julilili42/papers huggingface dataset:
How Insulin Receptor Substrate Proteins Regulate the Metabolic Capacity of the Liver - Implications for Health and Disease
2008-06-01

The liver plays a key role in glucose homeostasis, lipid and energy metabolism. Its function is primarily controlled by the anabolic hormone insulin and its counterparts glucagon, catecholamines and glucocorticoids. Dysregulation of this homeostatic system is a major cause for development of the metabolic syndrome and type 2 diabetes mellitus. The features of the underlying dynamic molecular network that coordinates systemic nutrient homeostasis are less clear. But recently, considerable progress has been made in elucidating molecular pathways and potential factors involved in the regulation of energy and lipid metabolism and affected in diabetic states. In this review we will focus on important stations in the complex network of molecules that control the balance between glucose production, glucose utilization and regulation of lipid metabolism. Special attention will be paid to the insulin receptor substrate (IRS) proteins with the two major isoforms IRS-1 and IRS-2 as a critical node in hepatic insulin signalling. IRS proteins act as docking molecules to connect tyrosine kinase receptor activation to essential downstream kinase cascades, including activation of the PI-3 kinase or MAPK cascade. IRS-1 and IRS-2 are complementary key players in the regulation of hepatic insulin signalling and expression of genes involved in gluconeogenesis, glycogen synthesis and lipid metabolism. The function of IRS proteins is regulated by their expression levels and posttranslational modifications. This regulation within the dynamic molecular network that coordinates systemic nutrient homeostasis will be outlined in detail under the following conditions: after feeding, during fasting and during exercise. Dysfunction of IRS proteins initially leads to post-prandial hyperglycemia, increased hepatic glucose production, and dysregulated lipid synthesis and is discussed as major pathophysiological mechanism for the development of insulin resistance and type 2 diabetes mellitus. Understanding the molecular regulation and the pathophysiological modifications of IRS proteins is crucial in order to identify new sites for potential intervention to treat or prevent hepatic insulin resistance and type 2 diabetes mellitus.
Cortical pathology in multiple sclerosis
2008-06-01

In summary, recent years have opened our eyes to the extensive grey matter involvement in multiple sclerosis. Studies on the pathogenesis of cortical demyelination, cortical damage, and repair will elucidate basic principles of multiple sclerosis lesion formation. However, more sensitive imaging tools are required to study the impact of cortical lesions on clinical symptoms, disability, and disease progression.
Blunted IgE-Mediated Activation of Mast Cells in Mice Lacking the Ca2+-Activated K+ Channel KCa3.1
2008-06-01

Abstract Mast cell stimulation by Ag is followed by the opening of Ca2+-activated K+ channels, which participate in the orchestration of mast cell degranulation. The present study has been performed to explore the involvement of the Ca2+-activated K+ channel KCa3.1 in mast cell function. To this end mast cells have been isolated and cultured from the bone marrow (bone marrow-derived mast cells (BMMCs)) of KCa3.1 knockout mice (KCa3.1−/−) and their wild-type littermates (KCa3.1+/+). Mast cell number as well as in vitro BMMC growth and CD117, CD34, and FcεRI expression were similar in both genotypes, but regulatory cell volume decrease was impaired in KCa3.1−/− BMMCs. Treatment of the cells with Ag, endothelin-1, or the Ca2+ ionophore ionomycin was followed by stimulation of Ca2+-activated K+ channels and cell membrane hyperpolarization in KCa3.1+/+, but not in KCa3.1−/− BMMCs. Upon Ag stimulation, Ca2+ entry but not Ca2+ release from intracellular stores was markedly impaired in KCa3.1−/− BMMCs. Similarly, Ca2+ entry upon endothelin-1 stimulation was significantly reduced in KCa3.1−/− cells. Ag-induced release of β-hexosaminidase, an indicator of mast cell degranulation, was significantly smaller in KCa3.1−/− BMMCs compared with KCa3.1+/+ BMMCs. Moreover, histamine release upon stimulation of BMMCs with endothelin-1 was reduced in KCa3.1−/− cells. The in vivo Ag-induced decline in body temperature revealed that IgE-dependent anaphylaxis was again significantly (by ∼50%) blunted in KCa3.1−/− mice. In conclusion, KCa3.1 is required for Ca2+-activated K+ channel activity and Ca2+-dependent processes such as endothelin-1- or Ag-induced degranulation of mast cells, and may thus play a critical role in anaphylactic reactions.
Robust non-local denoising of colored depth data
2008-06-01

