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Alterations of the architecture of cerebral white matter in the developing human brain can affect cortical development and result in functional disabilities.
A line scan diffusion-weighted magnetic resonance imaging (MRI) sequence with diffusion tensor analysis was applied to measure the apparent diffusion coefficient, to calculate relative anisotropy, and to delineate three-dimensional fiber architecture in cerebral white matter in preterm (n = 17) and full-term infants (n = 7). | scifact_0 |
To assess effects of prematurity on cerebral white matter development, early gestation preterm infants (n = 10) were studied a second time at term.
In the central white matter the mean apparent diffusion coefficient at 28 wk was high, 1.8 microm2/ms, and decreased toward term to 1.2 microm2/ms.
In the posterior limb of the internal capsule, the mean apparent diffusion coefficients at both times were similar (1.2 versus 1.1 microm2/ms). | scifact_1 |
Relative anisotropy was higher the closer birth was to term with greater absolute values in the internal capsule than in the central white matter.
Preterm infants at term showed higher mean diffusion coefficients in the central white matter (1.4 +/-
0.24 versus 1.15 +/-
0.09 microm2/ms, p = 0.016) and lower relative anisotropy in both areas compared with full-term infants (white matter, 10.9 +/- 0.6 versus 22.9 +/-
3.0%, p = 0.001; internal capsule, 24.0 +/-
4.44 versus 33.1 +/-
0.6% p = 0.006). | scifact_2 |
3.0%, p = 0.001; internal capsule, 24.0 +/-
4.44 versus 33.1 +/-
0.6% p = 0.006).
Nonmyelinated fibers in the corpus callosum were visible by diffusion tensor MRI as early as 28 wk; full-term and preterm infants at term showed marked differences in white matter fiber organization.
The data indicate that quantitative assessment of water diffusion by diffusion tensor MRI provides insight into microstructural development in cerebral white matter in living infants. | scifact_3 |
Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis.
Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. | scifact_4 |
These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors.
Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. | scifact_5 |
These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells.
S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. | scifact_6 |
Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype.
These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS. | scifact_7 |
ID elements are short interspersed elements (SINEs) found in high copy number in many rodent genomes.
BC1 RNA, an ID-related transcript, is derived from the single copy BC1 RNA gene.
The BC1 RNA gene has been shown to be a master gene for ID element amplification in rodent genomes.
ID elements are dispersed through a process termed retroposition.
The retroposition process involves a number of potential regulatory steps. | scifact_8 |
The retroposition process involves a number of potential regulatory steps.
These regulatory steps may include transcription in the appropriate tissue, transcript stability, priming of the RNA transcript for reverse transcription and integration.
This study focuses on priming of the RNA transcript for reverse transcription.
BC1 RNA gene transcripts are shown to be able to prime their own reverse transcription in an efficient intramolecular and site-specific fashion. | scifact_9 |
This self-priming ability is a consequence of the secondary structure of the 3'-unique region.
The observation that a gene actively amplified throughout rodent evolution makes a RNA capable of efficient self-primed reverse transcription strongly suggests that self-priming is at least one feature establishing the BC1 RNA gene as a master gene for amplification of ID elements. | scifact_10 |
DNA methylation plays an important role in biological processes in human health and disease.
Recent technological advances allow unbiased whole-genome DNA methylation (methylome) analysis to be carried out on human cells. | scifact_11 |
Using whole-genome bisulfite sequencing at 24.7-fold coverage (12.3-fold per strand), we report a comprehensive (92.62%) methylome and analysis of the unique sequences in human peripheral blood mononuclear cells (PBMC) from the same Asian individual whose genome was deciphered in the YH project.
PBMC constitute an important source for clinical blood tests world-wide. | scifact_12 |
PBMC constitute an important source for clinical blood tests world-wide.
We found that 68.4% of CpG sites and <0.2% of non-CpG sites were methylated, demonstrating that non-CpG cytosine methylation is minor in human PBMC.
Analysis of the PBMC methylome revealed a rich epigenomic landscape for 20 distinct genomic features, including regulatory, protein-coding, non-coding, RNA-coding, and repeat sequences. | scifact_13 |
Integration of our methylome data with the YH genome sequence enabled a first comprehensive assessment of allele-specific methylation (ASM) between the two haploid methylomes of any individual and allowed the identification of 599 haploid differentially methylated regions (hDMRs) covering 287 genes.
