We report on observations of GRB 080503, a short gamma-ray burst (GRB) with very bright extended emission (about 30 times the gamma-ray fluence of the initial spike) in conjunction with a thorough ...comparison to other short Swift events. In spite of the prompt-emission brightness, however, the optical counterpart is extraordinarily faint, never exceeding 25 mag in deep observations starting at ~1 hr after the Burst Alert Telescope (BAT) trigger. The optical brightness peaks at ~1 day and then falls sharply in a manner similar to the predictions of Li & Paczynski (1998) for supernova-like emission following compact binary mergers. However, a shallow spectral index and similar evolution in X-rays inferred from Chandra observations are more consistent with an afterglow interpretation. The extreme faintness of this probable afterglow relative to the bright gamma-ray emission argues for a very low density medium surrounding the burst (a 'naked' GRB), consistent with the lack of a coincident host galaxy down to 28.5 mag in deep Hubble Space Telescope imaging. The late optical and X-ray peak could be explained by a slightly off-axis jet or by a refreshed shock. Our observations reinforce the notion that short GRBs generally occur outside regions of active star formation, but demonstrate that in some cases the luminosity of the extended prompt emission can greatly exceed that of the short spike, which may constrain theoretical interpretation of this class of events. This extended emission is not the onset of an afterglow, and its relative brightness is probably either a viewing-angle effect or intrinsic to the central engine itself. Because most previous BAT short bursts without observed extended emission are too faint for this signature to have been detectable even if it were present at typical level, conclusions based solely on the observed presence or absence of extended emission in the existing Swift sample are premature.
With novel therapies in development, there is an opportunity to consider asthma remission as a treatment goal. In this Rostrum, we present a generalized framework for clinical and complete remission ...in asthma, on and off treatment, developed on the basis of medical literature and expert consensus. A modified Delphi survey approach was used to ascertain expert consensus on core components of asthma remission as a treatment target. Phase 1 identified other chronic inflammatory diseases with remission definitions. Phase 2 evaluated components of those definitions as well as published definitions of spontaneous asthma remission. Phase 3 evaluated a remission framework created using consensus findings. Clinical remission comprised 12 or more months with (1) absence of significant symptoms by validated instrument, (2) lung function optimization/stabilization, (3) patient/provider agreement regarding remission, and (4) no use of systemic corticosteroids. Complete remission was defined as clinical remission plus objective resolution of asthma-related inflammation and, if appropriate, negative bronchial hyperresponsiveness. Remission off treatment required no asthma treatment for 12 or more months. The proposed framework is a first step toward developing asthma remission as a treatment target and should be refined through future research, patient input, and clinical study.
Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. ...However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB–PTPIP51 interaction and ER–mitochondria associations. These disruptions are accompanied by perturbation of Ca2+ uptake by mitochondria following its release from ER stores, which is a physiological read‐out of ER–mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS‐expressing cells; mitochondrial ATP production is linked to Ca2+ levels. Finally, we demonstrate that the FUS‐induced reductions to ER–mitochondria associations and are linked to activation of glycogen synthase kinase‐3β (GSK‐3β), a kinase already strongly associated with ALS/FTD.
Synopsis
This study shows that FUS, by disrupting ER and mitochondria associations, regulates calcium uptake into and ATP production by mitochondria, with implications for amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD).
FTD/ALS‐associated fused in sarcoma (FUS) disrupts ER–mitochondria associations and links calcium homoeostasis and mitochondrial ATP production.
FUS‐induced disruption of ER–mitochondria associations involves activation of GSK‐3β and breaking of the VAPB–PTPIP51 ER–mitochondria tethering proteins.
This study shows that FUS, by disrupting ER and mitochondria associations, regulates calcium uptake into and ATP production by mitochondria, with implications for amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD).