We give a brief discussion of denoising algorithms for depth data and introduce a novel technique based on the NL-Means Filter. A unified approach is presented that removes outliers from depth data and accordingly achieves an unbiased smoothing result. This robust denoising algorithm takes intra-patch similarity and optional color information into account in order to handle strong discontinuities and to preserve fine detail structure in the data. We achieve fast computation times with a GPU-based implementation. Results using data from a time-of-flight camera system show a significant gain in visual quality.
Direct and Natural Killer Cell-Mediated Antitumor Effects of Low-Dose Bortezomib in Hepatocellular Carcinoma
2008-06-01

Abstract Purpose: Hepatocellular carcinoma (HCC) displays particular resistance to conventional cytostatic agents. Alternative treatment strategies focus on novel substances exhibiting antineoplastic and/or immunomodulatory activity enhancing for example natural killer (NK) cell antitumor reactivity. However, tumor-associated ligands engaging activating NK cell receptors are largely unknown. Exceptions are NKG2D ligands (NKG2DL) of the MHC class I-related chain and UL16-binding protein families, which potently stimulate NK cell responses. We studied the consequences of proteasome inhibition with regard to direct and NK cell–mediated effects against HCC. Experimental Design: Primary human hepatocytes (PHH) from different donors, hepatoma cell lines, and NK cells were exposed to Bortezomib. Growth and viability of the different cells, and immunomodulatory effects including alterations of NKG2DL expression on hepatoma cells, specific induction of NK cell cytotoxicity and IFN-γ production were investigated. Results: Bortezomib treatment inhibited hepatoma cell growth with IC50 values between 2.4 and 7.7 nmol/L. These low doses increased MICA/B mRNA levels, resulting in an increase of total and cell surface protein expression in hepatoma cells, thus stimulating cytotoxicity and IFN-γ production of cocultured NK cells. Importantly, although NK cell IFN-γ production was concentration-dependently reduced, low-dose Bortezomib neither induced NKG2DL expression or cell death in PHH nor altered NK cell cytotoxicity. Conclusions: Low-dose Bortezomib mediates a specific dual antitumor effect in HCC by inhibiting tumor cell proliferation and priming hepatoma cells for NK cell antitumor reactivity. Our data suggest that patients with HCC may benefit from Bortezomib treatment combined with immunotherapeutic approaches such as adoptive NK cell transfer taking advantage of enhanced NKG2D-mediated antitumor immunity.
Continuous rise in incidence of childhood Type 1 diabetes in Germany
2008-06-01

Abstract Aims To assess the incidence and the trend in incidence of Type 1 diabetes (T1DM) in children and adolescents &lt; 15 years of age in Baden‐Württemberg (BW), Germany. Methods BW is Germany's third largest federal state. All 31 paediatric departments in BW and one diabetes centre participated in the study. Case registration was done according to the EURODIAB criteria. The degree of ascertainment was 97.2%. Results From 1987 to 2003, the age‐ and sex‐standardized incidence rate was 14.1/100 000 per year [95% confidence interval (CI) 13.7, 14.6, n = 4017]. The estimated annual increase in incidence was 3.8% (95% CI 1.1, 6.6). Compared with the first years of our registry, the current mean number of new cases of T1DM has doubled (1987–1989, n = 153; 2000–2003, n = 302). Generally, the highest rise in incidence occurred in the youngest age group of 0–4‐year‐old patients (5.8%; 95% CI 2.5, 9.3), followed by the age groups 5–9 (3.4%; 95% CI 0.8, 6.0) and 10–14 (2.7%; 95% CI 0.3, 5.1). Conclusions In Germany, the number of children and adolescents with new‐onset T1DM has been rising at a faster pace than expected. A distinct shift to younger age at onset has been observed in Germany.
Common Cellular and Diverse Genetic Basis of Thymoma‐associated Myasthenia Gravis
2008-06-01