Of these, 76 genes had hDMRs within 2 kb of their transcriptional start sites of which >80% displayed allele-specific expression (ASE). | scifact_14 |
These data demonstrate that ASM is a recurrent phenomenon and is highly correlated with ASE in human PBMCs.
Together with recently reported similar studies, our study provides a comprehensive resource for future epigenomic research and confirms new sequencing technology as a paradigm for large-scale epigenomics studies. | scifact_15 |
Two human Golli (for gene expressed in the oligodendrocyte lineage)-MBP (for myelin basic protein) cDNAs have been isolated from a human oligodendroglioma cell line.
Analysis of these cDNAs has enabled us to determine the entire structure of the human Golli-MBP gene.
The Golli-MBP gene, which encompasses the MBP transcription unit, is approximately 179 kb in length and consists of 10 exons, seven of which constitute the MBP gene. | scifact_16 |
The human Golli-MBP gene contains two transcription start sites, each of which gives rise to a family of alternatively spliced transcripts.
At least two Golli-MBP transcripts, containing the first three exons of the gene and one or more MBP exons, are produced from the first transcription start site.
The second family of transcripts contains only MBP exons and produces the well-known MBPs. | scifact_17 |
The second family of transcripts contains only MBP exons and produces the well-known MBPs.
In humans, RNA blot analysis revealed that Golli-MBP transcripts were expressed in fetal thymus, spleen, and human B-cell and macrophage cell lines, as well as in fetal spinal cord.
These findings clearly link the expression of exons encoding the autoimmunogen/encephalitogen MBP in the central nervous system to cells and tissues of the immune system through normal expression of the Golli-MBP gene. | scifact_18 |
They also establish that this genetic locus, which includes the MBP gene, is conserved among species, providing further evidence that the MBP transcription unit is an integral part of the Golli transcription unit and suggest that this structural arrangement is important for the genetic function and/or regulation of these genes. | scifact_19 |
Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs).
GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets.
We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. | scifact_20 |
To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). | scifact_21 |
Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis. | scifact_22 |
The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays.
The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts.
In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. | scifact_23 |
Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation.
Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival. | scifact_24 |
A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type. | scifact_25 |
Realizing the full potential of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) requires efficient methods for genetic modification.
However, techniques to generate cell type–specific lineage reporters, as well as reliable tools to disrupt, repair or overexpress genes by gene targeting, are inefficient at best and thus are not routinely used. | scifact_26 |
Here we report the highly efficient targeting of three genes in human pluripotent cells using zinc-finger nuclease (ZFN)–mediated genome editing.
First, using ZFNs specific for the OCT4 (POU5F1) locus, we generated OCT4-eGFP reporter cells to monitor the pluripotent state of hESCs.
Second, we inserted a transgene into the AAVS1 locus to generate a robust drug-inducible overexpression system in hESCs. | scifact_27 |
Finally, we targeted the PITX3 gene, demonstrating that ZFNs can be used to generate reporter cells by targeting non-expressed genes in hESCs and hiPSCs. | scifact_28 |
BACKGROUND Microarrays offer great potential as a platform for molecular diagnostics, testing clinical samples for the presence of numerous biomarkers in highly multiplexed assays.
In this study applied to infectious diseases, data from a microarray designed for molecular serotyping of Streptococcus pneumoniae was used, identifying the presence of any one of 91 known pneumococcal serotypes from DNA extracts. | scifact_29 |
This microarray incorporated oligonucleotide probes for all known capsular polysaccharide synthesis genes and required a statistical analysis of the microarray intensity data to determine which serotype, or combination of serotypes, were present within a sample based on the combination of genes detected. | scifact_30 |
RESULTS We propose an empirical Bayesian model for calculating the probabilities of combinations of serotypes from the microarray data.
The model takes into consideration the dependencies between serotypes, induced by genes they have in common, and by homologous genes which, although not identical, are similar to each other in sequence. | scifact_31 |
For serotypes which are very similar in capsular gene composition, extra probes are included on the microarray, providing additional information which is integrated into the Bayesian model.
