ALMA Observations of the Largest Proto-Planetary Disk in the Orion Nebula, 114-426: A CO Silhouette

We present ALMA observations of the largest protoplanetary disk in the Orion Nebula, 114-426. Detectable 345 GHz (856 micron) dust continuum is produced only in the 350 AU central region of the ~1000 AU diameter silhouette seen against the bright H-alpha background in HST images. Assuming optically thin dust emission at 345 GHz, a gas-to-dust ratio of 100, and a grain temperature of 20 K, the disk gas-mass is estimated to be 3.1 +/- 0.6 Jupiter masses. If most solids and ices have have been incorporated into large grains, however, this value is a lower limit. The disk is not detected in dense-gas tracers such as HCO+ J=4-3, HCN J=4-3, or CS =7-6. These results may indicate that the 114-426 disk is evolved and depleted in some light organic compounds found in molecular clouds. The CO J=3-2 line is seen in absorption against the bright 50 to 80 K background of the Orion A molecular cloud over the full spatial extent and a little beyond the dust continuum emission. The CO absorption reaches a depth of 27 K below the background CO emission at VLSR ~6.7 km/s about 0.52 arcseconds (210 AU) northeast and 12 K below the background CO emission at VLSR ~ 9.7 km/s about 0.34 arcseconds (140 AU) southwest of the suspected location of the central star, implying that the embedded star has a mass less than 1 Solar mass .Comment: 20 pages, 4 figure

ALMA Observations of the Orion Proplyds

We present ALMA observations of protoplanetary disks ("proplyds") in the Orion Nebula Cluster. We imaged 5 individual fields at 856um containing 22 HST-identified proplyds and detected 21 of them. Eight of those disks were detected for the first time at submillimeter wavelengths, including the most prominent, well-known proplyd in the entire Orion Nebula, 114-426. Thermal dust emission in excess of any free-free component was measured in all but one of the detected disks, and ranged between 1-163 mJy, with resulting disk masses of 0.3-79 Mjup. An additional 26 stars with no prior evidence of associated disks in HST observations were also imaged within the 5 fields, but only 2 were detected. The disk mass upper limits for the undetected targets, which include OB stars, theta1Ori C and theta1Ori F, range from 0.1-0.6 Mjup. Combining these ALMA data with previous SMA observations, we find a lack of massive (>3 Mjup) disks in the extreme-UV dominated region of Orion, within 0.03 pc of O-star theta1Ori C. At larger separations from theta1Ori C, in the far-UV dominated region, there is a wide range of disk masses, similar to what is found in low-mass star forming regions. Taken together, these results suggest that a rapid dissipation of disk masses likely inhibits potential planet formation in the extreme-UV dominated regions of OB associations, but leaves disks in the far-UV dominated regions relatively unaffected.Comment: ApJ, in pres

ALMA Observations of Asymmetric Molecular Gas Emission from a Protoplanetary Disk in the Orion Nebula

We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of molecular line emission from d216-0939, one of the largest and most massive protoplanetary disks in the Orion Nebula Cluster (ONC). We model the spectrally resolved HCO$^+$ (4--3), CO (3--2), and HCN (4--3) lines observed at 0\farcs5 resolution to fit the temperature and density structure of the disk. We also weakly detect and spectrally resolve the CS (7--6) line but do not model it. The abundances we derive for CO and HCO$^+$ are generally consistent with expected values from chemical modeling of protoplanetary disks, while the HCN abundance is higher than expected. We dynamically measure the mass of the central star to be $2.17\pm0.07\,M_\odot$ which is inconsistent with the previously determined spectral type of K5. We also report the detection of a spatially unresolved high-velocity blue-shifted excess emission feature with a measurable positional offset from the central star, consistent with a Keplerian orbit at $60\pm20\,\mathrm{au}$. Using the integrated flux of the feature in HCO$^+$ (4--3), we estimate the total H$_2$ gas mass of this feature to be at least $1.8-8\,M_\mathrm{Jupiter}$, depending on the assumed temperature. The feature is due to a local temperature and/or density enhancement consistent with either a hydrodynamic vortex or the expected signature of the envelope of a forming protoplanet within the disk.Comment: 19 pages, 12 figures, accepted for publication in A

Glial cells are functionally impaired in juvenile neuronal ceroid lipofuscinosis and detrimental to neurons.