Generation of autoreactive CD4 + effector T cells and defective production of regulatory CD4 + T cells inside thymomas contribute to the development of myasthenia gravis (MG) in &gt;90% of MG(+) thymomas. The molecular basis of these abnormalities is unknown. We report here that a) expression levels of class II major histocompatibility complex (MHCII) genes are variably decreased in thymomas, most prominently in histological WHO types A and AB; b) epithelial cells of type A and AB thymomas exhibit signal transducer and activator of transcription (STAT‐1)‐related defects of interferon‐γ (IFN‐γ) signaling and human leukocyte antigen (HLA)‐DR expression in vitro ; c) the promoter III (pIII)‐ and pIV‐driven splice variants of the MHCII transactivator (CIITA) play a key role in MHCII gene expression in thymus and thymomas; and d) the pIV CIITA promoter is heavily methylated in thymomas. Recently, we also found that expression of the autoimmune regulator (AIRE) gene is absent from ∼95% of thymomas. Among all theses abnormalities, only better preserved expression levels of MHCII ( P &lt; 0.001) in thymomas were significantly associated with the presence of MG. Taking the association of a gain‐of‐function polymorphism of the CTLA‐4 and PTPN22 gene with MG in thymomas into account, we conclude that these acquired cellular abnormalities of the thymoma microenvironment in concert with inherited genetic high‐risk polymorphisms of immunoregulatory genes have an impact on intratumorous thymopoiesis and appear to tip the balance toward central tolerance failure and development of MG. The findings imply that IFN‐γ and STAT‐1 signaling play a role in MHCII expression in the human thymus and in the pathogenesis of paraneoplastic MG.
TonB-dependent maltose transport by Caulobacter crescentus
2008-06-01

We have shown previously that Caulobacter crescentus grows on maltodextrins which are actively transported across the outer membrane by the MalA protein. Evidence for energy-coupled transport was obtained by deletion of the exbB exbD genes which abolished transport. However, removal of the TonB protein, which together with the ExbB ExbD proteins is predicted to form an energy-coupling device between the cytoplasmic membrane and the outer membrane, left transport unaffected. Here we identify an additional tonB gene encoded by the cc2334a ORF, which when deleted abolished maltose transport. MalA contains a TonB box that reads EEVVIT and is predicted to interact with TonB. Replacement of valine number 15 in the TonB box by proline abolished maltose transport. Maltose was transported across the cytoplasmic membrane by the MalY protein (CC2283). Maltose transport was induced by maltose and repressed by the MalI protein (CC2284). In addition to MalA, MalY and MalI, the mal locus encodes two predicted cytoplasmic alpha-amylases (CC2285 and CC2286) and a periplasmic glucoamylase (CC2282). The TonB dependence together with the previously described ExbB ExbD dependence demonstrates energy-coupled maltose transport across the outer membrane. MalY is involved in maltose transport across the cytoplasmic membrane by a presumably ion-coupled mechanism.
Human Melanoma Cytolysis by Combined Inhibition of Mammalian Target of Rapamycin and Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor-2
2008-06-01

Abstract Vascular endothelial growth factor (VEGF) plays a vital role in tumor angiogenesis. VEGF is produced by human melanomas, and the VEGF receptor 2 (VEGFR-2) is expressed by most advanced stage melanomas, suggesting the possibility of an autocrine loop. Here, we show that bevacizumab, an anti-VEGF antibody, inhibits proliferation of VEGFR-2+ melanoma cell lines by an average of 41%; however, it failed to inhibit proliferation of VEGFR-2neg melanoma cell lines. The growth inhibitory effect of bevacizumab was eliminated by VEGFR-2 knockdown with small interfering RNA, showing that VEGF autocrine growth in melanoma is mediated through VEGFR-2. However, bevacizumab inhibition of autocrine signals did not completely inhibit cell proliferation nor cause cell death. Cell survival is mediated partially through mammalian target of rapamycin (mTOR), which is inhibited by rapamycin. Combination of bevacizumab with rapamycin caused loss of half of the VEGFR-2+ melanoma cells, but no reduction in the number of VEGFR-2neg melanoma cells. The results show (a) an autocrine growth loop active in VEGFR-2+ melanoma, (b) a nonangiogenic mechanism for inhibition of melanoma by blocking autocrine VEGFR-2 activation, and (c) a possible therapeutic role for combination of inhibitors of mTOR plus VEGF in selected melanomas. [Cancer Res 2008;68(11):4392–7]
Olanzapine Treatment During Breast Feeding: A Case Report
2008-06-01

