julilili42/papers huggingface dataset:
Pathophysiology and Pharmacological Treatment of Insulin Resistance*
2000-12-01

Abstract Diabetes mellitus type 2 is a world-wide growing health problem affecting more than 150 million people at the beginning of the new millennium. It is believed that this number will double in the next 25 yr. The pathophysiological hallmarks of type 2 diabetes mellitus consist of insulin resistance, pancreatic β-cell dysfunction, and increased endogenous glucose production. To reduce the marked increase of cardiovascular mortality of type 2 diabetic subjects, optimal treatment aims at normalization of body weight, glycemia, blood pressure, and lipidemia. This review focuses on the pathophysiology and molecular pathogenesis of insulin resistance and on the capability of antihyperglycemic pharmacological agents to treat insulin resistance, i.e., α-glucosidase inhibitors, biguanides, thiazolidinediones, sulfonylureas, and insulin. Finally, a rational treatment approach is proposed based on the dynamic pathophysiological abnormalities of this highly heterogeneous and progressive disease.
Mesalazine Inhibits Activation of Transcription Factor Nf-κB in Inflamed Mucosa of Patients With Ulcerative Colitis
2000-12-01

OBJECTIVES: The salicylate mesalazine is commonly used for the treatment of inflammatory bowel diseases, yet its precise mechanism of action is unknown. Because transcription factor NF-κB plays an important role in inflammatory bowel diseases, we investigated the effects of mesalazine therapy on NF-κB activation in patients with ulcerative colitis. METHODS: A total of 20 patients with moderately active ulcerative colitis received mesalazine for 8 wk. Biopsies were taken before and after drug administration and analyzed for NF-κB activation using an antibody specific for active NF-κB. RESULTS: In biopsies of active ulcerative colitis but not in noninflamed mucosa, activation of NF-κB was detected predominantly in macrophages. Mesalazine therapy resulted in a strong abrogation of NF-κB activation in situ. CONCLUSIONS: Our results suggest that the therapeutic properties of mesalazine rely at least in part on the inhibition of NF-κB activation, resulting in the suppression of proinflammatory gene expression in the inflamed mucosa.
Recent advances in exploring physiology and biodiversity of ectomycorrhizas highlight the functioning of these symbioses in ecosystems
2000-12-01

Ectomycorrhizas, the dominating mycorrhizal symbiosis in boreal, temperate and some tropical forests, are formed by 5000-6000 species of the asco- and basidiomycetes. This high diversity of fungal partners allows optimal foraging and mobilisation of various nitrogen and phosphorus forms from organic soil layers. In this review, two approaches to study the functioning of this multitude of symbiotic associations are presented. On selected culture models, physiological and molecular investigations have shown that the supply of hexoses has a key function in controlling the plant-fungus interaction via partner-specific regulation of gene expression. Environmental factors which affect fungal carbon supply, such as increased nitrogen availability, also affect mycorrhiza formation. Based on such laboratory results, the adaptative capability of ectomycorrhizas to changing field conditions is discussed. The second approach consists of analysing the distribution of mycorrhizas in ecosystem compartments and to relate distribution patterns to variations of ecological factors. Recent advances in identification of fungal partners in ectomycorrhizas by analysing the internal transcribed spacer of ribosomal DNA are presented, which can help to resolve sampling problems in field studies. The limits of the laboratory and the field approaches are discussed. Despite some problems, this combined approach is the most promising. Direct investigation of gene expression, which has been introduced for soil bacteria, will be difficult in the case of mycorrhizal fungi which constitute organisms with functionally varying structures.
Tropism of human cytomegalovirus for endothelial cells is determined by a post-entry step dependent on efficient translocation to the nucleus
2000-12-01

