for AP activity in the luminal plasmalemma, in its deep invaginations, in delimiting membranes of pinocytic vesicles, and in tubulo-canalicular structures, we conclude that all types of transport structures derive from the same 100A thick exoplasmic plasmalemmal membranes. Further, besides the pinocytic vesicular transport system (PTS), the canalicular transport system (CTS) appears to serve as an additional important mechanism for macromolecular transport across the damaged mammalian BBB.

Animals↗
PubMed1993

Competition of Li(I) and Mg(II) for ATP binding: a 31P NMR study.

We have examined the changes in the 31P NMR chemical shifts of ATP in aqueous solution, upon addition of NaCl and LiCl at ambient temperature. NaCl and LiCl cause qualitatively similar downfield changes, although the effect of LiCl is somewhat larger. For a 2:1 mixture of Na-ATP or tris-ATP and MgCl2 at 0 degrees C, separate beta-P peaks are observed for uncomplexed ATP and ATP complexed with Mg(II) at 121.6 MHz. Addition of LiCl slightly shifts the uncomplexed Na-ATP or tris-ATP peak downfield but does not measurably shift the Mg-ATP peak or change relative intensities. Thus, Li behaves more like Na than Mg in its ATP complexation behavior, making this system a poor model for competition between Li and Mg for macromolecular binding.

Adenosine Triphosphate↗
PubMed1993

Cloning and characterization of differentially expressed genes from in vitro-grown 'amastigotes' of Leishmania donovani.

Leishmanial parasites routinely undergo cyclic differentiation from promastigotes to amastigotes during their life cycle. This process involves both morphological and macromolecular changes. To study such changes, we used a axenic culture system which permits the continuous generation and cycling of Leishmania donovani from promastigotes to 'amastigotes' in vitro. cDNA libraries were constructed from poly(A)+ RNA isolated from both the pro- and amastigote forms. Using differential cDNA hybridization techniques, 3 unique cDNAs clones (P17, A41 and A45) were isolated from the amastigote library. To assess whether these clones were differentially expressed by the pro-or 'amastigotes' forms, they were hybridized to RNA isolated from each of these parasite forms in Northern and slot-blots. Results of these analyses showed that 'amastigotes' had approx. 2-fold higher levels of the A41 and A45 RNAs compared to the promastigotes. Conversely, promastigotes showed approx. 2-fold higher levels of the P17 RNA than 'amastigotes'. Nucleotide sequence analysis and comparison with those in Gene bank, revealed that the 3 cDNAs represent unique leishmanial genes. Comparison of the deduced amino acid sequences revealed that P17 open reading frame (ORF) had significant similarity with a soybean ribosomal protein S11; A41 ORF with a Bacillus subtilis spore germination gene (gerC) and A45 ORF with yeast stress-inducible protein (STI1). It is of interest to note that, of the 3 cDNAs identified, the A45-encoded protein was recognized by sera from patients with clinically active visceral leishmaniasis and was encoded by a single copy gene.

Amino Acid Sequence↗
PubMed2005

ABC transporter architecture and regulatory roles of accessory domains.

We present an overview of the architecture of ATP-binding cassette (ABC) transporters and dissect the systems in core and accessory domains. The ABC transporter core is formed by the transmembrane domains (TMDs) and the nucleotide binding domains (NBDs) that constitute the actual translocator. The accessory domains include the substrate-binding proteins, that function as high affinity receptors in ABC type uptake systems, and regulatory or catalytic domains that can be fused to either the TMDs or NBDs. The regulatory domains add unique functions to the transporters allowing the systems to act as channel conductance regulators, osmosensors/regulators, and assemble into macromolecular complexes with specific properties.

ATP-Binding Cassette Transporters↗
PubMed2006

Spontaneous assembly of viruses on multilayered polymer surfaces.

