The Luminosities of Protostars in the Spitzer c2d and Gould Belt Legacy Clouds

Motivated by the long-standing "luminosity problem" in low-mass star formation whereby protostars are underluminous compared to theoretical expectations, we identify 230 protostars in 18 molecular clouds observed by two Spitzer Space Telescope Legacy surveys of nearby star-forming regions. We compile complete spectral energy distributions, calculate Lbol for each source, and study the protostellar luminosity distribution. This distribution extends over three orders of magnitude, from 0.01 Lsun - 69 Lsun, and has a mean and median of 4.3 Lsun and 1.3 Lsun, respectively. The distributions are very similar for Class 0 and Class I sources except for an excess of low luminosity (Lbol < 0.5 Lsun) Class I sources compared to Class 0. 100 out of the 230 protostars (43%) lack any available data in the far-infrared and submillimeter (70 um < wavelength < 850 um) and have Lbol underestimated by factors of 2.5 on average, and up to factors of 8-10 in extreme cases. Correcting these underestimates for each source individually once additional data becomes available will likely increase both the mean and median of the sample by 35% - 40%. We discuss and compare our results to several recent theoretical studies of protostellar luminosities and show that our new results do not invalidate the conclusions of any of these studies. As these studies demonstrate that there is more than one plausible accretion scenario that can match observations, future attention is clearly needed. The better statistics provided by our increased dataset should aid such future work.Comment: Accepted for publication in AJ. 21 pages, 10 figures, 4 table

Frailty of Māori, Pasifika, and non-Māori/non-Pasifika older people in New Zealand: a national population study of older people referred for home care services

Little is known about the prevalence of frailty in indigenous populations. We developed a frailty index for older New Zealand Māori and Pasifika who require publicly funded support services.A frailty index (FI) was developed for New Zealand adults aged ≥65 years who had an interRAI-Home Care assessment between 1 June 2012 and 30 October 2015. A frailty score for each participant was calculated by summing the number of deficits recorded and dividing by the total number of possible deficits. This created a FI with a potential range from 0 to 1. Linear regression models for FIs with ethnicity were adjusted for age and sex. Cox proportional hazards models were used to assess the association between the FI and mortality for Māori, Pasifika, and non-Māori/non-Pasifika.Of 54,345 participants, 3,096 (5.7%) identified as Māori, 1,846 (3.4%) were Pasifika, and 49,415 (86.7%) identified as neither Māori nor Pasifika. New Zealand Europeans (48,178, 97.5%) constituted most of the latter group. Within each sex, the mean FIs for Māori and Pasifika were greater than the mean FIs for non-Māori and non-Pasifika, with the difference being more pronounced in females. The FI was associated with mortality (Māori SHR 2.53, 95% CI 1.63 to 3.95; Pasifika SHR 6.03, 95% CI 3.06 to 11.90; non-Māori and non-Pasifika SHR 2.86, 95% 2.53 to 3.25).This study demonstrated differences in FI between the ethnicities in this select cohort. After adjustment for age and sex, increases in FI were associated with increased mortality. This suggests that FI is predictive of poor outcomes in these ethnic groups

Design and development of MOSFIRE: the Multi-Object Spectrometer For Infra-Red Exploration at the Keck Observatory

MOSFIRE is a unique multi-object spectrometer and imager for the Cassegrain focus of the 10 m Keck 1 telescope. A refractive optical design provides near-IR (0.97 to 2.45 μm) multi-object spectroscopy over a 6.14' x 6.14' field of view with a resolving power of R~3,270 for a 0.7" slit width (2.9 pixels in the dispersion direction), or imaging over a field of view of 6.8' diameter with 0.18" per pixel sampling. A single diffraction grating can be set at two fixed angles, and order-sorting filters provide spectra that cover the K, H, J or Y bands by selecting 3rd, 4th, 5th or 6th order respectively. A folding flat following the field lens is equipped with piezo transducers to provide tip/tilt control for flexure compensation at the 0.1 pixel level. A special feature of MOSFIRE is that its multiplex advantage of up to 46 slits is achieved using a cryogenic Configurable Slit Unit or CSU developed in collaboration with the Swiss Centre for Electronics and Micro Technology (CSEM). The CSU is reconfigurable under remote control in less than 5 minutes without any thermal cycling of the instrument. Slits are formed by moving opposable bars from both sides of the focal plane. An individual slit has a length of 7.1" but bar positions can be aligned to make longer slits. When masking bars are removed to their full extent and the grating is changed to a mirror, MOSFIRE becomes a wide-field imager. Using a single, ASIC-driven, 2K x 2K H2-RG HgCdTe array from Teledyne Imaging Sensors with exceptionally low dark current and low noise, MOSFIRE will be extremely sensitive and ideal for a wide range of science applications. This paper describes the design and testing of the instrument prior to delivery later in 2010