Postpartum psychosis constitutes a severe complication that entails risk for both mother and child. Little is known about the use of olanzapine in the treatment of postpartum psychosis. In previous studies, it has been reported on mothers receiving relatively low doses of olanzapine. We report a 38-year-old patient who was admitted to the hospital for an acute psychotic exacerbation. She was breast feeding her 5-month-old child, and she wished to continue breast feeding. Olanzapine treatment was started with a daily dosage of 15 mg. The weight-corrected maternal dose was 270 mug/kg. The olanzapine concentration in the mother's plasma was 24 ng/mL. The analysis of olanzapine in breast milk applying two different high-performance liquid chromatography procedures revealed similar results: 12.2 ng/g without and 11.5 ng/g with additional hydrochloric acid extraction, respectively. In addition, breast milk of an unmedicated mother was used for establishing the analytical procedure so that the validity of the results was better confirmed. The milk-plasma ratio arising from our data was 0.5, and the relative infant dose was 0.3%. The olanzapine concentration was below the limit of detection (<5 ng/mL) in the infant's plasma sample. No adverse effects were noticed, and the mother experienced a rapid improvement in her psychopathology during her hospital stay. In future studies, long-term follow-up of both mother and child would be useful.
Prediction of Nodal Involvement in Breast Cancer Based on Multiparametric Protein Analyses from Preoperative Core Needle Biopsies of the Primary Lesion
2008-06-01

Abstract Purpose: Identification of molecular characteristics that are useful to define subgroups of patients fitting into differential treatment schemes is considered a most promising approach in cancer research. In this first study of such type, we therefore investigated the potential of multiplexed sandwich immunoassays to define protein expression profiles indicative of clinically relevant properties of malignant tumors. Experimental Design: Lysates prepared from large core needle biopsies of 113 invasive breast carcinomas were analyzed with bead-based miniaturized sandwich immunoassays specific for 54 preselected proteins. Results: Five protein concentrations [fibroblast growth factor-2 (FGF-2), Fas, Fas ligand, tissue inhibitor of metalloproteinase-1, and RANTES] were significantly different in the groups of patients with or without axillary lymph node metastasis. All 15 protein parameters that resulted in P values &amp;lt;0.2 and other diagnostic information [estrogen receptor (ER) status, tumor size, and histologic grading] were analyzed together by multivariate logistic regression. This yielded sets of five (FGF-2, Fas, Fas ligand, IP10, and PDGF-AB/BB) or six (ER staining intensity, FGF-2, Fas ligand, matrix metalloproteinase-13, PDGF-AB/BB, and IP10) parameters for which receiver-operator characteristic analyses revealed high sensitivities and specificities [area under curve (AUC) = 0.75 and AUC = 0.83] to predict the nodal status. A similar analysis including all identified parameters of potential value (15 proteins, ER staining intensity, T) without selection resulted in a receiver-operator characteristic curve with an AUC of 0.87. Conclusion: We clearly showed that this approach can be used to quantify numerous proteins from breast biopsies accurately in parallel and define sets of proteins whose combined analyses allow the prediction of nodal involvement with high specificity and sensitivity.
Behavioral relevance of gamma‐band activity for short‐term memory‐based auditory decision‐making
2008-06-01

Abstract Oscillatory activity in the gamma‐band range has been established as a correlate of cognitive processes, including perception, attention and memory. Only a few studies, however, have provided evidence for an association between gamma‐band activity (GBA) and measures of behavioral performance. Here we focused on the comparison between sample and test stimuli S1 and S2 during an auditory spatial short‐term memory task. Applying statistical probability mapping to magnetoencephalographic recordings from 28 human subjects, we identified GBA components distinguishing nonidentical from identical S1–S2 pairs. This activity was found at frequencies between 65 and 90 Hz and was localized over posterior cortical regions contralateral to the hemifield in which the stimuli were presented. The 10 best task performers showed higher amplitudes of this GBA component than the 10 worst performers. This group difference was most pronounced between about 150 and 300 ms after stimulus onset. Apparently the decision about whether test stimuli matched the stored representation of previously presented sample sounds relied partly on the oscillatory activation of networks representing differences between both stimuli. This result could be replicated by reanalyzing the combined data from two previous studies assessing short‐term memory for sound duration and sound lateralization, respectively. Similarly to our main study, GBA amplitudes to nonmatching vs. matching S1–S2 pairs were higher in good performers than poor performers. The present findings demonstrate the behavioral relevance of GBA.
A new concept in the electrophysiological evaluation of syringomyelia
2008-06-01

