The majority of short gamma-ray bursts (SGRBs) are thought to originate from the merger of compact binary systems collapsing directly to form a black hole. However, it has been proposed that both ...SGRBs and long gamma-ray bursts (LGRBs) may, on rare occasions, form an unstable millisecond pulsar (magnetar) prior to final collapse. GRB 090515, detected by the Swift satellite was extremely short, with a T90 of 0.036 ± 0.016 s, and had a very low fluence of 2 × 10−8 erg cm−2 and faint optical afterglow. Despite this, the 0.3–10 keV flux in the first 200 s was the highest observed for an SGRB by the Swift X-ray Telescope (XRT). The X-ray light curve showed an unusual plateau and steep decay, becoming undetectable after ∼500 s. This behaviour is similar to that observed in some long bursts proposed to have magnetars contributing to their emission. In this paper, we present the Swift observations of GRB 090515 and compare it to other gamma-ray bursts (GRBs) in the Swift sample. Additionally, we present optical observations from Gemini, which detected an afterglow of magnitude 26.4 ± 0.1 at T+ 1.7 h after the burst. We discuss potential causes of the unusual 0.3–10 keV emission and suggest it might be energy injection from an unstable millisecond pulsar. Using the duration and flux of the plateau of GRB 090515, we place constraints on the millisecond pulsar spin period and magnetic field.
Here, we investigate the mechanism and function of LKB1, a Ser/Thr kinase mutated in Peutz-Jegher syndrome (PJS). We demonstrate that LKB1 physically associates with p53 and regulates specific ...p53-dependent apoptosis pathways. LKB1 protein is present in both the cytoplasm and nucleus of living cells and translocates to mitochondria during apoptosis. In vivo, LKB1 is highly upregulated in pyknotic intestinal epithelial cells. In contrast, polyps arising in Peutz-Jegher patients are devoid of LKB1 staining and have reduced numbers of apoptotic cells. We propose that a deficiency in apoptosis is a key factor in the formation of multiple benign intestinal polyps in PJS patients, and possibly for the subsequent development of malignant tumors in these patients.
We present the Swift observations of the faint burst GRB 050421. The X-ray light-curve shows at least two flares: the first flare peaking at similar to 110 s after the BAT trigger (T sub(0)) and the ...second one peaking at similar to 154 s. The first flare presents a flux variation of delta F/F sub(peak) similar to 3.7 and a short timescale ratio delta t/t sub(peak) similar to 0.07. The second flare is smaller and presents a flux variation of delta F/F sub(peak) similar to 1.7 and a short timescale ratio delta t/t sub(peak) similar to 0.03. We argue that the mechanism producing these flares is probably late internal shocks. The X-ray light-curve is consistent with a rapid decline with a temporal index alpha similar to 3.1, which decays from delta 10 super(-9) erg cm super(-2) s super(-1) at T sub(0) + 100 s to <7 x 10 super(-13) erg cm super(-2) s super(-1) at T sub(0) + 900s. A possible spectral softening is also observed with time, from beta similar to 0.1 to similar to 1.2. A good joint fit to the BAT and XRT spectra before T sub(0) + 171 s with beta sub(XRT-BAT) similar to 0-2 indicates that the early X-ray and Gamma-ray emissions are likely produced by the same mechanism. We argue that the X-ray spectral softening, if any, is due to a shift of the peak of the prompt emission spectrum down to lower energies, and that the rapid decline of the X-ray emission is probably the tail of the prompt emission. This suggests that the X-ray emission is completely dominated by high latitude radiation and the external shock, if any, is extremely faint and below the detection threshold. GRB 050421 is likely the first "naked burst" detected by Swift.
Acetaminophen (APAP) is the most commonly used analgesic and antipyretic drug in the world. Yet, it poses a major risk of liver injury when taken in excess of the therapeutic dose. Current clinical ...markers do not detect the early onset of liver injury associated with excess APAP—information that is vital to reverse injury progression through available therapeutic interventions. Hence, several studies have used transcriptomics, proteomics, and metabolomics technologies, both independently and in combination, in an attempt to discover potential early markers of liver injury. However, the casual relationship between these observations and their relation to the APAP mechanism of liver toxicity are not clearly understood. Here, we used Sprague-Dawley rats orally gavaged with a single dose of 2 g/kg of APAP to collect tissue samples from the liver and kidney for transcriptomic analysis and plasma and urine samples for metabolomic analysis. We developed and used a multi-tissue, metabolism-based modeling approach to integrate these data, characterize the effect of excess APAP levels on liver metabolism, and identify a panel of plasma and urine metabolites that are associated with APAP-induced liver toxicity. Our analyses, which indicated that pathways involved in nucleotide-, lipid-, and amino acid-related metabolism in the liver were most strongly affected within 10 h following APAP treatment, identified a list of potential metabolites in these pathways that could serve as plausible markers of APAP-induced liver injury. Our approach identifies toxicant-induced changes in endogenous metabolism, is applicable to other toxicants based on transcriptomic data, and provides a mechanistic framework for interpreting metabolite alterations.
