julilili42/papers huggingface dataset:
Architecture and Dynamics of C18 Bonded Interphases with Small Molecule Spacers
2009-11-11

The relationship between alkyl phase structure and chromatographic performance is investigated for a series of octadecyl (C(18))-modified silica surfaces with defined spacing of the alkyl surface by a "pre-end-capping" technique. Stationary phases were prepared by a two step process with (1) reaction with less than stochiometric amounts of a small monofunctional silane, followed by (2) solution or surface polymerization with octadecyltrichlorosilane. The results of solid-state and suspension nuclear magnetic resonance (NMR) spectroscopy are correlated with the chromatographic behavior regarding shape selective separations. Two sets of six different stationary phases were prepared by solution and surface polymerization approaches, yielding materials with surface coverages from 2.7 to 5.6 micromol/m(2). (13)C cross-polarization magic angle spinning (CP/MAS) NMR spectra show a predominance of trans conformations for the set of surface polymerized phases with a C(18) coverage greater than 4.5 micromol/m(2). For the solution polymerized phases, no predominance for the trans conformation was observed, even for surface coverages greater than 5.1 micromol/m(2). Proton spectra in suspension indicate the trend that a higher coverage for the surface polymerized materials correlates with a more rigid alkyl chain conformation. The set of solution polymerized stationary phases confirms this tendency but minor deviations are observed for high coverages. These structural abnormalities are confirmed by differences in the (29)Si CP/MAS spectra. Furthermore, the (29)Si CP/MAS spectra indicate a lower amount of cross-linking for the materials with the highest amount of placeholder (spacer). The use of the different spectroscopic and chromatographic methods provides a wealth of information on the surface morphology of the systematically prepared C(18) materials and extends the understanding of surface morphology of alkyl modified silica and its influences of the molecular recognition process in liquid chromatography.
The Bacterial Defensin Resistance Protein MprF Consists of Separable Domains for Lipid Lysinylation and Antimicrobial Peptide Repulsion
2009-11-12

Many bacterial pathogens achieve resistance to defensin-like cationic antimicrobial peptides (CAMPs) by the multiple peptide resistance factor (MprF) protein. MprF plays a crucial role in Staphylococcus aureus virulence and it is involved in resistance to the CAMP-like antibiotic daptomycin. MprF is a large membrane protein that modifies the anionic phospholipid phosphatidylglycerol with l-lysine, thereby diminishing the bacterial affinity for CAMPs. Its widespread occurrence recommends MprF as a target for novel antimicrobials, although the mode of action of MprF has remained incompletely understood. We demonstrate that the hydrophilic C-terminal domain and six of the fourteen proposed trans-membrane segments of MprF are sufficient for full-level lysyl-phosphatidylglycerol (Lys-PG) production and that several conserved amino acid positions in MprF are indispensable for Lys-PG production. Notably, Lys-PG production did not lead to efficient CAMP resistance and most of the Lys-PG remained in the inner leaflet of the cytoplasmic membrane when the large N-terminal hydrophobic domain of MprF was absent, indicating a crucial role of this protein part. The N-terminal domain alone did not confer CAMP resistance or repulsion of the cationic test protein cytochrome c. However, when the N-terminal domain was coexpressed with the Lys-PG synthase domain either in one protein or as two separate proteins, full-level CAMP resistance was achieved. Moreover, only coexpression of the two domains led to efficient Lys-PG translocation to the outer leaflet of the membrane and to full-level cytochrome c repulsion, indicating that the N-terminal domain facilitates the flipping of Lys-PG. Thus, MprF represents a new class of lipid-biosynthetic enzymes with two separable functional domains that synthesize Lys-PG and facilitate Lys-PG translocation. Our study unravels crucial details on the molecular basis of an important bacterial immune evasion mechanism and it may help to employ MprF as a target for new anti-virulence drugs.
Ras is an indispensable coregulator of the class I B phosphoinositide 3-kinase p87/p110γ
2009-11-12