For each serotype combination with high probability, a second model, a Bayesian random effects model is applied to determine the relative abundance of each serotype. | scifact_32 |
CONCLUSIONS To assess the accuracy of the proposed analysis we applied our methods to experimental data from samples containing individual serotypes and samples containing combinations of serotypes with known levels of abundance.
All but two of the known serotypes of S. pneumoniae that were tested as individual samples could be uniquely determined by the Bayesian model.
The model also enabled the presence of combinations of serotypes within samples to be determined. | scifact_33 |
The model also enabled the presence of combinations of serotypes within samples to be determined.
Serotypes with very low abundance within a combination of serotypes can be detected (down to 2% abundance in this study).
As well as detecting the presence of serotype combinations, an approximate measure of the percentage abundance of the serotypes within the combination can be obtained. | scifact_34 |
Summary.
We consider the problem of comparing complex hierarchical models in which the number of parameters is not clearly defined.
Using an information theoretic argument we derive a measure pD for the effective number of parameters in a model as the difference between the posterior mean of the deviance and the deviance at the posterior means of the parameters of interest. | scifact_35 |
In general pD approximately corresponds to the trace of the product of Fisher's information and the posterior covariance, which in normal models is the trace of the ‘hat’ matrix projecting observations onto fitted values.
Its properties in exponential families are explored.
The posterior mean deviance is suggested as a Bayesian measure of fit or adequacy, and the contributions of individual observations to the fit and complexity can give rise to a diagnostic plot of deviance residuals against leverages. | scifact_36 |
Adding pD to the posterior mean deviance gives a deviance information criterion for comparing models, which is related to other information criteria and has an approximate decision theoretic justification.
The procedure is illustrated in some examples, and comparisons are drawn with alternative Bayesian and classical proposals.
Throughout it is emphasized that the quantities required are trivial to compute in a Markov chain Monte Carlo analysis. | scifact_37 |
Likelihood ratios are one of the best measures of diagnostic accuracy, although they are seldom used, because interpreting them requires a calculator to convert back and forth between “probability” and “odds” of disease.
This article describes a simpler method of interpreting likelihood ratios, one that avoids calculators, nomograms, and conversions to “odds” of disease.
Several examples illustrate how the clinician can use this method to refine diagnostic decisions at the bedside. | scifact_38 |
On recognition of influenza virus (Flu) by TLR7, plasmacytoid dendritic cells (pDCs) produce type I IFN in significant amounts.
Synthetic TLR7 ligands induce the maturation of pDCs, as evidenced by the expression of costimulatory molecules and the production of proinflammatory cytokines; however, they induce only low-level production of IFN-alpha. | scifact_39 |
To dissect the TLR7 signaling in pDCs and how these different profiles are induced, we studied the effects of 2 TLR7 ligands (Flu and CL097) on the activation of blood-isolated pDCs and the human GEN2.2 pDC cell line.
Type I IFN production by pDCs correlates with differential interferon regulatory factor 7 (IRF7) translocation into the nucleus induced by the 2 TLR7 ligands. | scifact_40 |
Surprisingly, with both activators we nevertheless observed the rapid expression of the IFN-inducible genes mxa, cxcl10, and trail within 4 hours of stimulation.
This expression, controlled by STAT1 phosphorylation, was independent of type I IFN.
STAT1 activation was found to be strictly dependent on the PI3K-p38MAPK pathway, showing a new signaling pathway leading to rapid expression of IFN-inducible genes after TLR7 triggering. | scifact_41 |
Thus, pDCs, through this unusual TLR7 signaling, have the capacity to promptly respond to viral infection during the early phases of the innate immune response. | scifact_42 |
OBJECTIVE The purpose of this study was to characterize the relationship between adipose tissue phenotype and depot-specific microvascular function in fat. | scifact_43 |
METHODS AND RESULTS In 30 obese subjects (age 42±11 years, body mass index 46±11 kg/m(2)) undergoing bariatric surgery, we intraoperatively collected visceral and subcutaneous adipose tissue and characterized depot-specific adipose phenotypes.
We assessed vasomotor function of the adipose microvasculature using videomicroscopy of small arterioles (75-250 μm) isolated from different fat compartments. | scifact_44 |
Endothelium-dependent, acetylcholine-mediated vasodilation was severely impaired in visceral arterioles, compared to the subcutaneous depot (P<0.001 by ANOVA).