The idea that randomly arranged supermolecular species incorporated in a network medium can ultimately create ordered structures at the surface may be counterintuitive. However, such order can be accommodated by regulating dynamic and equilibrium driving forces. Here, we present the ordering of M13 viruses, highly complex biomacromolecules, driven by competitive electrostatic binding, preferential macromolecular interactions and the rigid-rod nature of the virus systems during alternating electrostatic assembly. The steric constraints inherent to the competitive charge binding between M13 viruses and two oppositely charged weak polyelectrolytes leads to interdiffusion and the virtual 'floating' of viruses to the surface. The result is the spontaneous formation of a two-dimensional monolayer structure of viruses atop a cohesive polyelectrolyte multilayer. We demonstrate that this viral-assembled monolayer can be a biologically tunable scaffold to nucleate, grow and align nanoparticles or nanowires over multiple length scales. This system represents an interface that provides a general platform for the systematic incorporation and assembly of organic, biological and inorganic materials.

Acrylic Resins↗
PubMed2004

Probing the role of water in protein conformation and function.

Life began in a bath of water and has never escaped it. Cellular function has forced the evolution of many mechanisms ensuring that cellular water concentration has never changed significantly. To free oneself of any conceptual distinction among all small molecules, solutes and solvents, means that experiments to probe water's specific role in molecular function can be designed like any classical chemical reaction. Such an 'osmotic stress' strategy will be described in general and for an enzyme, hexokinase. Water behaves like a reactant that competes with glucose in binding to hexokinase, and modulates its conformational change and activity. This 'osmotic stress' strategy, now applied to many very different systems, shows that water plays a significant role, energetically, in most macromolecular reactions. It can be required to fill obligatory space, it dominates nearest non-specific interactions between large surfaces, it can be a reactant modulating conformational change; all this in addition to its more commonly perceived static role as an integral part of stereospecific intramolecular structure.

Glucose↗
PubMed1994

Development of Non-Intensified Charge-Coupled Device Area X-ray Detectors.

Area X-ray detectors based on charge-coupled device imagers can provide excellent performance in terms of spatial resolution, sensitivity and dynamic range. Improvements in the fabrication of the primary converter, either scintillator or phosphor, mean that it is becoming possible to dispense with prestorage intensifiers and still provide outstanding low-level signal performance. Structured CsI scintillators are presented as one method of providing high efficiency and excellent spatial resolving power for this primary converter. Characterization of detector performance, in terms of such parameters as the detective quantum efficiency, point-spread function and dynamic range, needs to be directly related to the specific application of the detector. This contribution emphasizes the interplay of these parameters in the optimum design of detector systems. Performance prediction, based on measurements taken from prototype development systems, illustrates how such detectors will meet the exacting requirements of macromolecular crystallography.

Journal Article↗
PubMedDate not supplied

A review of normal tissue hydrogen NMR relaxation times and relaxation mechanisms from 1-100 MHz: dependence on tissue type, NMR frequency, temperature, species, excision, and age.

The longitudinal (T1) and transverse (T2) hydrogen (1H) nuclear magnetic resonance (NMR) relaxation times of normal human and animal tissue in the frequency range 1-100 MHz are compiled and reviewed as a function of tissue type, NMR frequency, temperature, species, in vivo versus in vitro status, time after excision, and age. The dominant observed factors affecting T1 are tissue type and NMR frequency (V). All tissue frequency dispersions can be fitted to the simple expression T1 = AVB in the range 1-100 MHz, with A and B tissue-dependent constants. This equation provides as good or better fit to the data as previous more complex formulas. T2 is found to be multicomponent, essentially independent of NMR frequency, and dependent mainly on tissue type. Mean and raw values of T1 and T2 for each tissue are tabulated and/or plotted versus frequency and the fitting parameters A, B and the standard deviations determined to establish the normal range of relaxation times applicable to NMR imaging. The mechanisms for tissue NMR relaxation are reviewed with reference to the fast exchange two state (FETS) model of water in biological systems, and an overview of the dynamic state of water and macromolecular hydrogen compatible with the frequency, temperature, and multicomponent data is postulated. This suggests that 1H tissue T1 is determined predominantly by intermolecular (possibly rotational) interactions between macromolecules and a single bound hydration layer, and the T2 is governed mainly by exchange diffusion of water between the bound layer and a free water phase. Deficiencies in measurement techniques are identified as major sources of data irreproducibility.

