Miracle-dz/UniFAR-FTUs huggingface dataset:
Increased Production of Apolipoprotein B-containing Lipoproteins in the Absence of Hyperlipidemia in Transgenic Mice Expressing Cholesterol 7α-Hydroxylase*

The finding that expression of a cholesterol 7α-hydroxylase (CYP7A1) transgene in cultured rat hepatoma cells caused a coordinate increase in lipogenesis and secretion of apoB-containing lipoproteins led to the hypothesis that hepatic production of apoB-containing lipoproteins may be linked to the expression of CYP7A1 (Wang, S.-L., Du, E., Martin, T. D., and Davis, R. A. (1997) J. Biol. Chem. 272, 19351–19358). To examine this hypothesis in vivo, a transgene encoding CYP7A1 driven by the constitutive liver-specific enhancer of the human apoE gene was expressed in C56BL/6 mice. The expression of CYP7A1 mRNA (20-fold), protein (∼10-fold), and enzyme activity (5-fold) was markedly increased in transgenic mice compared with non-transgenic littermates. The bile acid pool of CYP7A1 transgenic mice was doubled mainly due to increased hydrophobic dihydroxy bile acids. In CYP7A1 transgenic mice, livers contained ∼3-fold more sterol response element-binding protein-2 mRNA. Hepatic expression of mRNAs encoding lipogenic enzymes (i.e. fatty-acid synthase, acetyl-CoA carboxylase, stearoyl-CoA desaturase, squalene synthase, farnesyl-pyrophosphate synthase, 3-hydroxy-3-methylglutaryl-CoA reductase, and low density lipoprotein receptor) as well as microsomal triglyceride transfer protein were elevated ∼3–5-fold in transgenic mice. CYP7A1 transgenic mice also displayed a >2-fold increase in hepatic production and secretion of triglyceride-rich apoB-containing lipoproteins. Despite the increased hepatic secretion of apoB-containing lipoproteins in CYP7A1 mice, plasma levels of triglycerides and cholesterol were not significantly increased. These data suggest that the 5-fold increased expression of the low density lipoprotein receptor displayed by the livers of CYP7A1 transgenic mice was sufficient to compensate for the 2-fold increase production of apoB-containing lipoproteins. These findings emphasize the important homeostatic role that CYP7A1 plays in balancing the anabolic lipoprotein assembly/secretion pathway with the cholesterol catabolic bile acid synthetic pathway.
The role of histamine in neurogenic inflammation

The term ‘neurogenic inflammation’ has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene‐related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene‐related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to summarize the most recent findings on the role of histamine in neurogenic inflammation, with particular regard to nociceptive pain, as well as neurogenic inflammation in the skin, airways and bladder.
Prevention of Pneumococcal Disease in Mice Immunized with Conserved Surface-Accessible Proteins

ABSTRACT The development of a vaccine against Streptococcus pneumoniae has been complicated by the existence of at least 90 antigenically distinct capsular serotypes. Common protein-based vaccines could represent the best strategy to prevent pneumococcal infections, regardless of serotype. In the present study, the immunoscreening of an S. pneumoniae genomic library allowed the identification of a novel immune protein target, BVH-3. We demonstrate that immunization of mice with BVH-3 elicits protective immunity against experimental sepsis and pneumonia. Sequence analysis revealed that the bvh-3 gene is highly conserved within the species. Since the BVH-3 protein shows homology at its amino-terminal end with other pneumococcal proteins, it was of interest to determine if protection was due to the homologous or to the protein-specific regions. Immunoprotection studies using recombinant BVH-3 and BVH-3-related protein fragments as antigens allowed the localization of surface-exposed and protective epitopes at the protein-specific carboxyl termini, thus establishing that BVH-3 is distinct from other previously reported protective protein antigens. Immunization with a chimeric protein comprising the carboxyl-terminal regions of BVH-3 and of a BVH-3-related protein improved the protection by targeting two surface pneumococcal components. Thus, BVH-3 and the chimeric protein hold strong promise as vaccine components to control pneumococcal disease.
Interferometry with ENVISAT wide swath ScanSAR data