Object The current neurophysiological assessment of syringomyelia is inadequate. Early-stage syringomyelia is anatomically predisposed to affect decussating spinothalamic fibers that convey pain and sensation primarily. Silent periods have been proven to be a sensitive tool for detecting alterations in this pathway. Methods Thirty-seven patients with syringomyelia were included in this prospective study. Routine electrophysiological measurements were applied including somatosensory evoked potential (SSEP) and motor evoked potential (MEP) recordings for all extremities. The silent periods were recorded from the pollicis brevis muscle, and electrical stimuli were applied to the ipsilateral digiti II. To establish baseline values, the authors had 28 healthy controls undergo monitoring. Sensitivity and specificity values were statistically evaluated according to the main clinical symptoms (paresis, dissociative syndrome, and pain). Results All control individuals had normal silent periods in voluntarily activated muscle. In syringomyelia patients, the affected limb showed pathological silent periods with all symptoms (sensitivity 30–50%). Pain was the most specific symptom (90%), despite SSEP and MEP values that were within the normal range. Conclusions Silent period testing is a sensitive neurophysiological technique and an invaluable tool for preoperative assessment of syringomyelia. Silent periods are associated with early dysfunction of thin myelinated spinothalamic tract fibers, even when routine electrophysiological measurements still reveal normal values. Conduction abnormalities that selectively abolish the silent periods can distinguish between hydromyelia (a physiologically dilated central canal) and space-occupying syringomyelia.
Adaptive encryption for the realization of real-time transmission of sensitive medical video streams
2008-06-01

This paper presents an analysis of the potential of adaptive encryption of streaming video data over 3G networks. The results obtained promote the design of a network component (the so called ldquointelligent networkrdquo) that facilitates the secure real-time transmission of video data. Case studies involving the sensitive area of telemedicine can be implemented by means of this component. The transport layer protocol SCTP is the basis for technical realization, which has interesting features and extensions. The combination of these features and the management of the intelligent network allows the implementation of sensitive applications.
SANchk: SQL-based SAN configuration checking
2008-06-01

Storage Area Networks (SANs) connect groups of storage devices to servers over fast interconnects. An important challenge lies in managing the complexity of the resulting massive SAN configurations. Policy-based validation using new logical frameworks has been proposed earlier as a solution to this configuration problem. SANchk offers a new solution that uses standard technologies such as SQL, XML, and Java, to implement a rule-based configuration checker. SANchk works as a light-weight extension to the relational databases of storage management systems; current support includes IBM's TPC and the open source Aperi storage manager. Some five dozen best practices rules for SAN configuration are implemented in SANchk, many of them with configurable parameters. Empirical results with several commercial SANs show that the approach is viable in practice.
NOREPINEPHRINE AND CEREBRAL BLOOD FLOW REGULATION IN PATIENTS WITH ARTERIOVENOUS MALFORMATIONS
2008-06-01

Chronically lowered perfusion pressure seems to induce the hypothesized adaptive down-regulation of sympathetic nervous system activity, yet protective up-regulation after a sudden elevation of cerebral perfusion pressure after AVM excision could not be shown in this study.
Effect of Vacuum Properties on Electroweak Processes – A Theoretical Interpretation of Experiments
2008-06-01

Recently for discharges in fluids induced nuclear transmutations have been observed. It is our hypothesis that these reactions are due to a symmetry breaking of the electroweak vacuum by the experimental arrangement. The treatment of this hypothesis is based on the assumption that electroweak bosons, leptons and quarks possess a substructure of elementary fermionic constituents. The dynamical law of these fermionic constituents is given by a relativistically invariant nonlinear spinor field equation with local interaction, canonical quantization, selfregularization and probability interpretation. Phenomenological quantities of electroweak processes follow from the derivation of corresponding effective theories obtained by algebraic weak mapping theorems where the latter theories depend on the spinor field propagator, i. e. a vacuum expectation value. This propagator and its equation are studied for conserved and for broken discrete symmetries. For combined CP- and isospin symmetry breaking it is shown that the propagator corresponds to the experimental arrangements under consideration. The modifications of the effective electroweak theory due to this modified propagator are discussed. Based on these results a mechanism is sketched which offers a qualitative interpretation of the appearance of induced nuclear transmutations. A numerical estimate of electron capture is given.