We report on strong H2 and CO absorption from gas within the host galaxy of gamma-ray burst (GRB) 080607. Analysis of our Keck/LRIS afterglow spectrum reveals a very large H I column density () and ...strong metal-line absorption at z GRB = 3.0363 with a roughly solar metallicity. We detect a series of A - X bandheads from CO and estimate N(CO) = 1016.5±0.3 cm-2 and T CO ex > 100 K. We argue that the high excitation temperature results from UV pumping of the CO gas by the GRB afterglow. Similarly, we observe H2 absorption via the Lyman-Werner bands and estimate with -300 K. The afterglow photometry suggests an extinction law with RV 4 and AV 3.2 mag and requires the presence of a modest 2175 A bump. Additionally, modeling of the Swift XRT X-ray spectrum confirms a large column density with N H = 1022.58±0.04 cm-2. Remarkably, this molecular gas has extinction properties, metallicity, and a CO/H2 ratio comparable to those of translucent molecular clouds of the Milky Way, suggesting that star formation at high z proceeds in similar environments as today. However, the integrated dust-to-metals ratio is sub-Galactic, suggesting the dust is primarily associated with the molecular phase while the atomic gas has a much lower dust-to-gas ratio. Sightlines like GRB 080607 serve as powerful probes of nucleosynthesis and star-forming regions in the young universe and contribute to the population of 'dark' GRB afterglows.
Malignant pleural effusion causes disabling dyspnea in patients with a short life expectancy. Palliation is achieved by fluid drainage, but the most effective first-line method has not been ...determined.
To determine whether indwelling pleural catheters (IPCs) are more effective than chest tube and talc slurry pleurodesis (talc) at relieving dyspnea.
Unblinded randomized controlled trial (Second Therapeutic Intervention in Malignant Effusion Trial TIME2) comparing IPC and talc (1:1) for which 106 patients with malignant pleural effusion who had not previously undergone pleurodesis were recruited from 143 patients who were treated at 7 UK hospitals. Patients were screened from April 2007-February 2011 and were followed up for a year.
Indwelling pleural catheters were inserted on an outpatient basis, followed by initial large volume drainage, education, and subsequent home drainage. The talc group were admitted for chest tube insertion and talc for slurry pleurodesis.
Patients completed daily 100-mm line visual analog scale (VAS) of dyspnea over 42 days after undergoing the intervention (0 mm represents no dyspnea and 100 mm represents maximum dyspnea; 10 mm represents minimum clinically significant difference). Mean difference was analyzed using a mixed-effects linear regression model adjusted for minimization variables.
Dyspnea improved in both groups, with no significant difference in the first 42 days with a mean VAS dyspnea score of 24.7 in the IPC group (95% CI, 19.3-30.1 mm) and 24.4 mm (95% CI, 19.4-29.4 mm) in the talc group, with a difference of 0.16 mm (95% CI, −6.82 to 7.15; P = .96). There was a statistically significant improvement in dyspnea in the IPC group at 6 months, with a mean difference in VAS score between the IPC group and the talc group of −14.0 mm (95% CI, −25.2 to −2.8 mm; P = .01). Length of initial hospitalization was significantly shorter in the IPC group with a median of 0 days (interquartile range IQR, 0-1 day) and 4 days (IQR, 2-6 days) for the talc group, with a difference of −3.5 days (95% CI, −4.8 to −1.5 days; P < .001). There was no significant difference in quality of life. Twelve patients (22%) in the talc group required further pleural procedures compared with 3 (6%) in the IPC group (odds ratio OR, 0.21; 95% CI, 0.04-0.86; P = .03). Twenty-one of the 52 patients in the catheter group experienced adverse events vs 7 of 54 in the talc group (OR, 4.70; 95% CI, 1.75-12.60; P = .002).
Among patients with malignant pleural effusion and no previous pleurodesis, there was no significant difference between IPCs and talc pleurodesis at relieving patient-reported dyspnea.
isrctn.org Identifier: ISRCTN87514420.