Class I B phosphoinositide 3-kinase γ (PI3Kγ) elicits various immunologic and cardiovascular responses; however, the molecular basis for this signal heterogeneity is unclear. PI3Kγ consists of a catalytic p110γ and a regulatory p87 PIKAP (p87, also p84) or p101 subunit. Hitherto p87 and p101 are generally assumed to exhibit redundant functions in receptor-induced and G protein βγ (Gβγ)-mediated PI3Kγ regulation. Here we investigated the molecular mechanism for receptor-dependent p87/p110γ activation. By analyzing GFP-tagged proteins expressed in HEK293 cells, PI3Kγ-complemented bone marrow–derived mast cells (BMMCs) from p110γ -/- mice, and purified recombinant proteins reconstituted to lipid vesicles, we elucidated a novel pathway of p87-dependent, G protein–coupled receptor (GPCR)-induced PI3Kγ activation. Although p101 strongly interacted with Gβγ, thereby mediating PI3Kγ membrane recruitment and stimulation, p87 exhibited only a weak interaction, resulting in modest kinase activation and lack of membrane recruitment. Surprisingly, Ras-GTP substituted the missing Gβγ-dependent membrane recruitment of p87/p110γ by direct interaction with p110γ, suggesting the indispensability of Ras for activation of p87/p110γ. Consequently, interference with Ras signaling indeed selectively blocked p87/p110γ, but not p101/p110γ, kinase activity in HEK293 and BMMC cells, revealing an important crosstalk between monomeric and trimeric G proteins for p87/p110γ activation. Our data display distinct signaling requirements of p87 and p101, conferring signaling specificity to PI3Kγ that could open up new possibilities for therapeutic intervention.
Novel Obesity Risk Loci Do Not Determine Distribution of Body Fat Depots: A Whole‐body MRI/MRS study
2009-11-12

A recent meta‐analysis of genome‐wide association studies has identified six new risk‐loci for common obesity. We studied whether these risk loci influence the distribution of body fat depots. We genotyped 1,469 nondiabetic subjects for the single‐nucleotide polymorphisms (SNPs) TMEM18 rs6548238, KCTD15 rs11084753, GNPDA2 rs10938397, SH2B1 rs7498665, MTCH2 rs10838738, and NEGR1 rs2815752. We assessed BMI, waist circumference, total body fat, and lean body mass (bioimpedance). All subjects underwent an oral glucose tolerance test (OGTT) for estimation of insulin sensitivity. In 332 subjects, we measured total adipose tissue (TAT), visceral adipose tissue (VAT), nonvisceral adipose tissue (NVAT), liver fat content, and intramyocellular lipids (IMCLs) using whole‐body magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). In the dominant inheritance model, the risk alleles of TMEM18 rs6548238 and MTCH2 rs10838738 were nominally associated with higher BMI ( P = 0.04, both). The risk allele of TMEM18 rs6548238 was additionally associated with higher waist circumference and total body fat ( P ≤ 0.03), the risk allele of NEGR1 rs2815752 with higher waist circumference ( P = 0.05) and unexpectedly with lower BMI ( P = 0.01). In the MR cohort, we found an association of the risk allele of SH2B1 rs7498665 with higher VAT ( P = 0.009) and of GNPDA2 rs10938397 with increased IMCLs ( P = 0.03). After Bonferroni correction for multiple comparisons (corrected α‐level: P = 0.0085), none of the SNPs was significantly associated with measures of adiposity or body fat distribution (all P &gt; 0.009, dominant inheritance model). Therefore, our results suggest that these new obesity SNPs, despite their influence on BMI, are neither associated with a metabolically unfavorable nor with a favorable body composition.
INTEGRAL probes the morphology of the Crab nebula in hard X-rays/soft $\\sf \\gamma$-rays
2009-11-12

