julilili42/papers huggingface dataset:
Reduced reactivation rate in mutant CuZnSOD and progression rate of amyotrophic lateral sclerosis
2004-05-26

Mutations in the SOD1 gene are associated with familial amyotrophic lateral sclerosis (fALS). The mechanisms by which these mutations lead to anterior horn cell loss are unknown, however, increased binding of Hsps on the demetallated mutant SOD1 has been described which would make the HSPs unavailable for other purposes, and reduce the SOD1 concentration in mitochondria, thereby creating a proapoptotic situation finally leading to motor neuron death. Here we report the recombinant expression of four human copper/zinc superoxide dismutase (CuZnSOD) variants, including the wild‐type enzyme and mutant proteins associated with familial ALS. The bacterial expression level of soluble mutated proteins was influenced by the mutations leading to drastically reduced levels of soluble CuZnSOD. Simultaneously, increasing levels of insoluble and probably aggregated mutated CuZnSOD were identified in bacterial cell pellets. In addition, altered reactivation kinetics of the purified mutant apoproteins after expression in bacterial culture was shown. Biophysical and biochemical analysis showed that zinc incorporation is severely reduced in the CuZnSOD proteins associated with the most severely forms of fALS (A4V, G93A). These data indicate that a reduced holoenzyme formation rate of mutant enzymes may be a critical factor in the etiopathology of fALS.
Lack of mutations in the epsilon‐sarcoglycan gene in patients with different subtypes of primary dystonias
2004-05-26

Abstract Primary dystonias represent a clinically and genetically heterogeneous group of movement disorders. Mutations in the ε‐sarcoglycan (SGCE) gene have been found recently to cause myoclonus–dystonia (MD). Considerable clinical variation of SGCE mutation carriers leads to the hypothesis that mutations in the SGCE gene might also be relevant for other subtypes of dystonias. To determine the contribution of mutations in the SGCE gene in patients with different subtypes of dystonias, we analyzed the coding sequence of the SGCE gene in a group of 296 patients with a clinical phenotype of primary dystonia and in 2 patients with a clinical phenotype of myoclonus–dystonia. Patients with mutations in the DYT1 gene were excluded. We could not detect a mutation in the SGCE gene in any of the 298 patients. Our results suggest that mutations in the SGCE gene cannot be held responsible for other subtypes of primary dystonia. © 2004 Movement Disorder Society
SQUID Theory
2004-05-26

This chapter contains sections titled: Josephson Junctions RCSJ Model Thermal Noise The 1/f Noise (I0, R fluctuations) Theory of the dc SQUID Introduction Basic Equations, dc SQUID Potential Thermal Fluctuations General Considerations Numerical Simulations (Langevin Equation) Analytical Theory of the dc SQUID Effect of Asymmetry Theory of the rf SQUID Introduction SQUID Potential and the Equation of Motion for the Phase Difference Unitary Theory for Output Signal and Noise Noise as a Small Perturbation Introduction Adiabatic Operation; Hysteretic Phase Diagram Non-adiabatic Regime
Practical DC SQUIDS: Configuration and Performance
2004-05-26

This chapter contains sections titled: Introduction Basic dc SQUID Design Uncoupled SQUIDs Coupled SQUIDs Magnetometers Overview Magnetometers for High Spatial Resolution Magnetometers for High Field Resolution Gradiometers Overview Thin-Film Planar Gradiometers Wire-Wound Axial Gradiometers 1/f Noise and Operation in Ambient Field General Remarks on 1/f Noise Critical Current Fluctuations Thermally Activated Motion of Vortices Generation of vortices Reduction of 1/f Noise Generated by Vortex Motion Overview Vortex pinning Narrow Linewidth Device Structures Flux Dams Other Performance Degrading Effects Hysteresis Radio-Frequency Interference Temperature Fluctuations and Drift
Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases: a histopathological challenge
2004-05-27