Marked interstrain differences in the endothelial cell (EC) tropism of human cytomegalovirus (HCMV) isolates have been described. This study aimed to define the step during the replicative cycle of HCMV that determines this phenotype. The infection efficiency of various HCMV strains in EC versus fibroblasts was quantified by immunodetection of immediate early (IE), early and late viral antigens. Adsorption and penetration were analysed by radiolabelled virus binding assays and competitive HCMV-DNA-PCR. The translocation of penetrated viral DNA to the nucleus of infected cells was quantified by competitive HCMV-DNA-PCR in pure nuclear fractions. The intracytoplasmic translocation of capsids that had penetrated was followed by immunostaining of virus particles on a single particle level; this was correlated with the initiation of viral gene expression by simultaneous immunostaining of viral IE antigens. The infectivity of nonendotheliotropic HCMV strains in EC was found to be 100–1000-fold lower when compared to endotheliotropic strains. The manifestation of this phenotype at the level of IE gene expression indicated the importance of initial replication events. Surprisingly, no interstrain differences were detected during virus entry. However, dramatic interstrain differences were found regarding the nuclear translocation of penetrated viral DNA. With nonendotheliotropic strains, the content of viral DNA in the cell nucleus was 100–1000-fold lower in EC when compared to endotheliotropic strains, thereby reflecting the strain differences in IE gene expression. Simultaneous staining of viral particles and viral IE antigen revealed that interstrain differences in the transport of penetrated capsids towards the nucleus of endothelial cells determine the EC tropism of HCMV.
Recent progress in enantiomer separation by capillary electrochromatography
2000-12-01

Enantiomer separation by electrochromatography (CEC) can be performed in three modes: (i) open-tubular capillary electrochromatography (o-CEC), in which the chiral selector is physically adsorbed coated, and thermally immobilized or covalently attached to the internal capillary wall; (ii) packed capillary electrochromatography (p-CEC), in which the capillary is either filled with chiral modified silica particles or with an achiral packing material, and a chiral selector is added to the mobile phase; and (iii) monolithic (rod)-capillary electrochromatography (rod-CEC) in which the chiral stationary phase (CSP) consists of a single piece of porous solid. We present an overview on methods and new trends in the field of electrochromatographic enantiomer separation such as CEC with either nonaqueous mobile phases or stationary phases with incorporated permanent charges, or with packing beds consisting of nonporous silica particles or particles with very small internal diameters.
Proteasome Inhibitor‐Induced Apoptosis of Glioma Cells Involves the Processing of Multiple Caspases and Cytochrome c Release
2000-12-01

Abstract: The proteasome is a multiprotein complex that is involvedin the intracellular protein degradation in eukaryotes. Here, we show thathuman malignant glioma cells are susceptible to apoptotic cell death inducedby the proteasome inhibitors, MG132 and lactacystin. The execution of theapoptotic death program involves the processing of caspases 2, 3, 7, 8, and 9.Apoptosis is inhibited by ectopic expression of X‐linked inhibitor ofapoptosis (XIAP) and by coexposure to the broad‐spectrum caspase inhibitor,benzoyl‐VAD‐fluoromethyl ketone (zVAD‐fmk), but not by the preferentialcaspase 8 inhibitor, crm‐A. It is interesting that specific morphologicalalterations induced by proteasome inhibition, such as dilated roughendoplasmic reticulum and the formation of cytoplasmic vacuoles and densemitochondrial deposits, are unaffected by zVAD‐fmk. Apoptosis is alsoinhibited by ectopic expression of Bcl‐2 or by an inhibitor of proteinsynthesis, cycloheximide. Further, cytochrome c release anddisruption of mitochondrial membrane potential are prominent features ofapoptosis triggered by proteasome inhibition. Bcl‐2 is a stronger inhibitor ofcytochrome c release than zVAD‐fmk. XIAP and crm‐A fail to modulatecytochrome c release. These data place cytochrome c releasedownstream of Bcl‐2 activity but upstream of XIAP‐ and crm‐A‐sensitivecaspases. The partial inhibition of cytochrome c release by zVAD‐fmkindicates a positive feedback loop that may involve cytochrome c release and zVAD‐fmk‐sensitive caspases. Finally, death ligand/receptorinteractions, including the CD95/CD95 ligand system, do not mediate apoptosisinduced by proteasome inhibition in human malignant glioma cells.
DETERMINING SIGNIFICANT FOLD DIFFERENCES IN GENE EXPRESSION ANALYSIS
2000-12-01