Aims. We use the IBIS/ISGRI telescope on-board INTEGRAL to measure the\\nposition of the centroid of the 20-200 keV emission from the Crab region.\\nMethods. We find that the astrometry of the IBIS telescope is affected by the\\ntemperature of the IBIS mask during the observation. After correcting for this\\neffect, we show that the systematic errors in the astrometry of the telescope\\nare of the order of 0.5 arcsec. In the case of the Crab nebula and several\\nother bright sources, the very large number of photons renders the level of\\nstatistical uncertainty in the centroid smaller or comparable to this value.\\nResults. We find that the centroid of the Crab nebula in hard X-rays (20-40\\nkeV) is shifted by 8.0 arcsec with respect to the Crab pulsar in the direction\\nof the X-ray centroid of the nebula. A similar shift is also found at higher\\nenergies (40-100 and 100-200 keV). We observe a trend of decreasing shift with\\nenergy, which can be explained by an increase in the pulsed fraction. To\\ndifferentiate between the contribution of the pulsar and the nebula, we divide\\nour data into an on-pulse and off-pulse sample. Surprisingly, the nebular\\nemission (i.e., off-pulse) is located significantly away from the X-ray\\ncentroid of the nebula. Conclusions. In all 3 energy bands (20-40, 40-100, and\\n100-200 keV), we find that the centroid of the nebula is significantly offset\\nfrom the predicted position. We interpret this shift in terms of a cut-off in\\nthe electron spectrum in the outer regions of the nebula, which is probably the\\norigin of the observed spectral break around 100 keV. From a simple\\nspherically-symmetric model for the nebula, we estimate that the electrons in\\nthe external regions of the torus (d ~ 0.35 pc from the pulsar) reach a maximal\\nenergy slightly below 10^14 eV.\\n
Resection of malignant brain tumors in eloquent cortical areas: a new multimodal approach combining 5-aminolevulinic acid and intraoperative monitoring
2009-11-13

Object Several studies have revealed that the gross-total resection (GTR) of malignant brain tumors has a significant influence on patient survival. Frequently, however, GTR cannot be achieved because the borders between healthy brain and diseased tissue are blurred in the infiltration zones of malignant brain tumors. Especially in eloquent cortical areas, resection is frequently stopped before total removal is achieved to avoid causing neurological deficits. Interestingly, 5-aminolevulinic acid (5-ALA) has been shown to help visualize tumor tissue intraoperatively and, thus, can significantly improve the possibility of achieving GTR of primary malignant brain tumors. The aim of this study was to go one step further and evaluate the utility and limitations of fluorescence-guided resections of primary malignant brain tumors in eloquent cortical areas in combination with intraoperative monitoring based on multimodal functional imaging data. Methods Eighteen patients with primary malignant brain tumors in eloquent areas were included in this prospective study. Preoperative neuroradiological examinations included MR imaging with magnetization-prepared rapid gradient echo (MPRAGE), functional MR, and diffusion tensor imaging sequences to visualize functional areas and fiber tracts. Imaging data were analyzed offline, loaded into a neuronavigational system, and used intraoperatively during resections. All patients received 5-ALA 6 hours before surgery. Fluorescence-guided tumor resections were combined with intraoperative monitoring and cortical as well as subcortical stimulation to localize functional areas and fiber tracts during surgery. Results Twenty-five procedures were performed in 18 consecutive patients. In 24% of all surgeries, resection was stopped because a functional area or cortical tract was identified in the resection area or because motor evoked potential amplitudes were reduced in an area where fluorescent tumor cells were still seen intraoperatively. Grosstotal resection could be achieved in 16 (64%) of the surgeries with preservation of all functional areas and fiber tracts. In 2 patients presurgical hemiparesis became accentuated postoperatively, and 1 of these patients also suffered from a new homonymous hemianopia following a second resection. Conclusions The authors' first results show that tumor resections with 5-ALA in combination with intraoperative cortical stimulation have the advantages of both methods and, thus, provide additional safety for the neurosurgeon during resections of primary malignant brain tumors in eloquent areas. Nonetheless, more cases and additional studies are necessary to further prove the advantages of this multimodal strategy.
Higher HLA class I expression in renal cell carcinoma than in autologous normal tissue
2009-11-13