•Toxic levels of acetaminophen induce rapid metabolic changes in rat-liver.•A genome-scale network model to analyze high-throughput data from multiple tissues.•Metabolomic and transcriptomic data indicate altered liver and kidney metabolism.•Coupled liver/kidney metabolic network model predicts circulating metabolites.•Changes in injury-specific pathways can serve as early indicators of liver damage.
Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying ...spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels. We sought to develop high-affinity T-type specific Ca(2+) channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca(2+) channel pharmacophore and a high-throughput fluorometric Ca(2+) influx assay, we identified the T-type Ca(2+) channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca(2+) channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.
One attraction of photonic crystals is the ability to control optical device characteristics by lithographically varying the geometry. In this letter, we demonstrate a 10/spl times/10 array of ...optically pumped two-dimensional (2-D) photonic crystal defect lasers with varying lattice parameters. By adjusting the photonic crystal interhole spacing as well as the hole diameter we are able to tune the laser wavelength from 1500 to 1625 nm on a monolithic InP-InGaAsP wafer. A wavelength resolution of 10 nm from device to device was obtainable, limited by the lithography and etching tolerances of our fabrication method.
Inflammation of ileal reservoir mucosa ("pouchitis") is a common sequelae in ulcerative colitis (UC) patients who have had a colectomy with ileal pouch anal-anastomosis (IPAA). Although several ...clinical, genetic, and laboratory parameters have been evaluated, reliable pathologic predictors for the development of pouchitis are lacking. The purpose of this case-control study was to determine whether there are any pathologic features in UC colectomy specimens that may help predict the subsequent development of pouchitis after an IPAA procedure. The study group consisted of 39 UC patients (male/female ratio: 21/18, mean age: 35 years), who had at least 1 episode of pouchitis after an IPAA procedure during the follow-up period (mean: 57 months, range: 12-121 months). There were 26 control patients (male/female ratio: 11/15, mean age: 37 years), all of whom also underwent a total colectomy and IPAA procedure for UC, but did not develop pouchitis during the follow-up period (mean: 78 months, range: 14-223 months). Routinely processed tissues from each colectomy specimen were evaluated for a variety of histologic features, such as extent of colitis, severity of colitis, extent of severe colitis, type and extent of ulceration, presence and severity of appendiceal inflammation, and the presence of active ileitis, and compared between the study and control patients. Pathologic features that were associated with the subsequent development of pouchitis included the presence of severe colitis that extended into the cecum (severe pancolitis), which was present in 7/39 (18%) pouchitis patients, but in none (0%) of the control patients (P = 0.03), early fissuring ulcers 9/39 (23%) pouchitis cases versus 1/26 (4%) controls (P = 0.04), active inflammation of the appendix 20/32 (63%) pouchitis patients versus 7/19 (31%) controls (P = 0.03), and appendiceal ulceration 13/32 (41%) pouchitis patients versus none (0%) of the controls (P = 0.002). No significant differences in patient gender or age, depth or extent of ulceration, or the presence or absence of "backwash ileitis" were identified between the 2 groups. In conclusion, there are several histologic features in colectomy specimens from UC patients who have undergone an IPAA procedure that may help predict the subsequent development of pouchitis. Of these features, appendiceal ulceration is highly associated with pouchitis.
The purpose of this study was to assess interocular corneal symmetry in average simulated keratometry, corneal thickness, and posterior corneal elevation.
This retrospective analysis included data ...from scanning slit topography (Orbscan II; Bausch and Lomb, Rochester, NY) on 242 eyes from 121 consecutive patients undergoing standard evaluation for consideration of elective laser vision correction. The symmetry between the right and left eye in average simulated keratometry, minimum central corneal thickness, and posterior corneal elevation was assessed by comparative data analysis.
Simulated keratometry ranged from 39.9 to 48.6 D. The interocular difference in average simulated keratometry was 0.47 D (standard deviation SD 0.43). The interocular Pearson correlation coefficient for average simulated keratometry was 0.90 (p < 0.001). The range of minimum corneal thickness was 432 to 628 microm. The interocular Pearson correlation coefficient for minimum central corneal thickness was 0.95 (p < 0.001). Right and left eye minimum corneal thickness differed by an average 8 microm (SD 7). The range of posterior elevation was -4 to 54 microm. The average difference in posterior corneal elevation between the right and left eye was 6 microm (SD 5). The interocular Pearson correlation coefficient for posterior corneal elevation was 0.72 (p < 0.001). The average posterior elevation was 19 microm (SD 11).
Although a wide range of values exists in simulated keratometry, minimum corneal thickness, and posterior corneal elevation, interocular symmetry in all these parameters was very high in this group of consecutive patients. Asymmetry of these interocular parameters may warrant repeat clinical testing for accuracy and may predict corneal abnormalities. Normative data on posterior cornea elevation is presented. This study points out potentially clinically important high interocular corneal symmetry data in simulated keratometry, corneal thickness, and posterior corneal elevation.
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