The possibility to get efficient topographic mapping and monitoring of large-scale motions with ScanSAR interferometry has been demonstrated with the Shuttle Radar Topography Mission and RADARSAT mission. The Environmental Satellite Advanced Synthetic Aperture Radar (ASAR) sensor has been designed to provide enhanced capabilities for interferometric applications. Different types of interferometric products can be obtained by combining the various ASAR modes as stripmap synthetic aperture radar [image mode (IM)] and ScanSAR [wide swath (WS) mode]. This letter deals with the possibility to use WS data to get either mixed-mode (IM/WS) or ScanSAR mode (WS/WS) differential interferograms. The impact of digital elevation model localization errors on IM/WS interferograms and of scan pattern synchronization on WS/WS interferograms is investigated. Experimental results are encouraging and show that ASAR ScanSAR data can be routinely used for interferometric applications in both cases
Cutting Edge: CD4-Independent Development of Functional FoxP3+ Regulatory T Cells1

The CD4 coreceptor is mandatory for the differentiation and function of conventional MHC class II-restricted T cells, but little is known about its contribution in regulatory T cells (Tregs). We thus investigated the Treg compartment in mice lacking CD4. CD3+CD8−FoxP3+ cells were readily detected in the periphery of CD4−/− mice, where their percentages were even increased as compared with wild-type animals. These cells had a classical CD25+CD152+GITR+ Treg phenotype, were enriched in memory-type Tregs, and displayed a diversified TCR repertoire. Functionally, CD4−/− Tregs were equally as suppressive as CD4+/+ Tregs in vitro as well as in vivo. Hence, the CD4 coreceptor is dispensable for the generation and function of FoxP3+ Tregs. Furthermore, CD3+CD8−FoxP3+ Tregs were also found to develop in the absence of both CD4 and MHC-II molecules, demonstrating that the generation of Tregs can occur independently of MHC-II recognition.
Unfavorable Socioeconomic Conditions in Early Life Presage Expression of Proinflammatory Phenotype in Adolescence

Objective: Unfavorable socioeconomic status (SES) circumstances early in life are associated with heightened vulnerability to respiratory and cardiovascular diseases in adulthood. However, little is known about mechanisms underlying this phenomenon. Methods: This study examined whether early-life SES predicts future activity of two genes involved in regulating inflammation. An ethnically diverse cohort of 136 adolescent females was enrolled in the study. SES was measured by home ownership. The messenger ribonucleic acid (mRNA) for glucocorticoid receptor (GR) and toll-like receptor 4 (TLR4) was quantified in peripheral blood leukocytes using real-time reverse transcriptase polymerase chain reaction (RT-PCR). Results: Three findings emerged: a) Years 2 to 3 of life were a critical period: the participants whose families owned homes during these childhood years showed higher GR mRNA and lower TLR4 mRNA during adolescence, a profile that suggests better regulation of inflammatory responses. b) These effects were not mediated through current economic circumstances, life stress, or health practices. C) Changes in SES during later years were unable to “undo” these effects. Conclusions: These findings suggest that unfavorable SES circumstances in the early years of life presage the expression of a proinflammatory phenotype in adolescence. To the extent that this proclivity toward inflammation persists over one’s lifespan it could explain the heightened incidence of respiratory and cardiovascular disease in low SES populations. GR = glucocorticoid receptor; mRNA = messenger ribonucleic acid; RT-PCR = reverse transcriptase polymerase chain reaction; SES = socioeconomic status; TLR4 = toll-like receptor 4.
Regions of Escherichia coli TonB and FepA proteins essential for in vivo physical interactions

