96 research outputs found
Temporal Changes in Cortical and Hippocampal Expression of Genes Important for Brain Glucose Metabolism Following Controlled Cortical Impact Injury in Mice
Traumatic brain injury (TBI) causes transient increases and subsequent decreases in brain glucose utilization. The underlying molecular pathways are orchestrated processes and poorly understood. In the current study, we determined temporal changes in cortical and hippocampal expression of genes important for brain glucose/lactate metabolism and the effect of a known neuroprotective drug telmisartan on the expression of these genes after experimental TBI. Adult male C57BL/6J mice (n = 6/group) underwent sham or unilateral controlled cortical impact (CCI) injury. Their ipsilateral and contralateral cortex and hippocampus were collected 6 h, 1, 3, 7, 14, 21, and 28 days after injury. Expressions of several genes important for brain glucose utilization were determined by qRT-PCR. In results, (1) mRNA levels of three key enzymes in glucose metabolism [hexo kinase (HK) 1, pyruvate kinase, and pyruvate dehydrogenase (PDH)] were all increased 6 h after injury in the contralateral cortex, followed by decreases at subsequent times in the ipsilateral cortex and hippocampus; (2) capillary glucose transporter Glut-1 mRNA increased, while neuronal glucose transporter Glut-3 mRNA decreased, at various times in the ipsilateral cortex and hippocampus; (3) astrocyte lactate transporter MCT-1 mRNA increased, whereas neuronal lactate transporter MCT-2 mRNA decreased in the ipsilateral cortex and hippocampus; (4) HK2 (an isoform of hexokinase) expression increased at all time points in the ipsilateral cortex and hippocampus. GPR81 (lactate receptor) mRNA increased at various time points in the ipsilateral cortex and hippocampus. These temporal alterations in gene expression corresponded closely to the patterns of impaired brain glucose utilization reported in both TBI patients and experimental TBI rodents. The observed changes in hippocampal gene expression were delayed and prolonged, when compared with those in the cortex. The patterns of alterations were specific to different brain regions and exhibited different recovery periods following TBI. Oral administration of telmisartan (1 mg/kg, for 7 days, n = 10 per group) ameliorated cortical or hippocampal mRNA for Glut-1/3, MCT-1/2 and PDH in CCI mice. These data provide molecular evidence for dynamic alteration of multiple critical factors in brain glucose metabolism post-TBI and can inform further research for treating brain metabolic disorders post-TBI
Exact General Relativistic Perfect Fluid Disks with Halos
Using the well-known ``displace, cut and reflect'' method used to generate
disks from given solutions of Einstein field equations, we construct static
disks made of perfect fluid based on vacuum Schwarzschild's solution in
isotropic coordinates. The same method is applied to different exactsolutions
to the Einstein'sequations that represent static spheres of perfect fluids. We
construct several models of disks with axially symmetric perfect fluid halos.
All disks have some common features: surface energy density and pressures
decrease monotonically and rapidly with radius. As the ``cut'' parameter
decreases, the disks become more relativistic, with surface energy density and
pressure more concentrated near the center. Also regions of unstable circular
orbits are more likely to appear for high relativistic disks. Parameters can be
chosen so that the sound velocity in the fluid and the tangential velocity of
test particles in circular motion are less then the velocity of light. This
tangential velocity first increases with radius and reaches a maximum.Comment: 22 pages, 25 eps.figs, RevTex. Phys. Rev. D to appea
tofacitinib treatment is associated with modest and reversible increases in serum lipids in patients with ulcerative colitis
Background & Aims Tofacitinib is an oral, small-molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We analyzed inflammation, lipid concentrations, and incidence rates of major adverse cardiovascular (CV) events (MACEs) in patients who received tofacitinib in worldwide studies. Methods We collected data from 1157 patients who participated in 3 8-week induction studies (1 phase-2 study and 2 phase-3 studies; patients received tofacitinib 10 mg twice daily or placebo), a 52-week phase-3 maintenance study of responders (patients received tofacitinib 5 or 10 mg twice daily or placebo), and an ongoing long-term extension study of patients who did and did not respond to induction or maintenance therapy (patients received tofacitinib 5 or 10 mg twice daily). Lipid concentrations were assessed from induction baseline to week 61 (week 52 of maintenance therapy). We calculated MACE incidence rates (patients with ≥1 event per 100 patient-years of exposure) and Reynolds risk score (RRS; a composite score used to determine CV risk) for patients given tofacitinib vs placebo. Results The mean RRS was P Conclusions In an analysis of data from 5 trials of patients with UC who received tofacitinib, we found reversible increases in lipids with treatment and inverse correlations with reduced levels of high-sensitivity C-reactive protein. We did not find clinically meaningful changes in lipid ratios or RRS. MACEs were infrequent and not dose-related. Clinical trial registration Clinicaltrials.gov : A3921063 ( NCT00787202 ); OCTAVE Induction 1 ( NCT01465763 ); OCTAVE Induction 2 ( NCT01458951 ); OCTAVE Sustain ( NCT01458574 ); OCTAVE Open ( NCT01470612
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Inferior Olivary nucleus degeneration does not lessen tremor in essential tremor
Background
In traditional models of essential tremor, the inferior olivary nucleus was posited to play a central role as the pacemaker for the tremor. However, recent data call this disease model into question.