A typical use for RNA expression microarrays is comparing the measurement of gene expression of two groups. There has not been a study reproducing an entire experiment and modeling the distribution of reproducibility of fold differences. Our goal was to create a model of significance for fold differences, then maximize the number of ESTs above that threshold. Multiple strategies were tested to filter out those ESTs contributing to noise, thus decreasing the requirements of what was needed for significance. We found that even though RNA expression levels appears consistent in duplicate measurements, when entire experiments are duplicated, the calculated fold differences are not as consistent. Thus, it is critically important to repeat as many data points as possible, to ensure that genes and ESTs labeled as significant are truly so. We were successfully able to use duplicated expression measurements to model the duplicated fold differences, and to calculate the levels of fold difference needed to reach significance. This approach can be applied to many other experiments to ascertain significance without a priori assumptions.
Glycosaminoglycan Therapy Prevents TGF-β1 Overexpression and Pathologic Changes in Renal Tissue of Long-Term Diabetic Rats
2000-12-01

Chronic induction of the prosclerotic cytokine transforming growth factor beta (TGF-beta) has been implicated in the pathogenesis of diabetic nephropathy. In a rat model of diabetes mellitus-induced glomerulosclerosis, daily administration of a modified heparin (mH) glycosaminoglycan (GAG) preparation with low anticoagulant activity prevented glomerular and tubular matrix accumulation, as well as overexpression of TGF-beta1 mRNA and albuminuria, without obvious side effects. To elucidate the molecular mechanisms of GAG/mH inhibitory actions on TGF-beta1, studies using cultured mesangial cells were also performed. In these cells, high glucose-induced, dose-dependent increases in TGF-beta1 mRNA and bioactive TGF-beta protein expression were inhibited by GAG/mH treatment, whereas basal TGF-beta1 expression was not affected. Both the heparin-derived GAG and dermatan sulfate were effective, indicating that the heparin chemical structure is not necessary for inhibitory activity. Coincubation of GAG with active TGF-beta1 demonstrated no inhibitory effect on TGF-beta1 bioactivity, excluding a neutralizing effect of GAG on TGF-beta1 a the protein level. Furthermore, it was demonstrated that GAG inhibited phorbol myristate acetate-induced translocation of protein kinase C-alpha (PKC-alpha) and -beta1 and activation of PKC-alpha, as well as high glucose-induced activation of PKC-alpha. These results suggest that GAG inhibit TGF-beta1 overexpression at the transcriptional level, possibly via inhibition of high glucose-activated PKC. The findings indicate the potential of GAG therapy for the prevention of diabetic glomerulosclerosis by the inhibition of chronic disease-induced TGF-beta1 mRNA overexpression.
Reduction of minimal erythema dose by sweating
2000-12-01

Background/Aims: Solar ultraviolet (UV) radiation is the most important environmental risk factor for melanoma and non‐melanoma skin cancer. It is known that tap water and saltwater baths have a photosensitizing capacity in subsequent UV irradiation of the skin. The aim of the present study was to determine the influence of sweating from heat or from physical activity on the photosensitivity of the skin. Methods: Minimal erythema dose to ultraviolet B (MED/UVB) was determined on the inner forearms of 22 healthy volunteers with a Saalmann Multitester ® . Sweating had been provoked by heat (sauna for 10 min) and, on another occasion, physical exercise (jogging for 15 min) followed by MED/UVB testing in a similar way. Results: Compared to baseline MED/UVB there was a highly significant decrease in MED/UVB of up to 31.6% (median 15.8%, mean 15.9%±10.0) after 10 min in the sauna and up to 40.9% (median 16.3%, mean 17.2%±12.5) after 15 min jogging ( P &lt;0.0001). Conclusion: Sweat influences the hydration of the horny layer of the skin, resulting in a decrease in reflection and dispersion of UV light. Moderate physical activities such as jogging and/or heat may facilitate erythema reaction. By sweating, outdoor workers and people practicing outdoor sports who are exposed to considerable amounts of solar UV radiation further increase their risk of sunburn.
Identification of oxygen containing volatiles in cephalic secretions of workers of Brazilian stingless bees
2000-12-01

The volatile constituents of cephalic secrections of 11 Brazilian social stingless bee species of the Tetragonisca - Tetragona line have been analysed. By gas chromatography/mass spectrometry 145 compounds could be identified which include 72 esters, 22 alcohols, 16 carboxylic acids, 13 terpenoids, 8 aldehydes, 7 ketones, 4 aromatic compounds, 2 lactones and 1 dihydropyran. Structural relations, origin, and distribution of these compounds are discussed. With respect to qualitative and quantitative composition, each species shows a specific odour pattern which is made up by less specific components. To a certain extent, closely related species show some similarities in the odour bouquets. The mass spectrometric fragmentation patterns of typical wax type esters and DMDS derivatives of unsaturated esters are discussed in detail.
Synaptic Localization and Presynaptic Function of Calcium Channel β4-Subunits in Cultured Hippocampal Neurons
2000-12-01