Aims: Although systemic mastocytosis (SM) with an associated clonal haematological non-mast cell lineage disease (SM-AHNMD) is a major subtype of SM, little is known about its frequency among myelogenous neoplasms, and mastocytosis in particular, or about AHNMD subtype frequencies. Methods: Approximately 19 500 routine bone marrow biopsies were evaluated. Immunostaining with antibodies against tryptase, KIT, and CD25 and molecular analysis for detection of C-KIT point mutations were performed in approximately 550/4100 myelogenous malignancies including mastocytosis, almost all subtypes of myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative syndrome (MDS/MPD), MPD, and acute myeloid leukaemia (AML). Results: SM was rare—it was diagnosed in only 64 bone marrows (0.3%) and made up 1.5% of myelogenous tumours. SM-AHNMD was the second most frequent subtype (20). SM-AHNMD was never included in the clinical differential diagnoses and was confirmed histologically in most cases only after appropriate immunostaining. The abnormal mast cell phenotype was confirmed by immunohistochemical demonstration of tryptase and CD25 coexpression. The following associated haematological neoplasms were found: MDS/MPS, AML, MPS, MDS, plasma cell myeloma, and unclassifiable myelogenous malignancy. C-KIT point mutations were detected in 16 of 20 cases. Conclusions: SM-AHNMD can be diagnosed histologically in bone marrow trephines only after immunostaining with antibodies against tryptase, KIT, and CD25. Eighteen of 20 AHNMDs were of myeloid origin. C-KIT point mutations were present in 16 of 20 cases. The prognostic relevance of detecting SM associated with another haematological neoplasm remains unclear, but mast cell resistance to most cytoreductive agents is of major importance for treatment planning.
Distinct Frontal Regions Subserve Evaluation of Linguistic and Emotional Aspects of Speech Intonation
2004-05-27

In addition to the propositional content of verbal utterances, significant linguistic and emotional information is conveyed by the tone of speech. To differentiate brain regions subserving processing of linguistic and affective aspects of intonation, discrimination of sentences differing in linguistic accentuation and emotional expressiveness was evaluated by functional magnetic resonance imaging. Both tasks yielded rightward lateralization of hemodynamic responses at the level of the dorsolateral frontal cortex as well as bilateral thalamic and temporal activation. Processing of linguistic and affective intonation, thus, seems to be supported by overlapping neural networks comprising partially right-sided brain regions. Comparison of hemodynamic activation during the two different tasks, however, revealed bilateral orbito-frontal responses restricted to the affective condition as opposed to activation of the left lateral inferior frontal gyrus confined to evaluation of linguistic intonation. These findings indicate that distinct frontal regions contribute to higher level processing of intonational information depending on its communicational function. In line with other components of language processing, discrimination of linguistic accentuation seems to be lateralized to the left inferior-lateral frontal region whereas bilateral orbito-frontal areas subserve evaluation of emotional expressiveness.
Palmitate, but Not Unsaturated Fatty Acids, Induces the Expression of Interleukin-6 in Human Myotubes through Proteasome-dependent Activation of Nuclear Factor-κB
2004-05-28

Circulating interleukin-6 (IL-6), insulin, and free fatty acid (FFA) concentrations are associated with impaired insulin action in obese and type 2 diabetic individuals. However, a causal relationship between elevated plasma FFAs and IL-6 has not been shown. Because skeletal muscle represents a major target of impaired insulin action, we studied whether FFAs may affect IL-6 expression in human myotubes. We demonstrate that specifically saturated FFAs, e.g. palmitate (0.25 mm), induce IL-6 mRNA expression and protein secretion by a proteasome-dependent mechanism that leads to a rapid and chronic activation of nuclear factor-kappaB. Insulin, high glucose concentrations, or unsaturated FFAs did not activate IL-6 expression. In fact, the unsaturated FFA linoleate inhibited palmitate-induced IL-6 production. Because inhibition of palmitate metabolism by the acyl-CoA synthetase inhibitor triacsin C did not abolish IL-6 expression, it appears that the palmitate molecule per se exerts the observed effects. Furthermore, we show that in human myotubes, IL-6 activates the phosphorylation of signal transducer and activator of transcription 3 in concentrations similar to hepatocytes. However, no inhibitory effect of IL-6 on insulin action, determined as phosphatidylinositol 3-kinase association with insulin receptor substrate-1, Akt phosphorylation, and glycogen synthesis, was detected. We conclude that IL-6 expression may be modulated by the composition of circulating FFA, e.g. by diet, and that skeletal muscle cells could be target cells for IL-6.
Molecular Cloning of Mouse Amino Acid Transport System B0, a Neutral Amino Acid Transporter Related to Hartnup Disorder
2004-05-28