Nonendothelium dependent responses to papaverine and nitroprusside were similar.
Endothelial nitric oxide synthase inhibition with N(ω)-nitro-l-arginine methyl ester reduced subcutaneous vasodilation but had no effect on severely blunted visceral arteriolar responses. | scifact_45 |
Visceral fat exhibited greater expression of proinflammatory, oxidative stress-related, hypoxia-induced, and proangiogenic genes; increased activated macrophage populations; and had a higher capacity for cytokine production ex vivo. | scifact_46 |
CONCLUSIONS Our findings provide clinical evidence that the visceral microenvironment may be intrinsically toxic to arterial health providing a potential mechanism by which visceral adiposity burden is linked to atherosclerotic vascular disease.
Our findings also support the evolving concept that both adipose tissue quality and quantity may play significant roles in shaping cardiovascular phenotypes in human obesity. | scifact_47 |
BACKGROUND Common carotid intima media thickness (CIMT) and ankle brachial pressure index (ABPI) are used as surrogate marker of atherosclerosis, and have been shown to correlate with arterial stiffness, however their correlation with global atherosclerotic burden has not been previously assessed.
We compare CIMT and ABPI with atheroma burden as measured by whole body magnetic resonance angiography (WB-MRA). | scifact_48 |
METHODS 50 patients with symptomatic peripheral arterial disease were recruited.
CIMT was measured using ultrasound while rest and exercise ABPI were performed.
WB-MRA was performed in a 1.5T MRI scanner using 4 volume acquisitions with a divided dose of intravenous gadolinium gadoterate meglumine (Dotarem, Guerbet, FR). | scifact_49 |
The WB-MRA data was divided into 31 anatomical arterial segments with each scored according to degree of luminal narrowing: 0 = normal, 1 = <50%, 2 = 50-70%, 3 = 70-99%, 4 = vessel occlusion.
The segment scores were summed and from this a standardized atheroma score was calculated. | scifact_50 |
RESULTS The atherosclerotic burden was high with a standardised atheroma score of 39.5±11.
Common CIMT showed a positive correlation with the whole body atheroma score (β 0.32, p = 0.045), however this was due to its strong correlation with the neck and thoracic segments (β 0.42 p = 0.01) with no correlation with the rest of the body. | scifact_51 |
ABPI correlated with the whole body atheroma score (β -0.39, p = 0.012), which was due to a strong correlation with the ilio-femoral vessels with no correlation with the thoracic or neck vessels.
On multiple linear regression, no correlation between CIMT and global atheroma burden was present (β 0.13 p = 0.45), while the correlation between ABPI and atheroma burden persisted (β -0.45 p = 0.005). | scifact_52 |
CONCLUSION ABPI but not CIMT correlates with global atheroma burden as measured by whole body contrast enhanced magnetic resonance angiography in a population with symptomatic peripheral arterial disease.
However this is primarily due to a strong correlation with ilio-femoral atheroma burden. | scifact_53 |
Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV).
Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections.
HCV-specific CD8(+) cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. | scifact_54 |
Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses.
To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women.
This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses. | scifact_55 |
CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply.
Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations.
Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness. | scifact_56 |
Hematopoietic stem cells (HSCs) develop during embryogenesis in a complex process that involves multiple anatomical sites.
Once HSC precursors have been specified from mesoderm, they have to mature into functional HSCs and undergo self-renewing divisions to generate a pool of HSCs.
During this process, developing HSCs migrate through various embryonic niches, which provide signals for their establishment and the conservation of their self-renewal ability. | scifact_57 |
These processes have to be recapitulated to generate HSCs from embryonic stem cells.
Elucidating the interactions between developing HSCs and their niches should facilitate the generation and expansion of HSCs in vitro to exploit their clinical potential. | scifact_58 |
The term spondyloarthropathy (SpA) describes and defines a group of related inflammatory joint disease that share characteristic clinical features and a unique association with the major histocompatibility complex class I molecule HLA-B27. | scifact_59 |
Five subgroups can be differentiated: ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated SpA. The sacroiliac joints are centrally involved in the SpA, most clearly and pathognomonic in ankylosing spondylitis, in which most patients are affected early in the disease. | scifact_60 |
Overcoming some of the diagnostic difficulties of early sacroiliitis, dynamic magnetic resonance imaging was shown to visualize both acute and chronic changes in the sacroiliac joints.
