Dysregulation of visual motion inhibition in major depression

Individuals with depression show depleted concentrations of the inhibitory neurotransmitter GABA in occipital (visual) cortex, predicting weakened inhibition within their visual systems. Yet, visual inhibition in depression remains largely unexplored. To fill this gap, we examined the inhibitory process of centersurround suppression (CSS) of visual motion in depressed individuals. Perceptual performance in discriminating the direction of motion was measured as a function of stimulus presentation time and contrast in depressed individuals (n¼27) and controls (n¼22). CSS was operationalized as the accuracy difference between conditions using large (7.5°) and small (1.5°) grating stimuli. Both depressed and control participants displayed the expected advantage in accuracy for small stimuli at high contrast. A significant interaction emerged between subject group, contrast level and presentation time, indicating that alterations of CSS in depression were modulated by stimulus conditions. At high contrast, depressed individuals showed significantly greater CSS than controls at the 66 ms presentation time (where the effect peaked in both groups). The results' specificity and dependence on stimulus features such as contrast, size and presentation time suggest that they arise from changes in early visual processing, and are not the results of a generalized deficit or cognitive bias.Accepted versio

Language Barriers in Health Care Settings: An Annotated Bibliography of Research Literature

Provides an overview of resources related to the prevalence, role, and effects of language barriers and access in health care

Atezolizumab for advanced alveolar soft part sarcoma

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. METHODS: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients \u3c18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. RESULTS: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. CONCLUSIONS: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.)

OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability.

BackgroundMitochondrial fusion protein mutations are a cause of inherited neuropathies such as Charcot-Marie-Tooth disease and dominant optic atrophy. Previously we reported that the fusion protein optic atrophy 1 (OPA1) is decreased in heart failure.Methods and resultsWe investigated cardiac function, mitochondrial function, and mtDNA stability in a mouse model of the disease with OPA1 mutation. The homozygous mutation is embryonic lethal. Heterozygous OPA(+/-) mice exhibit reduced mtDNA copy number and decreased expression of nuclear antioxidant genes at 3 to 4 months. Although initial cardiac function was normal, at 12 months the OPA1(+/-) mouse hearts had decreased fractional shortening, cardiac output, and myocyte contraction. This coincided with the onset of blindness. In addition to small fragmented mitochondria, aged OPA1(+/-) mice had impaired cardiac mitochondrial function compared with wild-type littermates.ConclusionsOPA1 mutation leads to deficiency in antioxidant transcripts, increased reactive oxygen species, mitochondrial dysfunction, and late-onset cardiomyopathy

Quantum dots to monitor RNAi delivery and improve gene silencing

A critical issue in using RNA interference for identifying genotype/phenotype correlations is the uniformity of gene silencing within a cell population. Variations in transfection efficiency, delivery-induced cytotoxicity and ‘off target’ effects at high siRNA concentrations can confound the interpretation of functional studies. To address this problem, we have developed a novel method of monitoring siRNA delivery that combines unmodified siRNA with seminconductor quantum dots (QDs) as multi color biological probes. We co-transfected siRNA with QDs using standard transfection techniques, thereby leveraging the photostable fluorescent nanoparticles to track delivery of nucleic acid, sort cells by degree of transfection and purify homogenously-silenced subpopulations. Compared to alternative RNAi tracking methods (co-delivery of reporter plasmids and end-labeling the siRNA), QDs exhibit superior photostability and tunable optical properties for an extensive selection of non-overlapping colors. Thus this simple, modular system can be extended toward multiplexed gene knockdown studies, as demonstrated in a two color proof-of-principle study with two biological targets. When the method was applied to investigate the functional role of T-cadherin (T-cad) in cell–cell communication, a subpopulation of highly silenced cells obtained by QD labeling was required to observe significant downstream effects of gene knockdown

Functional evaluation of ES cell-derived endodermal populations reveals differences between Nodal and Activin A-guided differentiation

Embryonic stem (ES) cells hold great promise with respect to their potential to be differentiated into desired cell types. Of interest are organs derived from the definitive endoderm, such as the pancreas and liver, and animal studies have revealed an essential role for Nodal in development of the definitive endoderm. Activin A is a related TGFβ member that acts through many of the same downstream signaling effectors as Nodal and is thought to mimic Nodal activity. Detailed characterization of ES cell-derived endodermal cell types by gene expression analysis in vitro and functional analysis in vivo reveal that, despite their similarity in gene expression, Nodal and Activin-derived endodermal cells exhibit a distinct difference in functional competence following transplantation into the developing mouse embryo. Pdx1-expressing cells arising from the respective endoderm populations exhibit extended differences in their competence to mature into insulin/c-peptide-expressing cells in vivo. Our findings underscore the importance of functional cell-type evaluation during stepwise differentiation of stem cells.Stem Cell and Regenerative Biolog