The transport of Fe(III)-siderophore complexes and vitamin B12 across the outer membrane of Escherichia coli is an active transport process requiring a cognate outer membrane receptor, cytoplasmic membrane-derived proton motive force, and an energy-transducing protein anchored in the cytoplasmic membrane, TonB. This process requires direct physical contact between the outer membrane receptor and TonB. Previous studies have identified an amino-terminally located region (termed the TonB box) conserved in all known TonB-dependent outer membrane receptors as being essential for productive energy transduction. In the present study, a mutation in the TonB box of the ferric enterochelin receptor FepA resulted in the loss of detectable in vivo chemical cross-linking between FepA and TonB. Protease susceptibility studies indicated this effect was due to an alteration of conformation rather than the direct disruption of a specific site of physical contact. This suggested that TonB residue 160, implicated in previous studies as a site of allele-specific suppression of TonB box mutants, also made a conformational rather than a direct contribution to the physical interaction between TonB and the outer membrane receptors. This possibility was supported by the finding that TonB carboxyl-terminal truncations that retained Gln-160 were unable to participate in TonB-FepA complex formation, indicating that this site alone was not sufficient to support the physical interactions involved in energy transduction. These studies indicated that the final 48 residues of TonB were essential to this physical interaction. This region contains a putative amphipathic helix which could facilitate TonB-outer membrane interaction. Amino acid replacements at one site in this region were found to affect energy transduction but did not appear to greatly alter TonB conformation or the formation of a TonB-FepA complex. The effects of amino acid substitutions at several other TonB sites were also examined.
Experimental study on carrier transport mechanism in ultrathin-body SOI nand p-MOSFETs with SOI thickness less than 5 nm

The electrical characteristics of ultrathin-body SOI CMOSFETs with SOI thickness ranging from 2.3 nm to 8 nm are intensively investigated. As a result, it is demonstrated, for the first time, that electron mobility increases as SOI thickness decreases, when SO, thickness is in the range from 3.5 nm to 4.5 nm. In addition, it is demonstrated that, when SOI thickness is thinner than 4 nm, slight (even atomic-level) SOI thickness fluctuations have a significant impact on threshold voltage, gate-channel capacitance, and carrier mobility of ultrathin-body CMOSFETs.
Strain and sex differences in repeated ethanol treatment‐induced motor activity in quasi‐congenic mice

The B6.C quasi‐congenic Recombinant QTL Introgression (RQI) strains of the b4i5 series have similar genetic background, but differ in about 5% of their genome from the C57BL/6ByJ (B6) background strain because they carry short chromosome segments introgressed from the BALB/cJ (C) donor strain. These RQI strains were derived from mouse lines selectively bred for high activity of mesencephalic tyrosine hydroxylase (TH/MES), therefore genetic variation in dopamine system‐related behaviours, such as ethanol‐induced motor activity, can be expected. Males and females of 17 RQI and two progenitor strains were tested for initial motor activity for 15 min after a habituating injection of saline, which was followed by an i.p. injection of saline or ethanol (2 g/kg) and an additional test of motor activity for 30 min. This procedure was repeated during 4 subsequent days. In all strains, the first‐day ethanol treatment showed an inhibitory effect. With repetition of the treatment the inhibitory effect decreased, and a stimulatory effect could be observed with significant strain‐ and sex‐dependent variation. Females exhibited higher activity in the saline group than males, and reached an equilibrium of inhibition and stimulation sooner than males with repetition of the ethanol treatment. The highest (> 25‐fold) difference in activity after repeated ethanol treatment was detected between females of the two strains B6.Cb4i5‐Alpha4/Vad and B6.Cb4i5‐Beta13/Vad. These results firstly suggest that females are more sensitive to repeated ethanol exposure than males, secondly they support the observations that ethanol has both inhibitory and stimulatory effects on motor activity, which are affected by sex, genotype, and repetition of treatment, and thirdly offer new quasi‐congenic animal models with highly different responses to ethanol allowing one to more quickly move to gene detection.
Partial Volume Correction using Median Priors in Penalized-Likelihood Image Reconstruction Methods