The inflammation in the sacroiliac joints in patients with SpA was recently examined in more detail; using immunohistology and in situ hybridrization, T cells, macrophages, and various cytokines were found in infiltrates. | scifact_61 |
Biopsy specimens were obtained under guided computed tomography, and in the same study, intra-articular corticosteroid treatment was successfully undertaken.
Further investigation of such biopsy specimens showed the absence of DNA of reactive arthritis-associated bacteria.
The pathogenesis of the SpA and the reason for the tropism for the sacroiliac joints is still obscure.
The nature of the relation of the genetic background of SpA to initially triggering bacterial infections remains to be established. | scifact_62 |
In chronic disease, autoimmune mechanisms might be more important. | scifact_63 |
Extraction of high-quality genomic DNA fromGossypium (cotton) species is difficult due to high levels of polysaccharide, oxidizable quinones, and other interfering substances.
We describe a procedure that consistently permits isolation of cotton genomic DNA of satisfactory size and quality for RFLP and PCR analysis, as well as for most routine cloning applications. | scifact_64 |
Several antioxidants, phenol-binding reagents, and phenol oxidase inhibitors are used throughout the procedure, and most polysaccharides are eliminated early in the procedure by isolation of nuclei. | scifact_65 |
The current reference curves of stature and weight for the UK were first published in 1966 and have been used ever since despite increasing concern that they may not adequately describe the growth of present day British children.
Using current data from seven sources new reference curves have been estimated from birth to 20 years for children in 1990.
The great majority of the data are nationally representative. | scifact_66 |
The great majority of the data are nationally representative.
The analysis used Cole's LMS method and has produced efficient estimates of the conventional centiles and gives a good fit to the data.
These curves differ from the currently used curves at key ages for both stature and weight.
In view of the concerns expressed about the current curves and the differences between them and the new curves, it is proposed that the curves presented here should be adopted as the new UK reference curves. | scifact_67 |
Bone tissue undergoes constant turnover supported by stem cells.
Recent studies showed that perivascular mesenchymal stem cells (MSCs) contribute to the turnover of long bones.
Craniofacial bones are flat bones derived from a different embryonic origin than the long bones.
The identity and regulating niche for craniofacial-bone MSCs remain unknown.
Here, we identify Gli1+ cells within the suture mesenchyme as the main MSC population for craniofacial bones. | scifact_68 |
They are not associated with vasculature, give rise to all craniofacial bones in the adult and are activated during injury repair.
Gli1+ cells are typical MSCs in vitro.
Ablation of Gli1+ cells leads to craniosynostosis and arrest of skull growth, indicating that these cells are an indispensable stem cell population.
Twist1(+/-) mice with craniosynostosis show reduced Gli1+ MSCs in sutures, suggesting that craniosynostosis may result from diminished suture stem cells. | scifact_69 |
Our study indicates that craniofacial sutures provide a unique niche for MSCs for craniofacial bone homeostasis and repair. | scifact_70 |
Arodent cardiac side population cell fraction formed clonal spheroids in serum-free medium, which expressed nestin, Musashi-1, and multi-drug resistance transporter gene 1, markers of undifferentiated neural precursor cells.
These markers were lost following differentiation, and were replaced by the expression of neuron-, glial-, smooth muscle cell–, or cardiomyocyte-specific proteins. | scifact_71 |
Cardiosphere-derived cells transplanted into chick embryos migrated to the truncus arteriosus and cardiac outflow tract and contributed to dorsal root ganglia, spinal nerves, and aortic smooth muscle cells.
Lineage studies using double transgenic mice encoding protein 0–Cre/Floxed-EGFP revealed undifferentiated and differentiated neural crest-derived cells in the fetal myocardium. | scifact_72 |
Undifferentiated cells expressed GATA-binding protein 4 and nestin, but not actinin, whereas the differentiated cells were identified as cardiomyocytes.
These results suggest that cardiac neural crest-derived cells migrate into the heart, remain there as dormant multipotent stem cells—and under the right conditions—differentiate into cardiomyocytes and typical neural crest-derived cells, including neurons, glia, and smooth muscle. | scifact_73 |
Understanding molecular mechanisms mediating epileptogenesis is critical for developing more effective therapies for epilepsy.