A total of 93 frozen primary renal cell carcinoma (RCC) samples and 31 frozen samples of corresponding normal renal tissue were analyzed for human leukocyte antigen (HLA) class I and HLA-DR expression. Unexpectedly, HLA class I expression was much higher on RCC cells than on normal renal tubular cells. Immunohistochemistry analysis of frozen and paraffin-embedded tissue samples, applying an extended panel of specific anti-HLA monoclonal antibodies, showed elevated HLA class I antigen expression in 95.6% of the tumors vs only 12.9% of normal renal tissues. These findings were confirmed by molecular analysis of HLA heavy chain and beta2-microglobulin (beta2m) transcription levels using quantitative real-time polymerase chain reaction (PCR) on microdissected tissue samples (isolated tumor nests and autologous normal renal tubules) from four patients. These results might help to explain the relatively high success rate of immunotherapy in patients with RCC. The molecular mechanism underlying the increased HLA class I expression in RCC has yet to be elucidated.
Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia
2009-11-16

Abstract\\n Background: Hereditary spastic paraplegias (HSP) are clinically and genetically highly heterogeneous. \\nRecently two novel genes, SPG11(spatacsin) and SPG15 (spastizin), associated with autosomal recessive HSP (AR-HSP) were identified. Clinically, both are characterized by complicated HSP and a rather similar phenotype consisting of early onset spastic paraplegia, cognitive deficits, thin corpus callosum (TCC), peripheral neuropathy and mild cerebellar ataxia. \\nObjective: To compare the frequency of SPG11 and SPG15 in patients with early onset complicated HSP and to further characterize the phenotype of SPG11 and SPG15.\\nResults: A sample of 36 index patients with early onset complicated HSP and a family history compatible with autosomal recessive inheritance was collected and screened for mutations in SPG11 and SPG15. Overall frequency of SPG11 was 14% (5 out of 36) but was considerably higher in patients with TCC (42%). One single patient with mental retardation and thinning of the corpus callosum was compound heterozygous for two novel SPG15 mutations. Additionally, several new polymorphisms and sequence variants of unknown significance have been identified in the SPG15 gene.\\nConclusions: TCC seems to be the best phenotypic predictor for SPG11 as well as SPG15. No clinical features could discriminate between SPG11 and SPG15. Therefore priority of genetic testing should be driven by mutation frequency that appears to be substantially higher in SPG11 than in SPG15.
Trypanosoma bruceiATG8: Structural insights into autophagic-like mechanisms in protozoa
2009-11-16

Bioinformatic searches of genome databases revealed that the number of autophagy-related genes (ATG) is considerably lower in trypanosomes than in higher eukaryotes and even in yeast. This raises the question of whether autophagy in this protozoan parasite is more primitive and represents a rudimentary paradigm due to its early branching off the evolutionary tree. We here present the crystal structure of TbATG8B. This molecule (MW 13.7 kDa) belongs to the ubiquitin-like proteins showing the typical ubiquitin fold and strong sequence homology to LC3, the human homologue. Due to its characteristic folding, it should readily bind to TbATG4.1 for being processed. This presumption was tested by molecular modeling approaches, docking TbATG8B to a homology model of TbATG4.1. Although exchanges of several amino acids are evident from sequence comparisons, the overall structure seems very much alike and the necessary catalytic triad (C-D-H) is well conserved in TbATG4.1. Thus membrane formation during appearance of the autophagic bodies seems very similar in trypanosomes and their higher eukaryotic counterpart.
Hyperquarks and bosonic preon bound states
2009-11-16

In a model in which leptons, quarks, and the recently introduced hyperquarks\\nare built up from two fundamental spin 1/2 preons, the standard model weak\\ngauge bosons emerge as preon bound states. In addition, the model predicts a\\nhost of new composite gauge bosons, in particular those responsible for\\nhyperquark and proton decay. Their presence entails a left-right symmetric\\nextension of the standard model weak interactions and a scheme for a partial\\nand grand unification of nongravitational interactions based on respectively\\nthe effective gauge groups SU(6)_P and SU(9)_G. This leads to a prediction of\\nthe Weinberg angle at low energies in good agreement with experiment.\\nFurthermore, using evolution equations for the effective coupling strengths, we\\ncalculate the partial and grand unification scales, the hyperquark mass scale,\\nas well as the mass and decay rate of the lightest hyperhadron.\\n
Elementary properties of CaV1.3 Ca2+ channels expressed in mouse cochlear inner hair cells
2009-11-17