The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of inherited, fatal neurodegenerative disorders of childhood. In these disorders, glial (microglial and astrocyte) activation typically occurs early in disease progression and predicts where neuron loss subsequently occurs. We have found that in the most common juvenile form of NCL (CLN3 disease or JNCL) this glial response is less pronounced in both mouse models and human autopsy material, with the morphological transformation of both astrocytes and microglia severely attenuated or delayed. To investigate their properties, we isolated glia and neurons from Cln3-deficient mice and studied their basic biology in culture. Upon stimulation, both Cln3-deficient astrocytes and microglia also showed an attenuated ability to transform morphologically, and an altered protein secretion profile. These defects were more pronounced in astrocytes, including the reduced secretion of a range of neuroprotective factors, mitogens, chemokines and cytokines, in addition to impaired calcium signalling and glutamate clearance. Cln3-deficient neurons also displayed an abnormal organization of their neurites. Most importantly, using a co-culture system, Cln3-deficient astrocytes and microglia had a negative impact on the survival and morphology of both Cln3-deficient and wildtype neurons, but these effects were largely reversed by growing mutant neurons with healthy glia. These data provide evidence that CLN3 disease astrocytes are functionally compromised. Together with microglia, they may play an active role in neuron loss in this disorder and can be considered as potential targets for therapeutic interventions

Expression of the Rap1 Guanine Nucleotide Exchange Factor, MR-GEF, Is Altered in Individuals with Bipolar Disorder

In the rodent forebrain GABAergic neurons are generated from progenitor cells that express the transcription factors Dlx1 and Dlx2. The Rap-1 guanine nucleotide exchange factor, MR-GEF, is turned on by many of these developing GABAergic neurons. Expression of both Dlx1/2 and MR-GEF is retained in both adult mouse and human forebrain where, in human, decreased Dlx1 expression has been associated with psychosis. Using in situ hybridization studies we show that MR-GEF expression is significantly down-regulated in the forebrain of Dlx1/2 double mutant mice suggesting that MR-GEF and Dlx1/2 form part of a common signalling pathway during GABAergic neuronal development. We therefore compared MR-GEF expression by in situ hybridization in individuals with major psychiatric disorders (schizophrenia, bipolar disorder, major depression) and control individuals. We observed a significant positive correlation between layers II and IV of the dorso-lateral prefrontal cortex (DLPFC) in the percentage of MR-GEF expressing neurons in individuals with bipolar disorder, but not in individuals with schizophrenia, major depressive disorder or in controls. Since MR-GEF encodes a Rap1 GEF able to activate G-protein signalling, we suggest that changes in MR-GEF expression could potentially influence neurotransmission

LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 4 (TLR4) is activated in response to cerebral ischemia leading to substantial brain damage. In contrast, mild activation of TLR4 by preconditioning with low dose exposure to lipopolysaccharide (LPS) prior to cerebral ischemia dramatically improves outcome by reprogramming the signaling response to injury. This suggests that TLR4 signaling can be altered to induce an endogenously neuroprotective phenotype. However, the TLR4 signaling events involved in this neuroprotective response are poorly understood. Here we define several molecular mediators of the primary signaling cascades induced by LPS preconditioning that give rise to the reprogrammed response to cerebral ischemia and confer the neuroprotective phenotype.</p> <p>Methods</p> <p>C57BL6 mice were preconditioned with low dose LPS prior to transient middle cerebral artery occlusion (MCAO). Cortical tissue and blood were collected following MCAO. Microarray and qtPCR were performed to analyze gene expression associated with TLR4 signaling. EMSA and DNA binding ELISA were used to evaluate NFκB and IRF3 activity. Protein expression was determined using Western blot or ELISA. MyD88-/- and TRIF-/- mice were utilized to evaluate signaling in LPS preconditioning-induced neuroprotection.</p> <p>Results</p> <p>Gene expression analyses revealed that LPS preconditioning resulted in a marked upregulation of anti-inflammatory/type I IFN-associated genes following ischemia while pro-inflammatory genes induced following ischemia were present but not differentially modulated by LPS. Interestingly, although expression of pro-inflammatory genes was observed, there was decreased activity of NFκB p65 and increased presence of NFκB inhibitors, including Ship1, Tollip, and p105, in LPS-preconditioned mice following stroke. In contrast, IRF3 activity was enhanced in LPS-preconditioned mice following stroke. TRIF and MyD88 deficient mice revealed that neuroprotection induced by LPS depends on TLR4 signaling via TRIF, which activates IRF3, but does not depend on MyD88 signaling.</p> <p>Conclusion</p> <p>Our results characterize several critical mediators of the TLR4 signaling events associated with neuroprotection. LPS preconditioning redirects TLR4 signaling in response to stroke through suppression of NFκB activity, enhanced IRF3 activity, and increased anti-inflammatory/type I IFN gene expression. Interestingly, this protective phenotype does not require the suppression of pro-inflammatory mediators. Furthermore, our results highlight a critical role for TRIF-IRF3 signaling as the governing mechanism in the neuroprotective response to stroke.</p