Case presentation
Our patient had progressive, long-standing, familial essential tremor. Upper limb tremor began at age 10 and worsened over time. It continued to worsen during the nine-year period he was enrolled in our brain donation program (age 85 – 94 years), during which time the tremor moved from the moderate to severe range on examination. On postmortem examination at age 94, there were degenerative changes in the cerebellar cortex, as have been described in the essential tremor literature. Additionally, there was marked degeneration of the inferior olivary nucleus, which was presumed to be of more recent onset. Such degeneration has not been previously described in essential tremor postmortems. Despite the presence of this degeneration, the patient’s tremor not only persisted but it continued to worsen during the final decade of his life.
Conclusions
Although the pathophysiology of essential tremor is not completely understood, evidence such as this suggests that the inferior olivary nucleus does not play a critical role in the generation of tremor in these patients
Inflationary solutions in the brane-world and their geometrical interpretation
We consider the cosmology of a pair of domain walls bounding a
five-dimensional bulk space-time with negative cosmological constant, in which
the distance between the branes is not fixed in time. Although there are strong
arguments to suggest that this distance should be stabilized in the present
epoch, no such constraints exist for the early universe and thus non-static
solutions might provide relevant inflationary scenarios. We find the general
solution for the standard ansatz where the bulk is foliated by planar-symmetric
hypersurfaces. We show that in all cases the bulk geometry is that of anti-de
Sitter (AdS_5). We then present a geometrical interpretation for the solutions
as embeddings of two de Sitter (dS_4) surfaces in AdS_5, which provide a simple
interpretation of the physical properties of the solutions. A notable feature
explained in the analysis is that two-way communication between branes
expanding away from one another is possible for a finite amount of time, after
which communication can proceed in one direction only. The geometrical picture
also shows that our class of solutions (and related solutions in the
literature) are not completely general, contrary to some claims. We then derive
the most general solution for two walls in AdS_5. This includes novel
cosmologies where the brane tensions are not constrained to have opposite
signs. The construction naturally generalizes to arbitrary FRW cosmologies on
the branes.Comment: 24 pages, 9 figure
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Panel-based Genetic Diagnostic Testing for Inherited Eye Diseases is Highly Accurate and Reproducible and More Sensitive for Variant Detection Than Exome Sequencing
Purpose Next-generation sequencing (NGS) based methods are being adopted broadly for genetic diagnostic testing, but the performance characteristics of these techniques have not been fully defined with regard to test accuracy and reproducibility. Methods: We developed a targeted enrichment and NGS approach for genetic diagnostic testing of patients with inherited eye disorders, including inherited retinal degenerations, optic atrophy and glaucoma. In preparation for providing this Genetic Eye Disease (GEDi) test on a CLIA-certified basis, we performed experiments to measure the sensitivity, specificity, reproducibility as well as the clinical sensitivity of the test. Results: The GEDi test is highly reproducible and accurate, with sensitivity and specificity for single nucleotide variant detection of 97.9% and 100%, respectively. The sensitivity for variant detection was notably better than the 88.3% achieved by whole exome sequencing (WES) using the same metrics, due to better coverage of targeted genes in the GEDi test compared to commercially available exome capture sets. Prospective testing of 192 patients with IRDs indicated that the clinical sensitivity of the GEDi test is high, with a diagnostic rate of 51%. Conclusion: The data suggest that based on quantified performance metrics, selective targeted enrichment is preferable to WES for genetic diagnostic testing
Disulfiram overcomes bortezomib and cytarabine resistance in Down-syndrome-associated acute myeloid leukemia cells
Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes
African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans
BACKGROUND: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry.
METHODS: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American-specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults.
RESULTS: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma.
CONCLUSIONS: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases
Mosaic Chromosomal alterations in Blood across ancestries Using Whole-Genome Sequencing
Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis
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