We recently found that the mammalian target of rapamycin (mTOR) signaling pathway is involved in epileptogenesis, and mTOR inhibitors prevent epilepsy in a mouse model of tuberous sclerosis complex.
Here, we investigated the potential role of mTOR in a rat model of temporal lobe epilepsy initiated by status epilepticus. | scifact_74 |
Acute kainate-induced seizures resulted in biphasic activation of the mTOR pathway, as evident by an increase in phospho-S6 (P-S6) expression.
An initial rise in P-S6 expression started approximately 1 h after seizure onset, peaked at 3-6 h, and returned to baseline by 24 h in both hippocampus and neocortex, reflecting widespread stimulation of mTOR signaling by acute seizure activity. | scifact_75 |
After resolution of status epilepticus, a second increase in P-S6 was observed in hippocampus only, which started at 3 d, peaked 5-10 d, and persisted for several weeks after kainate injection, correlating with the development of chronic epileptogenesis within hippocampus. | scifact_76 |
The mTOR inhibitor rapamycin, administered before kainate, blocked both the acute and chronic phases of seizure-induced mTOR activation and decreased kainate-induced neuronal cell death, neurogenesis, mossy fiber sprouting, and the development of spontaneous epilepsy.
Late rapamycin treatment, after termination of status epilepticus, blocked the chronic phase of mTOR activation and reduced mossy fiber sprouting and epilepsy but not neurogenesis or neuronal death. | scifact_77 |
These findings indicate that mTOR signaling mediates mechanisms of epileptogenesis in the kainate rat model and that mTOR inhibitors have potential antiepileptogenic effects in this model. | scifact_78 |
INTRODUCTION Endothelial activation leading to vascular barrier breakdown plays an essential role in the pathophysiology of multiple-organ dysfunction syndrome (MODS) in sepsis.
Increasing evidence suggests that the function of the vessel-protective factor Angiopoietin-1 (Ang-1), a ligand of the endothelial-specific Tie2 receptor, is inhibited by its antagonist Angiopoietin-2 (Ang-2) during sepsis. | scifact_79 |
In order to reverse the effects of the sepsis-induced suppression of Ang-1 and elevation of Ang-2 we aimed to investigate whether an intravenous injection of recombinant human (rh) Ang-1 protects against MODS in murine sepsis. | scifact_80 |
METHODS Polymicrobiological abdominal sepsis was induced by cecal ligation and puncture (CLP).
Mice were treated with either 1 μg of intravenous rhAng-1 or control buffer immediately after CLP induction and every 8h thereafter.
Sham-operated animals served as time-matched controls. | scifact_81 |
RESULTS Compared to buffer-treated controls, rhAng-1 treated septic mice showed significant improvements in several hematologic and biochemical indicators of MODS.
Moreover, rhAng-1 stabilized endothelial barrier function, as evidenced by inhibition of protein leakage from lung capillaries into the alveolar compartment. | scifact_82 |
Histological analysis revealed that rhAng-1 treatment attenuated leukocyte infiltration in lungs and kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression in rhAng-1 treated mice.
Finally, the protective effects of rhAng-1 treatment were reflected by an improved survival time in a lethal CLP model. | scifact_83 |
CONCLUSIONS In a clinically relevant murine sepsis model, intravenous rhAng-1 treatment alone is sufficient to significantly improve a variety of sepsis-associated organ dysfunctions and survival time, most likely by preserving endothelial barrier function.
Further studies are needed to pave the road for clinical application of this therapy concept. | scifact_84 |
Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes.
In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance.
When insulin resistance is accompanied by dysfunction of pancreatic islet β-cells — the cells that release insulin — failure to control blood glucose levels results. | scifact_85 |
Abnormalities in β-cell function are therefore critical in defining the risk and development of type 2 diabetes.
This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention. | scifact_86 |
Podocytes are critical in the maintenance of a healthy glomerular filter; however, they have been difficult to study in the intact kidney because of technical limitations.
Here we report the development of serial multiphoton microscopy (MPM) of the same glomeruli over several days to visualize the motility of podocytes and parietal epithelial cells (PECs) in vivo. | scifact_87 |
In podocin-GFP mice, podocytes formed sporadic multicellular clusters after unilateral ureteral ligation and migrated into the parietal Bowman's capsule.