New far-infrared and submillimeter photometry from the Herschel Space Observatory is presented for 61 nearby galaxies from the Key Insights on Nearby Galaxies: A Far-Infrared Survey with Herschel ...(KINGFISH) sample. The spatially integrated fluxes are largely consistent with expectations based on Spitzer far-infrared photometry and extrapolations to longer wavelengths using popular dust emission models. Dwarf irregular galaxies are notable exceptions, as already noted by other authors, as their 500 mu m emission shows evidence for a submillimeter excess. In addition, the fraction of dust heating attributed to intense radiation fields associated with photodissociation regions is found to be (21 + or - 4)% larger when Herschel data are included in the analysis. Dust masses obtained from the dust emission models of Draine & Li are found to be on average nearly a factor of two higher than those based on single-temperature modified blackbodies, as single blackbody curves do not capture the full range of dust temperatures inherent to any galaxy. The discrepancy is largest for galaxies exhibiting the coolest far-infrared colors.
Lightning increases the atmosphere's ability to cleanse itself by producing nitric oxide (NO), leading to atmospheric chemistry that forms ozone (O
) and the atmosphere's primary oxidant, the ...hydroxyl radical (OH). Our analysis of a 2012 airborne study of deep convection and chemistry demonstrates that lightning also directly generates the oxidants OH and the hydroperoxyl radical (HO
). Extreme amounts of OH and HO
were discovered and linked to visible flashes occurring in front of the aircraft and to subvisible discharges in electrified anvil regions. This enhanced OH and HO
is orders of magnitude greater than any previous atmospheric observation. Lightning-generated OH in all storms happening at the same time globally can be responsible for a highly uncertain, but substantial, 2 to 16% of global atmospheric OH oxidation.
Tissue factor (TF) is aberrantly expressed in solid cancers and is thought to contribute to disease progression through its procoagulant activity and its capacity to induce intracellular signaling in ...complex with factor VIIa (FVIIa). To explore the possibility of using tissue factor as a target for an antibody-drug conjugate (ADC), a panel of human tissue factor-specific antibodies (TF HuMab) was generated. Three tissue factor HuMab, that induced efficient inhibition of TF:FVIIa-dependent intracellular signaling, antibody-dependent cell-mediated cytotoxicity, and rapid target internalization, but had minimal impact on tissue factor procoagulant activity in vitro, were conjugated with the cytotoxic agents monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). Tissue factor-specific ADCs showed potent cytotoxicity in vitro and in vivo, which was dependent on tissue factor expression. TF-011-MMAE (HuMax-TF-ADC) was the most potent ADC, and the dominant mechanism of action in vivo was auristatin-mediated tumor cell killing. Importantly, TF-011-MMAE showed excellent antitumor activity in patient-derived xenograft (PDX) models with variable levels of tissue factor expression, derived from seven different solid cancers. Complete tumor regression was observed in all PDX models, including models that showed tissue factor expression in only 25% to 50% of the tumor cells. In conclusion, TF-011-MMAE is a promising novel antitumor agent with potent activity in xenograft models that represent the heterogeneity of human tumors, including heterogeneous target expression.
Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR,. Mutant ...forms of RARα, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger), locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARα APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARα patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.
Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. ...However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB-PTPIP51 interaction and ER-mitochondria associations. These disruptions are accompanied by perturbation of Ca2+ uptake by mitochondria following its release from ER stores, which is a physiological read-out of ER-mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS-expressing cells; mitochondrial ATP production is linked to Ca2+ levels. Finally, we demonstrate that the FUS-induced reductions to ER-mitochondria associations and are linked to activation of glycogen synthase kinase-3beta (GSK-3beta), a kinase already strongly associated with ALS/FTD. Synopsis This study shows that FUS, by disrupting ER and mitochondria associations, regulates calcium uptake into and ATP production by mitochondria, with implications for amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). FTD/ALS-associated fused in sarcoma (FUS) disrupts ER-mitochondria associations and links calcium homoeostasis and mitochondrial ATP production. FUS-induced disruption of ER-mitochondria associations involves activation of GSK-3beta and breaking of the VAPB-PTPIP51 ER-mitochondria tethering proteins.
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