Neurotransmitter release is triggered by the influx of Ca(2+) into the presynaptic terminal through voltage gated Ca(2+)-channels. The shape of the presynaptic Ca(2+) signal largely determines the amount of released quanta and thus the size of the synaptic response. Ca(2+)-channel function is modulated in particular by the auxiliary beta-subunits that interact intracellularly with the pore-forming alpha(1)-subunit. Using retrovirus-mediated gene transfer in cultured hippocampal neurons, we demonstrate that functional GFP-beta(4) constructs colocalize with the synaptic vesicle marker synaptobrevin II and endogenous P/Q-type channels, indicating that beta(4)-subunits are localized to synaptic sites. Costaining with the dendritic marker MAP2 revealed that the beta(4)-subunit is transported to dendrites as well as axons. The nonconserved amino- and carboxyl-termini of the beta(4)-subunit were found to target the protein to the synapse. Physiological measurements in autaptic hippocampal neurons infected with green fluorescent protein (GFP)-beta(4) revealed an increase in both excitatory post-synaptic current amplitude and paired pulse facilitation ratio, whereas the GFP-beta(4) mutant, GFP-beta(4)(Delta50-407), which demonstrated a cytosolic localization pattern, did not alter these synaptic properties. In summary, our data suggest a pre-synaptic function of the Ca(2+)-channel beta(4)-subunit in synaptic transmission.
The Arab middle east and the question of democratization: Some critical remarks
2000-12-01

While many of the contemporary writings on Middle Eastern political change contend that democratization is under way in the Arab world, this article maintains that much of the recent optimism is due to a lack of terminological clarity. Neither are there any Arab democracies today, nor is there any tangible democratization in this region. Adherents of the democratization hypothesis in the Arab world invoke mainly two arguments: that of a strengthened civil society and that of economic transformation, which are supposed to trigger democratization. Both arguments are discussed with the finding that they do not provide convincing evidence to support such hypotheses. Rather, systemic transitions from non‐democracies to other non‐democratic systems are likely developments in the Arab Middle East. Comparative research should therefore focus not only on the 'breakdown of democratic regimes' or 'democratic transitions', but develop models better to grasp non‐democratic transitions.
Lexical retrieval during fluent speech production
2000-12-01

We investigated the neural correlates of lexical retrieval during fluent speech production using fMRI. Blood oxygenation level dependent (BOLD) contrast was measured while subjects spoke about 7 Rorschach inkblots for 3 min each. Varying degrees of speech rate were elicited during each run. In a within-subject design, the number of words produced was correlated with the BOLD contrast in the two runs in each subject that showed the highest variance of speech output. The rate of articulation was positively correlated with activation in the left superior temporal (BA 22) and supramarginal (BA 39/ 40) gyri. The main negative correlations were in the fusiform gyri bilaterally (BA 19), the posterior cingulate (BA 30) and superior occipital gyrus (BA 19). Lexical retrieval during continuous language production engages areas in the left temporal and inferior parietal cortex. This pattern of activation differs from that evident during the generation of single words (verbal fluency), which is more associated with left prefrontal activation.
Lesion‐associated accumulation of uPAR/CD87‐ expressing infiltrating granulocytes, activated microglial cells/macrophages and upregulation by endothelial cells following TBI and FCI in humans
2000-12-01