The tracking of single cells in podocin-confetti mice featuring cell-specific expression of CFP, GFP, YFP or RFP revealed the simultaneous migration of multiple podocytes.
In phosphoenolpyruvate carboxykinase (PEPCK)-GFP mice, serial MPM found PEC-to-podocyte migration and nanotubule connections. | scifact_88 |
Our data support a highly dynamic rather than a static nature of the glomerular environment and cellular composition.
Future application of this new approach should advance our understanding of the mechanisms of glomerular injury and regeneration. | scifact_89 |
It is thought that the H19 imprinting control region (ICR) directs the silencing of the maternally inherited Igf2 allele through a CTCF-dependent chromatin insulator.
The ICR has been shown to interact physically with a silencer region in Igf2, differentially methylated region (DMR)1, but the role of CTCF in this chromatin loop and whether it restricts the physical access of distal enhancers to Igf2 is not known. | scifact_90 |
We performed systematic chromosome conformation capture analyses in the Igf2/H19 region over >160 kb, identifying sequences that interact physically with the distal enhancers and the ICR.
We found that, on the paternal chromosome, enhancers interact with the Igf2 promoters but that, on the maternal allele, this is prevented by CTCF binding within the H19 ICR. | scifact_91 |
CTCF binding in the maternal ICR regulates its interaction with matrix attachment region (MAR)3 and DMR1 at Igf2, thus forming a tight loop around the maternal Igf2 locus, which may contribute to its silencing.
Mutation of CTCF binding sites in the H19 ICR leads to loss of CTCF binding and de novo methylation of a CTCF target site within Igf2 DMR1, showing that CTCF can coordinate regional epigenetic marks. | scifact_92 |
This systematic chromosome conformation capture analysis of an imprinting cluster reveals that CTCF has a critical role in the epigenetic regulation of higher-order chromatin structure and gene silencing over considerable distances in the genome. | scifact_93 |
Telomerase-negative tumor cells use an alternative lengthening of telomeres (ALT) pathway that involves DNA recombination and repair to maintain their proliferative potential.
The cytological hallmark of this process is the accumulation of promyelocytic leukemia (PML) nuclear protein at telomeric DNA to form ALT-associated PML bodies (APBs).
Here, the de novo formation of a telomeric PML nuclear subcompartment was investigated by recruiting APB protein components. | scifact_94 |
We show that functionally distinct proteins were able to initiate the formation of bona fide APBs with high efficiency in a self-organizing and self-propagating manner.
These included: (1) PML and Sp100 as the constituting components of PML nuclear bodies, (2) telomere repeat binding factors 1 and 2 (TRF1 and TRF2, respectively), (3) the DNA repair protein NBS1 and (4) the SUMO E3 ligase MMS21, as well as the isolated SUMO1 domain, through an interacting domain of another protein factor. | scifact_95 |
By contrast, the repair factors Rad9, Rad17 and Rad51 were less efficient in APB nucleation but were recruited to preassembled APBs.
The artificially created APBs induced telomeric extension through a DNA repair mechanism, as inferred from their colocalization with sites of non-replicative DNA synthesis and histone H2A.X phosphorylation, and an increase of the telomere repeat length. | scifact_96 |
These activities were absent after recruitment of the APB factors to a pericentric locus and establish APBs as functional intermediates of the ALT pathway. | scifact_97 |
The genomic RNA of an alphavirus encodes four different nonstructural proteins, nsP1, nsP2, nsP3, and nsP4.
The polyprotein P123 is produced when translation terminates at an opal termination codon between nsP3 and nsP4.
The polyprotein P1234 is produced when translational readthrough occurs or when the opal termination codon has been replaced by a sense codon in the alphavirus genome. | scifact_98 |
Evolutionary pressures appear to have maintained genomic sequences encoding both a stop codon (opal) and an open reading frame (arginine) as a general feature of the O'nyong-nyong virus (ONNV) genome, indicating that both are required at some point.
Alternate replication of ONNVs in both vertebrate and invertebrate hosts may determine predominance of a particular codon at this locus in the viral quasispecies.
However, no systematic study has previously tested this hypothesis in whole animals. | scifact_99 |
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