Resorption of amino acids in kidney and intestine is mediated by transporters, which prefer groups of amino acids with similar physico-chemical properties. It is generally assumed that most neutral amino acids are transported across the apical membrane of epithelial cells by system B(0). Here we have characterized a novel member of the Na(+)-dependent neurotransmitter transporter family (B(0)AT1) isolated from mouse kidney, which shows all properties of system B(0). Flux experiments showed that the transporter is Na(+)-dependent, electrogenic, and actively transports most neutral amino acids but not anionic or cationic amino acids. Superfusion of mB(0)AT1-expressing oocytes with neutral amino acids generated inward currents, which were proportional to the fluxes observed with labeled amino acids. In situ hybridization showed strong expression in intestinal microvilli and in the proximal tubule of the kidney. Expression of mouse B(0)AT1 was restricted to kidney, intestine, and skin. It is generally assumed that mutations of the system B(0) transporter underlie autosomal recessive Hartnup disorder. In support of this notion mB(0)AT1 is located on mouse chromosome 13 in a region syntenic to human chromosome 5p15, the locus of Hartnup disorder. Thus, the human homologue of this transporter is an excellent functional and positional candidate for Hartnup disorder.
Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response
2004-06-01

While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation.
Looking Backward and Looking Forward: Anthropometric Research and the Development of Social Science History
2004-06-01

The editor of Social Science History at the time, James Q. Graham, hoped to expand the exploration of human heights and their economic and social correlates.He was one of the few journal editors convinced early on that such an agenda fit well into an interdisciplinary historical perspective. 4The collection gave a sense of excitement to the field by demonstrating the applicability of evolving methods to a wide range of problems; showing the availability of data;indicating the growing number of researchers in the field; and convincingly illustrating how new methods illuminated significant historical issues.Consequently, the issue attracted new researchers to the field, including one of the guest editors of this anniversary issue.Some of the interesting insights of the anthropometric research program were already hinted at in that issue: the negative relationship between height and mortality, the positive relationship between height and labor productivity, the cycling of heights, the antebellum puzzle, the miserable biological condition of the London underclass at the time of the Industrial Revolution, the biological advantages of the New World, and the high nutritional status of American slaves.Anthropometric history found a niche in scholarship because conventional approaches to living standards were not helpful in answering questions of interest to historians.There are many weaknesses in using conventional living-standard indicators such as per-capita GNP, per-capita income, or the hourly (daily) wages to assess the welfare of a population.The related issues are too complex to be discussed here in detail.Suffice it to say, that they do not incorporate the effect of environmental externalities, of cyclical fluctuations, of distribution of resources within the family, or inequalities at the societal level (Crafts 1997; Steckel and Floud 1997).In a historical context, the limitations of the conventional measures are accentuated by the fact that income data are generally unavailable and records of wages limited to some segments of the labor force.Moreover, their deflation by a consumer price index is typically rudimentary due to the lack of a representative "basket" of consumer goods.In addition, no obvious welfare indicators exist at all for very large segments of historical populations that were outside the paid labor force, including women, children, aristocrats, slaves, but prior to the onset of modern economic growth also the self-sufficient peasantry or farmers (Johnson and Nicholas 1995).These segments were by no means negligible --they made up well over three-quarters of most societies prior to industrialization.Moreover, the spatial component of welfare is also difficult, if not impossible, to study in a historical context using conventional approaches because of the scarcity of regional-level evidence.Hence, the limitations of conventional living-standard indicators are widespread and systematic, and often include modern societies for which data are lacking or are unreliable (Baten and
Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells
2004-06-01