An uncontaminated measurement of the escaping Lyman continuum at z∼3z\sim3

Observations of reionization-era analogs at $z\sim3$ are a powerful tool for constraining reionization. Rest-ultraviolet observations are particularly useful, in which both direct and indirect tracers of ionizing-photon production and escape can be observed. We analyse a sample of 124 $z\sim3$ galaxies from the Keck Lyman Continuum Spectroscopic Survey, with sensitive spectroscopic measurements of the Lyman continuum region. We present a method of removing foreground contamination from our sample using high-resolution, multi-band Hubble Space Telescope imaging. We re-measure the global properties of the cleaned sample of 13 individually-detected Lyman continuum sources and 107 individually-undetected sources, including a sample-averaged absolute escape fraction of $f_{\rm esc,abs}=0.06\pm0.01$ and a sample-averaged ratio of ionizing to non-ionizing ultraviolet flux density of $_{\rm out}=0.040\pm0.006$, corrected for attenuation from the intergalactic and circumgalactic media. Based on composite spectra, we also recover a strong positive correlation between $_{\rm out}$ and Ly$\alpha$ equivalent width (W$_\lambda$(Ly$\alpha$)) and a negative correlation between $_{\rm out}$ and UV luminosity. As in previous work, we interpret the relationship between $_{\rm out}$ and W$_\lambda$(Ly$\alpha$) in terms of the modulation of the escape of ionizing radiation from star-forming galaxies based on the covering fraction of neutral gas. We also use a W$_\lambda$(Ly$\alpha$)-weighted $_{\rm out}$ to estimate an ionizing emissivity from star-forming galaxies at $z\sim3$ as $\epsilon_{\rm LyC}\simeq5.5\times10^{24}$erg s$^{-1}$ Hz$^{-1}$ Mpc$^{-3}$. This estimate, evaluated using the uncontaminated sample of this work, reaffirms that galaxies provide the majority of the ionizing background at $z\sim3$ and beyond.Comment: 22 pages, 10 figures, submitted to MNRA

Chk1 Haploinsufficiency Results in Anemia and Defective Erythropoiesis

Erythropoiesis is a highly regulated and well-characterized developmental process responsible for providing the oxygen transport system of the body. However, few of the mechanisms involved in this process have been elucidated. Checkpoint Kinase 1 (Chk1) is best known for its role in the cell cycle and DNA damage pathways, and it has been shown to play a part in several pathways which when disrupted can lead to anemia.Here, we show that haploinsufficiency of Chk1 results in 30% of mice developing anemia within the first year of life. The anemic Chk1+/- mice exhibit distorted spleen and bone marrow architecture, and abnormal erythroid progenitors. Furthermore, Chk1+/- erythroid progenitors exhibit an increase in spontaneous DNA damage foci and improper contractile actin ring formation resulting in aberrant enucleation during erythropoiesis. A decrease in Chk1 RNA has also been observed in patients with refractory anemia with excess blasts, further supporting a role for Chk1 in clinical anemia.Clinical trials of Chk1 inhibitors are currently underway to treat cancer, and thus it will be important to track the effects of these drugs on red blood cell development over an extended period. Our results support a role for Chk1 in maintaining the balance between erythroid progenitors and enucleated erythroid cells during differentiation. We show disruptions in Chk1 levels can lead to anemia

Particle Production at Large Transverse Momentum with ALICE

We present transverse momentum distributions of inclusive charged particles and identified hadrons in $pp$ and Pb--Pb collisions at \rs= 2.76 TeV, measured by ALICE at the LHC. The Pb--Pb data are presented in intervals of collision centrality and cover transverse momenta up to 50 GeV/$c$. Nuclear medium effects are studied in terms of the nuclear modification factor \raa. The results indicate a strong suppression of high-$p_T$ particles in Pb--Pb collisions, consistent with a large energy loss of hard-scattered partons in the hot, dense and long-lived medium created at the LHC. We compare the preliminary results for inclusive charged particles to previous results from RHIC and calculations from energy loss models. Furthermore, we compare the nuclear modification factors of inclusive charged particles to those of identified $\pi^0$, $\pi^{\pm}$, K$^0_s$, and $\Lambda$.Comment: Talk given at Quark Matter 2011 conferenc

Ly{\alpha} profile shape as an escape-fraction diagnostic at high redshift

While the shape of the Ly$\alpha$ profile is viewed as one of the best tracers of ionizing-photon escape fraction ($f_{esc}$) within low redshift (z~0.3) surveys of the Lyman continuum, this connection remains untested at high redshift. Here, we combine deep, rest-UV Keck/LRIS spectra of 80 objects from the Keck Lyman Continuum Spectroscopic Survey with rest-optical Keck/MOSFIRE spectroscopy in order to examine potential correlations between Ly$\alpha$ profile shape and the escape of ionizing radiation within z~3 star-forming galaxies. We measure the velocity separation between double-peaked Ly$\alpha$ emission structure (v$_{\rm sep}$), between red-side Ly$\alpha$ emission peaks and systemic (v$_{\rm Ly\alpha,red}$), and between red-side emission peaks and low-ionization interstellar absorption lines (v$_{\rm Ly\alpha-LIS}$). We find that the IGM-corrected ratio of ionizing to non-ionizing flux density is significantly higher in KLCS objects with lower v$_{\rm Ly\alpha,red}$. We find no significant trend between measures of ionizing-photon escape and v$_{\rm Ly\alpha-LIS}$. We compare our results to measurements of z~0.3 "Green Peas" from the literature and find that KLCS objects have larger v$_{\rm sep}$ at fixed v$_{\rm Ly\alpha,red}$, larger $f_{esc}$ at fixed v$_{\rm Ly\alpha,red}$, and higher v$_{\rm Ly\alpha,red}$ overall than z~0.3 analogs. We conclude that the Ly$\alpha$ profile shapes of our high-redshift sources are fundamentally different, and that measurements of profile shape such as v$_{\rm Ly\alpha,red}$ map on to $f_{esc}$ in different ways. We caution against building reionization-era $f_{esc}$ diagnostics based purely on Ly$\alpha$ profiles of low-redshift dwarf galaxies. Tracing v$_{\rm sep}$, v$_{\rm Ly\alpha,red}$, and $f_{esc}$ in a larger sample of z~3 galaxies will reveal how these variables may be connected for galaxies at the epoch of reionization.Comment: 22 pages, 7 figures, submitted to Ap