Partial volume error (PVE) is an important problem in quantitative image reconstruction. PVE is induced due to the low resolution capabilities of the imaging system. Additionally, reconstructed images have non-uniform resolution across the field of view. This non-uniform resolution is a consequence of a number of physical and detector dependent effects, such as non-uniform object attenuation, scatter or crystal penetration effect. A specific problem being addressed is that of the variation of PVE resulting from spatial variations in reconstructed resolution. Regularization is preferably used to overcome variations in underlying signal and noise. The penalized-likelihood (PL) image reconstruction methods use some kind of penalty function to regularize the image and they impose certain conditions to obtain reconstructed images with acceptable signal to noise ratio. Among different penalty functions, median priors have reasonable smoothing and edge preserving properties. Though non-quadratic priors can be used for edge preservation, they require several parameters to be tuned. We have used quadratic (QP) and median priors (MP) to achieve better control of resolution characteristics and partial volume correction. The Geometric Transfer Matrix (GTM) method is one of the methods which try to extract mean activities in various regions of the object using geometric transfer coefficients through an application of partial volume correction at the same time. We implemented the GTM method with PL methods using MPs and compared the results with QPs.
Review: The role of the L-arginine-nitric oxide pathway in preeclampsia

Preeclampsia (PE) is a major cause of maternal and perinatal mortality, especially in developing countries. Its etiology involves multiple factors, but no specific cause has been identified. Evidence suggests that clinical manifestations are caused by endothelial dysfunction. Nitric oxide (NO), which is synthesized from L-arginine in endothelial cells by the endothelial nitric oxide synthase (eNOS), provides a tonic dilator tone and regulates the adhesion of white blood cells and platelet aggregation. Alterations in the L-arginine-NO pathway have been associated with the development of PE. Various studies, reporting decreased, elevated or unchanged levels of nitrite (NO2) and nitrate (NO3), two end products of NO metabolism, have been published. Our group contributed to those contradictory reports describing cases of PE with both elevated and decreased levels of NO2 and NO3. Apparently, diminished levels of NO could be related to deficiencies in the ingestion of dietary calcium associated to low levels of plasma ionic calcium, which is crucial to the eNOS' activity. Also, low levels of NO could be associated with the presence of eNOS polymorphisms or the presence of increased levels of ADMA, the endogenous inhibitor of NO. High levels of NO associated to low levels of cGMP suggest a decreased bioactivity of NO, which is probably related to an increased degradation of NO caused by a high production of superoxide in states of infection and inflammation. The present article analyses and reviews the reported paradoxical roles of the L-arginine-NO pathway in PE and gives a possible explanation for these results.
Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin

Muscle wasting and weakness are common features of patients with critical illnesses, and may impair their recovery. This study examines whether cytoskeletal and contractile proteins are damaged, and which proteolytic mechanisms might be involved, in the muscle fibre atrophy or necrosis associated with the acute myopathy of critically ill patients. Ninety‐eight muscle biopsies were obtained by the conchotome method from 57 critically ill patients and examined morphometrically and by immunohistochemical labelling. Sequential biopsies showed a mean reduction in fibre cross‐sectional areas of 3–4% per day. More intense immunolabelling for desmin was seen in the smaller fibres of 52% of the biopsies, while immunolabelling for dystrophin, actin and myosin heavy chains was maintained. Myosin ATPase activity was weak in the smaller fibres in some biopsies, and electron microscopy showed the loss of myosin filaments in atrophic fibres. These changes suggest that loss of the filamentous structure of myosin, without degradation of the immunolabelled epitopes, leads to the collapse of the intermyofibrillar desmin network. Fibres with abnormal desmin labelling showed increased cathepsin B, lysozyme and ubiquitin immunolabelling. Nine cases showed increased immunolabelling for heat shock protein 72. The changes in desmin immunolabelling were more prevalent in patients with higher APACHE II scores on admission, but were not related to other clinical features. The results indicate that fibre atrophy is associated with myosin filament depolymerization and the presence of several proteolytic enzymes. In our study, these changes occurred in patients who were critically ill but who did not receive large doses of steroids or neuromuscular blocking agents.
A comparison of the power of two tests for qualitative interactions.