The neoplastic production of the insulin-like growth factor binding protein (IGFBP)-2 often correlates with tumor malignancy and aggressiveness. Since IGFBP-2 contains an RGD motif in its C-terminus, it was hypothesized that this protein may act independently of IGF on tumor cells through integrins. To investigate this, integrin binding, intracellular signaling and the impact of IGFBP-2 on cell adhesion and proliferation were examined in two tumor cell lines. In tracer displacement studies, up to 30% of the added (125)I-hIGFBP-2 specifically bound to the cells. Bound (125)I-hIGFBP-2 was reversibly displaced by IGFBP-2, IGFBP-1 and RGD-(Gly-Arg-Asp)-containing peptides, but not by IGFBP-3, -4, -5, -6 and RGE-(Gly-Arg-Glu)-containing peptides. Blocking with antibodies directed against different integrins and with fibronectin demonstrated that IGFBP-2 cell surface binding is specific for alpha5beta1-integrin. Incubation of IGFBP-2 with equimolar quantities of IGF-I and IGF-II annihilated RGD-specific binding. IGFBP-2 binding at the cell surface led to dephosphorylation of the focal adhesion-kinase (FAK) of up to 37% (P&lt;0.01), and of the p42/44 MAP-kinases of up to 40% (P&lt;0.01). In addition, IGFBP-2 promoted de-adhesion of the cells dose-dependently by up to 30% (P&lt;0.05), and reduced proliferation by 24% (P&lt;0.01). Since one of the cell lines used does not express a functional IGF-I receptor, these data demonstrate that IGFBP-2 can act in an IGF-independent manner, at least in part by an interaction with alpha5beta1-integrin.
Protein Kinase C-ζ-induced Phosphorylation of Ser318 in Insulin Receptor Substrate-1 (IRS-1) Attenuates the Interaction with the Insulin Receptor and the Tyrosine Phosphorylation of IRS-1
2004-06-01

Insulin receptor substrate-1 (IRS-1) was recently identified as a novel upstream substrate for the insulin-activated protein kinase C (PKC)-zeta. This interaction down-regulates insulin signal transduction under hyper-insulinemic conditions. To clarify the molecular mechanism of this feedback loop, we sought to identify the PKC-zeta phosphorylation sites of IRS-1 and to investigate their biological significance. Upon incubation of recombinant IRS-1 fragments with PKC-zeta, we identified Ser(318) of rat IRS-1 (Ser(323) in human IRS-1) as the major in vitro phosphorylation site (confirmed by mutation of Ser(318) to alanine). To monitor phosphorylation of Ser(318) in cellular extracts, we prepared a polyclonal phosphosite-specific antibody. The biological significance was studied in baby hamster kidney cells stably expressing the insulin receptor (BHK(IR)). Using the phospho-Ser(318)-specific antibody we observed that insulin stimulates phosphorylation of Ser(318) in IRS-1, which is mediated, at least partially, by PKC-zeta. Moreover, we found that the previously described insulin-stimulated, PKC-zeta-mediated inhibition of the interaction of IRS-1 with the insulin receptor and the reduced tyrosine phosphorylation of IRS-1 was abrogated by mutation of IRS-1 Ser(318) to alanine. These results, generated in BHK(IR) cells, suggest that phosphorylation of Ser(318) by PKC-zeta might contribute to the inhibitory effect of prolonged hyperinsulinemia on IRS-1 function.
Evolutionary algorithms for the optimization of advective control of contaminated aquifer zones
2004-06-01