Adipose Tissue↗
PubMed1989

Secretory leukocyte protease inhibitor binding to mRNA and DNA as a possible cause of toxicity to Escherichia coli.

The expression of the positively charged human protein secretory leukocyte protease inhibitor (SLPI) in Escherichia coli causes severe cellular toxicity. After induction of SLPI synthesis in a high-level-expression strain, SGE61, the growth of the strain is arrested and total protein and RNA synthesis rates decline by 60 to 70%. The mechanism of SLPI-mediated inhibition of macromolecular synthesis was examined in cell-free transcription-translation systems. SLPI proved to be a potent inhibitor of translation in vitro. When SLPI was added to translation reactions at SLPI/mRNA ratios attained during maximal SLPI accumulation in SGE61, translation of a test mRNA was inhibited by 75%. The mechanism of translation inhibition was deduced from in vitro experiments showing that SLPI bound to mRNA and interfered with the interaction of RNA-metabolizing enzymes, such as RNase. In addition, SLPI bound to DNA in vitro, but transcription was not inhibited as strongly in cell-free reactions as it was in SGE61. Similar nucleic acid-binding and translation inhibition properties were displayed in vitro by another basic protein, chicken egg white lysozyme, but were not displayed by the relatively acidic protein bovine serum albumin. On the basis of these results, we concluded that SLPI binds to nucleic acids via charge interactions and inhibits translation by competing with ribosomes for binding to mRNA. Since SLPI-mRNA and SLPI-DNA binding occurred at SLPI/mRNA and SLPI/DNA ratios existing in SGE61, nucleic acid binding may contribute to the toxicity of SLPI to E. coli. These results indicate that, in general, high-level expression of basic recombinant proteins in E. coli may be problematic.

Bacterial Proteins↗
PubMed1977

An assessment of the effects of enzyme inducers on aryl hydrocarbon hydroxylase activity.

The aryl hydrocarbon hydroxylase activity for control, Aroclor 1254 and FireMaster BP-6 induced hepatic microsomes was determined using 4-chlorobiphenyl, a model PCB isomer, as the substrate. The assay system was used to quantitate the amount of metabolites, conjugates and macromolecular adducts formed for the induced and control microsomes. The metabolites and conjugates were designated detoxification (D) products and the macromolecular adducts designated as toxification (T) products. From the data it was then possible to determine a T/D index for each inducer and it is proposed that this index is useful in assessing the potential toxicity of microsomal enzyme inducers.

Animals↗
PubMed2003

Liver sinusoidal endothelial cells represents an important blood clearance system in pigs.

BACKGROUND: Numerous studies in rats and a few other mammalian species, including man, have shown that the sinusoidal cells constitute an important part of liver function. In the pig, however, which is frequently used in studies on liver transplantation and liver failure models, our knowledge about the function of hepatic sinusoidal cells is scarce. We have explored the scavenger function of pig liver sinusoidal endothelial cells (LSEC), a cell type that in other mammals performs vital elimination of an array of waste macromolecules from the circulation. RESULTS: 125I-macromolecules known to be cleared in the rat via the scavenger and mannose receptors were rapidly removed from the pig circulation, 50% of the injected dose being removed within the first 2-5 min following injection. Fluorescently labeled microbeads (2 &mgr;m in diameter) used to probe phagocytosis accumulated in Kupffer cells only, whereas fluorescently labeled soluble macromolecular ligands for the mannose and scavenger receptors were sequestered only by LSEC. Desmin-positive stellate cells accumulated no probes. Isolation of liver cells using collagenase perfusion through the portal vein, followed by various centrifugation protocols to separate the different liver cell populations yielded 280 x 107 (range 50-890 x 107) sinusoidal cells per liver (weight of liver 237.1 g (sd 43.6)). Use of specific anti-Kupffer cell- and anti-desmin antibodies, combined with endocytosis of fluorescently labeled macromolecular soluble ligands indicated that the LSEC fraction contained 62 x 107 (sd 12 x 107) purified LSEC. Cultured LSEC avidly endocytosed ligands for the mannose and scavenger receptors. CONCLUSIONS: We show here for the first time that pig LSEC, similar to what has been found earlier in rat LSEC, represent an effective scavenger system for removal of macromolecular waste products from the circulation.