'Qualitative' or 'crossover' interactions arise when a new treatment, compared with a control treatment, is beneficial in some subsets of patients and harmful in other subsets. We present a new range test for crossover interactions and compare it with the likelihood ratio test developed by Gail and Simon. The range test has greater power when the new treatment is harmful in only a few subsets, whereas the likelihood ratio test has greater power when the new treatment is harmful in several subsets. We provide power tables for both tests to facilitate sample size calculations for designing experiments to detect qualitative interactions and for interpreting the results of clinical trials.
Emerging treatments for narcolepsy and its related disorders

Importance of the field: Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and nocturnal sleep disruption. Non-pharmacological treatments (i.e., behavioral modification) are often helpful for the clinical management of narcoleptic patients. As these symptoms are often disabling, most patients need life-long treatments. Over 90% of diagnosed narcoleptic patients are currently prescribed medications to control their symptoms; however, available treatments are merely symptomatic. Areas covered in this review: This review presents a description of the clinical symptoms of narcolepsy, followed by a discussion of the state-of-the-art knowledge regarding the disorder and related emerging treatments. In preparing this review, an extensive literature search was conducted using Pubmed. Only selected references from 1970 to 2008 are cited. What the reader will gain: This review focuses on emerging treatments for human narcolepsy, and the reader will gain significant knowledge of current and future treatment for this and related disorders. Traditionally, amphetamine-like stimulants (i.e., dopaminergic release enhancers) have been used for clinical management to improve EDS, and tricyclic antidepressants have been used as anticataplectics. However, treatments have recently evolved which utilize better tolerated compounds, such as modafinil (for EDS) and adrenergic/serotonergic selective reuptake inhibitors (as anticataplectics). In addition, night time administration of a short-acting sedative, γ-hydroxybutyrate, has been used for the treatment for EDS and cataplexy. As a large majority of human narcolepsy is hypocretin peptide deficient, hypocretin replacement therapy may also be a new therapeutic option; yet, this option is still unavailable. In addition to the hypocretin-based therapy, a series of new treatments are currently being tested in animal and/or humans models. These potential options include novel stimulant and anticataplectic drugs as well as immunotherapy, based on current knowledge of the pathophysiology of narcolepsy with cataplexy. Take home message: We expect that more pathophysiology-based treatments, capable of curing and/or preventing narcolepsy and related diseases, will be available in near future. As cases of EDS, associated with other neurological conditions (i.e., symptomatic narcolepsy or narcolepsy due to medical conditions), are often linked with hypocretin deficiency, these novel therapeutic options may also be applied to treatment of these disabling conditions.
Visualizing ligand molecules in Twilight electron density.

Three-dimensional models of protein structures determined by X-ray crystallography are based on the interpretation of experimentally derived electron-density maps. The real-space correlation coefficient (RSCC) provides an easily comprehensible, objective measure of the residue-based fit of atom coordinates to electron density. Among protein structure models, protein-ligand complexes are of special interest, given their contribution to understanding the molecular underpinnings of biological activity and to drug design. For consumers of such models, it is not trivial to determine the degree to which ligand-structure modelling is biased by subjective electron-density interpretation. A standalone script, Twilight, is presented for the analysis, visualization and annotation of a pre-filtered set of 2815 protein-ligand complexes deposited with the PDB as of 15 January 2012 with ligand RSCC values that are below a threshold of 0.6. It also provides simplified access to the visualization of any protein-ligand complex available from the PDB and annotated by the Uppsala Electron Density Server. The script runs on various platforms and is available for download at http://www.ruppweb. org/twilight/.