Urokinase‐type plasminogen activator receptor (uPAR/CD87) together with its ligand, urokinase‐type plasminogen activator (uPA), constitutes a proteolytic system associated with tissue remodelling and leucocyte infiltration. uPAR is a member of the glycosyl phosphatidyl inositol (GPI) anchored protein family. The functional role of uPAR comprises fibrinolysis by conversion of plasminogen to plasmin. In addition, uPAR promotes cell adhesion, migration, proliferation, re‐organization of the actin cytoskeleton, and angiogenesis. Furthermore, uPAR is involved in prevention of scar formation and is chemoattractant to macrophages and leucocytes. In order to investigate the pathophysiological role of uPAR following human CNS injury we examined necrotic brain lesions resulting from traumatic brain injury (TBI; n = 28) and focal cerebral infarctions (FCI; n = 17) by immunohistochemistry. Numbers of uPAR + cells and uPAR + blood vessels were counted. Following brain damage, uPAR + cells increased significantly within 12 h, reached a maximum after 3–4 days and remained elevated until later stages. uPAR was expressed by infiltrating granulocytes, activated microglia/macrophages and endothelial cells. Numbers of uPAR + vessels increased in parallel subsiding earlier following FCI than post TBI. The restricted, lesion‐associated accumulation of uPAR + cells in the brain parenchyma and upregulated expression by endothelial cells suggests a crucial role for the influx of inflammatory cells and blood–brain barrier (BBB) disturbance. Through a failure in BBB function, uPAR participates in formation of brain oedema and thus contributes to secondary brain damage. In conclusion, the study defines the localization, kinetic course and cellular source of uPAR as a potential pharmacological target following human TBI and FCI.
Structure Identification of Aporphine Alkaloids by On‐Line Coupling of HPLC‐NMR with Loop Storage
2000-12-01

Abstract The potential of coupling HPLC separation methodology to on‐line high resolution nuclear magnetic resonance (NMR) spectroscopy has been demonstrated with a mixture of nine aporphine alkaloids. A loop storage procedure after separation has facilitated the identification of closely eluted peaks (α = k 2 /k 1 = 1.01 and Δv = 0.37 min = 367 μL). These were collected off‐line and identified by a 1D 1 H NMR spectrum. For this purpose an automated procedure has been implemented which includes the use of shaped pulses, multiple solvents suppression and 13 C satellite suppression of acetonitrile.
Differential impact of periodic and aperiodic speech-like acoustic signals on magnetic M50/M100 fields
2000-12-01

Voiced and unvoiced sounds, characterized by a periodic or aperiodic acoustic structure, respectively, represent two basic information-bearing elements of the speech signal. Using whole-head magnetencephalography (MEG), magnetic fields (M50/M100) in response to synthetic vowel-like as well as noise-like signals matched in spectral envelope were recorded in 20 subjects. Aperiodic events gave rise to increased M50 concomitant with reduced M100 activity as compared to their periodic cognates. Attention toward the auditory channel enhanced the effects of signal periodicity. These data provide first evidence that speech-relevant acoustic features differentially affect evoked magnetic fields as early as the M50 component. Conceivably, the M50 field reflects an ongoing monitoring process whereas the M100 component is bound to more specific operations such as detection of signal periodicity.
Streptolysin O-permeabilized granulocytes shed L-selectin concomitantly with ceramide generation via neutral sphingomyelinase
2000-12-01

Abstract Cleavage of membrane-associated L-selectin regulates leukocyte rolling on vascular endothelium at sites of inflammation. We report that rapid and massive shedding of L-selectin occurs from granulocytes attacked by the pore-forming bacterial toxin streptolysin O (SLO). Shedding was not induced by an SLO mutant that retained binding capacity but lacked pore-forming activity. Cells permeabilized with SLO exhibited a 1.5-fold increase in the activity of neutral sphingomyelinase, which was accompanied by increased ceramide formation. L-selectin cleavage was inducible by treatment of cells with bacterial sphingomyelinase, and also through exogenous application of a cell-permeable ceramide analog. Our data identify a novel path to the shedding process and show that activation of neutral sphingomyelinase with the generation of ceramide is an important event underlying enhanced sheddase function in cells permeabilized by a pore-forming toxin.
On the Diels−Alder Reaction of Allenes Bearing a Diphenylphosphoryl or (Trichloromethyl)sulfonyl Substituent
2000-12-01

Diels−Alder reactions of two allenes, diphenyl(1,2-propadienyl)phosphane oxide (4) and 1,2-propadienyltrichloromethyl sulfone (7), with cyclic dienes were studied. While 4 only reacted with cyclopentadiene, to provide the endo adduct 5, the allene 7 proved to be much more reactive. Thus, the cycloaddition between 7 and N-Boc-pyrrole gave a mixture of the endo and exo adducts 9. The observed reactivities could be rationalized by semiempirical MO calculations.