Mammalian cochlear inner hair cells (IHCs) are specialized to process developmental signals during immature stages and sound stimuli in adult animals. These signals are conveyed onto auditory afferent nerve fibres. Neurotransmitter release at IHC ribbon synapses is controlled by L‐type Ca V 1.3 Ca 2+ channels, the biophysics of which are still unknown in native mammalian cells. We have investigated the localization and elementary properties of Ca 2+ channels in immature mouse IHCs under near‐physiological recording conditions. Ca V 1.3 Ca 2+ channels at the cell pre‐synaptic site co‐localize with about half of the total number of ribbons present in immature IHCs. These channels activated at about −70 mV, showed a relatively short first latency and weak inactivation, which would allow IHCs to generate and accurately encode spontaneous Ca 2+ action potential activity characteristic of these immature cells. The Ca V 1.3 Ca 2+ channels showed a very low open probability (about 0.15 at −20 mV: near the peak of an action potential). Comparison of elementary and macroscopic Ca 2+ currents indicated that very few Ca 2+ channels are associated with each docked vesicle at IHC ribbon synapses. Finally, we found that the open probability of Ca 2+ channels, but not their opening time, was voltage dependent. This finding provides a possible correlation between presynaptic Ca 2+ channel properties and the characteristic frequency/amplitude of EPSCs in auditory afferent fibres.
Constitutive Expression of the Antimicrobial Peptide RNase 7 Is Associated withStaphylococcus aureusInfection of the Skin
2009-11-17

In conjunction with the existing evidence from in vitro studies, these findings suggest that antimicrobial peptides found at high baseline levels in healthy skin, such as RNase 7, confer protection against S. aureus infection of the skin.
EFNS guidelines on the molecular diagnosis of mitochondrial disorders
2009-11-17

Objectives: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. Background: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. Search strategy: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta‐analyses, review papers, and guideline recommendations were reviewed. Results: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work‐up of MIDs. Recommendations: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.
Endoglin in African Children withPlasmodium falciparumMalaria: A Novel Player in Severe Malaria Pathogenesis?
2009-11-17

High sEng levels may attenuate anti-inflammatory response resulting in clinical deterioration of patients with P. falciparum malaria. Our results further corroborate the role of the vascular compartment, especially the endothelium, in severe malaria pathogenesis.
Inhibition of the ER Ca2+ pump forces multidrug-resistant cells deficient in Bak and Bax into necrosis
2009-11-18

Tumor cells deficient in the proapoptotic proteins Bak and Bax are resistant to chemotherapeutic drugs. Here, we demonstrate that murine embryonic fibroblasts deficient for both Bak and Bax are, however, efficiently killed by thapsigargin, a specific inhibitor of ER Ca2+ pumps that induces ER stress by depleting ER Ca2+ stores. In the presence of Bak and Bax, thapsigargin eliminates cells by release of mitochondrial cytochrome c and subsequent caspase activation, which leads to the proteolytic inactivation of the molecular necrosis switch PARP-1 and results in apoptosis. By contrast, in the absence of Bak and Bax, a failure to activate caspases results in PARP-1-mediated ATP depletion. The subsequent necrosis is not prevented by autophagy as an alternative energy source. Moreover, in cells deficient for both Bak and Bax, thapsigargin induces permanent mitochondrial damage by Ca2+ overload, permeability transition and membrane rupture. Thus, even though deficiency in Bak and Bax protects these cells against apoptosis, it does not compromise necrosis induced by SERCA inhibitors. Importantly, thapsigargin induces caspase-independent cell death also in colon and prostate carcinoma cells deficient in Bak and Bax expression. Therefore, targeted application of ER stressors such as thapsigargin might be a promising approach for the treatment of Bak- and Bax-deficient, drug-resistant tumors.