Journal Article↗
PubMed2006

Drug-target residence time and its implications for lead optimization.

Much of drug discovery today is predicated on the concept of selective targeting of particular bioactive macromolecules by low-molecular-mass drugs. The binding of drugs to their macromolecular targets is therefore seen as paramount for pharmacological activity. In vitro assessment of drug-target interactions is classically quantified in terms of binding parameters such as IC(50) or K(d). This article presents an alternative perspective on drug optimization in terms of drug-target binary complex residence time, as quantified by the dissociative half-life of the drug-target binary complex. We describe the potential advantages of long residence time in terms of duration of pharmacological effect and target selectivity.

Binding, Competitive↗
PubMed1996

Engineering human immunodeficiency virus 1 protease heterodimers as macromolecular inhibitors of viral maturation.

Dimerization of human immunodeficiency virus type 1 protease (HIV-1 PR) monomers is an essential prerequisite for viral proteolytic activity and the subsequent generation of infectious virus particles. Disruption of the dimer interface inhibits this activity as does formation of heterodimers between wild-type and defective monomers. A structure-based approach was used to identify amino acid substitutions at the dimer interface of HIV-1 PR that facilitate preferential association of heterodimers and inhibit self-association of the defective monomers. Expression of the designed PR monomers inhibits activity of wild-type HIV-1 PR and viral infectivity when assayed in an ex vivo model system. These results show that it is possible to design PR monomers as macromolecular inhibitors that may provide an alternative to small molecule inhibitors for the treatment of HIV infection.

Amino Acid Sequence↗
PubMed1986

Perinatal dietary supplementation with a soy lecithin preparation: effects on development of central catecholaminergic neurotransmitter systems.

Previous work has shown that exposure of developing rats to soy lecithin preparations (SLP) influences macromolecular constituents of immature brain cells and causes abnormal behavioral patterns. To determine if synaptic mechanisms are adversely affected by SLP, we examined the developmental characteristics of noradrenergic and dopaminergic pathways in discrete brain regions. Although transmitter levels were unaffected, the utilization rates of both catecholamines were profoundly disturbed in an age-dependent, regionally-selective manner. Utilization tended to be subnormal in the preweanling stage, but demonstrated a postweaning elevation in cerebellum and midbrain + brainstem. Enhanced utilization persisted in the latter region only, and cerebral cortex actually showed a lowered utilization rate in adulthood (60 days of age). Transmitter uptake capabilities were also affected by developmental exposure to SLP, as was tyrosine hydroxylase activity. The patterns of effects on these two variables indicated that the altered transmitter utilization rate probably reflected a change in impulse activity in the affected neuron populations, with promotion of activity in the midbrain + brainstem and reduced activity in the cerebral cortex. These data indicate that dietary supplementation with SLP throughout perinatal development alters synaptic characteristics in a manner consistent with disturbances in neural function.

Aging↗
PubMed2004

Novel techniques in electron microscopy.

Emerging techniques in electron microscopy promise to yield a wide range of new information about the nervous system. Aided by the development of detectors, electron optics, energy filters, computer automation and preparative methods, electron tomography now provides three-dimensional structures over a scale ranging from single receptor molecules to synapses and neurons. To relate structure to function, a variety of correlative methods are being developed, including protein tags observable both by light microscopy of living cells and, subsequently, by electron microscopy. It is also becoming possible to measure functionally important ions like Ca(2+) in cellular compartments at a scale of about 10 nm by exploiting new advances in electron energy loss and X-ray spectroscopic imaging.

Animals↗