Combined anti-inflammatory and neuroprotective treatments have the potential to impact disease phenotypes in Cln3−/− mice

Batten disease, or juvenile NCL, is a fatal neurodegenerative disorder that occurs due to mutations in the CLN3 gene. Because the function of CLN3 remains unclear, experimental therapies for JNCL have largely concentrated upon the targeting of downstream pathomechanisms. Neuron loss is preceded by localized glial activation, and in this proof-of-concept study we have investigated whether targeting this innate immune response with ibuprofen in combination with the neuroprotective agent lamotrigine improves the previously documented beneficial effects of immunosuppressants alone. Drugs were administered daily to symptomatic Cln3 -/- mice over a 3 month period, starting at 6 months of age, and their impact was assessed using both behavioral and neuropathological outcome measures. During the treatment period, the combination of ibuprofen and lamotrigine significantly improved the performance of Cln3 -/- mice on the vertical pole test, slowing the disease-associated decline, but had less of an impact upon their rotarod performance. There were also moderate and regionally dependent effects upon astrocyte activation that were most pronounced for ibuprofen alone, but there was no overt effect upon microglial activation. Administering such treatments for longer periods will enable testing for any impact upon the neuron loss that occurs later in disease progression. Given the partial efficacy of these treatments, it will be important to test further drugs of this type in order to find more effective combinations

A Sub-Millimeter Search of Nearby Young Stars for Cold Dust: Discovery of Debris Disks around Two Low-Mass Stars

(Abridged) We present results from a JCMT/SCUBA 850 um search for cold dust around nearby young stars belonging to the beta Pic (t~12 Myr) and the Local Association (t~50 Myr) moving groups. Unlike most past sub-mm studies, our sample was chosen on the basis of stellar age. Our observations achieve about an order of magnitude greater sensitivity in dust mass compared to previous work in this age range. We detected two of the three M dwarfs in our sample at 850 um, GJ 182 and GJ 803. GJ 182 may also possess a 25 um excess, indicative of warm dust in the inner few AU of its disk. For GJ 803 (AU Mic), sub-mm mapping finds that the 850 um emission is unresolved. A non-detection of the CO 3-2 line indicates the system is gas-poor, and the SED suggests the presence of a large inner disk hole (~17 AU = 1.7 arcsec in radius). These are possible indications that planets at large separations can form around M dwarfs within \~10 Myr. In a companion paper (Kalas, Liu & Matthews 2004), we confirm the existence of a dust disk around GJ 803 using optical coronagraphic imaging. Given its youthfulness, proximity, and detectability, the GJ 803 disk will be a valuable system for studying disk, and perhaps planet, formation in great detail. Overall, sub-mm measurements of debris disks point to a drop in dust mass by a factor of about 10^3 within the first ~10 Myr, with the subsequent decline in the masses of sub-mm detected disks consistent with t^{-0.5} to t^{-1}.Comment: 9 pages, ApJ, in press. Minor changes made to reflect final published manuscrip

CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development

The C-type lectin receptor CLEC-2 signals through a pathway that is critically dependent on the tyrosine kinase Syk. We show that homozygous loss of either protein results in defects in brain vascular and lymphatic development, lung inflation and perinatal lethality. Furthermore, we find that conditional deletion of Syk in the haematopoietic lineage, or conditional deletion of CLEC-2 or Syk in the megakaryocyte/platelet lineage, also causes defects in brain vascular and lymphatic development, although the mice are viable. In contrast, conditional deletion of Syk in other haematopoietic lineages had no effect on viability or brain vasculature and lymphatic development. We show that platelets, but not platelet releasate, modulate the migration and intercellular adhesion of lymphatic endothelial cells through a pathway that is dependent on CLEC-2 and Syk. These studies demonstrate that megakaryocyte/platelet expression of CLEC-2 and Syk is required for normal brain vasculature and lymphatic development and that platelet CLEC-2 and Syk directly modulate lymphatic endothelial cell behaviour in vitro