Simple genetic algorithms (SGAs) and derandomized evolution strategies (DESs) are employed to adapt well capture zones for the hydraulic optimization of pump‐and‐treat systems. A hypothetical contaminant site in a heterogeneous aquifer serves as an application template. On the basis of the results from numerical flow modeling, particle tracking is applied to delineate the pathways of the contaminants. The objective is to find the minimum pumping rate of up to eight recharge wells within a downgradient well placement area. Both the well coordinates and the pumping rates are subject to optimization, leading to a mixed discrete‐continuous problem. This article discusses the ideal formulation of the objective function for which the number of particles and the total pumping rate are used as decision criteria. Boundary updating is introduced, which enables the reorganization of the decision space limits by the incorporation of experience from previous optimization runs. Throughout the study the algorithms' capabilities are evaluated in terms of the number of model runs which are needed to identify optimal and suboptimal solutions. Despite the complexity of the problem both evolutionary algorithm variants prove to be suitable for finding suboptimal solutions. The DES with weighted recombination reveals to be the ideal algorithm to find optimal solutions. Though it works with real‐coded decision parameters, it proves to be suitable for adjusting discrete well positions. Principally, the representation of well positions as binary strings in the SGA is ideal. However, even if the SGA takes advantage of bookkeeping, the vital high discretization of pumping rates results in long binary strings, which escalates the model runs that are needed to find an optimal solution. Since the SGA string lengths increase with the number of wells, the DES gains superiority, particularly for an increasing number of wells. As the DES is a self‐adaptive algorithm, it proves to be the more robust optimization method for the selected advective control problem than the SGA variants of this study, exhibiting a less stochastic search which is reflected in the minor variability of the found solutions.
Patterns of Circulating Hepatitis B Virus Serum Nucleic Acids during Lamivudine Therapy
2004-06-01

A bstract : Lamivudine treatment of individuals with chronic HBV infection leads to a rapid decline of hepatitis B virus (HBV) serum DNA. Because HBV replication quickly reaches pretreatment values following cessation of the drug, we addressed the question of whether changes during therapy in composition and amount of discernible circulating viral DNA and RNA might provide an explanation for this phenomenon. Nucleic acids were extracted from serial serum samples of two chronically infected patients. The first patient was treated with lamivudine for 14 weeks, whereas the second one, who displayed an HBV virus with a core gene mutation, received lamivudine for 10 weeks. Three sequence segments of the HBV genome synthesized successively during replication, namely, X, C, and X‐preC, were analyzed via competitive polymerase chain reaction (PCR) and reverse transcriptase (RT)/PCR. HBV transcripts were also analyzed for differential polyadenylation. At the start of treatment, identical DNA copy numbers (10 9 /mL) were found for all three segments in the first patient. C segment DNA displayed the expected rapid decline. X‐preC, a target contiguous only on plus‐strand DNA, behaved similarly. In contrast, the X segment DNA copy numbers showed a less pronounced decrease, remaining at higher values (10 7 /mL) than the C and X‐preC segments (both about 2 × 10 5 /mL) at the end of therapy. X segment RNA displayed a persisting copy number of about 10 7 /mL, whereas C and X‐preC RNA decreased to about 10 5 copies/mL. Polyadenylated HBV RNA, both full‐length and truncated, initially persisted at 10 5 but decreased to 10 4 to 10 3 copies/mL at the end of treatment. As expected, C segment DNA and RNA were not detected in the second patient, whereas X and X‐preC segments showed essentially the same pattern as the first patient, although at a slightly lower level. We conclude that: (1) actual numbers of HBV genome equivalents during lamivudine therapy can be assessed only via X segment DNA, because it is reverse transcribed first; (2) lamivudine induces coexistence of DNA and RNA for the C and X segments at similar levels, indicating drug‐arrested intermediates of reverse‐transcribed HBV DNA minus‐strand; and (3) packaged HBV RNA lacks a poly(A) tail, whereas polyadenylated RNA is likely not packaged.
Effects of microsite on growth ofPinus cembrain the subalpine zone of the Austrian Alps
2004-06-01

We examined growth in <em>Pinus cembra</em> L. (28 years old) across the treeline ecotone from 1900 to 2 100 m elevation in the Alps. Eighteen plots were chosen at different microsites which are defined as a combination of elevation and steepness (gentle vs. steep slope) on a south-facing slope in the Schmirn Valley, Tyrol/Austria. Over the range of altitudes studied, elevation and steepness had influences on growth depending on tree size: (1) Elevation and steepness had little effect on growth as long as trees were very small (&lt;0.5 m in height); (2) Both elevation and steepness affected tree growth significantly when the tree height was between 0.5 and 3 m; (3) As trees exceeded 3 m in height, tree canopies fully covered the ground surface and created a forest microclimate causing growth to decline with increasing elevation, irrespective of steepness. We conclude that the microsite related to microclimate, controls growth during the early life stages of trees, but following canopy closure the local climate (mesoclimate) associated with topography begins to determine tree growth.