MOSFIRE, the multi-object spectrometer for infra-red exploration at the Keck Observatory

This paper describes the as-built performance of MOSFIRE, the multi-object spectrometer and imager for the Cassegrain focus of the 10-m Keck 1 telescope. MOSFIRE provides near-infrared (0.97 to 2.41 μm) multi-object spectroscopy over a 6.1' x 6.1' field of view with a resolving power of R~3,500 for a 0.7" (0.508 mm) slit (2.9 pixels in the dispersion direction), or imaging over a field of view of ~6.9' diameter with ~0.18" per pixel sampling. A single diffraction grating can be set at two fixed angles, and order-sorting filters provide spectra that cover the K, H, J or Y bands by selecting 3rd, 4th, 5th or 6th order respectively. A folding flat following the field lens is equipped with piezo transducers to provide tip/tilt control for flexure compensation at the <0.1 pixel level. Instead of fabricated focal plane masks requiring frequent cryo-cycling of the instrument, MOSFIRE is equipped with a cryogenic Configurable Slit Unit (CSU) developed in collaboration with the Swiss Center for Electronics and Microtechnology (CSEM). Under remote control the CSU can form masks containing up to 46 slits with ~0.007-0.014" precision. Reconfiguration time is < 6 minutes. Slits are formed by moving opposable bars from both sides of the focal plane. An individual slit has a length of 7.0" but bar positions can be aligned to make longer slits in increments of 7.5". When masking bars are retracted from the field of view and the grating is changed to a mirror, MOSFIRE becomes a wide-field imager. The detector is a 2K x 2K H2-RG HgCdTe array from Teledyne Imaging Sensors with low dark current and low noise. Results from integration and commissioning are presented

MOSFIRE, the multi-object spectrometer for infra-red exploration at the Keck Observatory

This paper describes the as-built performance of MOSFIRE, the multi-object spectrometer and imager for the Cassegrain focus of the 10-m Keck 1 telescope. MOSFIRE provides near-infrared (0.97 to 2.41 μm) multi-object spectroscopy over a 6.1' x 6.1' field of view with a resolving power of R~3,500 for a 0.7" (0.508 mm) slit (2.9 pixels in the dispersion direction), or imaging over a field of view of ~6.9' diameter with ~0.18" per pixel sampling. A single diffraction grating can be set at two fixed angles, and order-sorting filters provide spectra that cover the K, H, J or Y bands by selecting 3rd, 4th, 5th or 6th order respectively. A folding flat following the field lens is equipped with piezo transducers to provide tip/tilt control for flexure compensation at the <0.1 pixel level. Instead of fabricated focal plane masks requiring frequent cryo-cycling of the instrument, MOSFIRE is equipped with a cryogenic Configurable Slit Unit (CSU) developed in collaboration with the Swiss Center for Electronics and Microtechnology (CSEM). Under remote control the CSU can form masks containing up to 46 slits with ~0.007-0.014" precision. Reconfiguration time is < 6 minutes. Slits are formed by moving opposable bars from both sides of the focal plane. An individual slit has a length of 7.0" but bar positions can be aligned to make longer slits in increments of 7.5". When masking bars are retracted from the field of view and the grating is changed to a mirror, MOSFIRE becomes a wide-field imager. The detector is a 2K x 2K H2-RG HgCdTe array from Teledyne Imaging Sensors with low dark current and low noise. Results from integration and commissioning are presented

SAD phasing using iodide ions in a high-throughput structural genomics environment

The Seattle Structural Genomics Center for Infectious Disease (SSGCID) focuses on the structure elucidation of potential drug targets from class A, B, and C infectious disease organisms. Many SSGCID targets are selected because they have homologs in other organisms that are validated drug targets with known structures. Thus, many SSGCID targets are expected to be solved by molecular replacement (MR), and reflective of this, all proteins are expressed in native form. However, many community request targets do not have homologs with known structures and not all internally selected targets readily solve by MR, necessitating experimental phase determination. We have adopted the use of iodide ion soaks and single wavelength anomalous dispersion (SAD) experiments as our primary method for de novo phasing. This method uses existing native crystals and in house data collection, resulting in rapid, low cost structure determination. Iodide ions are non-toxic and soluble at molar concentrations, facilitating binding at numerous hydrophobic or positively charged sites. We have used this technique across a wide range of crystallization conditions with successful structure determination in 16 of 17 cases within the first year of use (94% success rate). Here we present a general overview of this method as well as several examples including SAD phasing of proteins with novel folds and the combined use of SAD and MR for targets with weak MR solutions. These cases highlight the straightforward and powerful method of iodide ion SAD phasing in a high-throughput structural genomics environment

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies